Mechanisms of Disease 1

Mechanisms of Disease 1

Module coordinators:

Dr. S.M. Arend

LUMC, Department of Infectious Diseases

E-mail: [email protected]

Dr. I.M. Bajema

LUMC, Department of Pathology

E-mail: [email protected]

M O D U L E B O O K

Bachelor Medicine, second year

Course year 2014-2015

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Contents

Module committee and teachers ..............................................................................................................................................1

Preface..........................................................................................................................................................................................3

Introduction and general information .....................................................................................................................................5

1.1 Summary and relation to other modules .....................................................................................................................5

1.2 Subjects and themes........................................................................................................................................................7

1.3 Main study goals of the module....................................................................................................................................9

1.4 Prerequisites ...................................................................................................................................................................10

1.5 Teaching activ ities (study methods) ..........................................................................................................................10

1.6 English and Dutch in the module ...............................................................................................................................13

1.7 Assessment .....................................................................................................................................................................13

1.7.1 Summative tests.....................................................................................................................................................13

1.7.2 Formative tests.......................................................................................................................................................14

1.8 Exam matrix ...................................................................................................................................................................16

1.9 Study books ....................................................................................................................................................................17

1.10 Relevant websites........................................................................................................................................................17

1.11 The ‘rules of the game’ ..............................................................................................................................................17

1.12 Module schedule overview (see also Attachment 7 for complete schedule) ....................................................20

1.13 Overv iew of lectures in module Mechanisms of Disease 1.................................................................................21

1. Theme I: The immune system and its opponents ...........................................................................................................23

1.1 Theme I.A: Global overview of host defence mechanisms and ‘key players’ of the immune system ..............24

1.1.1 Introduction ............................................................................................................................................................24

1.1.2 Theme-related objectives (What you will learn) .............................................................................................24

1.1.3 Study methods and study plan ............................................................................................................................24

1.1.4 Reading list.............................................................................................................................................................25

1.1.5 SSA ..........................................................................................................................................................................27

1.2 Theme I.B. Pathology of injury and repair ...............................................................................................................29

1.2.1 Introduction ............................................................................................................................................................29



1.2.4 Reading list.............................................................................................................................................................31

1.2.5 Work group 1 .........................................................................................................................................................31

1.2.6 SSA ..........................................................................................................................................................................33

2. Theme II: Microorganisms as cause of disease ..............................................................................................................35

2.1 Introduction ....................................................................................................................................................................35

2.2 Theme-related objectives (What you will learn) .....................................................................................................36

2.3 Study methods and study plan ....................................................................................................................................36

2.4 Reading list.....................................................................................................................................................................37

2.5 SSA ..................................................................................................................................................................................38

3. Theme III: Infectious Diseases ..........................................................................................................................................43

3.1 Theme III.A: Host-pathogen interactions .................................................................................................................45

3.1.1 Introduction ............................................................................................................................................................45



3.1.4 Reading list.............................................................................................................................................................46

3.1.5 Virulence factors ...................................................................................................................................................47

3.1.6 SSA ..........................................................................................................................................................................48

3.1.7 Instructions Extended Matching Questions Theme III.A ...............................................................................49

3.2 Theme III.B: Clinical presentations and diagnostics..............................................................................................53

3.2.1 Introduction ............................................................................................................................................................53



3.2.4 Reading list.............................................................................................................................................................55

3.2.5 Work group 2 .........................................................................................................................................................55

3.2.6 Instructions Extended Matching Questions Theme III.B ...............................................................................57

3.3 Theme III.C: Therapy of infectious diseases ............................................................................................................63

3.3.1 Introduction ............................................................................................................................................................63



3.3.4 Reading list.............................................................................................................................................................65

3.3.5 Concepts of pharmacology and prescribing antimicrob ial therapy ..............................................................66

3.3.6 SSA ..........................................................................................................................................................................68

3.3.7 Tables antimicrobial therapy ...............................................................................................................................69

3.4 Essential Microorganisms ...........................................................................................................................................73

3.4.1 Tables with ‘Essential microorganis ms’ ...........................................................................................................73

3.4.2 Reading for Essential microorganisms ..............................................................................................................75

4. Theme IV: Epidemiology, prevention and control of infect ious diseases .................................................................77

4.1 General information theme IV ....................................................................................................................................77

4.1.1 Why study epidemio logy, prevention and control of infectious diseases? .................................................77



4.1.4 Reading list.............................................................................................................................................................79

4.1.5 Work group 3 .........................................................................................................................................................79

4.2 Theme IV.A: Epidemiology..........................................................................................................................................81

4.2.1 Introduction ............................................................................................................................................................81

4.2.2 The infection chain ...............................................................................................................................................81

4.2.3 Reproductive rate ..................................................................................................................................................82

4.2.4 SSA ..........................................................................................................................................................................82

4.2.5 Instructions Extended Matching Questions Theme IV.A. .............................................................................83

4.3 Theme IV.B: Prevention and control .........................................................................................................................85

4.3.1 Introduction ............................................................................................................................................................85

4.3.2 Healthcare-associated infections ........................................................................................................................86

4.3.3 SSA ..........................................................................................................................................................................87

4.3.4 Instructions Extended Matching Questions Theme IV.B. ..............................................................................91

5. Theme V: A llergy ................................................................................................................................................................93

5.1 Introduction ....................................................................................................................................................................93



5.4 Reading list.....................................................................................................................................................................94

5.5 SSA ..................................................................................................................................................................................95

6. Theme VI: Auto-immunity ................................................................................................................................................97

6.1 Introduction ....................................................................................................................................................................97



6.4 Immunosuppressive pharmacotherapy ......................................................................................................................99

6.5 Reading list...................................................................................................................................................................100

6.6 Work group 4 ...............................................................................................................................................................100

6.7 Academic Assignment................................................................................................................................................102

6.8 SSA ................................................................................................................................................................................103

7. Theme VII: Transplantation.............................................................................................................................................107

7.1 Introduction ..................................................................................................................................................................107

7.2 Theme-related objectives (What you will learn) ...................................................................................................107

7.3 Study methods and study plan ..................................................................................................................................108

7.4 Reading list...................................................................................................................................................................109

7.5 SSA ................................................................................................................................................................................109

Attachment 1: Tab les for SSA II.1......................................................................................................................................111

Attachment 2: Tab les for SSA III.A.1 and III.A.2 ...........................................................................................................114

Attachment 3: Tab le fo r SSA IV.A.1 and IV.B.1.............................................................................................................116

Attachment 4: Tab le fo r SSA IV.B.3..................................................................................................................................117

Attachment 5: Tab le fo r SSA VI.6......................................................................................................................................121

Attachment 6: Practicals Bacteriology and Parasitology ................................................................................................122

PRACTICAL 1: Bacteriology .........................................................................................................................................122

PRACTICAL 2: Parasitology ..........................................................................................................................................127

Attachment 7: The module at a glance ...............................................................................................................................133

1

Module committee and teachers

Module coordinators

Dr. S.M. Arend

Dept. of Infectious Diseases

LUMC C5P-40

[email protected]

Coordinator Infectious

Diseases

LT, SM, PD, PR,

WG*

Dr. I.M. Bajema

Dept. of Pathology

LUMC P2-28

[email protected]

Coordinator

Immunology and

Pathology

LT, WG

* abbreviations: see next page

Secretariate

Mw. M. Veelenturf

Dept. of Pathology

P0-044

LUMC

Phone: 071 5266564

Email: [email protected]

Secretarial support practicals:

Mw. E.M. van Rijn


Logistical support:

D.O.O.

[email protected]

Module committee

Dr. S.G. van Duinen

Dept. of Pathology

[email protected]

WG

Dr. J. Gooskens

Dept. of Microbiology

[email protected]

PR

Dr. A. Lankester

Dept. of Pediatrics

[email protected]

SM

Dr. E.A. van Lieshout

Dept. of Parasitology

[email protected]

LT, PR

Dr. P.H. Nibbering


[email protected]

Dr. M.E.J. Reinders

Dept. of Nephrology

[email protected]

PD

Dr. R. Rissmann

Dept. of Pharmacology

[email protected]

LT

Prof. Dr. V.T.H.B.M. Smit

Dept. of Pathology

[email protected] l

LT,WG

Dr. J.J.C de Vries

Dept. of Microbiology

[email protected]

LT,SM

2

Teachers

Immunology (various Departments)

Bekker, V. (Pediatrics) WG

Bergen, J. van (IHB§) WG

Bredius, R.G.M. (Pediatrics) SM

Claas, F.H.J. (IHB) LT

Griffioen, M. (Exp. hematology) WG

Halteren, A.G.S. van (Pediatrics) LT

Hiemstra, P.S. (Pulmonary Dis.) LT

Lankester, A.C. (Pediatrics) SM

Roelen, D. WG

Roep, B.O. (IHB) LT

Rood, J.J. van (Europdonor) LT

Schilham, M. (Pediatrics) WG

Smits, H.H. (Parasitology) WG

Tol, M.J.D. van (Pediatrics) SM

Trouw, L.A. (Rheumatology) WG

Verschuuren J.J.G.M. (Neurology) LT

§ Dept. of Immunohematology and Blood bank

Department of Infectious Diseases

Arend, S.M. LT,SM,PD,WG,PR

Bauer, M.P. SM,WG

Boer, M.G.J. de LT,SM,WG

Geluk, A. LT

Groeneveld, G.H. PR

Haverkamp, M.H. WG

Jolink, H. WG

Marbus, S.D. PR

Kroon, F.P. WG

Roestenberg, M. PR#, WG

Scheper, H. PR

Schippers, E.F. PR

Stalenhoef, J.E. WG

Visser, L.G LT,PD,PR

Vollaard, A.M. PR

Department of Microbiology

Beek, M.T. van der PR#

Bentvelsen, R.G. PR

Brienen, E.A.T. PR

Bernards, A. WG

Engel, M.F. PR

Feltkamp, M.C.W. WG

Gooskens, J. PR# (coordinator

PR1)

Klink, A.L. PR

Konstaninovski, M.M. PR

Knoester, M. WG

Kroes, A.C.M. LT,SM

Scoop, D.W.L. PR

Terveer, E.M. PR

Veldkamp, K.E. SM,PR#

Vossen, A.C.T.M. WG

Vries, J.J.C. de LT

Wong, M.C. PR

Wunderink, H.F. PR

Department of Parasitology

Brienen, E.A.T. PR

Kos, van Oosterhoud, J. PR

Kroeze, J. PR

Lieshout, E.A. van LT,PR#

(coordinator PR2)

Ramesar, J. PR

Department of Pathology

Bajema, I.M. LT, WG

Boer, H. de WG

Bosse, T. LT, WG

Bovee, J. WG

Bruijn, J.A. WG

Cleve, A. WG

Crobach, S. WG

Duine, S. van WG

Hout, M. van den WG

Kelder, T.P. WG

Koens, L. WG

Smit, V. LT, WG

Wilhelmus, S. WG

Department of Nephrology

Koning, E. de LT

Reinders, M PD

Rotmans, J PD

Pharmacology

Hessel, M.H.M. LT

Rissmann, R. LT

*Participates in:

LT = lecture

SM = seminar

PD = patient session

PR = practical (PR#=presiding practicals)

WG = work group

3

Preface

Throughout history, concepts of the causes of disease have gone hand in hand with contemporary

knowledge. Around 2500 B.C. a disease was considered to be a patient’s own fault, or the result of an

intervention by gods, demons or spirits. From 300 B.C. until about 1500 A.D., clinical observations

and autopsies (gross, morbid or macroscopic anatomy) led to new concepts about the origin of

disease. In this period, the cause of a disease was attributed to an imbalance in the bodily fluids

(humora). From 1500 until about 1800, diseases were often believed to be a consequence of

spontaneous generation of pathogens from dead material (abiogenesis). It was not until the nineteenth

century that Rudolf Virchow put forth the idea that disease was caused by alterations in cells.

Nowadays, the concept of disease can be summarized as follows: molecular changes lead to cellular

changes that result in tissue (organ) changes and subsequently cause clinical signs and symptoms.

The normal host defence mechanisms play a crucial role in the homeostasis and are a prerequisite for a

healthy life. These responses are involved in repair of injury as well as in the defence against

omnipresent viruses, bacteria, fungi and parasites. However, microorganisms may be too virulent or

the immune system may malfunction, which in both cases can result in disease.

In this module, the three disciplines immunology, pathology and infectious diseases are presented in a

fully integrated manner. These 3 disciplines were not chosen at random. Obviously, it is not difficult

to think of a number of scenarios in which they closely interact.

During this 6 weeks course, the student will not only learn different mechanisms that can lead to

disease, but will also make the first steps to become a medical expert who can recognize characteristic

clinical presentations of immune-mediated and/or infectious diseases, explain their pathogenesis and

make a targeted diagnostic plan and a rational choice from the available pharmaco-therapeutical

arsenal of immunosuppressive or antimicrobial drugs. The competence health advocate is elaborated

on during the theme ‘Prevention and control of infectious diseases’. In addition, there will be special

assignments to train and challenge the scholarly talents (‘academic assignment’). In the final theme

‘Transplantation-associated pathology’ all knowledge that was acquired throughout the module comes

together.

The coordinators of the Mechanisms of Disease 1 module wish you an enjoyable learning experience!

ME CH A N ISMS O F D ISE A SE 1

5

Introduction and general information

1.1 Summary and relation to other modules

This course elaborates on the first year modules of Medicine in which the normal anatomy, physiology

and homeostasis were taught. Disease often results from a disturbance in the structural integrity and/or

normal function of (part of) the body and/or the response to this disturbance. The second year starts with

the modules Mechanisms of Disease 1 and 2, focusing on the 7 different mechanisms of disease (see

figure).

The Pathogenesis Pie

Acute and chronic

inflammation

Disordered immunity

(immunodeficiency

and immunopathology)

Cell/tissue injury and

repair

Haemodynamic

disorders

Congenital

abnormalities (genetic,

non-genetic)

Metabolic and

degenerative

disorders

Growth disorders

(neoplastic, non-

neoplastic)

Mechanisms of disease 1Mechanisms of disease 2

In module G2MD1 the focus is mainly on inflammation, cell/tissue injury and repair and disordered

immunity but there will be some overlap with the remaining mechanisms which will be addressed in

module G2MD2. In the following course, G2MD2 , the main focus will be on neoplastic and non-

neoplastic growth disorders next to the other mechanisms of disease on the left side of the pie, for which

knowledge obtained in G2MD1 is a prerequisite.

IN TRO D U CTIO N A N D G E N E RA L IN FO RMA TIO N

6

Place of Module Mechanisms of Diseases 1 in the Curriculum Bachelor of Medicine

The concepts learned in module G2MD1 will continue to be used in all subsequent modules that address

clinical problems (’vraagstukken blokken’). In subsequent modules, additional specific diseases will be

addressed, expanding the differential diagnostic potential of the student for which a basis was laid in

module G2MD1.

ME CH A N ISMS O F D ISE A S E 1

7

1.2 Subjects and themes

A varied menu of teaching methods, including lectures, seminars, weekly patient demonstrations, work

groups, microscopy practicals and e-learning modules is offered to the students. Together, these will guide

you through the module. Moreover, we will provide you with regular test exams in order for you to assess

your state of knowledge. Your capacity to apply this knowledge to actual cases will be tested in one

component exam during the course and one final exam at the end. Collectively, these test results will

determine your final grade.

G2MD1 is organized in 7 main themes which together cover the subjects for study in coherent

components and determine the structure and contents of the module. The themes are dealt with

sequentially, continuously integrating knowledge and insight from previous themes.

THEMES of G2MD1

I. Normal host response to pathological stimuli

I. A. Brief overview of the defence mechanisms and key components of the normal immune

response

I.B. Histology of injury and response

II. Microorganisms as cause of disease

III. Infectious Diseases

III.A. Host-pathogen interactions

III.B. Clinical aspects of infectious diseases: clinical presentations and diagnostics

III.C. Clinical aspects of infectious diseases: therapy

IV. Prevention and control of infectious diseases

IV.A. Epidemiology of infectious diseases

IV.B. Prevention and control of infectious diseases

V. Allergy

Hyper-responsiveness of the immune system to non-self: allergy

VI. Auto-immunity

VI.A. Hyper-responsiveness of the immune system to self: auto-immunity

VI.B. Clinical aspects of auto-immunity: clinical presentations and diagnostics

VI.C. Clinical aspects of auto-immunity: therapy

VII. Transplantation-associated pathology


8

In short:

Theme I deals with the components and function of the normal immune system such as normal

anatomical barriers, specific and nonspecific cellular and humoral immunity, lymph nodes and spleen;

these components collectively represent the host defence. The histology of the response to injury or

infection is taught.

Theme II addresses the classification, structure and physiology of microorganisms, forming the link to the

next theme.

Theme III focuses on infection as the outcome of the interaction between the host and a microorganism.

Classical clinical presentations of common or interesting infections are discussed, as are the

diagnostic methods used in medical microbiology and parasitology including microscopy, culture and

susceptibility testing, serology, and molecular biological techniques. The basic principles of antimicrobial

therapy and application to simple cases are taught.

Theme IV is focused on the epidemiology, prevention and control of infectious diseases. Knowledge

about epidemiology is the basis for successful prevention and control of infectious diseases. Some

infectious diseases can spread from a carrier, patient, animal or environmental source to a new host, and

some are known for their ability to become pandemic. ‘Prevention is better than cure’ is a well-known

saying, which almost always proves to be right.

Theme V addresses the classic division of the hypersensitivity reactions into types I to IV. Basic

principles behind this subdivision together with a number of typical examples of diseases that exemplify

these principles will be dealt with. Histological changes and immunological mechanisms underlying the

different hypersensitivity reactions will be explained.

Theme VI will elaborate on the knowledge obtained in theme V, and a number of immune mediated

diseases will be presented into more detail, such as ANCA-associated vasculitis and Systemic Lupus

Erythematosus (SLE). The histopathological changes in the kidney will be the central point from which

differential diagnostic and therapeutic considerations will be discussed.

Theme VII is the last theme of this course, in which all disciplines will interact to provide a general

overview of the complex situation of solid organ and bone marrow transplantation. The clinical setting,

histopathological findings, immunological aspects, infectious threats and therapeutic challenges of the

transplanted patient will be discussed.


9

1.3 Main study goals of the module

Themes Relates to

competences

(**)

STUDY GOALS: The student

1. describes individual components and interactions between components of the defense mechanisms

which underlie normal response and repair mechanisms for the maintenance of tissue homeostasis

I K 1

2. recognizes and classifies histological features of acute or chronic inflammation, necrosis and repair

responses, and deduces the consequences of these processes for tissue/organ function

I T 1

3. categorizes different classes of micro-organisms, describes the structural characteristics and relates

structural components to physiology of micro-organisms

II T 1

4. explains the pathogenesis of diseases that result from an interaction between the immune system

and pathological stimuli, with focus on microorganisms, and deduces the clinical symptoms that

result from this interaction

II, III T 1,2

5. categorizes the causes of failing defense mechanisms and hyperresponsiveness of the immune

system (type I-IV allergies and auto-immune diseases) and explains the pathogenesis and clinical

symptoms of diseases resulting from these disorders

I, III, V, VI T 1,2

6. distinguishes the immunological principles of solid organ transplantation and transplantation of the

hematopoetic system, names factors which affect transplantation outcome and describes the

pathogenesis of clinical problems associated with transplantation

I, VII B 1

7. given a description of diagnostic test results in a study population, the student interprets these

results, calculates sensitivity, specificity and positive/negative predictive value and predicts the

effect of a change in pretest probability on these parameters

III, V, VI T 1,6

8. analyzes a scientific paper on immunological or infectious diseases subject III, V, VI T 1,6

For a number of infections and immune disorders that are part of the module (listed in the Module

book), the student

9. recognizes characteristic clinical presentations III, V, VI K 1,7

10. explains the pathogenesis III, V, VI T 1,7

11. selects appropriate diagnostic and therapeutic options, indicates mechanism of action of selected

immunosuppressive, immune enhancing and antimicrobial drugs

III, V, VI T 1,4,7

12. given a microscopic image, the student names the most likely microorganism, infectious syndrome,

or immune disorder

I, II, III, V,

VI, VII

B 1

13. analyzes the infection chain (reservoir, source, transmission route and host factors) and applies the

principles of prevention and control of infectious diseases to concise but realistic problems and

situations

IV T 1,3,4,5,6,7

Subjects from previous modules

recognizes normal cells, tissues and organs;

describes normal temperature and blood pressure regulation

KBT*

14. K 1

* K: kennis (knowledge); B: begrip (understanding); T: toepasssing (application)

** see next paragraph

Competences

From the CanMeds roles framework three competences are explicitly addressed in the module

G2MD1, which will be further elaborated on in the line courses:

1= Medical expert (Medisch deskundige)

2= Communicator (Communicator)

3= Collaborator (Samenwerker)

4= Manager (Organisator)

5= Health advocate (Gezondheidsbevorderaar)

6= Scholar (Academicus)

7= Professional (Beroepsbeoefenaar)


10

Medical Expert

The student will learn to recognize characteristic clinical presentations, make a differential

diagnosis, choose appropriate diagnostic tests, explain the pathogenesis and apply the basic

concepts of treatment of immune-based or infectious diseases.

Health Advocate

In theme IV, the rational choice of the various methods of prevention and control, such as

isolation measures, source finding and elimination, vaccination, prophylaxis, disinfection,

sterilization, antisepsis and vector control, is trained for a number of common and/or transmissible

infections including health care infections. This will help the student to become a true health advocate.

Scholar

The correct interpretation of (clinical) scientific publications is an important component of the

life-long medical learning process. In this module one or more examples will be discussed in

which specialists from various disciplines will take part. In addition it will be taught how and why

the interpretation of diagnostic test results for an individual patient depends on test sensitivity and

specificity as well as the pre-test risk of disease. Finally, important and interesting historical developments

in the field of infectious diseases are presented.

1.4 Prerequisites

Knowledge of the structure of the normal human cell and the most important physiological and

biochemical processes of the cell;

Knowledge of the normal histology of tissues and organs;

Knowledge of the concepts of molecular recognition, receptor specificity, receptor-ligand

interaction;

Understanding of normal regulation of blood pressure and temperature;

Insight into causes and mechanisms of pain sensation;

Knowledge of epidemiological terminology;

Ability to apply basic arithmetic (use of calculator allowed);

Usage of English at level B2 (Common European Framework of Reference for Languages).

1.5 Teaching activities (study methods)

This module provides a great variety of teaching activities, each of which makes a significant contribution

to the study goals. It is, however, important to realize that self-study takes up the greater part of the

scheduled time (70%).This means that the student should not rely on the contact teaching activities only.

Self-study

The assignments for self-study are described within each theme (indicated with a figure starting with the

Roman numeral of the theme, e.g. assignment II.A.4), and require basic knowledge from previous

modules. Each of the assignments specifically indicates what is expected from the student. The product of

the self-study is what has been learned from the assignments. Schemes and tables with the assignments are

provided in the appendices. After the work groups related to the themes, the answers to the self-study

assignments are placed on Blackboard. Note that effective learning requires that you first phrase your own

answers before checking them!


11

Lectures

The module includes in total 42 lectures.

Theme I: 10

Theme II: 4

Theme III: 8 + 1 pharmacotherapy

Theme IV: 2

Theme V: 2

Theme VI: 8 + 2 pharmacotherapy

Theme VII: 5

The titles of all lectures are provided on page 21 and the contents are summarized with the information on

study methods per theme.

Seminars

The module includes 3 different seminars during which interaction between teacher and students is an

essential part. The seminars are mostly based on cases or on specific practical situations. Each seminar is

given in 2 lecture rooms simultaneously (resp. Dutch and English version). Dutch students may attend the

English seminar (advantage: lower number of students thus higher teacher/student ratio).

-Theme I: Diagnostics of immune deficiencies (Seminar 2).

-Theme II/III: Diagnostics of infectious diseases (Seminar 1).

-Theme IV: Health advocate (‘gezondheidsbevordering’; Seminar 3).

Patient sessions

This module includes one patient session each week, together illustrating the palette of immunological,

pathological and infectious diseases problems (contents of these demos are part of the study material):

- Week 1 Febrile inflammatory illness.

- Week 2 Infection, host defence disorder.

- Week 3 Transmissible and reportable infection.

- Week 4 Allergy.

- Week 5 Auto-immune disease.

- Week 6 Transplantation-associated pathology.

Work groups

There are 4 work groups during the module. These represent an essential component of the module. Work

groups are obligatory and active participation will be assessed, see under ‘rules of the game’ in 1.11.

During each work group there will be a short formative test (open questions), followed by a discussion of

the answers.


12

Work group

Main themes

Subjects

General

study goals*

Disease specific

study goals* Tutor(s)

1 I

Normal host defence, acute and chronic inflammation, causes of fever, expla in

symptoms caused by inflammation 1, 2 9, 10 Immunologist or pathologist

2 II , I I I

Cases: pathogenesis of infections (host vs invader), rational selection of diagnostic

tests , therapeutic principles 3, 4, 7 9..13 Infectiologist or microbiologist

3 II , I I I , IV

Cases/subjects related to competence health advocate: prevention hospita l

infections , i solation measures , prophylaxis , active and pass ive

immunization 3 4 13

Infectiologist or

microbiologist

4 I , V, VI

Cases (or problems) with

immunodeficiency or overrespons iveness , analyze

pathogenesis , symptoms, diagnostics , therapy 2, 5 9..13

Immunologist or pathologist

*See table page 9

Practicals

The two practicals bacteriology and parasitology (these are obligatory: see ‘rules of the game’) represent

an introduction to the use of microscopy in bacteriology and parasitology, which is presented in a clinical

context. The student learns to interpret the results of the tests. At the exams, most questions related to

infectious diseases will also be patient-based. At the end of the practical there will be a short formative

test consisting of open questions, followed by a discussion of the answers.

NOTE. The practical includes assessment of Gram stains, for which colour vision is required. The

component and final exam will include assessment of Gram stains and histology. Students with problems

of colour vision should report this to the module coordinator during the module.

E-learning

G2MD1 includes e-learning modules in Theme II (1 module), Theme III (2 modules). These modules are

strongly advised as they are part of the study material for the exam. For themes II and IV additional

optional E-learning modules are available.

All e-learning modules and the TRC (Teaching Resource Center) referred to in the module book are

accessible via Blackboard → Module Mechanisms of Disease 1 → E-learning for G2MD1. The e-learning

modules are also accessible via www.medischonderwijs.nl (you may need to make a personal account)

search term ‘G2MD1’ will lead to the modules of Themes II and III, search term’ infectiepreventie’ to the

optional modules of Theme IV). More specific information about the e-learning modules is provided with

the corresponding themes.

Alternative ways of accessing the TRC are:

You can use Teaching Resource Centre Pharmacology without personalization at

http://coo.lumc.nl/TRC/default.aspx?direct=true

You can download the TRC iPad app (‘TRC pharmacology’) from the App Store or iTunes.

You can download the TRC Android app (‘TRCapp’) from Google Play.

http://www.medischonderwijs.nl/

http://coo.lumc.nl/TRC/default.aspx?direct=true


13

1.6 English and Dutch in the module

The module will be attended by a number of non-Dutch speaking foreign students. All lectures will be in

English. Therefore the following arrangements have been made:

All lectures and slides will be in English.

The program also contains three seminars which will each be presented in parallel; one of these

sessions will be in English.

The patient demonstrations will be in Dutch during the interaction with the patient. In case of an

ensuing presentation or discussion without the participation of the patient , this will be done in

English on request.

One of the 7 sessions per practical and two series of workgroups will be in English.

In the module book the Dutch translation of the English for medical jargon or vice versa is

sometimes provided. It is indicated in the module book if a Dutch translation of a table or list is

available on Blackboard.

The optional e-learning modules on prevention of hospital infections are only available in Dutch.

During the lecture Prevention and control of infectious diseases, the main points of this subject will

be taught.

The exams will be in Dutch for Dutch students and in English for the others. If Dutch students

prefer an English version instead of a Dutch version, they must send a formal request by e-mail to

the secretary before the end of week 2 (September 12th

) for the component exam and before the end

of week 4 (September 26th

) for the final exam.

Please be aware that training yourself to gain access to scientific knowledge through the English language

is a vital part of your further career; you need to be able to search for medical facts and figures in books,

websites, conferences and other media. Please try to train yourself to speak up and ask your teachers

whatever you do not understand. Active participation of, and open communication between students and

teachers are vital aspects of academic training.

1.7 Assessment

The module includes summative and formative tests:

In this module, assessment consists of two summative tests, based on which the grade will be determined

(summative tests count for the grade).

Formative tests are provided for practice and self-evaluation (formative tests do not count).

1.7.1 Summative tests

Summative testing is organized in one component exam in week 4 and one large final exam, both of which

contribute to the final mark. Use of books or electronic devices is not allowed during the exams

COMPONENT EXAM (max. 20 points in total, which make up ~15% of the final grade))

NOTE. Participation in the component exam is voluntary, this means it is NOT a prerequisite for release

of the final grade. If a component exam is missed this implicates 0 points. There will be no opportunity for


14

a component re-exam during this module. However, the student can participate in the final exam and the

grade will be released if all obligations are fulfilled.

Date and time: Monday September 22nd

at 10:00-11:40 am

Location: USC-sportcentrum

Duration: 100 minutes

Subjects: all lectures, seminars, patient demos, e-learning, practicals and self-study assignments of themes

I, II and III.A and III.B

Competence: Medical expert

Type of exam: 15 written, mostly case-based short open questions (maximum score 7,5 points) and 25

multiple choice questions (0,5 point each, maximum score 12,5 points). The exam will include assessment

of microscopic images. For distribution of questions per theme see Exam matrix on page 16.

Assessment: MC by ICLON, open questions by module teachers based on a correct answer model. The

individual score by student number will be made known via Blackboard within one week.

FINAL EXAM (max. 95 points)

Date: Friday October 10th

at 13.00-16.00 (week 6)

Duration: 180 minutes.

Subjects: all lectures, seminars, patient demos, work group contents, practicals, e-learnings and self-study

assignments plus indicated pages from the study books.

Competences: Medical expert (±80%), Health advocate, Scholar.

Type: Multiple Choice (N=57, 1 point each), Extended Matching (N=15, 2 points each) and

Comprehensive Integrated Puzzle (one 44 puzzle consisting of 16 items worth 0.5 point per correct

answer, maximum of 8 points). For distribution of questions per theme see Exam matrix.

The final grade is determined by the sum of the points for the component exam and the final exam.

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Component exam Final exam

Max.

95 points

Max.

20 points

Grade

~15% ~85%

1.7.2 Formative tests

Formative tests are frequently given in this module to allow the student to assess whether the level of

knowledge is sufficient or where there are gaps:

In week 1 through 5 of the module (week 36-40) a set of test questions is provided, either during lectures

with use of voting boxes (direct feedback) or via Blackboard. On one occasion a question and discussion

hour is held on Monday morning before the lectures.


15

On the Monday of week 6 (week 41) a larger formative test is provided via Blackboard containing

questions on all themes, of which the answers will be released the next day. On Wednesday of week 6

three response lectures are held (immunology, pathology, infectious diseases), where students can pose

questions (preferably email your questions to the coordinator of the theme that the question relates to).

This is followed by a last practice test with voting boxes.

Work groups will start with a short formative written test consisting of open questions regarding the theme

of the work group, followed by a discussion of the answers (total duration 20 minutes).

During the practical bacteriology (week 3) a short formative written test exam consisting of open

questions is given during the final 20-30 minutes, with direct discussion of the answers. The same will be

done in a short format during the practical parasitology (10 minutes). The contents of these formative tests

will be related to themes II and III, with emphasis on what was learned during the practicals (assessment

of a microscopic image in relation to a case).

Week 1 Week 2 Week 3 Week 4 Week 5

Work group

1 3 42

Practicals

B P

Week 6

Formative tests

(during PR or WG)

Formative tests

Open questions, during

WG or practical

Feedback is direct

Week 1 Week 2 Week 6Week 3 Week 4 Week 5

Formative tests

(Lecture room

or at home)

Feedback

Lecture room

with voting boxes

Feedback is directVia Blackboard

Feedback via BB or seminar


16

All summative and formative tests together:

Week 1 Week 2 Week 3 Week 4 Week 5

Work group

1 3 42

Practicals

B P

Week 6

Formative tests

(during PR or WG)

Formative tests

Summative tests

In addition:

All self-study assignments are de facto formative test questions.

During many lectures there will be test questions.

The practicals and work groups are mainly structured around cases with questions.

The e-learning modules contain a large number of test questions and/or learning questions through

which additional knowledge will be acquired.

1.8 Exam matrix

The subjects of the exam questions by theme are roughly as follows (minor deviation is possible):

THEME

sub-

theme TITLE MC (a 0,5 pt)

Open questions (a

0,5 pt) points per theme MC ( a 1 pt) EM (a 2 pt) CIP (a 8 pt)

Points per

theme

Subjects previous modules 4 4

I

Normal host response to

pathological stimuli 15 5 10 12 12

II

Micro-organisms as cause of

disease 5 3 4 5 5

III.A

Infectious diseases: host-pathogen

interaction 3 3

III.B

Clinical aspects of infectious

diseases: clinical presentations and

diagnostics 3 6

III.C

Clinical aspects of infectious

diseases: therapy 2 26

IV.A Epidemiology of infectious diseases 2 3

IV.B

Prevention and control of infectious

diseases 2 3 16

V.A

Hyperresponsiveness of the

immune system to non-self: allergy 3

V.B

Clinical aspects of allergy: clinical

presentations and diagnostics 3

V.C Clinical aspects of allergy : therapy 2 8

VI.A

Hyperresponsiveness of the

immune system to self: auto-

immunity 7

VI.B

Clinical aspects of auto-immune

diseases: clinical presentations and

diagnostics 2

1 (NOTE: CIP can

be about any

theme)

VI.C

Clinical aspects of auto-immune

diseases: therapy 2 19

VII VII

Transplantation associated

pathology 5 5

Subtotal 25 MC 15 Open questions 20 57 MC x 1 15 EM x 2 1 CIP x 8 95

maximum

FINAL GRADE BASED ON: COMPONENT + FINAL EXAM 115

Component exam

(~15% of final mark)

Final exam

(~85% of final mark)

III

IV

V

VI

5 7 6

The final grade is determined according to the method Cohen Schotanus (pass at 60% of the score of the

best 5% of students after adjustment for guessing).


17

After the final exam, students have the opportunity to comment on questions or answers during one week.

The final answers are determined taking into account these comments and the psychometric analysis in

accordance with the procedure of the national progression exam (‘voortgangstoets’). The final answer key

and an elucidation of adjusted or frequently missed questions will be published on Blackboard.

1.9 Study books

The module uses 4 obligatory study books:

Immunology: The Immune System, 3rd

edition, Peter Parham, Garland Science 2009.

Infectious Diseases: Sherris Medical Microbiology, 6th

edition. Ryan and Ray, McGraw Hill 2014.

NOTE. For students having Sherris 5th

edition published in 2010, the reading lists for the 5th

edition will be made available via Blackboard (PDF format).

Pathology: Kumar, Abbas and Fausto. Robbins and Cotran Pathologic Basis of Disease. Elsevier

Saunders, 8th

edition, 2009

Global health: Skolnik; Global Health 101, 2nd

edition 2012

With each theme or subtheme in the module book the pages or subjects to study are indicated, where the

abovementioned books are referred to briefly as ‘Parham’, ‘Sherris 6th

’, ‘Robbins’ and ‘Skolnik’.

1.10 Relevant websites

Blackboard: http://blackboard.leidenuniv.nl. Here you will find logistical information regarding

work groups and practicals, folders with PDFs of lectures and seminars, supplementary materials

regarding assignments, links to e-learning modules, translations, test exams etc.

All e-learning modules can be accessed via links on Blackboard or via www.medischonderwijs.nl.

1.11 The ‘rules of the game’

Contact

PLEASE NOTE: For questions please email the secretary Mrs. M. Veelenturf ([email protected]).

Do NOT directly email the module coordinators. The module coordinators will be around on most

teaching occasions, where you can ask questions in relation to the contents.

Lectures

Please be in the lecture room in time. If you arrive late, please take the high entrance and do not disturb

the lecture. Please refrain from talking during the lecture unless a question is asked. All lectures will be

placed on Blackboard afterwards.

Seminars

Please come in time. If you arrive late, please take the high entrance and do not disturb the seminar.

Professional behavior of students includes an active and participating attitude during seminars. Ask

your questions and raise your doubts. All seminars will be placed on Blackboard afterwards.

Patient demonstrations

http://blackboard.leidenuniv.nl/


mailto:[email protected]


18

NOTE: Patient demonstrations are in Dutch. Late arrivals are not allowed during a patient demonstration.

Professional behavior of students dictates that you discuss patients only with your colleague students if

this cannot be overheard by others. Patient demonstrations will not be placed on Blackboard.

Work groups

Attendance of at least 75% of the work groups, thus at least 3 work groups of this module, is obligatory

(an attendance list is signed) and thus are a prerequisite for the release of your grade. It is best to attend all

work groups. With each theme in the module book the required preparation for the corresponding work

group is indicated. Students are expected to prepare for the work group and participate actively!! The

work group teacher will make notes if students do not fulfill these requirements and the participation

assessments will be made available to the coordinator of the line professional education.

Be present on the indicated hour. The work groups start with formative test, followed by a discussion of

the answers. Students arriving late are asked to wait outside until the formative test is made, they can enter

when the discussion starts.

NOTE. Your work group number is the same as your practical group number. It is not possible to

change a work group unless there are special circumstances (in which case to can email to the module

secretary at [email protected] with a motivated request for a change). Missed work groups cannot be

caught up later.

Practicals

The two microscopy practicals (PR1 bacteriology and PR2 parasitology), are obligatory (an attendance

list is signed) and thus a prerequisite for the release of your grade. It is not possible to change practical

groups and it is NOT possible to participate in another practical group because the number of microscopes

is limited. If there is an urgent reason why you need to change practical groups you may contact the

secretary of the module ([email protected]) and ask for a motivated exception.

Missed practical

If you cannot attend a practical for legitimate reasons you should report this to the secretary with the

following requirements:

by email;

in advance and not later than 06.00 A.M. on the day of the practical;

documentation of your declared reason may be requested.

If these requirements are fulfilled you will be listed for a concise alternative teaching session on Monday

October 6th

(15.30-17.30) in the last week of the module, during which the essentials of the missed

practical(s) will be taught so that

1 you have the required knowledge at the final exam and

2 you have fulfilled your obligation for release of the grade

Your grade will only be released if all obligations (i.e. participation in at least three work groups and both

practicals or the alternative session) are fulfilled. Otherwise you can follow the work groups or practical(s)

of next year’s module.

Exam

Component exam: Enrollment for the component exam is required. However, only students who are

enrolled for the module can participate.

Final exam: Students have the opportunity to sign up for the final exam until 10 working days before the

exam (i.e. until Monday September 29th

23.59 P.M.) exactly. Students can and should check via uSis

(deelhistorie student) whether they are on the list. After the closure time, the list with registered students


19

will be published on Blackboard. Students who are not on the Blackboard list while the enrollment is

listed in uSis ‘deelhistorie student’ must bring a printout of (or show on smartphone) the deelhistorie to

the exam as proof of registration!! Students who are not on the list AND do not have a printed or digital

proof of registration are NOT allowed to do the exam and will be sent away.

It is possible to sign off for the exam until 10 working days before the exam (i.e. until Monday September

30th

24.00 P.M. exactly. If after that time point unforeseen circumstances arise that prohibit doing the

exam, the student must notify their study advisor at DOO and provide an explanation.

During the component exam as well as the final exam the use of books, notes, internet or mobile phone is

NOT allowed and these have to be stored and switched off. You may use a simple calculator without text

options (this will be checked).

The rules for release of blocked exam marks, (as indicated by DOO) will be followed strictly.


20

1.12 Module schedule overview (see also Attachment 7 for complete schedule)

Monday Tuesday Wednesday Thursday Friday

week 1

OPENING

ACADEMIC YEARLINE DAY

LT1

LT2

LT3

LT4

LT5

LT6

LT7

LT8

LT9

LT10

Pat demo 1

Test exam in

lecture room

week 2LT11

LT12

LT13

LT14LINE DAY Work group 1

LT15

LT16

LT17

LT18

LT19

LT20

LT21

Pat demo 2

(Test Questions on

Blackboard)

week 3Question hour

LT22

LT23

(afternoon)

PR1

group B,F,G

LINE DAY

PR1 group C,A,D,E

&

Work group 2

LT24

LT25

Pat demo 3

(afternoon)

PR2 (groups A,B,C)

PR2

group D,E,F,G

(Test Questions on

Blackboard)

week 4 COMPONENT EXAM

(afternoon)

SM1

SM2

SM3

LINE DAY

Voortgangstoets

(afternoon)

LT26

LT27

Pat demo 4

Work group 3

LT28

LT29

LT30

LT31

week 5 LT32

LT33

LT34

Test exam in lecture

room

LINE DAY

LT35

LT36

LT37

Pat demo 5 Work group 4

3 OCTOBER

HOLIDAY

‘LEIDENS ONTZET’

(Test Questions on

Blackboard)

week 6 LT38

LT39

LT40

LT41

(afternoon)

LT42

Pat demo 6

(Test Questions on

Blackboard)

LINE DAY

Response lectures

1. Immunology

2. Pathology

3. Infectious Diseases

No program(afternoon)

FINAL EXAM

Legend: LT: lecture; Pat demo: patient session; PR: practical, SM: seminar


21

1.13 Overview of lectures in module Mechanisms of Disease 1

Theme Lecture nr (abbreviated) Title Teacher

I LT1 LT2 LT3 LT4 LT5 LT6 LT7 LT8 LT9 LT10

Introduction to G2MD1 Introduction to the immune system Innate and adaptive immune responses Pathology of normal immune response Mechanisms of adaptive immunity B- and T-cell generation and diversity Pathology of inflammatory reactions Pathology of inflammatory reactions: a case Tissue injury and repair Repair mechanisms

Arend/Bajema Van Halteren Van Halteren Bajema Schilham Trouw Bajema Bajema Bosse Bosse

II LT11 LT12 LT13 LT14

Introduction to infectious diseases Bacteria Viruses Fungi and parasites

Arend Arend Kroes Van Lieshout

III LT15 LT16 LT17 LT18 LT19 LT20 LT21 LT22 LT23

Invader (virulence factors) Host versus invader Immune deficiencies and infection risk Pathology of infection Diagnostics of infectious diseases Interpretation of diagnostic test results Essential microorganisms Antimicrobial therapy Principles of antibiotic pharmacotherapy

Arend Arend Arend Smit De Vries Arend Arend Visser Hessel

IV LT24 LT25

Epidemiology of infectious diseases Prevention and control

De Boer Arend

V LT26 LT27

Mechanisms of allergy Pathology of allergy

Geluk Bajema

VI LT28 LT29 LT30 LT31 LT32 LT33 LT34 LT35 LT36 LT37

Cells in auto-immunity Pathology of auto-immunity Vasculitis Systemic Lupus Erythematodes HLA and auto-immunity Infections and auto-immunity Interactive cases Pharmacology: immune suppression 1 Pharmacology: immune suppression 2 Discussion academic assignment

Roep Bajema Bajema Bajema Verschuuren Bajema/Arend Bajema/Arend Rissmann Rissmann Bajema

VII LT38 LT39 LT40 LT41 LT42

Introduction transplantation Transplantation immunology Histopathology of Tx and rejection Islet cell transplantation Transplantation and infection risk

Van Rood Claas Bajema De Koning Arend


23

1. Theme I: The immune system and its opponents

Coordinator: Dr. I.M. Bajema

Already in 1796 Dr. Edward Jenner, the ‘father of immunology’ , performed the first successful

vaccination against smallpox by injecting the related cowpox virus into the son of his gardener. The

rationale for this brave experiment was his earlier observation that milkmaids were generally immune to

smallpox, while milkmaids were often infected with cowpox, a disease similar to smallpox, but much less

virulent, during their work. Jenner postulated that the pus in the blisters from cowpox protected them from

smallpox. In his time, physicians had no clue regarding the function of our immune system or the

mechanisms by which its opponents caused disease. According to Jenner’s colleagues, his unique

contribution was not that he injected cowpox virus but the fact that he proved, by subsequent challenges

with live variola (smallpox) virus, that his study subjects were protected against this infectious

microorganism by vaccination, a term derived from the Latin word vacca which means cow. Without any

knowledge of the immune system, he used its function for the purpose of preventing disease.

It took more than 150 years and substantial technical innovation before scientists collected sufficient

experimental data to understand the function of the key players of our immune system. This process was

boosted by some major breakthroughs which were rewarded by the Noble prize for Medicine. To date,

immunologists have a far more complete picture of the immune system and how we can exploit it in order

to protect our body from infections caused by known microorganisms. In Theme I, the basic knowledge of

the immune system will be presented, as summarized schematically in figure I.1.

Figure I.1: The components and key players of the immune system.

ComplementImmuno-

globulins

T cells

-Th1

-CTL

INNATE ADAPTIVE

CELLULAR

HUMORAL

Granulocytes

Macrophages

NK cells

BARRIERS

http://en.wikipedia.org/wiki/Pus

http://en.wikipedia.org/wiki/Cowpox

TH E ME I : TH E IMMU N E SY STE M

24

1.1 Theme I.A: Global overview of host defence

mechanisms and ‘key players’ of the immune

system

1.1.1 Introduction

Before you can appreciate how excessive immune reactions, or dysfunctional immune responses, may

cause disease, a basic understanding of the functional properties of our immune system is required.

During the first week of this course, we will provide you with some basic insights and we will discuss

some examples of immune-driven inflammatory reactions. By the end of this theme, you will know how

the human body protects itself against invading pathogens as well as some clinical consequences of

immune failure.

1.1.2 Theme-related objectives (What you will learn)

The student will be able to describe the components and function of normal human defence mechanisms

(innate and adaptive immune system) against various pathological stimuli, in particular microorganisms,

and to analyse simple clinical cases. The main topics are:

anatomical/chemical barriers and physical actions as first line of defence

normal haematopoiesis leading to the generation of various types of immune cells

key lymphoid organs and tissue sites where different steps of the immune response take place

the molecular basis of immune recognition

the mechanism of action mediated by the innate (granulocytes, macrophages, NK cells) and

acquired immune system (B and T cells) and the key cytokines involved

B- and T-cell generation and diversity including selection in the thymus

the principles of effector and memory T and B cell formation in relation to natural exposure to

pathogens and vaccination

clinical presentation and diagnosis of inborn immune deficiencies

the available therapeutic options for enhancement or restoration of dysfunctional immune

responses.

1.1.3 Study methods and study plan

Lectures Immunology

LT2: ‘Introduction to the immune system’. This first lecture focuses on the origin of immune cells,

their functional and phenotypic characteristics and their sites of action.

LT3: ‘Innate and adaptive immune responses and key cytokines’. This lecture explains how the

two distinct ‘arms’ of the immune system cooperate in clearing invading pathogens.

LT5: ‘Mechanisms of adaptive immunity’. This lecture zooms in on the mechanisms underlying T

and B cell activation and the generation of effector cells.

LT6: ‘B- and T-cell generation and diversity’. This lecture explains how B and T cells acquire

functional antigen receptors which enables them to respond to a vast number of pathogens.


25

LT8: ‘Pathology of inflammatory reactions: a case. This lecture will focus on the findings of an

autopsy case which shows inflammatory reactions in many organs.

Seminar 2: diagnostics of immune deficiencies

Diagnostics of classical types of inherited or acquired immune deficiencies: case-based interactive session

during which diagnostic tests must be chosen and results interpreted.

Work group 1: instructions for the work group are given under 1.2.5 of theme I.B

Self-study assignments: see 1.1.5 below

Study plan

Study the pages indicated in the reading list, preferably before attending the lectures

Follow the lectures and the seminar

Perform the self-study assignment (SSA)

Prepare for and participate actively in WG1

1.1.4 Reading list

From ‘Parham’ study:

Chapter From …up to Keywords, tables, figures

1

2

6

1-27

54-57

159-161

physical barriers fig 1.5-1.6

innate immune response fig 1.7, 1.8, 1.17,

adaptive immune response fig 1.9-1.11, 1.26, (in addition 6.20, 6.22)

neutrophil accumulation and function in inflammation fig 2.31, 2.32

immune cells and characteristic features fig 1.12, 1.14, 1.15 (+ 6.1-6.4)

primary and secondary lymphoid organs fig 1.18-1.22

2 33-40

44-47

49-53

58-59

65

the different complement systems and their function 2.3, 2.5, 2.10

pathogen lysis by complement components fig 2.12, 2.13

innate immune receptors for pathogens fig 2.19, 2.21, 2.22

inflammation induced by activated macrophages fig 2.27, 2.29, 2.36

inflammation induced by NK cells fig 2.47

3 71-75

78-85

83-85

structure of immunoglobulins and T cell receptors fig 3.1, 3.2

antigen recognition by B and T cell receptors fig 3.7, 3.8, 3.12, 3.13

antibody- and complement-mediated mechanisms for clearance of

infection fig 3.14


26

4 95

96-97

99-100

102-105

105-109,

(167-168)

115-119

one B cell one antibody principle fig 4.1,

antibody structure fig 4.2, 4.5

hypervariable region is the antigen-binding site (fig 4.8) and properties

of epitopes (fig 4.9 and 4.10)

mono/polyclonal antibodies and their application in clinical practice fig

4.14. 4.15

germline configuration in gene segments and RAG-induced somatic

recombination for generation of diversity fig 4.16-4.18, 4.20, 4.22,

(+6.11, 6.25)

isotype switching fig 4.22, 4.26, 4.30, 4.32

5 125-129

133-137

137, 140

143-144

146-148,

149-151

151-152

genomic organization and structure of T cell receptor complex fig 5.3,

5.6

functionally different T cells recognizing different MHC molecules fig

5.12-5.14

antigen processing into peptide fragments fig 5.20

MHC molecules are differentially expressed fig 5.23

MHC polymorphisms and T cell restriction fig 5.24, 5.25

MHC allele variation and pathogen-driven selection fig 5.33

7 187-189

199

T cell development fig 7.1, 7.3, 7.15,

positive/negative selection fig 7.16. 7.18, 7.21

8 211-213, 215,

222

224-231

237-240

241-242

T cell activation requires co-stimulation fig 8.1, 8.4, 8.10, 8.18

cytokines affecting T cell function fig 8.17, 8.19, 8.27, 8.39

CD4 T cell-driven macrophage activation fig 8.34, 8.36

CD4 T cell-driven B cell activation fig 8.37

9

254-255,

262-263

264-272

275

T helper cell -induced B cell activation, isotype switching and memory

cell formation fig 9.9, 9.19

antibodies in blood and mucosal surfaces and their function fig 9.23,

9.24, 9.25, 9.28

removal of immune complexes from the circulation fig 9.35

The key-words, figures and tables mentioned in the reading list are guidelines for the more detailed

knowledge you should have of these topics!


27

1.1.5 SSA

SSA I.A.1 Activation and the various effector functions of the immune system

1 Skin injury is often followed by translocation of bacteria into the deeper layer of the skin (dermis).

Describe the processes and key molecules which lead to inflammation due to, and clearance of this

primary infection.

2 Explain why it takes up to several days after initiation of inflammation before T cells specific for the

invading bacteria are detectable at the site of injury. At which sites reside the bacteria-specific B

cells?

3 Indicate the intrinsic differences in bacterial antigens which are recognized by the involved T (fig 3.7

Parham) and B cells (fig 3.12 Parham) respectively. How do these antigens arrive at the sites where

naïve T and B cells become activated (Parham page 82)?

4 Indicate the key effector molecules produced by T and B cells which assist in the clearance of

invading bacteria (fig 3.13 Parham).

5 T cells function by making contact with other immune cells (fig. 5.12 Parham). There are two types of

T cells as defined by the expression of the CD4 or CD8 co-receptor on their cell surface. Which type

of T cells are primarily involved in the induction of antibody production and subsequent clearance of

extracellular pathogens? Which MHC molecule is involved in the activation of these T cells?

6 Study the picture of a skin biopsy of a 52 year-old male, with an itchy papule on his arm.

The description of the light microscopy is as follows:

Skin biopsy showing a hair follicle with dilated

osteum in which numerous neutrophilic granulocytes

are found. Surrounding the follicle, an inflammatory

infiltrate with predominantly lymphocytes is present.

Additional staining shows that Gram-positive cocci

are present.

Can you relate the description to what you see in the

picture? What would be your diagnosis?

SSA I.A.2 Diversity of T and B cell repertoires

During their development in the bone marrow, random joining of variable (V), diversity (D), joining (J)

and constant (C) gene segments allows the formation of a large number of unique DNA sequences

expressed by a highly diverse set of functionally different T and B cells. This process is schematically

displayed in fig 4.17 and fig. 5.3 from Parham for respectively B and T cells. The set of enzymes needed

to recombine V, D and J segments is called the V(D)J recombinase. Two of the several component

proteins facilitating recombination at the DNA level are uniquely expressed by lymphocytes; they are

specified by the recombination-activating genes (RAG) 1 and 2.


28

1 The number of functional gene segments available to construct both the variable and constant region

of the immunoglobulin heavy and light chains are displayed in fig 4.18 Parham. Calculate how many

different heavy (H) chains can be formed. Make similar calculations for respectively the and

chain. Now use these figures to calculate the total number of possible immunoglobulin molecules

formed by combining the available heavy and light chains.

2 Provide a rationale why, from an evolutionary standpoint, our genome does not contain a gene for

each unique immunoglobulin molecule.

3 The number of functional V, D and J gene segments available to construct a functional T cell

receptor, comprised of an and chain (fig 5.6 Parham), are displayed in Parham (fig. 5.9)

Combining the available gene segments results in at least 5.8106 different DNA sequences; each

sequence encodes a T cell receptor with a unique antigen-recognition part (=hypervariable region). As

you can see in the table, the estimated total diversity of immunoglobulins and T cell receptors

expressed by naïve lymphocytes is far greater. Explain the discrepancy.

4 Unlike the B cell receptor, the T cell receptor only serves as a cell surface receptor for activation.

Which key proteins transmit activation signals to the nucleus after the T cell receptor binds to its

cognate antigen?

5 Genetic defects which result in either the total or partial absence of one of RAG proteins are

associated with a rare syndrome called severe combined immunodeficiency disease (SCID). Describe

the composition of leukocytes in a peripheral blood sample collected from untreated SCID patients.

Are the numbers of T cells expressing the alternative T cell receptor also affected in these patients?

Note that more details on the SCID syndrome will be discussed in the seminar


29

1.2 Theme I.B. Pathology of injury and repair

1.2.1 Introduction

In clinical pathology, macroscopic and microscopic observations are important tools to establish a

differential diagnosis. Insight into cellular processes is essential for the understanding of the

morphological changes in organs caused by a disease. Both intracellular and extracellular changes affect

cell functioning; extracellular changes may lead to morphological changes both in cells and tissue. Our

knowledge of these changes has contributed to the identification and the classification of diseases. The

understanding of the underlying mechanisms of such changes helps to determine the cause of a disease,

explains findings at clinical examinations and provides a basis for appropriate therapy.

A disease process is characterized by its cause, development and outcome. The cause (aetiology) of

disease can be known or unknown. The mechanisms of disease leading to cellular alterations are referred

to as the pathogenesis of disease. During its development, the disease may cause tissue alterations such as

hypertrophy, atrophy, hyperplasia, metaplasia: these alterations are usually part of an adaptive process,

and can be reversible or irreversible. The functional consequences of disease lead to more or less

characteristic clinical manifestations.

Inflammation is an important and often non-specific response to tissue injury. Inflammation is not a

disease, it is rather a manifestation of the presence of a disease. The purpose of an inflammatory reaction

is to eliminate the noxious (e.g. infectious) agents and to allow repair of injured tissue. Alternatively,

inflammation may cause disease, for example a swelling caused by an inflammatory response in the throat

may compress the airway and cause suffocation. Inflammation is classified according to its time course

and cell composition. We distinguish acute inflammation (usually the initial and transient reaction) from

chronic inflammation (usually the subsequent and prolonged reaction). Chronic inflammation may (but

need not) follow an acute inflammation. Chronic inflammation may also occur as a primary reaction

(chronic inflammation "ab initio").

Inflammatory responses are usually described by the suffix ‘-itis’ (e.g. inflammation of the appendix is

called appendicitis). Although the causes of inflammatory reactions differ, the inflammatory response

invariably involves a vascular reaction, resulting in increased local blood flow and increased capillary

permeability, and a cellular reaction, resulting in the influx of leukocytes (such as granulocytes,

monocytes and lymphocytes) from blood to tissue. After an inflammatory reaction has taken place, the

inflicted damage has to be restored. This can either be accomplished by regeneration or by healing, the

latter resulting in scar formation and fibrosis.

During this subtheme, the student will become familiar with some of the basic principles of general

pathology. Via the study of morphological changes in the affected tissues and organs, the origin of a

number of fundamental cell injury mechanisms and their effects on cells and tissue will be studied. The

consequences of these changes will be related to the patient’s clinical symptoms and signs.


30


By the end of this theme, the student will be able to:

Recognize and explain the different adaptive responses of cells.

Recognize the morphological alterations (and explain the biochemical processes) that occur after

reversible and irreversible cell injury.

Explain the biochemical processes that occur after ischemia.

Explain the different mechanisms that lead to intracellular accumulations.

Describe the macroscopic and microscopic characteristics of acute and chronic inflammation.

Explain the essential differences between acute and chronic inflammatory reactions.

Describe the essential aspects of a granulomatous inflammatory reaction.

Describe the characteristics of wound healing.

Describe and understand immune-pathological processes causing the clinical signs and symptoms

of a limited number of immune mediated diseases and conditions.

Recognize, name and describe changes (morphological and structural alterations) in tissue

specimens with respect to immune mediated conditions.


Lectures

LT4: Introductory lecture, "Pathology of the normal immune response". Explains the essential

features of the immune system from a pathological point of view and describes the cell types that

participate in acute or chronic inflammatory responses.

LT7: In depth lecture, "Pathology of Inflammatory Reactions": gives an overview of chapter 2

from Robbins & Cotran, focussing on stimuli and mediators of acute and chronic inflammation,

reactions of blood vessels and leukocytes in inflammation, granulomatous inflammation, and the

outcome of inflammation.

LT9: In depth lecture, "Tissue Injury and Repair": first part of the overview of chapter 1 from

Robbins & Cotran, focussing on cellular responses to injury, reversible versus irreversible injury,

adaptation in the form of hypertrophy, hyperplasia, atrophy and metaplasia.

LT10: In depth lecture, "Repair Mechanisms": second part of the overview of chapter 1 from

Robbins & Cotran, focussing on the different types of necrosis and the essential differences

between apoptosis and necrosis, intracellular accumulations, pathologic calcification and cellular

aging.

Patient demonstration: "An inflammatory disease": Illustrates the clinical and pathological signs

and symptoms caused by inflammation.

Work group: see 1.2.5

Self-study assignments: see 1.2.6

Study plan

Study the pages indicated in the reading list, preferably before the lectures;

Follow the lectures;

Perform the self-study assignment (SSA);

Prepare for and participate actively in work group 1.


31

1.2.4 Reading list

Robbins and Cotran:


1

4-41

Etiology, pathogenesis, morphological changes,

adaptation, reversible versus irreversible cell injury,

hypertrophy, hyperplasia, atrophy, metaplasia, necrosis,

apoptosis, ischemia, hypoxia, intracellular

accumulations, steatosis, hyaline change, glycogen,

calcification

Figures: 1-1, 1-2, 1-3, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-16,

1-22, 1-29, 1-30, 1-33, 1-34, 1-36.

Tables: 1-1, 1-2,

2

44-75 Acute inflammation, chronic inflammation, reactions of

blood vessels and leukocytes, leukocyte migration,

chemoaxis of leukocytes, mediators of inflammation,

cytokines, chemokines, complement system,

coagulation, serous inflammation, fibrinous

inflammation, purulent inflammation, abscess,

granulomatous inflammation

Figures: 2-1, 2-2, 2-3, 2-4, 2-5, 2-7, 2-10, 2-12, 2-13, 2-

16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 2-25,

2-26, 2-27

Tables: 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8



1.2.5 Work group 1

During this work group knowledge obtained during the lectures, seminar and self-study of themes I.A and

I.B is applied. For this work group each student should bring Parham and Robbins (book or digital)

to look up information during the work group (the students arrange that several copies of each book are

present). Students should also bring along their computers in order to look up histopathology slides on

the internet and prepare assignments.

Before the work group, the student must have studied the literature and completed the self-study

assignments of theme I. It is essential that you prepare for the work group.

During the work group

A formative test with open questions will be given to the students. Answers will be discussed directly

afterwards

students get the opportunity to ask questions that came up while doing the self-study;

the tutor will discuss with the students 2 cases which must be prepared beforehand at home. In

addition, students will work in small groups on 2 new cases, which will be distributed by the tutor

during the work group.


32

Cases which should be prepared before you come to Work Group 1:

Case 1: A boy with recurrent infections

A 9-months old boy is referred to the LUMC for unexplained recurrent infections in skin, gastro-intestinal

tract and the respiratory tract. An EDTA blood sample is drawn and sent to the laboratory to obtain the

basic blood cell counts. While the levels of all other leukocyte subtypes are normal, the neutrophil counts

were extremely high. Levels of immunoglobulin subtypes are normal. The pediatrician decides to collect a

skin biopsy for evaluation by the pathologist, who detects a high bacterial load, but no polymorphic or

mononuclear cells in situ. Material sent to the Microbiology Department reveals the presence of

Staphylococcus aureus in the infected skin (this bacterium will be discussed further in Theme II).

Questions:

1 As depicted in fig. 9.24 (Parham), infants display different levels of immunoglobulin subtypes

compared to adults. Describe the major subtype(s) of antibodies which will be found in the serum of

this boy and explain the major effector function of this immunoglobulin subtype(s) (see also fig 4.32

Parham).

2 Coating invading bacteria with specific antibodies, a process called opsonisation, facilitates the

uptake and degradation of bacteria by phagocytes such as macrophages and neutrophils (see also fig

3.14 Parham). Apparently, this defence mechanism is not functioning in this boy given the high

bacterial load in his skin and other mucosal tissues. Which typical feature described in the pathology

report could hint towards his diagnosis?

3 Genetic screening eventually revealed that this boy has an inherited defect in a gene encoding one of

the components of a molecule called LFA-1. At the following site

(http://www.whfreeman.com/Catalog/static/whf/kuby/content/anm/kb01an01.htm1) you can watch an

animation describing the key process of leukocyte extravasation from the circulation. Which proteins

are essential for firm binding of leukocytes to blood endothelial cells (fig 2.31 Parham)?

Case 2: A girl with fever and tonsillitis

A 13-year old girl is seen by her general practitioner (GP). She has suffered from fatigue and episodes of

fever for a substantial number of weeks. After physical examination, it becomes clear that her tonsils (fig.

1.18 Parham) are red and swollen. The GP draws an EDTA blood sample as well as a serum sample and

sends the tubes to the laboratory. From the blood cell count it becomes clear that the numbers of

mononuclear cells (fig 1.12 Parham) are substantially increased. The serum contains IgM as well as IgG

antibodies directed against Epstein-Barr virus (EBV). Hence, the diagnosis is ‘glandular fever’ or

infectious mononucleosis.

Questions:

1 Which of the above described clinical symptoms or laboratory findings indicate that B cells are the

primary target for EBV infection?

2 A primary EBV infection is usually cleared after some time. Which type of T cells are responsible for

the reduction in virus titers in the serum? What is the origin and molecular nature of the antigens

which trigger T cells involved in controlling the infection?


33

3 Provide a rationale for the term mononucleosis: which specific type of lymphocyte do you expect to

be increased in the blood? Which simple marker could be used to identify these cells by routine flow

cytometry analysis (see also fig. 4.14 Parham)?

4 EBV is never completely cleared from the body and persists in a latent infection stage hidden at

immune privileged sites. From here the virus may temporarily reactivate, but this usually does not

cause problems in healthy individuals. Which type of T cells are required for long-term control of

EBV reactivation?

5 Given that the virus remains present in the body, albeit at very low levels, can you predict the course

(het verloop) of the antibody response which is induced upon primary EBV infection? This question

refers to fig. 1.26 Parham.

6 Which type of patients are highly susceptible for EBV reactivation?

7 Study the 2 pictures below of a tonsil biopsy of a 15-year old female with mononucleosis infectiosa.

The description of the light microscopy depicted in the figure on the left is as follows: In some parts

of the tonsil, an intact architecture is found of the follicles, but there are also areas with necrosis and

accumulation of granulocytes.

Can you relate the description to what you see in the picture?

What do you think is the additional technique which was used to further establish the diagnosis,

represented in the figure on the right?

EBV will be further elaborated on in themes II, III and IV

1.2.6 SSA

SSA I.B.1 Microscopy assignment

Study Robbins & Cotran, Chapter 1, and answer the following questions. Figures 1-20 to which the

questions refer to, can be found on Blackboard (under Supplementary materials – Theme I).

1 Give definitions of hypertrophy, hyperplasia, atrophy and metaplasia.


34

2 Study Figures 1 to 4, showing you the light microscopy of 4 normal organs. Which epithelia do you

recognize?

3 Figures 5 to 8 show changes of either hypertrophy, hyperplasia, atrophy or metaplasia in the 4 organs

of question 2. Combine the figures and indicate which change took place. What could have caused

this change?

4 What are differences between apoptosis and necrosis?

5 Figures 9 to 11 show 3 different types of necrosis. Can you indicate which types?

6 Can you think of an organ which is particularly prone to fatty changes? Give a summary of the

mechanisms leading to lipid accumulation in this organ. Which of the figures 12-14 depicts fatty

changes? What are general causes of this fatty change?

7 Study Figures 15-17 of a bruise. Make a diagram which depicts mechanisms of disease reflecting the

changes in bruises from time 0 (trauma) to the end-point (bruise resolved, skin looks normal again).

8 Figures 18-20 show three stages of a myocardial infarction. Describe the mechanisms of disease

responsible for the light microscopic changes that you see.

35

2. Theme II: Microorganisms as cause of disease

Coordinator: Dr. S.M. Arend

2.1 Introduction

During evolution humans had to deal with a large number of microorganisms that inhabit the same

environment and as a result the defence systems are capable of combating most quite effectively. The

human body has even come to live in symbiosis with large numbers of microorganisms, of which bacteria

make up a large part. While human defence mechanisms are highly adequate at maintaining homeostasis

and preventing illness, a number of microorganisms can cause disease. In almost every patient with an

infectious disease inflammatory processes play a crucial role. Therefore, it is appropriate to introduce

microorganisms to the student at this place in the course.

The focus in this theme will be on the classification and structure of microorganisms, basic aspects of

the way they can cause disease (virulence factors) and on the possible types of host immune response.

In theme III on Infectious diseases the knowledge that will be acquired by studying this theme will be

extended when the interaction between host and invader is explored and the diagnosis and therapy of

infectious diseases are studied. Theme IV will focus on the epidemiology, prevention and control of

infectious diseases.

Infectious diseases can be caused by a wide variety of microorganisms: bacteria, viruses, fungi, protozoa

and worms. Protozoa and worms are together often called ‘parasites’. In this theme the student is

introduced to each of these groups of pathogens, and will learn their classification. It will gradually

become clear that infectious diseases are not always caused by one specific microorganism and that

pathogens from a different group may cause identical clinical presentations. On the other hand, one

particular microorganism may cause different clinical presentations. Although the concepts of physiology,

metabolism and genetics, i.e. DNA, RNA, protein synthesis and glucose metabolism are not completely

new to the student, it is essential to be able to distinguish between these processes in the human cell and in

a microorganism, in which specific and unique processes may take place, such as peptidoglycan synthesis,

spore formation, reproduction by fission, and the exploitation of human cells for its own ends.

War is a widely used metaphor of infectious disease. It is a struggle for power between microorganisms

and man. The weapons of the attacker are its virulence factors, and for their defence, humans have

developed defence mechanisms. The outcome of the battle depends on the balance of power (Figure II.1).

Figure II.1. Interaction between host and invader

bacterium

virus

fungus

protozoon

helminth

human

animal

Invader Host

virulence factors

defense mechanisms

bacterium

virus

fungus

protozoon

helminth

human

animal

Invader Host

virulence factors

defense mechanisms

TH E ME I I : MICRO O RG A N ISMS

36

An infectious disease is the expression of a battle between host and microorganism, but not every

encounter results in a battle. Many bacteria live in symbiosis with man and, in normal circumstances, do

not cause disease. In fact, disease is a violation of the symbiosis between man and microorganism, and

non-pathogenic organisms, i.e. commensal flora, often serve important functions in their host. Some

intestinal bacteria produce vitamin K, and as such contribute to our blood coagulation. Our commensal

flora protects us from, or hinders colonization by pathogenic microorganisms and contributes to our

defence against infectious diseases.

2.2 Theme-related objectives (What you will learn)

The student

classifies microorganisms and indicates the various cell components of and physiological processes

in bacteria, viruses, fungi, protozoa and worms, and their function;

names which body sites are normally sterile;

describes normal flora in/on humans, and explains its role in health and disease;

explains the difference between colonization, carrier state, primary pathogens and opportunistic

microorganisms and recognizes pathogenic microorganisms that can also be found as colonizing

flora;

lists possible sources of different types of pathogens (endogenous, environmental, animal or human

source);

describes the main methods for detection of microorganisms (visualization and culture);

explains the significance of structural components for the behaviour of microorganisms (e.g.

environmental requirements) and interaction with the host;

2.3 Study methods and study plan

Lectures

LT11: Introductory lecture providing an overview of the theme Infectious Diseases.

LT12: Bacteria.

LT13: Viruses.

LT14: Fungi and parasites.

These lectures focus on classification, structure, physiology and basic aspects of virulence and on the

relation between host response to components of microorganisms and symptoms/signs.

E-learning

This theme includes an e-learning module that introduce the student to diagnostics of bacterial infections

(diagnostics of other classes of pathogens are addressed in theme III):

Diagnostics of bacterial infection: introduction to laboratory methods for detection of bacteria

(indications, sample selection, staining and culture methods, determination, interpretation,

antibiotic susceptibility).

(Optional: Safe Microbiological Techniques: short module with focus on disinfection,

sterilization etc. This knowledge has more general application in medical practice.)

It is advised to study the module before the lectures. The module can be found on Blackboard (E-

learning) or at www.medischonderwijs.nl with search term G2MD1.



37

Work groups

Theme II-associated knowledge about microorganisms is required in the following work groups:

Work group 2: Infectious diseases (see 3.2.5 under theme III)

Work group 3: Epidemiology, prevention and control of infectious diseases (see 4.1.5 under theme IV)

Self-study assignments: see 2.5

Study plan

Study the pages indicated in the reading list

Follow the lectures

Accomplish the e-learning module


Prepare for and participate actively in the work groups

2.4 Reading list

Robbins:

Pages From …up to Keywords, tables, figures

332-336 Categories of infectious…..

Special techniques for

diagnosing infectious agents

Prions, viruses, bacteria, chlamydiae, rickettsiae,

mycoplasmas, fungi, protozoa, helminths, ectoparasites, table

8-1, fig. 8-2, fig. 8-3.

342-348 How microorganisms….… Viral

infections

Mechanisms of viral injury. Mechanisms of bacterial injury,

injurious effects of host immunity, immune evasion.

Suppurative inflammation, mononuclear and granulomatous

inflammation, cytopathic-cytoproliferative reaction, necrosis,

chronic inflammation. Fig. 8-5, fig. 8-6



Sherris 6th

edition:

Chapter Pages From .....up to… Keywords*, tables, figures

1 4-8 Infectious Agents…..The human

microbiota

*

Fig. 1-2, 1-3, Table 1-1, 1-2.

4 61-63 Culture………Culture media Fig. 4-7

6 98-105 Virus structure……….Classification of viruses

* Fig. 6-1, 6-2, 6-7

21 353-363 Bacterial structure………Bacterial growth and metabolism

* Fig. 21-1 up to and including 21-7, 21-9, 21-10,21-11, Table 21-1

21 382-388 Genetic exchange…… Bacterial

classification

*

Fig. 21-33, 21-34, 21-35, 21-36.


38

42 697-699 The nature of fungi……..Fungal morphology and growth

* Fig. 42-1, 42-2

48 763-771 Whole chapter *

Table 48-2, 48-3

* For keywords: see blue text in margins of Sherris.

2.5 SSA

SSA II.1 Cases

Below, 5 cases (patients A-E) are presented. A different microorganism infects each patient: a bacterium,

virus, fungus, protozoon or parasite. From these examples you will learn general concepts about the

structure, physiology and pathogenicity of microorganisms.

First study the pages indicated in the reading list.

Read the cases and compare the characteristics (structure, physiology) of the infectious agents. Use

self-study Tables II.1.1 (structure) and II.1.2 (physiology).

Name the virulence factors of the infectious agents that caused disease in patients A-E. Indicate for

each infection the pathogenesis (failing of or interaction with component of the immune system)

and type of inflammatory reaction. Use self-study Table II.1.3 (pathogenesis). The tables are

provided in the Attachments.

II.1 Patient A

Patient A is a 28-year-old woman. She consults her general practitioner (GP = huisarts) because she has

had painful micturition since one day and frequently passes small quantities of urine. She had the same

complaints two months earlier, and was then treated for cystitis. This time she feels ill and reports pain in

the lower right lumbar area. Her temperature is 38.9°C. Upon examination she is found to have right-sided

pain in the loin (slagpijn in de flank). The urine nitrite test is negative, but the white cell count in the

sediment (see Figure) is high. She is diagnosed with pyelonephritis, and a urine culture is made. Her GP

prescribes amoxicillin/clavulanic acid, 500/125 mg three times daily for 14 days. The culture yields

Escherichia coli, susceptible to nitrofurantoin, trimethoprim, amoxicillin/clavulanic acid and

cotrimoxazole and resistant to amoxicillin and sulfamethizole.

Figure Patient A: microscopy of urine with leukocytes

II.1 Patient B

Patient B is a 23-year-old man who visits the outpatient clinic because his friend observed that his skin

and eyes had become yellow. Since a week he feels unwell with complaints of nausea and fatigue. His


39

body temperature is 37.9 °C. He is known at the outpatient clinic with HIV infection for which he takes

antiviral therapy since two years. CD4+ counts are about 500 106/L (normal: 560-1490) and HIV (viral

load) is undetectable in the blood. Two months ago he has visited Greece. During this holiday he had

unprotected sexual contacts. The blood examination reveals increased levels of bilirubin, alkaline

phosphatase, transaminases and gamma-glutamyltransferase indicating hepatitis. IgM antibodies against

hepatitis A virus are negative. Tests for hepatitis B: HBsAg (hepatitis B surface antigen) and antibodies

against HB (hepatitis B) core antigen are both positive. The diagnosis is acute hepatitis B.

Figure Patient B: yellow sclerae in jaundice (best seen in natural light)

II.1 Patient C

Patient C is a 42-year-old man. He is seen by his GP with recurrent splits between his toes. Upon

examination he is found to have scales between the toes of both feet, especially near the left big toe. The

GP diagnoses him with foot eczema, which is a wrong term, because it is a fungal infection (tinea pedis),

which is confirmed in a skin scale preparation (see figure patient C on Blackboard). Tinea pedis is caused

by dermatophytes, such as Trichophyton mentagrophytes. The GP prescribes miconazole cream to cure

the infection.

Figure Patient C: Microscopy of KOH preparation of skin sample showing hyphae

II.1 Patient D

Patient D, a 57-year-old man returns from a business trip to South Africa. He visited various African

countries in 10 days. Four days after his return, he becomes ill and shivery, and his temperature rises to

39.4°C. He has a headache and muscular pains. Before his trip he was vaccinated against yellow fever and

hepatitis A, and to ward off malaria, he took mefloquine (Lariam®) tablets according to prescription,

which includes taking the tablets up to 4 weeks after his return. As he had been told he might get malaria

despite the mefloquine prophylaxis, patient D consults his GP. The GP thinks he might have a viral

infection (his temperature is 37.8°C), but decides to rule out malaria by testing the blood of patient D (see

figure patient D on Blackboard). The blood film shows Plasmodium falciparum, parasitemia 0.2%. No

schizonts are found. The patient is put on artemeter/lumefantrin and recovers within a few days.

More information about malaria can be found in chapter 50 of Sherris and at

http://www.dpd.cdc.gov/DPDx/HTML/Malaria.htm

http://www.dpd.cdc.gov/DPDx/HTML/Malaria.htm


40

Figure Patient D: Microscopy of thick blood smear showing Plasmodium falciparum parasites (red blood

cells have been lysed for optimal sensitivity; the large structure is a phagocyte). For calculation of the

parasitemia level, a thin blood smear is needed in which the red blood cells are left intact (you will

observe this yourself during the Practical Parasitology).

II.1 Patient E

Patient E, a 28-year-old woman has been referred to a specialist on account of blood in her urine. She does

not feel ill and has no further complaints. Upon inquiry she appears to have traveled through Africa for 3

months about 7 months ago. She swam in lakes and rivers regularly, and after her return home she had a

short spell of fever, skin rash and swollen lymph glands, for which she consulted her GP, who tested her

negative for malaria. After some time her complaints subsided. Upon further inquiry, she remembers to

have been itching all over shortly after a swim in Africa. The specialist requests a blood test. The blood

test shows a high count of eosinophil granulocytes. The specialist suspects schistosomiasis to explain her

hematuria, and requests serology, which confirms this diagnosis. In her urine live Schistosoma

hematobium eggs are found (see figure). Patient E is treated with praziquantel, and soon recovers.

More information about schistosomiasis is given at chapter 56 of Sherris and

http://www.dpd.cdc.gov/DPDx/HTML/Schistosomiasis.htm

Figure Patient E: Microscopy of urine showing Schistosoma egg. Note the caudal spike, characteristic of

Schistosoma hematobium (lateral spike in Schistosoma mansoni)

http://www.dpd.cdc.gov/DPDx/HTML/Schistosomiasis.htm


41

SSA II.2

Study how the following characteristics of microorganisms can be explained by structure or function

(information from lectures, Sherris, e-learning modules):

1 the characteristic of bacteria to stain either pink or blue/purple in a Gram stain

2 the susceptibility of viruses for drying

3 the susceptibility of viruses for detergents (soap)

4 the susceptibility of bacteria for lysozyme

5 motility of bacteria

6 acid fast staining of mycobacteria

7 survival of some bacteria and fungi under extreme circumstances

8 survival of some protozoa under extreme circumstances

9 exchange or transmission of DNA (plasmidal or chromosomal) between bacteria

10 persistence of some viruses in humans

11 the capacity of some viruses to become pandemic


42

Significant events in the history of infectious diseases*

1546 Girolamo Fracastoro ascribes the origin of an infectious disease to germs, and thereby introduces the ‘germ

theory’ to explain infectious diseases.

1677 Antonie van Leeuwenhoek builds microscopes and discovered “animalculi” in water and dental plaque. It is

generally believed that he saw bacteria.

1798 Edward Jenner publishes his results on cow pox (vaccinia) to inoculate against small pox. His method is

considered safer than inoculation with the small pox virus.

1850 Ignaz Semmelweis proves that puerperal fever can be prevented if physicians disinfect their hands before

they examine pregnant women

1864 Louis Pasteur demonstrates that bacteria do not arise spontaneously, giving strong evidence for the germ

theory

1876 Joseph Lister introduces antisepsis in surgery and wound care. By using carbolic acid to disinfect, he

prevented wound infection and speeded up the cure.

1876 Robert Koch publishes his findings on anthrax and validates the germ theory.

1880 Louis Pasteur develops a method to weaken a pathogen in order to use it as a vaccine.

1880 Alphonse Laveran identifies the malaria parasite in erythrocytes. It was not until 1897-99 that Sir Ronald

Ross and Batista Grassi came independently to the conclusion that the mosquito was both the vector and

host of the malaria parasite.

1881 Robert Koch develops the technique to culture bacteria in a solidified medium.

1882 Ilya Ilich Metchnikoff discovers that various cells in the body consume bacteria. He calls this phagocytosis

and postulates cellular immunity.

1882 Robert Koch isolates the tuberculosis pathogen: Mycobacterium tuberculosis.

1884 Edward Gram develops a dye system for identifying bacteria: the Gram-stain, which is still used in bacterial

diagnostics.

1885 Supervised by Louis Pasteur, the first patient is vaccinated against rabies.

1890 Emil von Behring and Shibasaburo Kitasato develop a diphtheria antitoxin serum.

1891 Paul Ehrlich proposes that antibodies are responsible for immunity to infectious diseases.

1892 Dimitri Ivanoski identifies pathogens smaller than bacteria. Filters that retain bacteria do not retain viruses.

1899 Martinus Beijerinck identifies the tobacco mosaic virus. A filtrate free of bacteria retains ability to caus e a

viral disease in plants after repeated dilutions. He calls the organism contagium vivum fluidum.

1900 Based on work of Walter Reed, it is demonstrated that Yellow Fever is caused by a virus. This is the first

report of a viral agent known to cause human disease.

1912 Paul Ehrlich announces the discovery of Salvarsan to cure syphilis.

1915-17Frederick Twort and Felix d’Herelle describe viruses that infect bacteria, and coin the name ‘bacteriophage’.

1929 Alexander Fleming publishes the first paper describing penicillin, the first antibiotic.

1935 Gerhard J. Domagk introduces Prontosil to treat streptococcal infections.

1949 John Franklin Enders, Thomas H. Weller and Frederick Chapman Robbins develop a method to grow the

polio virus, and thereby introduce the possibility to isolate a virus and study it.

1979 The WHO declares smallpox officially eliminated. The last case was seen in Somalia in 1977.

1982 Stanley Prusiner finds a new class of pathogens, prions, which cause disease both in man and animal.

*the specific names and dates will not be asked at the exam

43

3. Theme III: Infectious Diseases


Every student will know a number of infections and most or all will have suffered from an

infection at some time in the past. Most infections are mild and self-limited but some can be

serious or even life-threatening. Novel emerging infections are frequently in the news, there is

always a threat of a new flu pandemic and the increasing resistance of bacteria to antibiotics is a

threat to the future opportunities for treatment of infections. Whether GP or specialist, every

physician will encounter infectious diseases problems and the knowledge acquired in this theme

is therefore highly relevant for your future career.

The Theme is based on two approaches:

First the general principles are addressed in the three subthemes. In summary the subjects and

questions that will be addressed are

Theme III.A: How do microorganisms cause illness, what types of virulence mechanisms

exist and what is the relation between host defence disorders and specific classes of

microorganisms?

Theme III.B: When are diagnostic tests indicated, which diagnostic tests are suitable for

infections with which type of microorganism and how should test results be interpreted?

Theme III.C: What are the principles of antimicrobial therapy? This includes getting

acquainted with different classes of antimicrobial agents and choosing a therapy for a

simple case.

For a more focused study of infectious diseases a number of Essential Microorganisms is

chosen. These include pathogens from different classes that together represent the possible

different aspects with regard to pathogenesis, clinical syndromes or epidemiology.

The list of Essential microorganisms and the corresponding pages of Sherris to study can be

found after the subthemes on page 73. NOTE. Many but possibly not all of these Essential

Microorganisms will be discussed during lectures, seminars, patient demos, e-learning, work

groups or practicals.

TH E ME II I : IN FE CTIO U S D ISE A SE S

44


45

3.1 Theme III.A: Host-pathogen interactions

3.1.1 Introduction

Essential to the understanding of infectious diseases is the concept that an infection is the result

of the interaction between an invader and a host (Figure III.A.1).

The invader acts through its virulence mechanisms and the host through his or her defence

mechanisms. Virulence mechanisms and defence mechanisms may both contribute to the

clinical signs and symptoms of the disease. In this theme your knowledge about virulence

mechanisms is extended. The main objective is to combine your microbiological and

immunological knowledge so that from now on you will be able to understand what is going on

in a patient with an infectious disease.

Figure III.A.1. Interaction between host and invader


The goals as indicated for this theme will be focused on the list of Essential Microorganisms

(see 3.4) that includes pathogens that together represent different aspects with regard to

pathogenesis, clinical syndromes or epidemiology.

For simple cases with an infection with one of these microorganisms the student can apply this

knowledge in order to explain the host-pathogen interaction, explain or choose diagnostic tests,

and recognize relevant characteristics to determine type of antibiotic treatment.

Study goals Theme III.A

The student

indicates the consequences of the interaction between host and pathogen and can apply

this knowledge to simple cases;

indicates the roles of various structural components, products and/or other characteristics

(together representing the virulence mechanisms) of bacteria, viruses, fungi, protozoa and

worms from the list of Essential Microorganisms in the pathogenesis and clinical signs

and symptoms of infectious diseases;

explains the role of the immune response in pathogenesis and signs and symptoms of

infectious diseases (immuno-pathology);

assesses a patient’s host defence and recognizes and names disorders of host defence that

lead to increased susceptibility to infectious diseases;


46

indicates which specific pathogens cause infections in patients with a particular host

defence disorder, and explain the link between pathogen and disorder;

describes the spectrum of inflammatory responses to infection. From several infections

presented in the module (e.g. pneumonia, tuberculosis): the student recognizes, names

and describes changes (morphological and structural alterations) in tissue specimens with

respect to the conditions.


Lectures

LT15: Invader: virulence factors of microorganisms are discussed and two clinically

relevant examples are elaborated.

LT16: Host versus invader: this lecture addresses the balance between the interaction

between host and invader and this determines the outcome as colonization, carrier,

asymptomatic (subclinical) infection, moderate illness, progressive severe illness, chronic

infection, endogenous or exogenous recurrent infection.

LT17: Immune deficiencies and infection risk: addresses how a disorder in one of the

components of the host defence system is associated with an increased risk of infection

with certain classes of microorganisms.

Patient session

A patient with an infection as a result of an immune disorder will be presented.

Illustration of the importance of the balance between host defence and virulence of

microorganisms, pathogenesis of symptoms and signs and diagnostic aspects.

Work group 2

See under 3.2.5 with theme III.B for work group preparation and contents.

Self-study assignments: see 3.1.6

Study plan


Follow the lectures and patient session

Perform the self-study assignments (SSA)

Prepare for and participate actively in the work group

3.1.4 Reading list

From Sherris 6th

edition study:

Chapter Start page

From… (empty indicates from start pg)

End page

up to…. (empty indicates up to end pg)

1 8 the human microbiota 12 infectious disease

2 39 adverse effects of.. 42

6 107 figure 6-8 only

6 112 only figure 6-11


47

6 113 only figure 6-12

6 122 human viruses 124 quantitation of viruses

7 132 140 viral transformation

7 147 148 virus induced immunosuppression

22 393 entry: beating innate host defences 403 genetics of bacterial…

43 705 708 (CORRECTION: l ine 11 from bottom: Th2 must be Th1!)

49 773 777

From ‘Parham’ study:


11

329-334

333-334

337

338-348

351-356

359-361

immune invasion by genetic variati on (fig 11.1), antigenic drift (fig

11.2) or antigenic shift (fig 11.3)

latent viral infections fig 11.5

immune reaction-driven pathology

inherited immune deficiencies fig 11.9, 1.10, 11.12, 11.14)

acquired immune deficiencies such as AIDS fig 11.22-11.24

opportunistic infections in immune compromised individuals fig 11.30

all diseases that are in the list of Extended Matching Options under

Invader-host interaction: assessment of host defence (e.g. ‘Chronic

granulomatous disease’ etc.)

3.1.5 Virulence factors

During the lecture Invader virulence factors will be classified but only a few will be elaborated

on in detail. The three classes of, and most common virulence factors are:

Virulence factors aiding entry into the host (cells):

Adhesion proteins or -glycoproteins

Endocytosis induced by microorganism

Fimbriae (= pili)

Hyphae

(Lipo)teichoic acid

Virulence factors causing (direct or indirect) damage to the host

Proteins that bind iron

Enzymes inhibiting DNA- and mRNA-synthesis

Enzymes destructing tissue

Glycoproteins inducing syncytium formation

Hyphae


48

Lipopolysaccharide (endotoxin)

(Lipo)teichoic acid

Peptidoglycan

Toxin that activates adenylate cyclase

Toxin acting as superantigen

Toxin inhibiting release of neurotransmitter

Toxin with cytotoxic activity

Ability to lyse infected host cells

Virulence factors that help evade or downregulate host immune responses

Antigenic shift

Antigenic variation

Biofilm

Protein inhibiting opsonisation

Intracellular survival

Capsule

Molecular mimicry

Ability to remain latently in host

During your self-study you should focus on the mechanism by which these factors contribute to

the pathogenesis and on indicating the main virulence factor(s) of each of the Essential

Microorganisms (in Sherris, the essentials are indicated in blue text in the margin).

3.1.6 SSA

SSA III.A.1

Our defence system protects us from being continuously invaded by microbes.

a. Describe the roles of natural barriers, complement, antibodies, phagocytes and cell-

mediated immunity in the defence against bacteria, viruses, fungi, protozoa and worms

respectively. Use self-study table III.A.1 in the Attachments.

b. Explain how the lower airways and urinary bladder, which are in contact with the

outside world, remain sterile.

c. Explain why antibodies play an important role in the protection against encapsulated

bacteria.

SSA III.A.2

For patients A-E (see SSA theme II under 2.5) now answer the questions: which host defence

mechanism failed, and how originated the clinical signs and symptoms (pathophysiological

explanation of signs and symptoms)? Use self-study table III.A.2 in the Attachments.

SSA III.A.3

Answer the questions to the patient cases below.

1. A 30 year-old male is taken to a hospital intensive care department after a car accident. As

fractured ribs interfere with his breathing, he is put on artificial respiration. An intravenous

catheter is brought into the right subclavian vein, and a urinary catheter into his bladder. To

facilitate his breathing, he is put on a sedative (which makes him sleep continuously), and to

prevent haemorrhage of the stomach he is given an antacid. After 3 days his blood pressure


49

drops and his temperature rises considerably. On suspicion of sepsis he is empirically (thus

without proof of the diagnosis) treated with antibiotics. His blood culture grows Escherichia

coli.

a. Give your opinion of the patient’s host defence

b. Explain how and why Escherichia coli causes high temperature and low blood pressure.

2. A 49 year-old female is admitted into the hospital with pneumonia, sinusitis maxillaris and

ethmoidalis, loss of weight and diarrhoea. She had pneumonia 3 and 4 years ago, and has had

sinusitis continuously thereafter. Her blood is found to contain pneumococci, and in the faeces

Giardia lamblia as well as Campylobacter jejuni are found.

a. Which immune disorder is most likely in this patient?

b. Which tests would you do to confirm this disorder?

c. What is the likely pathogenesis of the diarrhoea syndrome?

d. If the disorder you suspect is confirmed, which are the (non)-possibilities to treat the

patient?

3.1.7 Instructions Extended Matching Questions Theme III.A

During the module a formative test is provided via Blackboard including some Extended-

matching questions for this theme, as will also be the case at the final exam. During your self-

study you should therefore use this list in order to get acquainted with the options. In Dutch the

list is alphabetical (all EM options lists in Dutch for G2DM1 can be found on Blackboard-

Module G2MD1-Course documents-Translations).

Extended-matching question

Theme III.A: Invader-host interaction: assessment of host defence

Options:

a. Presence of corpus alienum (foreign body)

b. Break in skin integrity

c. Break in mucous membrane integrity

d. ‘Chronic granulomatous disease’

e. ‘Common variable immunodeficiency’

f. Complement deficiency

g. Granulocyte function disorder

h. Granulocytopenia

i. Leukocyte adhesion deficiency

j. Spleen dysfunction or asplenia

k. Incomplete emptying of urinary bladder

l. ‘Severe combined immunodeficiency’ (SCID)

m. Lack of gastric acid

n. Impaired coughing

o. Impaired ‘cell-mediated immunity’

p. Impaired intestinal peristalsis

q. Impaired colonisation resistance

r. Impaired ciliary function

s. ‘X-linked agammaglobulinaemia’

t. –


50

u. –

v. –

w. –

x. No host resistance defect has played a role

Task: Indicate which disorder of host defence has likely played a major role in

the pathogenesis of the described case. If no host defence disorder

played a role you must mark compartment x on the computer form. The

exact number of requested options is indicated. When you mark

more than the indicated number of options, you will get negative points.

However, even when you do not have all options correct you will get

points.

Cases:

1. A 73-year-old man is consulting his general practitioner with dysuria (painful micturition)

since one day. Since a year he sometimes feels the urge to urinate but the urine does not come at

that moment. Often he has to go the toilet again shortly after micturition. In that case he again

produces only a small amount of urine. Examination of the urine shows many leukocytes.

Rectal examination reveals an enlarged prostate. Give one option.

2. A 30-year-old woman is treated for acute leukaemia with cytostatic drugs. She has a high

fever and from the blood Pseudomonas aeruginosa (a Gram-negative bacterium) is cultured. She

has a subclavian catheter for the administration of her medication. Since two days she has

bloody diarrhoea. Blood parameters: granulocytes 0,02109/L (normal 4,5 –10,0109/L),

thrombocytes 11109/L (normal 150-450 109/L). Give three options.

Answer 1: <k>

Answer 2: <b,c,h(a also correct)>


51


52

Robert Koch

Robert Koch (1843-1910) was a district medical officer in

Wollstein, in what is now Poland, when he started his

research into anthrax in 1874. Without adequate quarters or

conditions to support him, he studied the blood of animals

that had recently died of anthrax, and found a high

concentration of bacteria. A rabbit inoculated with the blood

became ill and died. The tissue and blood of the rabbit

counted many bacteria. Koch managed to grow the anthrax

bacilli in vitro on the aqueous humour of a rabbit’s eye, and

found the anthrax bacilli to produce spores (see picture

below). Thus he not only found that infected animals could infect other animals, but also that healthy

animals could be infected through spores in dust and soil.

Koch published the results of his study in 1876 and

thereby validated the germ theory, which said that a

contagium, i.e. a living microorganism, caused an

infectious disease. Up till then, the role of

microorganisms in infectious disease had been denied by

famous pathologists, such as Virchow and Billroth, while

Henle had hypothesised the germ theory as early as 1840

without being able to prove it. After the discovery of

Bacillus antracis, Koch discovered two more pathogens:

Mycobacterium tuberculosis (1882) and Vibrio cholerae

(1884). Koch invented a new method to grow bacilli in a pure culture on solid media. In a publication

dated 1881 he wrote: A simple observation which anyone can repeat has led me to this approach. If a

boiled potato is cut in half and the cut surface is exposed to the air for several hours and then placed in a

moist chamber such as a moistened bell jar in order to prevent it from drying, then, depending on the

temperature of the chamber, one will find in the following day or two, on the surfac e of the potato, a

large number of very small droplets, all of which seem to be different from each other.

Microscopic investigation of the droplets showed that each droplet contained different microorganisms.

On the basis of this observation, Koch mixed the medium fluid

with gelatine, poured the mixture onto a slide, on which it

solidified (see picture on the right). Koch hereby introduced the

solid medium, which is still widely used in a bacteriology

laboratory. Koch’s research into the causative agent of tuberculosis

did not only lead to the discovery of Mycobacterium tuberculosis,

but also to the laying down of the conditions, known as Koch’s

postulates , which must be satisfied before it can be accepted that

specific microorganims cause a particular infectious disease.

53

3.2 Theme III.B: Clinical presentations and

diagnostics

3.2.1 Introduction

In the medical process diagnostics are an essential source of information and a vehicle to arrive at a

definitive diagnosis (Fig. III.B.1). In infectious diseases, laboratory diagnosis aims at the identification

of the pathogen or the host response, and when the pathogen is a bacterium, it’s susceptibility to

antibiotics is tested. Indirect diagnostic methods include serology, which is often used for viral

infections and some parasitic diseases, but also a number of specific bacterial infections.

Diagnostics serve a specific aim. A question is formulated and the tests are chosen in such a way that

an answer to this question can be obtained. Examples of indications for diagnostics in infectious

diseases are: working out a differential diagnosis, confirmation of the initially suspected diagnosis,

identification of a pathogen, antibiotic susceptibility testing, collecting basic information necessary for

choosing antibiotic therapy, for instance on a patient’s renal function. Diagnostic investigations can

also be done to obtain information about the prevalence of pathogens. In that case diagnostics serve

the community rather than an individual.

Figure III.B.1. The medical process

Diagnostics

Collecting information

Symptoms

Medical problem

Differential diagnosis

(Working)diagnosis

(empirical) Therapy

Infection

Differential diagnosis

pathogens

Empirical therapy

(if indicated)

Microbiological diagnostics

Definitive therapy

Evaluation of therapy


54


Study goals Theme III.B:

The student

explains the diagnostic principles of infectious diseases, and applies these to simple cases;

explains the available microbiological diagnostic tests;

knows the immunological principles in clinical diagnostics (humoral immune response:

mechanism of ELISA for detection of antigen or antibodies, IgG vs IgM, IgG affinity, IgE

response to allergens or parasitic infections), cellular immune response: leukocytosis, left shift,

lymphocytosis, lymphopenia, type IV allergic response in skin test;

describes indications for diagnostic tests;

draws up a diagnostic plan for simple infection problems;

recognizes the clinical syndrome or causative microorganism from a short case description (the

‘Clinical Capsules’ in Sherris);

names the most likely pathogen(s) from an image (microscopy or macroscopy) of a diagnostic

specimen given a simple case;

interprets the results of diagnostic tests in relation to the prior probability of disease (Bayes

theorem), and calculates sensitivity, specificity and positive or negative predictive value.


Lectures

LT18: Pathology of infection: in this lecture the histopathological changes will be shown of

the most important infections discussed in this theme.

LT19: Diagnostics of infectious diseases: general principles of diagnostic tests

for infections giving a framework for the self-study of this topic.

LT20: Interpretation of diagnostic test results: this depends not only on test

characteristics but also on the pre-test (prior) risk of a particular disease (focus on

sensitivity/specificity as opposed to positive and negative predictive value).

LT21: Essential microorganisms: in this lecture microorganisms are related to clinical

presentations and vice versa.

Seminar 1: diagnostics of infectious diseases

During the seminar a number cases will be presented for which you will be asked to answer the

questions essential to diagnostics of infectious diseases:

How do you define the medical problem?

What is your differential diagnosis?

Which reason(s) do you have for microbiological diagnostics?

Which patient materials do you send to the laboratory?

Which tests do you request?

What is your interpretation of the results?

Work group 2: see 3.2.5

E-learning

Two modules that continue the e-learning module in theme II:

Diagnostics of infectious diseases: this lesson guides the student through the self-study.

Diagnosis of pathogens – 25 cases: for self-assessment.


55

Practicals

During both practicals, standard bacteriological and parasitological diagnostic methods will be

demonstrated in the setting of clinical patient problems. Both practicals are obligatory (see

Rules of the game) and include diagnostic microscopy based on clinical cases.

Practical 1: Bacteriology. NOTE. Practical bacteriology includes a 20 minutes test exam at the

end (for details: see Assessment on pg. 13-16).

Practical 2: Parasitology. (including a 10 minutes test exam at the end)

Preparation for the practicals: at least all 3 e-learning modules regarding diagnostics of Theme II and

III.B must be completed, for Practical 2 it is useful to have studied the life cycles of the protozoa

(especially Plasmodium) and helminths from the list of Essential Microorganisms.

Study plan

Follow the lectures and seminar


Accomplish the e-learning modules

Prepare for and participate actively in the practicals Bacteriology and Parasitology


3.2.4 Reading list

What you need to know about diagnostics of the Essential microorganisms is mainly learned from the

lecture, seminar and e-learning modules.

From Sherris 6th

edition study:

Chapter Start page


End page

up to…. (empty indicates end pg)

4 55 63 …….culture media

4 72 Antibody detection 76

42 708 Laboratory diagnosis 709 .. antigen and antibody detection

3.2.5 Work group 2

During this work group knowledge obtained during the lectures, seminars and self-study of themes I

and II is applied. For this work group each student should bring Sherris (book or digital) to look

up information during the work group.

It is essential that you prepare for the work group. Before the work group, the student must

have completed the self-study assignments of themes II and III.A;

have completed all four e-learning modules on diagnostics;

be acquainted with the items in the extended matching question option lists of themes III.A and

III.B.


56

Students get the opportunity to ask questions that came up while doing the self-study.

NOTE. During this work group instructions and/or materials for preparing for the component exam 3

will be provided.

During the work group the students will work in small groups to answer the following questions on

cases that will be distributed by the tutor:

1 Which microorganism caused the disease?

2 Which virulence mechanisms played a crucial role?

3 Which host defences failed?

4 What mechanisms caused the clinical signs and symptoms of the disease?

5 Which (additional) diagnostic test(s) are indicated, if any?

6 Is antimicrobial therapy indicated and, if yes, what would be a rational choice?


57

3.2.6 Instructions Extended Matching Questions Theme III.B

During the module a formative test is provided via Blackboard including a number of Extended-

matching questions on this theme, as will also be part of the final exam. During your self-study you

should therefore use these option lists in order to get acquainted with the options. In Dutch the list is

alphabetical (all EM options lists in Dutch for G2DMD1 can be found on Blackboard-Module

G2MD1-Course documents-Translations).


Theme III.B: Diagnostics: interpretation of microscopic preparations

Options:

a. Ancylostoma duodenale

b. Ascaris lumbricoides

c. Aspergillus fumigatus

d. Candida albicans

e. Clostridium perfringens

f. Echinococcus granulosus

g. Entamoeba histolytica

h. Escherichia coli

i. Giardia lamblia

j. Mycobacterium tuberculosis

k. Neisseria gonorrhoeae

l. Neisseria meningitidis

m. Plasmodium falciparum

n. Plasmodium vivax

o. Salmonella species

p. Staphylococcus aureus

q. Staphylococcus epidermidis

r. Streptococcus pneumoniae

s. Streptococcus pyogenes

t. Schistosoma species

u. Strongyloides stercoralis

v. Toxoplasma gondii

w. Treponema pallidum

x. Trichuris trichiura

Task: Examine the microscopic preparation and indicate which organism is the cause

of the described signs and symptoms. The precise number of requested

options is indicated. When you mark more than the indicated number of

options, you will get negative points. However, you will get points even when

you do not have all options correct.


58

Cases:

1. A 54-year-old woman has had an operation of the right mamma one week earlier. Now, the wound

is red and there is purulent discharge. A Gram stain of the discharge is made. Give one option.

Figure with case 1

2. A 30-year-old woman from Morocco has a swelling in the right side of her neck. Inspection reveals

that the swelling is an enlarged lymph node. A diagnostic aspiration is performed. A Ziehl-Neelsen

preparation is made from the material. Give one option.

Figure with case 2 (Sherris, Figure 27-2).


59


Theme III.B: Diagnostics: choosing a diagnostic test

Options

a. Antigen assay, bacterial

b. Antigen assay, protozoa

c. Antigen assay, viral

d. DNA/RNA detection (PCR)

e. Electron microscopy

f. Culture, bacterial

g. Culture, fungal

h. Culture, viral

i. Culture, worms

j. Microscopy, auramine stain

k. Microscopy, thick and thin blood smear

l. Microscopy, dark field

m. Microscopy, cysts, eggs and larvae

n. Microscopy, Gram stain

o. Microscopy, KOH-preparation

p. Microscopy, Ziehl-Neelsen stain

q. Serology

r. Toxin assay

s. -

t. -

u. -

v. -

w. -

x. No test, diagnostics not necessary

Task: Indicate for each case the preferred diagnostic test. This concerns tests that are

routinely used in daily practice. If no diagnostic is necessary mark

compartment x on the computer form. The precise number of requested

options is indicated. When you mark more than the indicated number of

options, you will get negative points. However, you will get points even when

you do not have all options correct.

Case:

3. A 62-year-old man is admitted to the hospital with bile stones and an inflamed gall bladder

(cholecystitis). He has cold chills and a rapidly rising temperature. He is pale and feels sweaty. His

blood pressure is 80/45 mmHg, his pulse rate 146/min. The doctor in charge considers a septic shock.

Give one option.


60

Extended-matching questions

Theme III.B: Differential diagnosis of (possible) pathogens

Options:

a. Aspergillus fumigatus

b. Candida albicans

c. Cytomegalovirus

d. Echinococcus granulosus

e. Entamoeba histolytica

f. Epstein-Barr-virus

g. Escherichia coli

h. Giardia lamblia

i. Herpes simplex virus

j. Human immunodeficiency virus

k. Influenzavirus

l. Mycobacterium tuberculosis

m. Neisseria meningitidis

n. Plasmodium falciparum

o. Plasmodium vivax

p. Schistosoma species

q. Staphylococcus aureus

r. Staphylococcus epidermidis

s. Streptococcus pneumoniae

t. Streptococcus pyogenes

u. Strongyloides stercoralis

v. Toxoplasma gondii

w. Treponema pallidum

x. Varicella-zoster virus

Task: Indicate for each case which microorganism most likely caused the disease.

The precise number of requested options is indicated. When you mark more

than the indicated number of options, you will get negative points. However,

you will get points even when you do not have all options correct.

Cases:

4. A 3-year-old boy, who had previously been in good health, has vesicles over his whole body. Some

vesicles are broken and on other vesicles crusts have formed. The child is not very ill with light fever

(38,1 C). Give one option.

5. A 4-year-old boy is admitted because of fever (39,1 C). He vomits and is weak. Examination of the

cerebrospinal fluid shows a strongly increased number of granulocytes. Give two options.

Answers

1: <p>

2: < j>

3: <f>

4: <x>

5: <m,s>


61


62

Alexander Fleming

In 1929 Alexander Fleming published an article in the British

Medical Journal, entitled “On the antibacterial action of

cultures of a Penicillium, with special reference to their use in

the isolation of B. influenzae”. The article begins as follows:

While working with staphylococcus variants a number of

culture-plates were set aside on the laboratory bench and

examined from time to time. In the examinations these plates

were necessarily exposed to the air and they became

contaminated with various microorganisms. It was noticed that

around a large colony of a contaminating mould the

staphylococcus colonies became transparent and were obviously undergoing lysis (photo).

Fleming realised that the fungus, which came to be called

Penicillium notatum, produced a substance with

antibacterial properties; an antibiotic. Earlier research had

shown that fungi inhibited bacterial growth. In 1870 the

British physician Sanderson had found that bacteria did not

grow in tubes exposed to the air and filled with Pasteur’s

medium in which Penicillium colonies had grown.

Sanderson’s explanation was that bacteria did not occur in

the air, but that fungi did. Lister, a famous surgeon, did not

believe this, and on the basis of his own experiments he

concluded that Penicillium inhibited bacterial growth. He

used extracts of fungal cultures to treat abscesses. The physicist John Tyndall thought that the fungus used up the

air in the culture and thus created a shortage of air, which prevented bacteria from growing.

At the time Fleming discovered penicillin, he thought of applying

it to culture bacteria, but never thought of it as a possible remedy

for infectious diseases. In 1929 there was hardly any treatment for

infections. The first chemotherapy to treat syphilis, an arsenic

compound called salvarsan, had been introduced by Paul Ehrlich

in 1912. In 1935 Gerhard J. Domagk developed prontosil, which

proved a remedy against streptococcal infections. In 1940

penicillin was refined and became available as a remedy against

infectious diseases. After the discovery that both fungi and

bacteria produced substances with antibacterial properties, the

active search in nature for such agents began, and since that time,

many antibiotics have been

developed, some of which

are listed here.

1929 Penicillin, (unrefined)

1939 Polymyxin

1940 Penicillin G

1944 Streptomycin

1945 Cephalosporin C

1947 Chloramphenicol

1948 Chlortetracyclin

1950 Erythromycin

1955 Vancomycin

1955 Amphotericin B

1955 Lincomycin

1959 Rifamycine

1960 Methicillin

1963 Gentamicin

1981 Ceftazidime

1985 Ciprofloxacin

1988 Meropenem

1989 Clarithromycin

2002 Linezolid


63

3.3 Theme III.C: Therapy of infectious diseases

3.3.1 Introduction

The first choice for the treatment of an infectious disease that comes to our mind is an antibiotic,

which can indeed be a powerful remedy, but by no means the only (see Table III.C.1).

Table III.C.1 Treatment of infectious diseases

Symptomatic therapy

Pharmacotherapy, not antimicrobial

Surgery

Immunotherapy

Antimicrobial therapy

Not all infections can or should be treated with antimicrobial therapy. The symptoms of many

infectious diseases can be sufficiently treated with an analgesic and antipyretic drug. Other infectious

diseases, such as abscesses, require surgery. In some cases a drug not aimed at the infectious agent is

sufficient, such as a bronchodilator in bronchitis. Immunotherapy is another option.

This theme focuses on antimicrobial therapy. Figure III.C.1 shows the interactions between the

invader, the host and the antimicrobial drug. The target site of an antimicrobial drug is the pathogen

(pharmacodynamic activity); the counteraction of the pathogen is resistance; the antimicrobial drug

may have unintentional effects in the host (side effects and toxicity); the host ingests the antimicrobial

drug, metabolises and eliminates it (pharmacokinetics) or may be allergic.

Figure III.C.1: the interactions between the host, invader and antimicrobial therapy

Pharmacodynamics in antimicrobial therapy requires a special interpretation. Instead of a receptor on

or in a human cell, as is usual in pharmacotherapy, the target site of an antimicrobial drug is the

Antimicrobial

therapy

Host

Pharmacodynamics:

activity

Invader

Resistance

Pharmacodynamics:

Side effects

and toxicity Pharmacokinetics

Defence mechanisms

Virulence mechanisms


64

causative microorganism (bacterium, virus, fungus or parasite). As the structure of pathogens differs

from that of the human cell, it has become feasible to introduce drugs that have a target that is lacking

in the human body (selective toxicity). This does not imply that antimicrobial drugs are non-toxic, or

do not have side effects. The extensive use of antimicrobials has led to the development of resistance

of many microorganisms, which considerably diminished the initial success of antibiotic drugs.


Study goals Theme III.C.

The student

indicates the mechanisms of action of the major (groups of) antibiotics;

describes the principles of treatment of infectious diseases, and applies these to simple

problems (e.g. recognizes the indications for bactericidal antibiotics);

applies pharmacokinetic principles to simple cases, e.g. analyses serum levels in relation to

dosing schedule;

indicates the major mechanisms and the genetic background of antibiotic resistance, and the

potential ways of transmission of resistance between bacteria;

indicates the role of antibiotic drug use in the development and spread of resistance.


Lectures

LT22: Antimicrobial therapy: Classes of antimicrobial drugs and mechanism of action:

examples of the mechanism of action of commonly used antimicrobial agents.

LT23: Principles of antibiotic pharmacotherapy: antibiotics are to be used prudently to

safeguard their use for future generations and this lecture addresses the principles that should

guide antimicrobial therapy.

Work group 2:

See 3.2.5 under theme III.B for work group preparation and contents. This work group includes cases

for which therapeutic decisions must be made.

E-learning

Information about specific antimicrobial drugs can be found in the study book and/or in the

TRC database.

Optional: treatment of infectious diseases: 4 cases to practice (you do not need to know the

6STEP method but should focus on the concepts explained in 3.3.5).

Study plan

Study the general information in the module book


Follow the lectures

(optional: TRC pharmacology database)

(optional: e-learning modules 6-step TRC Infectious Diseases)




65

Assessment

Regarding pharmacology/pharmacotherapy, the exam will consist of multiple-choice questions on the

principles and pharmacology of drugs used in infectious diseases. You can expect that one of these

questions will require you to evaluate renal function in order to determine an appropriate therapy.

3.3.4 Reading list

From Sherris 6th

edition study:

Chapter Start page


End page

up to…. (empty indicates end pg)

8 151 only: general considerations

8 154 acyclovir 155 ganciclovir

23 407 Antibacterial agents and therapy 418

23 422

Bacterial resistance (only principles: table 23-2 and figure 23-7) 424

44 713 (not table 44-1) 715 including figure 44-1

50 See *NOTE

*NOTE: you may limit your study to the antibiotic drugs as listed in the table at the end of this

chapter!

These subjects can, alternatively or additionally, be studied from other sources such as the TRC (via

Blackboard) or the pharmacology textbook:

TRC database chapter "INFECTIOUS DISEASES" to learn about the various agents used as

antibiotics, antivirals, antifungals, antihelminths, antiprotozoals and antimalarials (see also

under self-study assigment).

You can read more about drugs in infectious diseases in:

Farmacotherapeutisch Kompas (www.fk.cvz.nl). See the background information in the chapter

on “drugs with infectious diseases” and also the links from the TRC to the specific drugs.

Rang & Dale Pharmacology (6th edition) Ch. 45-50: Drugs used in the treatment of infections

[p. 647-717]

Tables antimicrobial therapy

At the end of this chapter you will find tables with facts about antibacterial, antiviral, antifungal and

antiparasitic drugs. NOTE. These tables will be provided at the final examination. So, don't learn

the information presented in the tables by heart, but learn to use the information for choosing

antimicrobial therapy for the cases you find in this chapter and which you will find in your

examination. However, you need to know the mechanisms of action and adverse effects by studying

Sherris and/or the TRC and/or Rang & Dale, regarding the drugs mentioned in the table.

http://www.fk.cvz.nl/


66

3.3.5 Concepts of pharmacology and prescribing antimicrobial therapy

Concepts of pharmacology

This module teaches a number of concepts and principles of pharmacology (Table III.C.2).

Table III.C.2: Pharmacotherapeutical concepts in the treatment of infectious diseases

Pharmacodynamics

minimal inhibition concentration (MIC )

killing curve, concentration-effect curve, synergism, antagonism

measures for activity, such as time above MIC and AUC

allergy and cross-allergy

selective toxicity

antibacterial spectrum

post-antibiotic effect

Pharmacokinetics

dose, distribution volume, clearance, half-life, concentration-time curve, diffusion, diffusion

barriers, blood-brain/cerebrospinal fluid barrier

drug interaction

protein binding

active transport in kidney, cerebrospinal fluid space, and eye

Prescribing antimicrobial therapy

Before you prescribe an antimicrobial drug to a patient, it is important to first answer the following

questions:

1. Does the patient have an infection?

When it comes to the prescription of antimicrobial therapy the essential question is whether the patient

has an infection or not. The answer to this question is not always obvious; fever does not always imply

an infection, and not every inflammatory reaction implies an infection.

2. What is/are the likely pathogens causing this infection?

Symptoms and signs of an infection may be highly characteristic, but usually different microorganisms

can cause similar clinical presentations. When you have answered the question whether there is an

infection positively, the next question is: which is the (possible) pathogen or which are the (possible)

pathogens causing this infection? It does not suffice to say that the patient has for example pneumonia,

but you have to add a differential diagnosis of pathogens. For the example of pneumonia this could be:

Streptococcus pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae. During this module

you need only to recognize characteristic clinical presentations as are described during the lectures and

in the clinical capsules in Sherris.

3. Are antimicrobial agents indicated?

Not every infection requires antimicrobial therapy. The infection may be mild and self-limited or

treatment may not have a beneficial effect. An example of the latter is acute hepatitis B. Antiviral


67

drugs against HBV are available but in general have no place in the treatment of acute HBV infection

for lack of effect on the outcome.

4. If antimicrobial therapy is indicated, provide the rationale for the best treatment for this

patient.

If treatment is indicated, list the options and rationalize which is best suited for your patient. Table

III.C.3 can be used as an outline of things to consider for the choice for an antimicrobial drug for your

patient. Also evaluate the patient’s specific data (Table III.C.4) to determine if adjustments in drug

choice and/or dosing need to be made. Pharmacokinetics are important for a number of antibiotics and

therefore interfere with dosing. Several examples will be discussed during lectures, seminars and work

groups.

Table III.C.3. Choosing antimicrobial therapy

Selection criterion Determinants

Effectiveness Bactericidal versus bacteriostatic action*

In vitro activity

Clinical activity

Resistance a priori

Accessibility of target

Host resistance

Safety Toxicity, side effects

The span of the spectrum

Risk of development of resistance during treatment

Contraindications due to allergy, drug interactions, hearing

loss, impairment of kidney or liver function

Suitability Preferred route of administration (oral or i.v.)

Costs Costs of drug, administration and drug monitoring

* It is not always necessary to use bactericidal antibiotics. However, this is strongly preferred in the

following circumstances:

in the presence of bacteria in the blood stream (bacteraemia or sepsis)

infection of a site with limited access of normal immunity (endocarditis, meningitis)

patient with granulocytopenia.

Table III.C.4. Patient specific data

Selection criterion Determinants

Pharmacokinetic characteristics Age

Renal function

Liver function

Interactions Other drugs

Intoxications (alcohol, drugs)

Other Co-morbidity

Presence of implants (heart valve, joint prosthesis etc)

Allergy

Compliance (acceptable frequency of dosing)


68

3.3.6 SSA

SSA III.C.1

The epidemiology of resistance of pathogens to antibiotics is important for the choice of empirical

treatment and dictates the possibilities for definitive therapy. For MRSA answer the following

questions:

1 Explain the name MRSA. To which antibiotic is MRSA resistant?

2 What is the mechanism of the resistance?

3 Which are the 2 types of MRSA? (Tip: http://www.kiza.nl/content/verspreiding-epidemiologie-

44)

4 What are risk groups for MRSA infection in the Netherlands?

5 What percentage of S. aureus in the Netherlands are MRSA? (Tip: Use NETHMAP 2013 at

http://www.rivm.nl/Documenten_en_publicaties/Algemeen_Actueel/Uitgaven/Infectieziekten/NE

THMAP_MARAN_2013 where you will find a report with the information on page 65-66)

6 What is the percentage in e.g. Belgium (foreign students: look up for your country of origin)?

(Tip: http://www.kiza.nl/content/verspreiding-epidemiologie-44)

Note; the indicated internet sites are in Dutch: foreign students should team up with a Dutch student.

http://www.kiza.nl/content/verspreiding-epidemiologie-44


http://www.rivm.nl/Documenten_en_publicaties/Algemeen_Actueel/Uitgaven/Infectieziekten/NETHMAP_MARAN_2013

http://www.rivm.nl/Documenten_en_publicaties/Algemeen_Actueel/Uitgaven/Infectieziekten/NETHMAP_MARAN_2013


69

3.3.7 Tables antimicrobial therapy

Antibacterial drugs

Indication

Bactericidal or

-static

Resistance

Toxicity

Spectrum

Administration

Cost per day

Penicillin G Gram-positive cocci and rods;

Gram-negative cocci

Bactericidal 80% S. aureus Allergic reaction Narrow Intravenous € 3.40

Feniticillin Gram-positive cocci and rods;

Gram-negative cocci

Bactericidal 80% S. aureus Allergic reaction Narrow Oral € 1.15

Amoxicillin Identical to Penicillin G, plus

aerobic Gram-negative rods

Bactericidal E. coli 30-40%

H. influenzae 8-10%

Allergic reaction In between narrow

and broad

Intravenous

Oral

€ 6.35

€ 0.91

Amoxicillin +

clavulanic acid (co-amoxiclav)

Identical to Penicillin G, plus

aerobic Gram-negative rods, plus

anaerobes

Bactericidal ± 5% Allergic reaction broad Intravenous

Oral

€ 8.50

€ 2.50

Flucloxacillin Gram-positive cocci , especially

S. aureus

Bactericidal < 1% S. aureus (in the

Netherlands)

Allergic reaction Narrow Intravenous

Oral

€ 18.15

€ 4.99

Cefuroxim Gram-positive cocci, aerobic

Gram-negative rods

Bactericidal <10%

P.aeruginosa always

resistant

Allergic reaction In between narrow

and broad

Intravenous € 26.32

Gentamicin Aerobic Gram-negative rods Bactericidal < 10% Ototoxicity

Nephrotoxicity

Narrow Intravenous € 19.06

Erythromycin

Clarithromycin

Gram-positive and -negative

cocci;

Mycoplasma pneumoniae,

Legionella pneumophila

Bacteriostatic Gram-positive cocci ±

5%

Nausea Narrow Intravenous (ery-

thromycin only)

Oral

i.v. € 49.80

p.o. € 3.63

Ciprofloxacin Aerobic Gram-negative rods

Legionella pneumophila

Mycoplasma pneumoniae

Bactericidal < 10% Intestinal complaints

Complaints central nervous

system

In between narrow

and broad

Intravenous

Oral

€ 143.39

€ 36.30

Metronidazole Anaerobic bacteria

Bactericidal Seldom resistance Neuropathy

Nausea and other mild side

effects

Narrow Intravenous

Oral

€ 0.50

Doxycyclin Gram-positive and -negative,

aerobic and anaerobic bacteria,

Mycoplasma pneumoniae

Bacteriostatic Gram positive cocci

5%

E. coli 30-40%

Dental discoloration in young

children (contraindicated

<8y)

Broad Intravenous

Oral

€ 3.63

€ 0.41

Nitrofurantoin Gram-negative aerobic rods and

Gram-positive cocci

Batericidal < 3% Intestinal complaints,

headache

Broad Oral € 0.50

Vancomycin Gram-positive cocci Bactericidal < 1% Red man syndrome,

intestinal complaints, loss of

hearing

Narrow Intravenous € 48.00

TH E ME I I I : IN FE CTIO U S D ISE A SE S

70

continued

anti-parasitic drugs

Indication

Resistance

Toxicity

Spectrum

Administration

Cost per day

artesunate Plasmodium falciparum, particularly

severe cases

partial resistance limited to

Cambodja

anaphylactic reactions intravenous € 381 (may vary)

arthemeter/

lumefantrine

Plasmodium falciparum, non-severe

cases

partial resistance limited to

Cambodja

Conduction abnormalities in

patients with prolonged QTc

interval

oral € 26.51 * (see

note)

atovaquone/ proguanil Plasmdium falciparum, non-severe

cases

little resistance Commonly only mild side effects oral € 31.95 *

Quinine Plasmodium falciparum, particularly

severe cases

no resistance Headache, sometimes deafness oral, parenteral € 6.87 *

chloroquine treatment of infection with Plasmodium

vivax

very common in P. falciparum

but not in other Plasmodium species

Commonly only mild side effects oral € 1.21 *

primaquine to avoid relapses of P. vivax-infections rare partial resistance Risk of haemolytic anemia oral € 4.13

pyrimethamine folic acid antagonists; together with

sulfonamids: toxoplasmosis, malaria

frequent resistance when used for

malaria prophylaxis

Higher dosages: teratogenic oral (€ 0.10/tablet)

metronidazole intestinal protozoal infections:

Entamoeba histolytica and Giardia

lamblia

occasionally non-responding

parasite strains

Neuropathy

nausea and other mild side effects

broad Intravenous

oral

€ 0.50

mebendazole broad spectrum anthelmintic, not

resorbed. Used in many nematode

infections

common in veterinary medicine

but not yet in man

Mild or none broad oral € 15.00

albendazole as mebendazole though slightly better

resorbed

as mebendazole In high dosages: leukopenia broad oral € 6.30

ivermectine Strongyloides stercoralis and some

filarial infections

common in veterinary medicine

but not yet in man

Mostly marginal fairly broad oral € 15.70

praziquantel schistosomiasis and other trematode

infections

no resistance proven, so far Mostly mild sometimes malaise fairly broad oral € 32.00

* NOTE. For antimalarials, the price refers to a complete course, because the duration of treatment differs between the drugs.


71

continued

Antiviral drugs

Indication

Class

Resistance

Toxicity

Administration

Cost per day

Aciclovir Herpes simplex virus

(HSV) 1 / 2, varicella-

zoster virus (VZV)

DNA polymerase inhibitor Rare, only with prolonged

use

Intestinal complaints,

reversible neurological

disorders

Intravenous

€ 65,00 - 130,00

Valaciclovir Herpes simplex virus

(HSV) 1 / 2, varicella-

zoster virus (VZV)

DNA polymerase inhibitor Rare, only with prolonged

use

Intestinal complaints,

reversible neurological

disorders

Oral € 3,00 (HSV)

€ 18,00 (VZV)

Ganciclovir Cytomegalovirus (CMV) DNA polymerase inhibitor Rare, only with prolonged

use

Neutropenia (frequent) Intravenous

€ 80,00

Valganciclovir Cytomegalovirus (CMV) DNA polymerase inhibitor Rare, only with prolonged

use

Neutropenia (frequent) Oral € 50,00

Lamivudine Human immunodeficiency

virus (HIV), hepatitis B

virus (HBV)

Reverse transcriptase/

DNA polymerase inhibitor

Often, in particular with

monotherapy

Minimal side effects Oral € 6,50 (HIV)

€ 3,00 (HBV)

Lopinavir + ritonavir Human immunodeficiency

virus (HIV)

Protease inhibitor Often, in particular with

monotherapy

Dyslipidaemia Oral € 14.50

Nevirapine Human immunodeficiency

virus (HIV)

Non-nucleoside reverse

transcriptase inhibitor

Often, in particular with

monotherapy

Hepatotoxicity, allergic

reactions

Oral € 7,50

Oseltamivir Influenza A virus,

influenza B virus

Neuraminidase inhibitor Not very common, but

increasingly reported

None Oral € 5,50

(not reimbursed)

TH E ME I I I : IN FE CTIO U S D ISE A SE S

72

continued

Antifungal drugs

Indication

Fungicidal or

fungistatic

Resistance

Toxicity

Spectrum

Administration

Cost per day

Amphotericin B Almost all yeasts and

moulds

Fungicidal Extremely rare Rare (no systemic

resorption)

Broad Oral (suspension or

compressed lozenge)

€ 0.35

Amphotericin B Almost all yeasts and

moulds

Fungicidal Extremely rare Nephrotoxicity

(significant)

Broad Intravenous € 13.74

Amphotericin B,

liposomal

Identical to

amphotericin B

Fungicidal Extremely rare Less nephrotoxic Broad Intravenous

€ 400

Fluconazole Candida species Fungistatic C.albicans: rare

Some other Candida

sp:common

Hepatotoxicity (usually

minor)

Headache

Narrow Intravenous

Oral

€ 58.22

€ 23

Caspofungin

Anidulafungin

Candida species

(severe cases or if

pretreated with azole)

Fungicidal rare Gastro-intestinal

complaints,

convulsions

Fairly broad Intravenous € 450

Voriconazole Candida species,

Aspergillus spp.,

some other yeasts and

moulds

Fungistatic (for

Candida)

Fungicidal (for

Aspergillus)

Rare Fever, transient

visual disturbances

Broad Intravenous

Oral

€ 300

€ 60

73

3.4 Essential Microorganisms

This list of microorganisms includes the most important pathogens among the many organisms that are

mentioned in your textbook. You must focus your attention on these microorganisms. See the

reading list for specific information about these microorganisms. Much of what you should know will

be addressed in the lectures, seminar diagnostics, E-learning modules and the practicals.

For your study in Sherris, you should focus on:

the main structural characteristics;

the main virulence factors (and their mechanism of action);

relation with specific host defence disorder;

the characteristic clinical presentations (Clinical capsules!) ;

appropriate diagnostic tests as learned in the subthemes;

basic aspects of therapy.

3.4.1 Tables with ‘Essential microorganisms’

Bacteria Microorganism Examples of infections

Staphylococcus aureus (Micrococcaceae) Boil, wound infection, sepsis

Coagulase-negative staphylococci, a.o. Staphylococcus

epidermidis (Micrococcaceae)

Infections of intravascular catheters and

implanted prostheses

Streptococcus species, a.o.

Streptococcus pyogenes and

Streptococcus pneumoniae (Streptococcaceae)

Tonsillitis, scarlet fever, otitis media

Pneumonia, otitis media, meningitis

Haemophilus influenzae Bronchitis, sinusitis, otitis media

Mycobacterium tuberculosis (Mycobacteriaceae) Tuberculosis

Neisseria meningitidis or meningococcus (Neisseriaceae) Meningitis

Neisseria gonorrhoea or gonococcus

(Neisseriaceae)

Urethritis (gonorrhoea)

Escherichia coli (Enterobacteriaceae) Urinary tract infection

Salmonella species (Enterobacteriaceae) Intestinal infection. Typhoid fever

Vibrio cholerae (Vibronaceae) Intestinal infection. Cholera

Campylobacter jejuni (Campylobacteriaceae) Intestinal infection

Anaerobes (Bacteroides fragilis, Peptostreptococcus,

Clostridium perfringens,C. tetani and C. difficile)

Wound infection (C. perfringens)

Tetanus (C. tetani)

Pseudomembranous colitis (C. difficile)

Borrelia burgdorferi Lyme disease

TH E ME II I : A L L E RG Y

74

Treponema pallidum Lues (syphilis)

Microorganism Examples of infections

Mycoplasma pneumoniae Pneumonia

Chlamydia trachomatis Urethritis

Coxiella burnetii Pneumonia (‘Q fever’), endocarditis

Legionella pneumophila Pneumonia

Viruses Microorganism Examples of infections

Influenzavirus (Orthomyxoviridae) Influenza

Human immunodeficiency virus (Retroviridae) AIDS

Enteroviruses (including poliovirus) Meningo-encefalitis

Herpes-simplex virus (Herpesviridae) Fever blister (koortslip)

Varicella-zoster virus (Herpesviridae) Varicella (waterpokken) and Shingles

(gordelroos)

Cytomegalovirus (Herpesviridae) Infectious mononucleosis-like illness;

Pneumonia, retinitis in patients with

impaired cell-mediated immunity

Epstein-Barr virus (Herpesviridae) Infectious mononucleosis, Post-

transplantation lymfoproliferative

disease

Hepatitis B virus (Hepadnaviridae) Hepatitis, asymptomatic carriership

Respiratory syncytial virus Bronchiolitis

Fungi and yeasts Microorganism Examples of infections

Candida albicans Stomatitis, vaginitis

Aspergillus fumigatus Pneumonia in patients with

granulocytopenia

Protozoa Microorganism Examples of infections

Entamoeba histolytica and Entamoeba dispar Amoebiasis, resp. apathogenic

Toxoplasma gondii Toxoplasmosis

Plasmodium vivax and Plasmodium falciparum Malaria

Giardia lamblia Intestinal infection



75

Worms (helminths) Microorganism Examples of infections

Schistosoma haematobium and Schistosoma mansoni Schistosomiasis (Bilharzia)

Strongyloides stercoralis Strongyloidiasis

Taenia saginata and Taenia solium Taeniasis (T. saginata; T. solium).

Cysticercosis (T. solium)

Echinococcus granulosus Echinococcosis

Ascaris lumbricoides Ascariasis

Trichuris trichiuria Trichuriasis

Hookworm Anemia

The lifecycles of the protozoa and worms are described in Sherris. More illustrative drawings are

depicted at the website http://www.dpd.cdc.gov/DPDx/HTML/Para_Health.htm (search the names of

the parasites in the alphabetic list)

3.4.2 Reading for Essential microorganisms

From Sherris, for each of the Essential microorganisms in the above tables you should study:

The structural and physiological characteristics (for parasites, focus on life cycle and

morphology);

Pathogenesis and main virulence factors;

Association with host defence disorders;

Epidemiology and transmission;

Common clinical presentation as explained in the ‘Clinical capsule’;

Which diagnostic tests are indicated (focus on e-learning modules);

The principles of antimicrobial therapy and choice drug for a simple case;

Rational prevention and control measures.

TIP. Sherris 6th

edition contains a part on syndromes and aetiology of infectious diseases (pg 911-

930). Paragraphs I, IV, V and VIII will be helpful to learn which micro-organisms cause which type of

infections.

NOTE. A suggestion for the pages to study is provided in a table: see Blackboard under Course

documents; you can choose the table based on your edition of Sherris and based on whether you want

a schedule for all pages to study or only for the pages for the essential microorganisms. The complete

table lists all pages from Sherris for this module, thus includes the pages as are also listed under

Themes II, IIIA, IIIB, IIIC and IV. You should focus on the essentials as indicated in blue text in the

margin, clinical capsules, figures and tables.

http://www.dpd.cdc.gov/DPDx/HTML/Para_Health.htm


77

4. Theme IV: Epidemiology, prevention and control

of infectious diseases


4.1 General information theme IV

4.1.1 Why study epidemiology, prevention and control of infectious diseases?

Good medical practice includes being aware of the risks of infection for an individual patient, group of

patients, health-care workers or the community, and of the potential preventive measures that can be

taken to forestall infections. Some examples of situations in which epidemiology, prevention and

control are important are:

An outbreak with a resistant microorganism on a surgical ward (e.g. MRSA) or intensive care

unit (e.g. multi-resistant Klebsiella).

A patient is admitted to the hospital with a transmissible infection (e.g. tuberculosis).

A visitor of a patient with impaired immunity has a transmissible infection (e.g. varicella).

A medical student pricks himself with a needle contaminated by blood of a patient.

Un unusually high number of patients is diagnosed with an infection (epidemic) caused by a

microorganism for which there is an environmental source (e.g. Legionella).

In a community in which many individuals are unvaccinated for religious reasons, a child is

diagnosed with an infection for which a vaccine exists (e.g. poliomyelitis).

A new strain of influenza emerges, that has a high case fatality rate but is not included in the

available vaccine.

A person will travel abroad and asks for advice regarding infection risks.

In each of these situations doing nothing is not the right thing. The situation must be analysed and

prevention and or control measures must be taken. Each situation asks for a different approach, as will

become clear during your studies for this theme.


General goal: For simple cases with an infection caused by one of the Essential Microorganisms and

for situations in which transmission of infection is a threat, the student analyzes the infection chain

and drafts a plan for effective prevention and/or control of the infection.

Theme IV.A. Epidemiology of infectious diseases

The student

- describes the components of the infection chain for microorganisms from the list of Essential

Microorganisms

- explains concepts of infectious diseases epidemiology and applies these to simple infection problems

Theme IV.B. Prevention and control of infectious diseases

The student

- explains the available methods for prevention and control based on the infection chain

(environmental measures, behavioral advise, various isolation methods, active and passive

immunization, disinfection, sterilization, antibiotic prophylaxis) and applies these to simple infection

problems

TH E ME IV: P RE VE N TIO N A N D CO N TRO L

78

- indicates the pathogenesis, clinical presentation and epidemiological characteristics of infections for

which vaccines are included in the present Dutch national vaccination policy

- describes the different types of isolation, knows where to find and uses existing protocols regarding

indications for isolation and choice of type of isolation

- indicates prevention and control measures for simple infection problems (case-based, outbreak or

situation in which a health care worker, including students, has an infection)

- explains why prevention and control measures can be expected to be effective in specific situations

- indicates infections from the list of Essential Microorganisms for which reporting is mandatory by

the Public Health Law as well as those infections for which immediate reporting is required


Lectures

LT24: Epidemiology of infectious diseases. Illustrates epidemiological terminology and

features that are specific for infectious diseases.

LT25: Prevention and control of infectious diseases. A selection of prevention and control

measures are discussed and illustrated, as a basis for self-study.

Seminar 3: Health Advocacy

During the seminar several cases or situations with an infection problem will be presented. The

students are asked to apply the epidemiological concepts as outlined in this chapter to the case. The

students are invited to ask questions about the topic.

Patient demonstration

A patient with a transmissible infection is presented. Questions that may arise are

How did the patient acquire the infection?

Was the infection (in theory) preventable?

What did it mean to have this infection for the patient and his or her contacts?

Which measures were taken?

Did it affect his or her later behaviour?

E-learning

The e-learning modules about hygiene teach the general principles of how to be hygienic while

working in health care to prevent transmission of microorganisms, healthcare-associated infections

and occupational infections. It consists of short 8 modules including one test (see: Blackboard- Course

document – e-learning modules or via www.medischonderwijs.nl). The assignment will take at least

one hour.

Note that these modules are voluntary. However, you will be expected to master this subject when you

will go into medical practice (including VPC) so you should study them at some time!

(These e-learning modules are in Dutch; foreign students should ask their own institution about

information on this subject).

Work group 3: see 4.1.5

Self-study assignments: See 4.2.4 (2h) and 4.3.3 (NOTE: these self-study assignments are extensive

and will take you at least 4h).


79

Study plan


Follow the lectures, seminar and patient demonstration

(optional: perform the E-learning modules)

Perform the self-study assignments (SSA)


4.1.4 Reading list

Concepts considered familiar: vaccine, vaccination, active and passive immunisation, as are discussed

in Parham, The Immune system.

From Sherris 6th

edition study:

Chapter Start page


End page


3 43 Definitions 44 Microbial kil ling

3 49 Infection control and nosocomial… 54

5 87 93

23 429 Antimicrobial stewardship 430

PLUS: the paragraphs addressing prevention for all microorganisms that are listed under Essential

Microorganisms (see 3.4)

From Robbins study:

Chapter Start page


End page


5 338 transmission 342 How microorganisms….

From Skolnik study:

Chapter Start page


End page


28 31

237

NOTE; not all, exact selection will be indicated on Blackboard. Main focus will be on epidemiology. 263

Get acquainted with the options of the Extended Matching option list (see below)

4.1.5 Work group 3

Preparation for work group 3: Contents of lectures, seminar, module book, (optional: e-learning)

and self-study assignments for theme IV.A and IV.B. During work group 2 the cases for work group 3

will be provided. These must be prepared BEFORE THE WORK GROUP (AT HOME)! The group


80

divides the cases; two or three students collaborate to prepare one case. It is, however, useful for every

student to prepare all cases. A short paper will be placed on Blackboard, you have to read this to

prepare for the pro-and contra discussion.

Work group 3 starts with a test exam (short open questions, 15-20 minutes). Students can only

participate in the test if present on time.

Cases (70-80 minutes): answer the following questions:

1 Which infection do you think this patient has, and what is/are the most likely causative

microorganism(s)? If you have problems at this stage, ask your tutor or the module coordinator

additional questions to rule in or rule out some diagnoses.

2 Analyse and describe the infection chain

3 Which measures for prevention and control are indicated in this case? Specify the measures (you

may use the list of extended matching options).

4 Is this a reportable infection and if so:

in which group is the infection listed (A, B1, B2, C: what does that implicate)?

does it have to be reported on suspicion, after diagnosis or in case of multiple cases?

Pro- and contra discussion of a topic about a short paper (20 minutes). This paper must be read at

home by all students. During the WG3 it will be decided who has to argue for or against the

proposition and who will lead the discussion..


81

4.2 Theme IV.A: Epidemiology

4.2.1 Introduction

Concepts such as prevalence, incidence, odds ratio, sensitivity and specificity, and methods of

epidemiological investigations are used in infectious diseases in the same way as for other diseases.

However, microorganisms as a cause of disease are special because they can be acquired from the

environment, animals or other humans and some features are unique for the epidemiology of

infectious diseases:

a patient may be the source of a disease

an individual may be a source of disease without being ill

an environmental source can cause an outbreak

in a population, individual immunity to a disease can influence its epidemiology

sometimes epidemiological investigations have to been done urgently

4.2.2 The infection chain

The scheme below (figure IV-1) can be applied to infections caused by bacteria, viruses and fungi. It

is not commonly used for parasitic infections, for which the life cycle of the parasite is often most

informative.

Figure IV.1. The infection chain

Reservoir and source

The reservoir of an infectious disease is the habitat (ecological niche) of the pathogen, where

multiplication takes place. The thing, person or animal responsible for the transmission of the disease,

is the source of the infection.

Host

The host is a living being that harbours and nourishes a pathogen. Some protozoa and worms have

various development stages in different hosts. The host in which the parasite passes its adult or sexual

existence is called the definitive or final host; the host in which it passes its larval or non-sexual

existence is called the intermediate host.

reservoir

transmission

source hostreservoir

transmission

source host


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Transmission

Transmission of a microorganism can be by direct or indirect contact, via the air (skin flakes, droplets,

droplet nuclei) or via a vector. This is further explained and exemplified in the lecture.

4.2.3 Reproductive rate

The reproductive rate (R) of an infectious disease is the rate at which it spreads in a community. The

basic reproductive rate (R0) is the average number of people in a non-immune community that is

directly infected by a contagious individual. The R0 of a disease depends on the attack rate, the number

of contacts that enable transmission and the duration of the contagiousness of a contagious person. In

case a vector transmits a disease, more factors are involved: the extrinsic incubation time, vector

mortality, the balance between number of vectors and hosts, and the transmission effectiveness from

vector to host and vice versa. The R0 of a great many infectious diseases has been assessed. For

measles it is 15-17; for whooping cough 15-17; mumps 10-12; rubella 7-8; diphtheria 5-6; and for

poliomyelitis 5-6.

The actual reproductive rate in a community as a rule is lower than R0 because of the number of

immune individuals in a community (either due to past infection or following vaccination), which

accounts for R = R0 X, X being the percentage of susceptible, non-immune individuals in a

community. If R > 1, the number of cases will increase and the disease becomes epidemic. If R = 1,

the disease is persistent in a community at a constant level (= endemic). If R < 1, the disease will

disappear. On the basis of such data, the number of individuals that must be immune in order to be

able to eliminate a disease can be assessed, i.e. to get measles to disappear, less than 6 percent of the

individuals in a community must be susceptible to the disease (R0 X < 1 16 X < 1 X <1/16

X <6%), in other words 94 percent must be immune.

4.2.4 SSA

IV.A.1

For a) the patients A-E (see SSA II.1 in 2.5).

b) each of the infectious diseases given in table IV-2

indicate:

1. the reservoir

2. the route of transmission

3. the geographical distribution

NB. Use self-study table IV.A.1 (Attachment).

IV.A.2

Classify the pathogens that cause the infections listed in table IV.2, all from the list of Essential

microorganisms, according to reservoir, route of transmission and geographical distribution, and

discuss the result: what strikes you making these different classifications? For the classification of

parasitic infections, the developmental stages and life cycle are helpful.

Table IV-2

Pulmonary tuberculosis Aspergillosis

Pneumococcal pneumonia Candidiasis

Cholera Amoebiasis

Herpes zoster Toxoplasmosis

Poliomyelitis Echinococcosis


83

4.2.5 Instructions Extended Matching Questions Theme IV.A.

During the module a formative test is provided via Blackboard including a number of Extended-


should therefore use this list in order to get acquainted with the options.

Theme IV.A: Transmission of infectious diseases

Options:

a. Animal bite

b. Blood transfusion

c. Breast feeding

d. Consumption of drinking water

e. Consumption of improperly washed vegetable

f. Consumption of insufficiently heated meat

g. Contact with soil

h. Contact with animal excreta

i. Contact with droplets of airway secretion

j. Contact with hands of health-care worker

k. Contact with secretions in the birth canal

l. Contact with seawater

m. Contact with freshwater

n. Direct skin-to-skin contact with a patient

o. Human faeco-oral contact

p. Inhalation of droplet nuclei

q. Inhalation of droplets of airway secretion

r. Inhalation of small droplets from the environment

s. Inhalation of spores in the air

t. Mosquito bite

u. Prick with a used injection needle

v. Sexual contact

w. Tick bite

x. Vertical transmission (during pregnancy)

Task: Select for each patient the most likely way of transmission, by which the

patient got the infectious disease. You are requested to select exactly the

number of options as indicated. When you mark more than the indicated

number of options, you will get negative points. You will get points even

when you do not have all options correct.

Example:

Case: A 23-year-old woman has made a 3-week trip through India. During the trip

she has had no complaints. Two days after her return to the Netherlands she

has bloody diarrhoea. Examination of fresh faeces reveals haematophagic

amoebae. Give one option.

Anwer: <o>

Note that d is also theoretically possible in a setting where there

is faecal contamination of drinking water supplies, but you were

requested to indicate the MOST LIKELY way of transmission.

Sometimes more than the requested number of options are

equally correct. In that case each of these will be considered

correct.


84


85

4.3 Theme IV.B: Prevention and control

4.3.1 Introduction

During the period 1840-1940 the incidence and mortality of infectious diseases in the Western World

have decreased dramatically, as is illustrated for tuberculosis in figure IV-2. This decrease can be

ascribed to a combination of improved nutrition and living and working conditions. After 1940,

vaccination has made a major contribution to the decrease of many other infections like smallpox

(eradicated in the 70’s), polio, tetanus, diphtheria and others. The contribution made by antimicrobial

therapy is less clear, and it may even have had adverse effects like the development of drug resistance

as happened in MDR and XDR Mycobacterium tuberculosis, methicillin-resistant Staphylococcus

aureus (MRSA), vancomycin-resistant enterococci, penicillin-resistant pneumococci and ESBL-

positive Gram-negative bacteria which are all increasing worldwide. This widespread drug resistance

has serious consequences for current medical practice.

F

Figure IV-2. Decrease in tuberculosis incidence.

From: Robert Koch. A Life in Medicine and Bacteriology. T.D. Brock. ASM Press, Washington, 1999.

Health Advocacy

The competence Health Advocacy has a key place in this module. Health care workers should always

be conscious of the possibility of infections and the risks involved for other patients, healthcare

workers and communities. Pathogenic microorganisms can be acquired from many different sources

and through various transmission routes. This creates a large number of different options for

prevention. A clear understanding of the infection chain (explained in theme IV.A) is essential to


86

establish rational prevention and control measures. The measures can be directed at the reservoir, the

source or transmission routes of pathogens, or at protection or isolation of the host (Figure IV-3), e.g.

Improvement of social conditions not only improves living conditions leading to elimination of

sources but also fortifies the hosts’ defence system thereby reducing the risk of disease.

Hygiene aims at elimination of the source and prevention of transmission. This may require vector

control if it concerns vector-mediated transmission. (The difference between disinfection and

sterilisation was explained in the COO lesson Safe Microbiological Techniques).

Immunisation protects the host from developing an infectious disease if exposed.

Antimicrobial prophylaxis aims at preventing infection with certain pathogens for which a patient

is at higher risk.

In the self-study assignments to this theme, different aspects of infection prevention and control will

be elaborated and applied.

reservoir source host

transmission

Elimination

- Cleaning

- Disinfection

- Sterilization

- Pasteurization

- Water purification

- Sewage treatment

- Adequate heating of food

- Screening of blood products

- Social development

Source isolation Protective isolation

Protection

- Vaccination

- Passive immunisation

- Antimicrobial prophylaxis

- Social development

Interruption of transmission

- Hand hygiene

- Vector control

- Asepsis

- Use of gloves, gowns, face masks

- Protection against insect bites

- Safe handling of sharps

- Safe sex

Figure IV-3. Summary of major prevention and control measures

4.3.2 Healthcare-associated infections

In order to understand infection control in healthcare institutions, you must be familiar with the

following terms:

Healthcare-associated infection

A healthcare-associated infection is an infection acquired as consequence of receiving healthcare.

Endogenous and exogenous


87

Endogenous healthcare-associated infections are caused by the patient’s own microorganisms.

Exogenous infections are caused by microorganisms that have been transmitted from an outside

source. Exogenous infections originating from another patient are often called cross-infections. It is

evident that endogenous and exogenous infections require completely different prevention measures.

The concepts reservoir, source, host, epidemic and endemic are used both in relation to hospital

infections and to epidemiology of infectious diseases in general (see Theme IV.A).

Prevention of healthcare-associated infections is based on active and passive immunisation (e.g.

hepatitis B vaccination and administration of hepatitis B immunoglobulin to prevent hepatitis B

infection), antimicrobial prophylaxis (e.g. to prevent post-operative wound infection), and hygiene .

Hygiene measures can be general and/or specific. General measures are taken regardless of a patient’s

disease, and comprise personal hygiene, hand hygiene, cleaning, disinfection, sterilisation and

asepsis. Asepsis means preventing contact between microorganisms and susceptible sites. A surgeon

operates aseptically, and a urinary catheter is inserted aseptically.

Depending on the disease, specific precautions may be required, such as source isolation and

protective isolation. Source isolation is implemented when a patient is contagious, such as in

tuberculosis or haemorrhagic fevers or is infected with, or colonised by multi-resistant bacteria. The

different forms of isolation are contact isolation, droplet isolation, aerogenic isolation or

combinations (see self-study assignment IV.B.4). Protective isolation measures are taken to protect

an immune-compromised host, i.e. a patient with granulocytopenia, from being exposed to potentially

pathogenic microorganisms.

4.3.3 SSA

IV.B.1. Prevention and control measures

In self-study assignment IV.A.1 you have identified the essential components of the infection chain or

life cycle. That information is the basis for prevention and control measures. Describe prevention and

control measures for the infectious diseases listed in table IV.B.1 (Attachment).

IV.B.2. Reportable infectious diseases

Until November 2008 the Infectious diseases law regulated the reporting of transmissible diseases.

From November 2008 this is laid down in the Public health law. In figure IV-4 the current rules for

reporting infectious diseases are summarized (figure in Dutch is placed on Blackboard). For the list of

Essential microorganisms look up which have to be reported, how this should be done (which

infections have to be reported already on suspicion) and which measures should be taken in the

interest of public health. On http://www.rivm.nl/cib/themas/meldingsplicht/ you find information on

the which, how and why of reportable infectious diseases. (Foreign students should look up the rules

for their country of origin.) (Note: Answers will not be placed on Blackboard)


88

Figure IV-4. Reportable Infectious diseases

IV.B.3. Vaccination

a. Dutch national vaccination programme

Go to the ‘Nationaal Kompas Volksgezondheid’ on the internet

(http://www.nationaalkompas.nl/preventie/van-ziekten-en-

aandoeningen/infectieziekten/rijksvaccinatieprogramma ) for information about the national

vaccination programme (‘rijksvaccinatieprogramma’) and

http://www.rivm.nl/Onderwerpen/Onderwerpen/R/Rijksvaccinatieprogramma/Het_programma/Verand

eringen_in_het_programma for the recent changes in the program and English summary.

Use self-study table IV.B.3 (Appendix) listing vaccines that are included in the

‘rijksvaccinatieprogramma’. In the table, the essentials of the diseases against which the vaccination is

aimed (class of microorganism, reservoir, endemicity in the Netherlands, source, route of infection,

clinical manifestations, outcome) are already summarized (NOTE. This is part of the study material).

Answer the following questions:

Who is vaccinated, at what age and frequency?

Is it a live or subunit/component vaccine?

http://www.nationaalkompas.nl/preventie/van-ziekten-en-aandoeningen/infectieziekten/rijksvaccinatieprogramma

http://www.nationaalkompas.nl/preventie/van-ziekten-en-aandoeningen/infectieziekten/rijksvaccinatieprogramma

http://www.rivm.nl/Onderwerpen/Onderwerpen/R/Rijksvaccinatieprogramma/Het_programma/Veranderingen_in_het_programma

http://www.rivm.nl/Onderwerpen/Onderwerpen/R/Rijksvaccinatieprogramma/Het_programma/Veranderingen_in_het_programma


89

Which vaccination offers the best protection and which one the least protection?

In which areas of the Netherlands are the lowest levels of vaccination found?

Who is responsible for the execution of the programme and who pays for the programme?

b. Vaccination and global health

The World Health Organization (WHO) is divided into regional offices, one of these offices is the

South East Asia Region Office (SEARO). The WHO has recently published a position paper on

immunization (http://www.who.int/immunization/policy/immunization_tables/en/index.html) as has

the SEARO Office:

(http://www.searo.who.int/entity/immunization/documents/immunization_factsheet__2012.pdf)

1. Compare the WHO recommendations with those from the SEARO Region and the

immunizations included in the Dutch ‘Rijks Vaccinatie Programma’ and try to explain the

differences

2. The Indian Minister of Health and Family Welfare wants to further reduce the child mortality

in India by adding another vaccine to the existing Indian immunisation programme. He requests

you to advise him on this issue. See the following websites for additional information and give

and motivate your advice:

http://www.who.int/gho/countries/ind.pdf

http://www.ima-india.org/RECOMMENDED_IMMUNIZATION.html

http://www.who.int/immunization/policy/immunizat ion_tables/en/index.html.

IV.B.4 Isolation measures

a. Types of isolation

The different types of isolation

aerogenic isolation

protective isolation (‘beschermende isolatie’)

contact isolation

droplet isolation

strict isolation

will be explained during the lecture prevention and control, with examples of diseases or pathogens for

which these types of isolation are used. Describe the components of each type of isolation, and give

the rationale of each component.

Optional: more information on isolation can be found via the home-page of LUMC intranet –

Protocollen – Iprova – infectiepreventie. NOTE. This website is in Dutch.

b. Indications for isolation

Look up which type of isolation is indicated for

MRSA

influenza virus

infectious diarrhoea

meningococcal infection

tuberculosis

a patient with granulocytopenia (e.g. after chemotherapy)

http://www.who.int/immunization/policy/immunization_tables/en/index.html

http://www.searo.who.int/entity/immunization/documents/immunization_factsheet__2012.pdf

http://www.who.int/gho/countries/ind.pdf

http://www.ima-india.org/RECOMMENDED_IMMUNIZATION.html

http://www.who.int/immunization/policy/immunization_tables/en/index.html


90

The answers to a. and b. will not be placed on Blackboard.

c. Health care worker with an infection

What should a health-care worker (including a student doing a clinical rotation) do in case of

Common cold;

’The flu’;

Diarrhoea;

Skin infection (impetigo, boil, cellulitis);

MRSA carriership.

IV.B.5 Healthcare-associated infections

Below, three cases are presented. For each, answer the following questions:

Is this a healthcare-associated infection?

If so, is it endogenous or exogenous?

What is the reservoir or the source?

What was the route of transmission?

What has led to the host’s susceptibility?

Is the disease epidemic or endemic?

Which precautions can be taken to prevent further problems?

Patient 1

A 77-year-old woman is admitted into the department of Internal Medicine. She is confused and has

lost weight. She is known to have diabetes mellitus. On day 5 of admission her temperature rises to

38.5°C. Her urinary examination on the day of admission was normal, but now counts numerous

leukocytes, and in a culture of the urine grows Escherichia coli.

Patient 2

A 62-year-old man who underwent brain surgery a year ago is transferred from a rehabilitation centre

and admitted to the department of Neurology with neurological abnormalities. He has a urinary

catheter and decubitus. On day two in the hospital his urine culture is positive for methicillin-resistant

Staphylococcus aureus (MRSA).

Patient 3

A 7 months old baby girl is in the paediatric ward after heart surgery for a congenital heart condition.

On the fifth day after the operation she has fever. A blood and an intravenous catheter tip culture are

found to have grown Klebsiella pneumoniae, which produces extended spectrum beta-lactamase

(ESBL). Five days earlier ESBL producing K. pneumoniae had been found in another child in

Paediatrics. Before that, this microorganism had never been cultured from patients in the paediatric

ward.

IV.B.6 Global burden of infectious diseases

Worldwide there are considerable differences in the causes of disease and mortality depending on the

economic situation. For this assignment, use Skolnik (the term DALYs has been introduced in year 1,

re-read pages 26 and 27 if you need to refresh this knowledge).


91

1 Study Table 2-3. Compare the list of the 10 most frequent causes of death and of DALYs in low-

and middle income countries, respectively high-income countries. How many are caused by

communicable diseases? Why is it valuable to have a composite indicator like DALY to measure

the burden of disease?

2 What might explain the differences between low- and high-income countries?

3 Study Table 2-8. Which are risk factors for infections in low- vs. high-income countries? Can you

think of risk factors for infections that are not in this list?

4 Find in pages 248 – 257 the burden of disease of the three ‘big killers’ malaria, AIDS and

tuberculosis. How many deaths are yearly caused by these infections? And how many DALYs are

lost? Compare this with number of death and DALYs lost by the “Neglected Tropical Diseases”.

What can you conclude?

5 How could the amount of DALYs lost be reduced? What are the limitations in this regard?

4.3.4 Instructions Extended Matching Questions Theme IV.B.

During the module a formative test is provided via Blackboard that includes a number of Extended-


should therefore use this list in order to get acquainted with the options.

Theme IV.B: Prevention and control of Infectious diseases

Options:

a. Adequate heating of food

b. Antimicrobial prophylaxis

c. Asepsis

d. Use of protective gown

e. Protection against mosquito bites

f. Disinfection of skin

g. Disinfection of instruments, surfaces, devices

h. Control of animal reservoir

i. Hand hygiene

j. Use of gloves, non-sterile

k. Use of gloves, sterile

l. Cold storage of food

m. Wearing a face mask, surgical

n. Wearing a face mask (FFP1, FFP2)

o. Passive immunisation

p. Sewage treatment

q. Cleaning with water and soap

r. Screening of blood products

s. Sterilisation

t. Vaccination

u. Vector control

v. Nursing in an isolation room

w. Water purification

x. No intervention or control measure necessary

Task: Indicate which measure(s) should be taken. Mark compartment x on the computer

form when you are of the opinion that no measure is necessary. You are requested to


92

select exactly the number of options as indicated. When you mark more than the

indicated number of options, you will get negative points. You will get points even

when you do not have all options correct.

Example

Case: Due to war activities a large number of refugees are looking for a safe place. The

refugees are housed in refugee camps. The government is afraid for a cholera

outbreak. The first cases have already been noted in the camps. Give 3 options.

Answer:< p, t, w>

Note that transmission of cholera is mainly by contaminated water, but can also be by faeco-oral

contact. Option i(hand hygiene) may help to prevent feco-oral transmission but will be of no

use when the source is contaminated water.


93

5. Theme V: Allergy


5.1 Introduction

Four different immunopathological reactions, so called hypersensitivity reactions, are drivers of

unwanted reactions of the immune system. It is important to keep in mind that these prototypical

immune mechanisms are part of the normal immune response against infectious microorganisms or

even to harmless substances like air- or food borne allergens. Particularly in individuals who express

certain susceptibility genes (‘genetically predisposed’ individuals), these immune responses can be

excessive and, thereby, cause unwanted immune-driven pathological responses requiring

immunosuppressive therapy. In this relatively short Theme V we introduce the basic concepts of

allergy, before moving onwards to the more broader Theme VI: Autoimmunity.


By the end of theme V, the student will be able to:

explain the basic mechanism of type I, II, III and IV allergic immune responses;

explain the pathogenesis of examples of specific allergies: asthma (type I), hemolytic anemia of

the neonate (type II), hypersensitivity pneumonitis (type III) and delayed type hypersensitivity

reactions as the basis of testing for contact allergy or infection (type IV );

recognize, name and describe histological characteristics of allergic response types in tissue

specimens in relation to type(s) of immune cells involved.

indicate the main symptoms and signs of allergic disorders discussed in this module;

describe and explain the immunopathological processes causing the clinical signs and symptoms;

chose appropriate diagnostic tests for these allergic conditions.

describe the available therapeutic options in allergic disorders (drugs, desensitization by

subcutaneous immunization);

list the different classes of anti-allergic, immunosuppressive agents, indicates the mechanism of

action and recognizes the agents commonly used for allergic disorders.


Lectures

LT26: Mechanisms of allergy. The clinical features and the immunological effector

mechanisms behind the four different types of hypersensitivity reactions are presented in this

lecture.

LT27: Pathology of allergy. The lecture provides an overview of clinicopathological aspects

of the hypersensitivity reactions, elaborating on techniques that can be used to identify which

reaction takes place.

TH E ME V: A L L E RG Y

94


A patient with allergic asthma (a common disease which is classified as a type I

hypersensitivity reaction) is interviewed followed by a case discussion.

Work group 4: In this workgroup, themes IV, V and VI will be discussed together. See 6.6 for a

description of the work group.


Study plan


Follow the lectures



5.4 Reading list

From ‘Robbins and Cotran’:


6 184- 208 up to: Auto-immune

diseases

Innate immunity, adaptive immunity, cells and tissues of

the immune system, types I to IV hypersensitivity

reactions

Tables: 6-2, 6-3, 6-4, 6-5, 6-6

Figures: 6-13 to 6-24

From ‘Parham’:

Chapter Pages, from …up to Keywords, tables, figures

12 365-370

376-377

377-378

379-380

380-383

384-385

allergens in relation to the 4 types of hypersensitivity

reactions (I-IV) fig 12.1-12.3

genetic basis of allergic disease

course of IgE-mediated allergic reactions (type I) fig

12.14, 12.17

anaphylactic shock fig 12.12 and 12.19

classic forms of IgE-mediated allergic diseases fig 12.21,

12.22-12.24

prevention and treatment of IgE-mediated allergic

disease

12 386-389 antibodies against (altered) components of human cells

causing type II hypersensitivity reactions fig 12.26

12 389-392 Immune complexes and complement in type III

hypersensitivity reactions fig 12.31, 12.32, 12.33, 12.34

12 392-393 T helper cells and cytokines in type IV hypersensitivity

reactions fig 12.35 and 12.36.


95



5.5 SSA

SSA V.1 Asthma

Asthma usually starts as allergic asthma resulting from the interplay between genetic predisposition

and the exposure to harmless environmental allergens. Repeated exposure gradually increases hyper-

responsiveness of the airways, allowing other factors such as air pollution or infection to ignite local

inflammatory responses. The end result is a chronic inflammatory disease which requires long-term

therapy. Early diagnosis and treatment are both essential to adequately treat this immune disorder.

Several therapeutic options are available.

1 Which type of T cells are involved in asthma? Describe how the main effector molecules

produced by these cells potentiate the mechanism behind this disease.

2 Two types of medication which are frequently prescribed to allergic patients are anti-histaminic

agents and corticosteroids. Describe how these drugs block the typical clinical symptoms of

asthma but do not provide a cure for these patients.

3 Why should steroid treatment be performed with more care than anti-histaminic drugs?

4 For some types of allergic diseases a process called desensitization can lead to waning of some of

the clinical symptoms (page 385 Parham). This process involves subcutaneous injections with

gradually increasing doses of the allergen involved. Explain the immunological principle of this

treatment. Why should this procedure only be performed in an outpatient setting (op de

polikliniek onder toezicht)?

SSA V.2 Glomerulonephritis

Rapidly progressive glomerulonephritis can have various causes. It is a serious condition, in which the

diagnostic work-up has to be quick in order to prevent dialysis dependency. A renal biopsy is usually

performed as well as a series of serological tests. As a typical case, a 50-year old male who has been

smoking for more than 30 years, presented with a rapidly deteriorating renal function, an active

urinary sediment, and mild proteinuria. He also complains of dyspnoea and chest pain. The

immunofluorescent staining for IgG revealed the following:

Figure: IgG staining in a glomerulus

1 Describe the pattern that you see: where is the IgG located, how is it distributed in the

glomerulus?

TH E ME V: A L L E RG Y

96

2 The pattern you see here in the IgG staning is pathognomonic for a renal disease which is

clinically characterized by rapidly progressive renal failure: which disease?

3 Which type of hypersensitivity reaction is involved in this disease?

4 Which serological test will be positive?

5 Do you have an explanation for his dyspnoea and chest pain?

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6. Theme VI: Auto-immunity


6.1 Introduction

The immune system is in constant battle with endogenous and exogenous antigens that attack our

health status. It has a variety of strategies to prevent us from developing disease. In some instances,

minor or extensive tissue damage occurs because the immune response is too strong, or because a flaw

occurs in what would otherwise be an effective method to eliminate the antigens. The various routes

by which these processes develop are known as hypersensitivity reactions, which were discussed

previously. Here we will discuss the histopathological characteristics of and mechanisms behind a

selected number of disorders of the immune system in which the immune response is directed towards

self-antigens, such as ANCA-associated systemic vasculitis, Sjögren’s Syndrome, Systemic Sclerosis

and Systemic Lupus Erythematosus.

While studying these diseases, it might be helpful to try to use the knowledge you have acquired at

this point of the Mechanisms of Disease Module in order to understand more of the pathogenesis of

these diseases. For each disease, ask yourself: which cell, which antibody, which type of

inflammation, which histological alteration is most important here? How can it lead to the clinical

manifestations that are most characteristic of this disease? And also: do we know the aetiology of this

disease? On which subjects is knowledge lacking, and what sort of research could bring us further in

order to diagnose and treat these patients?



understand the physiological basis of self/non-self-recognition by T cells;

explain the pathogenesis of auto-immune diseases caused by autoantibodies (e.g. myasthenia

gravis and SLE);

recognize and/or deduce the aetiology of the diseases and conditions discussed in this theme;

recognize, name and describe changes (morphological and structural alterations) in tissue

specimens with respect to auto-immune diseases discussed in this theme (e.g. SLE; ANCA-

associated vasculitis; diabetes; IgA nephropathy),

explain the pathogenesis of infection-associated auto-immune responses.

indicate the main symptoms and signs of auto-immune disorders discussed in this module (see

give an indication of some of the appropriate diagnostic tests for a selected number of immune

mediated diseases discussed in this theme.

describe a selected number of the available therapeutic options in a selected number of immune

mediated diseases discussed in this theme;

list the different classes of immune-suppressive or immune-modulating agents and indicates the

mechanism of action;

TH E ME VI: A U TO -IMMU N ITY

98


Lectures

LT28: In depth lecture, "Cells and Auto-immunity": This ‘in depth’ lecture focuses on the

disease mechanism involved in type 1 diabetes and new therapies which aim at curing this

prototypical auto-immune disease.

LT29: Introductory lecture, "Pathology of auto-immunity": makes a link to the previous

theme in order to explain the basic principle of auto-immunity. Discusses the criteria for calling

a disease an auto-immune disease, discusses why some diseases are referred to as immune

mediated diseases.

LT30: In depth lecture, "Vasculitis": histopathological characteristics of vasculitis are shown,

explaining how these characteristics link up to what today is known as ANCA-associated

vasculitis. What are similarities/differences between this group of diseases and vasculitis

encountered in numerous other conditions (sepsis, malignancies, etc)

LT31: In depth lecture, "Systemic Lupus Erythematosus": focusses on SLE as a typical

example of a type III hypersensitivity reaction. SLE is the prototype of auto-immune diseases.

LT32: HLA and auto-immunity. This lecture explains how HLA acts as a dominant genetic

factor affecting susceptibility to auto-immune diseases. Some classical examples of auto-

immune-driven neurological diseases will be discussed.

LT33: Infections and auto-immunity. Two examples of diseases in which an infection is or

might be aetiologically related to the development of an auto-immune response.

LT34: Interactive cases. In this lecture things are approached not by describing the features of

a particular illness but from a clinical point of view. Several cases will be discussed and based

on the presenting symptoms and signs you must make a differential diagnosis and choose and

interpret diagnostic tests. This is how it works in practice.

LT35 and LT36: Pharmacology: immune suppression. Two lectures on the mechanism of

action of various classes of drugs used in the setting of auto-immune diseases and

transplantation.

LT37: Chimerism: Students will be given an academic assignment of which the details will be

discussed during this lecture and in 6.7.


Auto-immune disease: Illustrates the clinical and pathological signs and symptoms occurring in

this disease with emphasis on complications and treatment.

Work group 4: see under 6.6

Academic assignment: see 6.7


Study plan


Follow the lectures, seminar and patient demonstration




99

6.4 Immunosuppressive pharmacotherapy

In G2MD1 a number of immunosuppressive drugs or therapies are studied. These relate to themes V,

VI and VII and are provided here together:

In relation to theme VI:

In relation to theme VII:

Abbreviations: GR: glucocorticoid receptor agonist; IL: interleukin; IMP: inosine-5'-monophosphate;

IS: immune suppression; GPA: granulomatosis with polyangiitis

Disease/setting Class ExamplesMechanism

of actionIndications Important side effects

Auto-immune diseases

Glucocorticoidsprednisolone,

dexamethasoneGR-agonists

AI diseases. For example SLE, GPA

Moon face, hypertension, diabetes, osteoporosis,

muscle loss

Antimetabolites azathioprine purine antagonistAI diseases.

Maintenance treatment GPA

nausea, vomiting, skin rash, cancers (bladder cancer),

anemia, infections

mycophenolatemofetil

IMP dehydrogenase

AI diseases. For example

maintenance therapy SLE

gastrointestinal side effects, leukopenia,

anaemia

Antimalarials chloroquine IS SLE

mood changes, gastrointestinal side effects, retinopathy,

cardiac toxicity

Alkylating agents cyclophosphamide Alkylating agentAIl diseases. For

example, GPA, first 3 months

nausea, vomiting, haemorrhagic cystitis,

diarrhoea, darkening of the skin/nails, hair loss) or

thinning of hair, lethargia

Disease/setting Class ExamplesMechanism


Auto-immune diseases

Glucocorticoidsprednisolone,

dexamethasoneGR-agonists

AI diseases. For example SLE, GPA

Moon face, hypertension, diabetes, osteoporosis,

muscle loss

Antimetabolites azathioprine purine antagonistAI diseases.

Maintenance treatment GPA

nausea, vomiting, skin rash, cancers (bladder cancer),

anemia, infections


IMP dehydrogenase

AI diseases. For example

maintenance therapy SLE

gastrointestinal side effects, leukopenia,

anaemia

Antimalarials chloroquine IS SLE

mood changes, gastrointestinal side effects, retinopathy,

cardiac toxicity

Alkylating agents cyclophosphamide Alkylating agentAIl diseases. For

example, GPA, first 3 months

nausea, vomiting, haemorrhagic cystitis,

diarrhoea, darkening of the skin/nails, hair loss) or

thinning of hair, lethargia

See previous table

Maintenance IS therapy after renal

transplantation. High dose rejection

treatment

GR-agonistprednisolone,

dexamethasoneGlucocorticoidsTransplantation

nephrotoxicity, hypertension,

hypercholesterolemia, diabetes mellitus (tacro>

cyclo)


transplantation.

Calcineurininhibitor, blocks

cytokines

cyclosporin, tacrolimus

Calcineurin inhibitors

gastrointestinal side effects, leukopenia, anemia


transplantation. IMP dehydrogenase


Antiproliferativeimmunosuppressants

anemia, leukopenia, thrombocytopenia, gastrointestinal side

effects, metabolic effects (hyperlipidemia),

proteinuria


transplantation.

Modulate the activity of mTOR,

inhibits IL-2 mediated signal

transduction

EverolimusMammalian target of

rapamycin (mTOR) inhibitor

gastrointestinal side effects, metabolic effects,

headache, tremor, hypersensitivity

Induction treatment renal

transplantationIL-2 antagonismbasiliximabAntibodies

hypotension, rigors, fever, shortness of breath,

bronchospasm, chills, and/or rash


transplantation.Also rejection

treatment.

Binds to CD52 (surface lymphocyte

marker)Alemtuzumab

Disease/Setting Class ExamplesMechanism


See previous table


transplantation. High dose rejection

treatment

GR-agonistprednisolone,

dexamethasoneGlucocorticoidsTransplantation

nephrotoxicity, hypertension,

hypercholesterolemia, diabetes mellitus (tacro>

cyclo)


transplantation.

Calcineurininhibitor, blocks

cytokines

cyclosporin, tacrolimus

Calcineurin inhibitors

gastrointestinal side effects, leukopenia, anemia


transplantation. IMP dehydrogenase


Antiproliferativeimmunosuppressants

anemia, leukopenia, thrombocytopenia, gastrointestinal side

effects, metabolic effects (hyperlipidemia),

proteinuria


transplantation.

Modulate the activity of mTOR,

inhibits IL-2 mediated signal

transduction

EverolimusMammalian target of

rapamycin (mTOR) inhibitor

gastrointestinal side effects, metabolic effects,

headache, tremor, hypersensitivity


transplantationIL-2 antagonismbasiliximabAntibodies

hypotension, rigors, fever, shortness of breath,

bronchospasm, chills, and/or rash


transplantation.Also rejection

treatment.

Binds to CD52 (surface lymphocyte

marker)Alemtuzumab

Disease/Setting Class ExamplesMechanism



100

6.5 Reading list

Robbins and Cotran:


208 –

226

Auto-immune Diseases … up

to Rejection of Tissue

Transplants

SLE, Rheumatoid Arthritis, Sjogren’s Syndrome, systemic

sclerosis, polyarteritis nodosa

Tables: 6-8, 6-9, 6-10

Figures: 6-30 – 6-33, 6-35, 6-36, 6-37, 6-38

678-679 From: The Lung

up to: Congenital Anomalies

Figure 15-1

694-696 From: Fibrosing Diseases

up to: Pneumoconioses

Fibrosing diseases, Figure 15-13, Figure 15-14, Figure

15-15

917-923 From: Nephritic Syndrome,

up to: Minimal-Change

Disease (p.923)

Table 20-5, Figure 20-9, Figure 20-10

Parham

Chapter Pages Keywords, tables, figures

13 403-407, 410-411

411-418

420-422

427-428

loss of self tolerance forms the basis of auto-immune

disorders caused by the same effector mechanisms as

hypersensitivity reactions fig 13.1 and 13.2, 13.8

the common types and the immune components

underlying these auto-immune disorders

HLA-associated risk for auto-immune disease fig 13.24

triggering of auto-immune disease by infections fig

13.31



6.6 Work group 4

Preparation for work group 4: Contents of lectures, seminar, module book and self-study assignments

for themes I, V and VI. Prepare cases 1 and 2 presented below BEFORE THE WORK GROUP.

Please bring your laptop to the work group. Work group 4 will start with a formative test exam

consisting of open questions. Answers will be discussed immediately afterwards. The two cases which

you prepared at home will be discussed and 2 new cases will be distributed for students to work on

and discuss during the work group.


101

Case 1: a patient with red spots on her legs

An 82-year-old woman presents to her general physician because she has red spots on her legs. They

look like this:

You, a second-year medical student has seen a

similar picture in one of the lectures of

Mechanisms of Disease 1, and you jump to a

diagnosis, which is:

Do you have any differential diagnoses?

What would you do next: would you consider taking a skin biopsy? Or would you, for instance,

ask for a serological test, and if so: which one.

In the meantime, the patient reports to you she has seen blood in her urine. You make a urine

sediment and see this:

What is this, and what does it mean?

Based on the findings in the urine sediment you ask for a number of laboratory tests and it appears

that her serum creatinine is much too high. Would you consider taking a renal biopsy?

Case 2: A lung biopsy in a patient with rheumatoid arthritis

An open lung biopsy is performed in a 46-year-old woman with rheumatoid arthritis. Because of

recent complaints consisting of dyspnoea and sneezing, an X-ray of the lungs was performed, showing

a small, nodular lesion in the right middle lobe.

Mention the differential diagnostic considerations on the basis of the information given above.

The open lung biopsy shows a lesion depicted below:

What kind of lesion is this?

Adjust your differential diagnostic considerations.


102

Are there any further tests you would like to do in view of your considerations?

Does your final diagnosis sufficiently explain for the patients’ complaints?

6.7 Academic Assignment

In this academic assignment, we ask you to study an academic paper on chimerism. The aim of this

assignment is to guide you into the critical appraisal of scientific publications, to study the data given

and conclusions drawn from them, and to think of new or alternative approaches that would take the

research yet one step further.

Below, you find a short introduction on the subject ‘chimerism’. The paper you have to study and a

detailed study assignment will be posted on blackboard by the end of week 3 of the module.

Chimerism

Chimerism is a medical term which is used to indicate the presence of 'non-self' cells in an individual,

mostly as a result of pregnancy, but also in the transplantation setting. The most frequently used

method to identify chimeric cells in tissues, is to search for male Y-chromosome positive cells in

female tissues by in situ hybridization. The Immunopathology research group published on chimeric

cells in renal transplants in the Lancet, in 2001. Shortly afterwards, in response to a study by Quaini et

al (NEJM, 2002), critics questioned the pre-transplantation status of pregnancy derived chimerism in

transplanted organs, stating that this could obscure the evidence for transplantation derived chimerism

in solid organ transplantation. More precisely, they argued that the Y-chromosome positivity which

was used in all studies to identify cells in female donor organs given to male recipients, could well be

the Y-chromosome positive cells of a previous pregnancy of the female donor with a son.

In response, we studied baseline levels of chimeric cells in normal solid organs of women in 2005.

Most of the work which was subsequently performed on chimerism and auto-immune disease hinged

on the hypothesis that chimeric cells may initiate a graft-versus-host-like response, thereby

contributing to the development of auto-immune disease. In short, it was argued that chimeric T-cells

of fetal origin are able to initiate an immune response at a certain time-point after pregnancy, a

pathogenic mechanism which finds its roots in experimental research performed in the 1980s,

demonstrating that a lupus-like disease can be induced in mice through chimeric T-cells.

Subsequently, we demonstrated chimeric cells at the tissue level in humans, focusing on the presence

and phenotype of chimeric cells in a variety of organs affected by Systemic Lupus Erythematosus

(SLE). Because of the limitations of current techniques that identify chimeric cells, a new technique to

detect chimeric cells on the basis of mismatches in insertions and deletions (indels) of two individuals

was successfully established at LUMC. With this technique, it became possible to pursue a number of

important research questions hitherto unanswered, that form the core of the current research grant

proposal. In short, we will investigate to whom the pool of chimeric cells belong that are present in

virtually every individual, what their relation is to pregnancy, in what amounts and how long after

pregnancy they persist, and most importantly: whether chimeric cells in humans are immune-

competent and therefore, able to initiate auto-immune diseases such as SLE.


103

6.8 SSA

SSA VI.1 Case: myasthenia gravis

A 25-year old woman experiencing double vision, ptosis (she could only partially lift her eyelids),

uncoordinated eye movements and weakness in her upper arms is referred to the neurology

department. The neurologists suspect myasthenia gravis , a diagnosis that is confirmed by the

presence of high levels of auto-antibodies against the acetylcholine receptor in her blood. The patient

is prescribed cholinesterase inhibitors in combination with corticosteroids. As a result of this

treatment, her neurological symptoms subside and the levels of anti-acetylcholine antibodies in her

serum decrease (although still being detectable). Two years later, this woman delivers a child that

exhibits symptoms of neonatal myasthenia gravis . Because of the medical history of the mother, this

was expected. The baby is immediately transferred to the intensive care unit, where it receives

artificial ventilation (is attached to a breathing machine) and feeding via a nasogastric tube. Antibodies

against acetylcholine receptor are initially detected in the baby’s blood, but these fall to undetectable

levels within several days. Four days after birth, the baby can be released from intensive care, and

from that moment on its development is fully normal.

Questions:

1 In contrast to most other auto-immune diseases involving auto-antibodies, the primary mechanism

of action of those directed against the acetylcholine receptor is not the infliction of tissue damage.

Specify the mechanism of action of the auto-antibodies in myasthenia gravis.

2 Specify the mechanism of action of the two drugs prescribed to this patient. Which of the two

drugs causes a decline of the levels of auto-antibodies?

3 The auto-antibodies in myasthenia gravis are primarily of IgG type. On the basis of this

information, explain why the newborn child of the woman exhibits symptoms of myasthenia

gravis. Why were the baby’s symptoms only transient?

4 Table 13.24 in Parham shows that there is an association between HLA-DR3 and risk for

developing myasthenia gravis. Explain this association on the basis of the immune effector

mechanism involved in this disease.

SSA VI.2 Case: SLE

Systemic lupus erythematosus (SLE) is a systemic auto-immune disease that can inflict immune

pathology to a diversity of tissues throughout the body. It is characterized by the presence of auto-

antibodies against DNA that cause the formation of immune complexes. Every day, many millions of

nuclei are extruded from red blood cell precursor cells in the bone marrow when these cells differentiate

into mature red blood cells. This event, amongst others, provides a rich source of antigen for the anti-DNA

auto-antibodies. Suppression of this disease involves lifelong treatment with a combination anti-

inflammatory and immunosuppressive drugs, including corticosteroids. We refer to www.nvle.org for

additional information on SLE from the patient’s perspective.

Questions:

1 SLE is caused by the formation of small immune complexes that are not efficiently cleared from

circulation. Explain why the immune complexes are small and why this hampers clearance (see

figure 12.31 in Parham).


104

2 Even though SLE is associated with auto-immune pathology in multiple tissues, the kidneys are in

many patients most severely affected, causing renal function deterioration. What is the

explanation for this?

3 One of the diagnostic markers of SLE is a low serum content of complement proteins, in

particular of C3. Explain the decrease of C3 concentration in the serum.

4 What are the risks of continuous treatment with anti-inflammatory drugs?

5 Symptoms of various immune disorders, including SLE, can worsen if patients contract an

infectious disease, such as the flu or even a bad cold. Explain this. (this question refers in part to

the clinical conference on SLE).

6 Describe and explain the typical pattern found by immunofluorescent markers for IgG, IgA, IgM,

C3 and C1q in lupus nephritis.

7 Comment on the clinical relevance of the classification for lupus nephritis.

8 How would you describe so-called proliferative lesions in lupus nephritis?

SSA VI.3 Case: Rheumatoid arthritis

Rheumatoid arthritis (RA) is a common auto-immune disease that affects 1-2 % of the adult population

in the developed world. Patients with RA, like those with SLE, are generally treated with a combination of

anti-inflammatory and immunosuppressive drugs. Recently, treatment with monoclonal antibodies against

the cytokine TNFα (tumor necrosis factor alpha) is also used to alleviate the symptoms.

Questions:

1 Why is it essential that RA is diagnosed early and that treatment with anti-inflammatory drugs is

initiated rapidly after diagnosis?

2 Explain why anti-TNFα antibodies can be highly effective in alleviating RA symptoms.

3 The efficacy of treatment with a preparation of anti-TNFα monoclonal antibody often decreases

after repeated administration. Explain this and provide a possible solution to circumvent this

problem. (this question refers in part to the clinical conference on rheumatoid arthritis).

4 Give a description of the typical biopsy findings in a synovial biopsy taken from a patient with

RA.

5 What sort of inflammation is found in a rheumatoid nodule? Where can they occur? Can you

think of an important differential diagnostic consideration on the basis of the histological

findings?

SSA VI.4 Case: Diabetes

A 12-year old girl, who was previously healthy, starts to perform poorly at school since several weeks. She

loses weight and displays an exceptional thirst that causes her to drink litres of liquid a day. When taken to

the doctor, increased levels of glucose are detected in her blood, leading to the diagnosis of insulin-

dependent diabetes mellitus (IDDM) or type 1 diabetes. Further analysis of her blood reveals the

presence of auto-antibodies against pancreatic β-cell antigens, confirming the diagnosis. She is prescribed

daily injections with insulin and, as a result of that, has no further complications of diabetes.

Questions:

1 Specify the type of immune reaction involved and explain how the auto-immune reaction in type I

diabetes results in high blood glucose levels.

2 If the diabetes becomes manifest in the kidneys, what kind of lesions will be found in the

glomeruli?


105

3 What kind of treatment can be given to patients with end stage renal failure due to diabetes?

4 Not all patients with type I diabetes display anti-β-cell auto-antibodies. What would be the

explanation for the fact that type I diabetes can develop in the absence of such antibodies?

5 In the past, the insulin used for treatment of diabetes patients was isolated from pancreases of

cattle. More recently, all patients receive recombinant human insulin. Why is this latter treatment

less likely to result in complications? (this question refers in part to the caput lecture on auto-

immune diabetes)

SSA VI.5 Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an auto-immune disorder that is clinically characterized

by muscle weakness and by autonomic dysfunction (e.g. dry mouth, constipation and, in men, impotence).

Similar to myasthenia gravis, this disease is caused by an auto-immune response directed against tissue-

specific antigens (calcium channels) that are expressed at the neuromuscular junction. As a result of this

auto-immune response, the transmission of nerve impulses to muscles is impaired. Approximately 50% of

LEMS patients have an underlying tumor: small cell lung cancer (SCLC). This is a tumor of neuro-

endocrine origin that expresses many proteins of neuronal origin, including the antigens expressed at the

neuromuscular junction against which the auto-immune response in LEMS patients is directed.

Questions:

1 The symptoms of LEMS are caused by the action of auto-antibodies of the IgG class, directed

against antigens expressed at the neuromuscular junction. Explain why the presence of these IgG

antibodies is indicative of an underlying auto-reactive CD4+ T-helper response.

2 Many auto-reactive CD4+ and CD8+ T cells are deleted from the T-cell repertoire in the thymus

(negative selection). Explain why this is apparently not the case for the T-cells that recognize the

target antigens expressed at the neuromuscular junction.

3 Explain how the presence of the tumor can trigger this auto-immune disease (3 points).

4 The median survival time of SCLC patients with LEMS is significantly longer than that of SCLC

patients without LEMS. Provide an explanation for this difference. (This question refers in part to

the caput lecture on neurological auto-immune disorders.)

SSA VI.6

This SSA will help you to get an overview of similarities and differences between a number of auto-

immune diseases. This is a good exercise for the question format ‘Comprehensive Integrated Puzzle’ as

will be used in the final exam.

For each of the following diseases answer the questions listed below:

SLE

Sjögren’s syndrome

GPA (granulomatosis with polyangiitis)

Churg Strauss syndrome

Rheumatoid arthritis

Systemic Sclerosis

Henoch Schönlein Purpura


106

Questions (use self-study table VI.6 in Attachment):

1 Which organs are mainly involved in this disease?

2 A biopsy from which organ could be helpful in establishing the diagnosis, and how?

3 Which serological test is most likely to be positive in this disease?

4 Is it known which type of hypersensitivity reaction plays a role in the development of this

disease?

5 Can you say anything about the patient’s prognosis or the general course of this diseas


107

7. Theme VII: Transplantation


7.1 Introduction

When a vital organ or tissue is irreparably damaged or non-functional, organ or tissue transplantation can

be a life-saving treatment. A transplant can originate from a deceased donor, a living donor (both

allogeneic setting) or from the recipient him or herself (autologous setting). Transplant procedures are

generally associated with transplantation-related complications which, in some cases, can even be lethal.

The topics which will be addressed in this last Theme are focused on common immunologic, pathologic

and infectious problems seen in the setting of allogeneic transplantation; these differ between organ and

bone-marrow or stem cell transplant recipients. Infections are a major risk in both groups of transplant

recipients, because various components of the immune system can be impaired temporarily or

permanently. Prevention, timely detection and adequate treatment are of utmost importance in this patient

group.

This theme will be illustrated by aspects involved in kidney transplantation and in combined

kidney/pancreas transplantation in patients with diabetes mellitus (DM). We will focus on rejection,

chronic allograft nephropathy, viral infections in the graft, and disease recurrence. In addition, some

histopathologic aspects of Graft-versus-Host Disease will be discussed as is seen after allogeneic

hematopoietic stem cell transplantation. World-wide, the number of patients with DM, especially DM

type 2, is increasing. In DM, vascular lesions may occur at any site in the body, but they can be

particularly harmful in the kidney, causing so-called diabetic nephropathy. Diabetic nephropathy is in the

top 3 of causes leading to end stage renal failure, and thus it is one of the most important indications for

renal transplantation. In a combined kidney/pancreas transplantation, the aim is not only to restore the

patient’s renal function, but also to make the patient insulin independent. As an alternative to ‘whole

pancreas’ transplantation, methods are being developed to transplant only the islets of Langerhans .

Infections are a major risk in transplant recipients, because various components of the immune system

can be impaired temporarily or permanently. Prevention, timely detection and adequate treatment are of

utmost importance in this patient group.



explain the difference between transplantation of a solid organ or tissue and functional repair of

the hematopoietic system by hematopoietic stem cell transplantation (HSCT);

describe and explain the pathogenesis of complications associated with hematopoetic stem cell

(HSCT) and solid organ transplantation (SOTx);

explain immunopathological processes causing the clinical signs and symptoms of rejection;

explain the principle of immune-based strategies to prevent graft rejection and graft versus host

disease (GVHD) in HSCT.

recognize histological features, describe the pathogenesis of and indicate the appropriate

diagnostic test(s) for several Tx-associated conditions (acute and chronic graft rejection; drug

toxicity; BK-virus nephropathy, acute and chronic GVHD);

TH E ME VI: TRA N SP L A N TA TIO N

TH E ME VII : TRA N SP L A N TA TIO N

108

indicate the mechanism of action of different classes of anti-rejection drugs;

classify the infection risks associated with transplantation;

list the most important infections for which pre-transplantation screening is possible and relevant;

classify (opportunistic) infections associated with transplantation and relates infections with the

specific time frame after transplantation;

recognize the clinical presentations of the most frequent opportunistic infections from the list of

Essential Microorganisms (CMV, VZV, EBV, HSV, aspergillosis, toxoplasmosis) and of

Pneumocystis jirovecii;

indicate risk indicators for infection (delayed immune recovery, prolonged immunosuppressive

medication, CMV status of transplant donor and recipient, GVHD, medical devices, de novo

exposure);

indicate general and specific measures to prevent infection after transplantation.


Lectures

LT38: Introduction to transplantation. This lecture presents the historical ‘bumpy road’ which

led to the discovery of HLA and the need for registries which nowadays help transplant

physicians to find a suitable transplant donor for their patients.

LT39: Transplantation immunology. This lecture zooms in on the role of allo-immune T and B

cells in acute or chronic allograft rejection and Graft-versus-Host Disease.

LT40: In depth lecture, Histopathology of Transplantation and Rejection: gives an overview

of the characteristic findings in solid organ transplantation, in particular in relation to renal

transplantation, in particular in relation to rejection, medication toxicity, and disease recurrence.

LT41: In depth lecture, Islet Cell Transplantation: shows techniques used for islet

transplantation and discusses advantages and disadvantages of islet cell transplantation in contrast

to whole pancreas transplantation.

LT42: Transplantation and infection risk. Relates the time-line of transplantation (solid organ

or HSCT) to defects in the various components of the host defence system and associated

infection risks and defines opportunities for primary, secondary or tertiary prevention.


"A patient with a solid organ transplantation": will illustrate the clinical history of a patient up

to the moment of transplantation, and a variety of events following renal transplantation

(rejection, infection, disease recurrence).

Study plan


Follow the lectures and patient demonstration

Make the self-study assignment


109

7.4 Reading list

Robbins and Cotran:


226-230 Rejection of Tissue

Transplants…. up to

Immunodeficiency

Syndromes

Acute rejection, chronic rejection, T-cell mediated

rejection, antibody-mediated rejection, graft survival

Figures: 6-39, 6-40

Parham:


15 456-467 transplantation antigens and immune-driven

complications caused by effector cells responding to

mismatched antigens fig 15.1, 15.3, 15.4, 15.7, 15.11

and 15.12

472-473 prevention of T cell -mediated complications in

transplantation



7.5 SSA

SSA VII.1: Case with a renal transplant

A 46-year-old man has been waiting 5 years for a renal transplant. Ten years ago he developed a

disease by which his renal function was destroyed.

Study the glomerulus in the figure and name the lesions which

are shown here.

The immunofluorescence pattern of his native biopsy showed a pauci-immune pattern. By which

disease was his renal function destroyed?

TH E ME VII : TRA N SP L A N TA TIO N

110

A cadaveric kidney becomes available. A time-zero biopsy is taken just before transplantation, shown

in this figure:

It showed one small focus with a few lesions. What are they

called?

And what does this tell you about the quality of the kidney

transplant?

The transplantation procedure goes without complications, but 5 days after transplantation, the graft is

not functioning yet. A renal biopsy is performed, showing the lesion on the slide.

What is your diagnosis?

Two years after transplantation, cells are found in the urine with large nuclei.

Study the slide: how are these cells called?

Why?

What does their presence in the urine mean?

Would you consider taking a renal transplant biopsy?

Three years after transplantation, the patient is admitted to hospital because of an acute deterioration

of his renal function and fever. He says he has not been well for two weeks, because of a cold. What

are your differential diagnostic considerations for his condition? What are you going to do in view of

the diagnostic work-up?

The patient recovers. During 5 years, his renal transplant

is doing quite well. Then, a slowly progressive

deterioration of renal function is noticed by the clinician.

A biopsy of the renal transplant is performed.

Study the slide. What is your diagnosis?


111

Attachment 1: Tables for SSA II.1

Self-study Table II.1.1 Comparison of pathogen structure

Characteristic Pt. A Pt. B Pt. C Pt. D Pt. E

Pathogen

Group

Size

Cell wall

Cytoplasmic membrane

Outer membrane

Peptidoglycan

Lipo-polysaccharide

(lipo)Teichoic acid

DNA / RNA

Porins

Periplasmic space

Capsule

Envelope

Flagellas

Fimbriae

Hyphae

Ribosomes

Nucleus

Nucleocapsid

Endoplasmic Reticulum

Lysosomes

Mitochondria

Plasmids

Gastro-intestinal tract

Testis or ovarium

A TTA CH ME N TS

112

Self-study Table II.1.2 Comparison of the physiology of pathogens

Characteristics Pt. A Pt. B Pt. C Pt. D Pt. E

Pathogen

Multiplication method

Peptidoglycan

Synthesis

Penicillin-binding

proteins

DNA synthesis

RNA synthesis

Protein synthesis

Glycolysis

Fermentation

Citric acid cycle

Anaerobic breathing

Conjugation

Transformation

Transduction

Spore formation

Sexual

Reproduction


113

Self-study Table II.1.3 Virulence factors of pathogens.

Pt. A Pt. B Pt. C Pt. D Pt. E

Pathogen

Virulence

factor

Pathogenesis

(including

interaction

with

components

of the

immune

system)

Type of

inflammatory

reaction

A TTA CH ME N TS

114

Attachment 2: Tables for SSA III.A.1 and III.A.2

Selfstudy Table III.A.1

The role of host defence in the protection against infectious diseases

Defence

Bacteria

Viruses

Fungi

Protozoa

Worms

Barriers

Complement

Antibodies

Phagocytes

Cell mediated

Immunity


115

Self-study Table III.A.2

Patient A Patient B Patient C Patient D Patient E

Pathogen

Virulence

factors

Pathogenesis

Type of

inflammatory

reaction

Host defence

failure (in

general for this

pathogen, not

for this specific

patient)

Pathophysiolo

gical

explanation of

signs and

symptoms

A TTA CH ME N TS

116

Attachment 3: Table for SSA IV.A.1 and IV.B.1

Assignment IV.A.1 Assignment IV.B.1

Pathogen Reservoir Transmission Geographical

spread

Prevention and

control measures

Patient A

Patient B

Patient C

Patient D

Patient E

Pulmonary

tuberculosis

Pneumococcal

pneumonia

Cholera

Shingles

(Herpes zoster)

Poliomyelitis

Aspergillosis

Candidiasis

Amoebiasis

Toxoplasmosis

Echinococcosis


117

Attachment 4: Table for SSA IV.B.3

See next page

A TTA CH ME N TS

118

Table IV.B.3 ‘Rijksvaccinatieprogramma’ (National Vaccination Program)

Vaccines in the

‘Rijksvaccinatieprogramma’

(per component; actual

products may contain several

components)

All children

or selection

Age(s) Antigen only or live

vaccine

Characteristics of disease if unvaccinated: a. microorganism b. Route of infection c. Major clinical presentation d. Person to person spread possible e. endemic in Netherlands?

Level of protection

1. Diphtheria a . Corynebacterium diphtheriae b. Droplet infection; c.

necrotizing pharyngitis, tracheitis, myocarditis d. Yes e. No

2. Pertussis (kinkhoest ) a . Bordetella pertussis b. Droplet infection; c. longlasting

bronchitis with characteristic coughing pattern d. Yes e. Yes

3. Tetanus

a . Clostridium tetani b. contact with environmental source of

spores; c. generalized muscle spasms, autonomic dysfunction,

high mortality d. No e. Yes

4. Poliomyelitis a . Pol iomyelitis vi rus a. feco-oral; droplet infection, c. flaccid

para lysis d. Yes e. No, except for occasional outbreaks in

unvaccinated communities

5. HIB a . Haemophilus influenzae b. Droplet infection; contact with

a i rways secretions c. most common is upper airways infection but

most threatening infection is meningitis d. Yes e. Yes

6. Pneumococcus a . Streptococcus pneumoniae b. Droplet infection; contact with

a i rways secretions c. upper and lower airways infections d. Yes e.

Yes

7. Mumps (bof)

a . Mumps vi rus b. Droplet infection; contact with saliva c.

parotitis, orchitis or oophoritis (risk of infertility), meningitis d.

Yes e. Previously only in unvaccinated communities. Recently

outbreak that s tarted among previously vaccinated s tudents.


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Table IV.B.3 continued

Vaccines in the

‘Rijksvaccinatieprogramma’

(per component)

All children or

selection

Age(s) Antigen only or live

vaccine

Characteristics of disease if unvaccinated:

a. Microorganism b. Route of infection

c. Major clinical presentation

d. Person to person spread possible

e. Endemic in Netherlands?

Level of protection

8. Measles a . Measles virus b. Droplet infection; contact with airways

secretions c. mostly fever and rash, rarely pneumonia or severe

encephalitis d. Yes e. No, except for occasional outbreaks in


9. Rubella (rode hond)

a . Rubella vi rus b. Droplet infection; contact with a irways

secretions c. cl inical illness mild, but if during pregnancy: high risk

of intrauterine infection and intrauterine death or congenital

abnormalities d. Yes e. No, except for occasional outbreaks in


10. MenC a . Neisseria meningitidis b. Droplet infection; c. meningitis or

sepsis d. Yes e. Yes

11. Hepatitis B virus

a . Hepatitis B vi rus b. vertical transmission; direct contact (e.g.

sexual); indirect contact (blood, needle s ticks); c. chronic

hepatitis (risk depends on age at time of infection), cirrosis, liver

cel l carcinoma d. Yes e. Yes.

12. Human PapillomaVirus a .Human Papilloma vi rus b.sexual transmission c. precancerous

cervica l lesions (detectable by PAP smear); cervix carcinoma d.

Yes e. Yes

121

Attachment 5: Table for SSA VI.6

1. Organs 2. Biopsy site

and result

3. Serology 4. Hypersensitivity

type

5. Course and

prognosis

SLE

Sjögren’s

syndrome

Granulomatosis

with poly-angiitis

Churg Strauss

syndrome

Rheumatoid

arthritis

Systemic

Sclerosis

Henoch

Schönlein

Purpura

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Attachment 6: Practicals Bacteriology and

Parasitology

PRACTICAL 1: Bacteriology

Preparation:

E-learning modules of themes II (1 modules) and III (2 modules);

Read the introductory texts with the cases below;

For answering the questions in this practical, use Sherris. You should have this book with you

during the practical.

Microscopy

To see bacteria in a Gram stain, magnification with a 100 oil immersion objective is absolutely

necessary. The best approach for microscopy is:

examine the slide with a 10 objective, to focus and to study the presence of leukocytes;

add one drop of mineral oil;

refocus again with the 10 objective;

turn to 100 objective, focus and study stained preparations in more detail for cells and bacteria;

after microscopy, do NOT clean the stained slide (you would wipe off the bacteria), ONLY clean

the oil immersion objective with a tissue.

Blood cultures

Blood cultures are usually drawn from patients who have developed fever and have a suspicion of a

bacterial infection. Importantly, fever is not a prerequisite for a bacterial infection. Some patients are

unable to develop fever as a representing symptom of an infection because of the use of

immunosuppressive therapy or anti-inflammatory medicines with antipyretic activity. Age is another

important factor, since elderly patients also develop fever less frequently, as is uraemia. The timing

schedule for drawing a number of blood cultures is dependent on the bacteremic pattern (transient,

intermittent, or continuous) of the infection and the need to initiate antimicrobial therapy.

For a blood culture, blood is obtained by venous puncture after thorough disinfection of the skin. Blood

should not be drawn from an indwelling venous or arterial catheter. Since the number of bacteria present

in blood is often low, samples of at least 10 ml should be collected from (adult) patients. The blood is

collected in a bottle with culture medium which favours growth of aerobic bacteria and in a second bottle

favouring growth of anaerobic bacteria. Since most pathogenic bacteria are facultative aerobes, growth

usually occurs in both bottles. It is generally advised to take two blood cultures before antibiotic therapy

is (empirically) started – if empirical therapy is deemed necessary. Blood cultures are usually incubated

during 5-7 days, so a negative result will reach you only after this period. However, if blood cultures

become positive this usually happens within 24-48 hours and almost always within 72 hours, so that if

growth has not occurred within this period, you may consider the blood culture negative for practical

purposes.

When a blood culture shows bacterial growth (nowadays usually determined automatically), a Gram-stain

is made of the cultured blood (a Gram stain of freshly taken blood is not useful). If judged clinically

relevant by the medical microbiologist, this result of the Gram-stain will directly be reported to the

physician. At the moment of the first report, only the result of this Gram-stain can be reported (although


123

some laboratories in tertiary care facilities use mass-spectrometry for rapid identification within a few

hours). Further determination of the bacterial species involved and of its resistance pattern to antibiotics

usually takes 24 hours, but may take longer in the case of slowly growing species, mixed infections or

difficult species determinations.

Always take into account that a blood culture can be contaminated with skin bacteria. Especially

coagulase-negative staphylococci and diphteroid Gram-positive rods can be grown as contaminants from

blood cultures. Such bacterial species with low pathogenic potential only have clinical relevance in

special situations, mainly in very severely immune-compromised patients or after introduction of

biomaterials (e.g. intravenous catheters, prosthetic valves or prosthetic joints).

Case 1

A 68-year-old woman, who suffers since years from rheumatoid arthritis and is treated with

corticosteroids for this disorder, presents with increased pain of the right knee since one day. The

rheumatologist notices a red, swollen joint. The temperature is 37.8°C. Two blood cultures and an

aspirate of the knee joint are drawn and sent to the microbiology laboratory. The Gram-stain of the fluid

from the knee shows many leukocytes but no bacteria. The next day, one of the bottles from the blood

culture shows bacterial growth.

Describe the Gram-stain which is made of the blood culture.

Give two possible reasons why this blood culture becomes positive.

Which bacterial species would be responsible in each of the cases?

Would you start antibiotic treatment? If so, which treatment would you give?

Case 2

A 34-year-old man has returned since one week from a four week lasting journey to Indonesia. During his

stay there, he was in good health, apart from a few days of diarrhoea. Now he has 40°C fever since 48

hours. His heart rate is 80 per minute, his blood pressure is 130/80 mm Hg. A slightly enlarged spleen is

noticed on physical examination and a few pink coloured spots (rose spots) are visible on his abdomen.

His white blood cell count is 4.8 x 109/l. A malaria smear is negative. A blood culture is drawn and the

patient is sent home without antibiotics. On the next day, bacteria grow from the blood culture.

Describe the Gram-stain which is made of the blood culture.

Which bacterial species would you consider responsible for the infection in this patient?

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124

Which antibiotic treatment would you consider?

Urine, sputum, pleural fluid, ascites, cerebrospinal fluid, pus.

Gram staining of these materials can be done directly and takes about 20-45 minutes. Rapid Gram stains

can be very useful in situations where the choice of the antibiotic regimen is critical. In Gram stains of

these specimens, the number of erythrocytes, leukocytes and squamous epithelial cells are also reported.

These numbers of cells are extremely important to judge the relevance of the bacteria which are

subsequently reported. Representative specimens from the respiratory or urinary tract should contain no

or only a few squamous epithelial cells, and in case of infection the number of leukocytes is usually high.

The presence of squamous epithelial cells indicates contamination by the flora of the upper respiratory

tract resp. vagina or preputium. It is important to differentiate squamous epithelial cells from columnar

ciliated epithelium (bronchi), alveolar cells and transitional epithelium (renal pelvis, bladder). In case of

materials that should be normally sterile, such as cerebrospinal, pleural, ascites or joint fluid, the presence

of many leukocytes indicate inflammation, which is mostly caused by bacterial infection.

Cultures are approximately tenfold more sensitive in comparison to direct smears. A negative Gram

smear of a cerebrospinal fluid specimen does not exclude bacterial infection, as the culture may become

positive. On the other hand, administration of antibiotics prior to collection of the specimen can lead to a

positive Gram-smear with bacteria, whereas bacterial growth remains negative. In these cases, bacteria

are still present, but lack viability to grow on artificial media.

Final reports of cultures of these specimens are usually available after 48 hours: 24 hours for initial

growth of bacteria, and another 24 hours for determination of bacterial species and resistance to

antibiotics. After 24 hours, a preliminary report can be given, if necessary (newly introduced

identification methods use mass-spectrometry and molecular biology, enabling more rapid identification,

but are not yet widely available). Reports may include an approximation of the number of bacteria present

in a given specimen. This can have relevance for clinical purposes: low numbers of bacteria may

sometimes be due to contamination of the specimen or to low-grade colonization of the patient with the

reported bacteria, whereas high colony counts of clinically relevant bacteria are almost always of

importance.

Whereas non-sterile specimens (urine, sputum) are routinely incubated for 48 hours only, specimens from

normally sterile fluids are often incubated for 5-7 days to allow detection of fastidious, slowly growing

bacterial pathogens as well. However, also from these specimens clinically relevant bacteria will grow

within 48 or at latest 72 hours in the majority of cases

Case 3

A 16-year-old boy suddenly became ill, with fever and chills since three hours. The physical examination

reveals a heart rate of 135 per minute, a blood pressure of 100/60 and a few petechiae on the legs. There

is nuchal rigidity. He is admitted to the paediatric intensive care and treated with broad-spectrum

antibiotics. After correction of the prolonged bleeding time, a lumbar puncture is taken.

Describe the Gram-stain which is made of the cerebrospinal fluid

Which bacterial species would you consider responsible for the infection in this patient?


125

Would it have been possible to diagnose this disease earlier?

Which antibiotic treatment would you give?

Case 4

A 4-year-old girl, with a history of recurrent urinary tract infections and presently on antibiotic

prophylaxis with trimethoprim, is admitted to the paediatric ward with high fever and abdominal pain. A

urinary specimen (and a blood culture) was sent to the laboratory.

Describe the Gram-stain which is made of the urinary specimen. Report also the number of

squamous epithelial cells and leukocytes!

Do you consider urinary tract infection likely in this patient? Which species is probably involved?


Is it very important to obtain an antibiotic resistance pattern of this strain? Is there a risk that the

strain is resistant to the chosen treatment?

Case 5

A 68-year-old man, known with insulin-dependent diabetes mellitus for over 20 years, is seen at the

Dermatology department because of a small ulcer on the right leg, accompanied by extensive

inflammation of the surrounding skin. He is known to be allergic to penicillin. A Gram-stain of the pus on

the ulcer is made.

Describe the Gram-stain which is made of the specimen. Report also the number of leukocytes!

Which bacterial species is probably responsible for the infection?


Case 6

A 23-year-old man originating from Somalia and now living in the Netherlands since 9 months, presents

with fever (38.2°C) which he has already since four months, loss of weight and night sweats. A chest X

ray shows a pulmonary infiltrate in the right apical lobe of the lung. A sputum sample is sent to the

laboratory for Gram-stain.

Describe the Gram-stain which is made of the specimen. Report also the number of epithelial cells

and leukocytes!

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126

Which bacterial species is probably responsible for the infection? Which additional staining

method would you request? Describe the results of this examination (slide 6A). What would be the

next step?

Is it very important to obtain an antibiotic resistance pattern of this strain? Is there a good chance

that the strain is resistant to the chosen treatment?


127

PRACTICAL 2: Parasitology

In this practical you will be introduced to the techniques most often applied in the diagnostics of parasitic

infections.

Be present at the indicated time.

A laboratory coat is not necessary.

Consumption of food (including chewing gum) or drinks is not allowed in the practical room.

Bring with you Sherris 6th

edition (if you have 5th edition: the pages to prepare can be found in the

PDF with reading list for 5th edtion on Blackboard) and your course book.

Changing practicals is not allowed without special permission.

Prepare for the assignments by

reading Sherris 6th

edition pages 777-778 (Parasitic infections-diagnosis), and by reading the text

below.

Study the lecture Parasitology of theme II, which has been placed on blackboard. Pay special

attention to the life cycles, pathogenesis and diagnosis of

1 Plasmodium falciparum and P. vivax (pages 787-797)

2 Entamoeba histolytica (pages 813-818)

3 Schistosoma mansoni and S. haematobium (pages 903-905)

4 Strongyloides stercoralis (pages 858-861)

Clear information about life cycles, pathogenesis and diagnosis can also be found at

http://www.dpd.cdc.gov/DPDx/HTML/Para_Health.htm (search the names of the parasites in the

alphabetic list)

Diagnosis of malaria – background information

In order to be able to differentiate the stages of the Plasmodium parasite in the blood preparations of

assignments P1-P3 one needs to study the figure of the life cycle below.

The sexual development of Plasmodium takes place in the final host, the female Anopheles mosquito.

There the parasite divides and forms sporozoites, which enter the human circulation through a bite of a

female mosquito. Within the human host the parasite undergoes asexual multiplication. The sporozoites

pass quickly into the liver where they multiply in the liver cells for 1-2 weeks, causing no symptoms. The

parasites burst from the liver cells and the merozoites rapidly penetrate the erythrocytes and start

multiplying again. The young parasite within the red blood cell is called trophozoite. The dividing stage,

showing multiple nuclei often in combination with parasite pigment, is called schizont. After some time

the eythrocyte with the schizont ruptures and releases 8-24 merozoites into the blood, which penetrate

within seconds other erythrocytes. This process all together is called schizogony.

http://www.dpd.cdc.gov/DPDx/HTML/Para_Health.htm

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128

The erythrocytic cycle takes 48-72 hours, depending on the species. Some trophozoites do not go through

schizogony, but develop within erythrocytes into male and female gametocytes. A biting mosquito ingests

the gametocytes, which leads to the completion of the parasite’s life cycle.

The clinical symptoms of malaria are mainly a result of the erythrocytic cycles: the release of

haemoglobin decomposition products (malaria pigment) after rupture of the infected erythrocytes, and (in

case of Plasmodium falciparum) sequestration of maturing trophozoites and schizonts in the capillaries of

organs.

Laboratory diagnosis is based on the erythrocytic cycles. In a blood film we may see trophozoites,

schizonts and gametocytes, depending on the Plasmodium species in combination with the severity and

duration of infection. The specific morphology of these stages helps to diagnose different malaria species

(differential diagnosis), which is very important for treatment.

In falciparum malaria (Dutch: malaria tropica) caused by Plasmodium falciparum, schizogony takes place

in the organs, and gametocytes do not develop until after a number of cycli. Non-immune persons are

mostly examined earlier, as soon as complaints start. Hence, in infections caused by P. falciparum we

mostly see immature trophozoites only (except in severe infections). In infections caused by other malaria

species, each of the erythrocytic cycles can be seen in peripheral blood. In benign malaria tertiana, caused

by Plasmodium vivax, the parasitemia is often lower than in many infections with P. falciparum, the

infected erythrocytes are enlarged, the parasites are a larger (filling the red blood cell), and the surface of


129

the infected erythrocytes is dotted. Besides this, we often see malaria pigment sedimentation (erythrocyte

metabolic decomposition products) in the later stages. In P.ovale and P.malariae various erythrocytic

stages can also be found in peripheral blood (see Sherris table 51-1, page 791). The characteristics of

these species are not discussed in this course.

Assignment P.1 Thick blood film and thin blood film preparation

Patient 1 is a 30 years old man from Ethiopia. He came to the Netherlands 3 months before and complains

of fever. Malaria has to be excluded. Therefore blood was taken and examined for the Plasmodium

parasite in the laboratory. On slide P1 you will find both a Giemsa stained thick blood film preparation

and a Giemsa stained thin smear. Listen carefully to the instructions given

Why is a thick blood film preparation preferred to diagnose malaria, and what is the use of

making, staining and examining a thin smear preparation?

When examining P1. start with 1010 magnification in order to adjust the position of the slide and the

accessory plate. Then examine both the thick smear and the thin smear with 10100 magnification in oil

immersion. Ask assistance with the microscopy if it is not clear.

Which stages do you see in the thick smear and which in the thin smear? Describe the morphology

of the different stages.

Which species of Plasmodium are you looking at?

What is the parasitemia level (rough estimation percentage of infected erythrocytes)?

Assignment P.2. Parasitemia level

Patient 2 is a Dutch KLM-pilot (man, 50 years) who did not take malaria prophylaxis when he went to

Togo and stayed there for 2 nights. Two weeks after his return he gets high fever. His blood is examined

for malaria.

Examine preparation P2 (thick smear and thin smear are on the same slide) in the same way as

preparation P2.

Which stages do you see?

What is the parasitemia level here? Why is this important to know?

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Assignment P.3. Differentiation between malaria species

Six months after patient 3 (a 24-year-old Dutch woman) had visited the Indonesian islands Java and Bali,

and New Guinea, she had periods of shivers and fever, which occurred at regular intervals. Here blood is

examined for malaria (P3, thick smear and thin smear at the same slide)

Observe the morphological characteristics of the parasites in P3 and name the different stages.

Compare both the infected red blood cell and the parasite itself with P1 and P2. Describe the

differences?

Which Plasmodium species do you see?

Why is the parasitemia level low? Is it important to know the parasitemia for this Plasmodium

species?

Assignment P.4. Worm eggs in urine

Patient 4 is a 36-year-old Dutch woman who went for holidays to Lake Malawi. Several months after her

return she notices bloody urine but feels otherwise well. Preparation P4 is her urine sediment. Examine

the slide, use 1010 magnification, and as soon as you find an egg, magnify to 1040 (do not use oil

immersion!).

What can you say about the aspects of the sediment (erythrocytes, leukocytes)?

Can you name the parasite species? How do you recognize the difference with a parasite of the

same genus?

Where are the worms situated who produce these eggs?


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What alternative diagnostic tests could be used?

Assignment P.5 Worm eggs in faeces

Patient 5 is a 27-year-old male refugee from Afghanistan who came to Holland a few months ago. He

consulted the refugee centre physician, complaining of belly aches and diarrhoea. His stool is examined.

Preparation P5 is an unstained preparation of his stool. Examine the preparation at 1010 magnification,

and in case you find an egg, enlarge 1040 (no oil immersion!). Study the drawings of Sherris, chapter

54 (Figs. 54-3, 54-6, 54-9, 54-11) to determine the type of worm infections.

How was this patient infected with three different worm species?

If not treated, how long will these worms stay alive? Will they multiply within the human host?

Assignment P.6. Protozoal cysts in faeces

Patient 6 is a 21-year-old Dutch student who made a low budget trip through India and Nepal. He stayed

in simple hotels, often spent the night with local families, who treated him to local dishes, which he had

been advised not to eat. During the greater part of his travelling he had recurring diarrhoea, which was no

surprise to him. But he noticed blood in his stool after his return to the Netherlands. This makes him

decide to go and see his GP. Normally, in routine diagnosis, an iodine-stained preparation of his stool

would be made. For practical reasons we now examine the unstained preparation P6.

Which parasites do you see after careful examination? (NB. magnification 1040, no oil

immersion!)

Compare the sizes of the parasites in preparation P6 with those in preparation P5.Which parasitic

stages do you see in the preparation? What is the function of this stage?

An iodine-stained stool sample will be demonstrated. What is the purpose of this staining, while in

preparation P5 the stool specimen is unstained?

For which reason may it be necessary to perform microscopy on a stool sample within an hour

after production? What is the alternative if this is not possible?

What alternative diagnostic tests could be used?

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Attachment 7: The module at a glance

The following three pages provide a week by week schedule, including all study and testing

methods by week, day, hour, theme and type. Hopefully this will give you a good overview of what

to expect and how to plan your studies. Please give feedback to your coordinators on the value of

this schedule.

Legend with the schedule:

IMMUNOLOGY

PATHOLOGY

INFECTIOUS DISEASES

PHARMACOTHERAPY

PATIENT DEMO

Self-study assignments

PRACTICALS

WORK GROUPS

E-learning

TEST

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134

Week 1 Time Monday 1 Sept Type Theme Tuesday 2 Sept Type Theme Wednesday 3 Sept Type Theme Thursday 4 Sept Type Theme Friday 5 Sept Type Theme

08.30 LT LT5: Mechanisms of adaptive immune response LT I.A LT9: Tissue injury and repair LT I.B

09.00 I.A I.B

09.30

LT2: Intoduction to the immune system: bone

marrow, thymus, spleen. All players of the

immune system and development LT I.A

LT6: B- and T-cell generation and diversity

LT I.A

LT10: Repair mechanisms

LT I.B

10.00 I.A I.A I.B

10.30 LT3: Innate and adaptive immune responses LT I.A

LT7: Pathology of inflammatory reactions

LT I.B

Patient demonstration 1

PD I

11.00 I.A I.B I

11.30 LT4: Pathology of the normal immune response LT I.B

LT8: Pathology of inflammatory reactions:

a case LT IFormative test (vote boxes)

RC I

12.00 I.B I

12.30

13.00

13.30 SSA I.A SSA I SSA I.B SSA I Self study SSA I

14.00

14.30

15.00

15.30 Preparing for WORK GROUP 1 SSA I

16.00

16.30

17.00

17.30


08.30 LT11: Introduction to infectious diseases LT II WORK GROUP 1 (THEME I) WG I LT15: Invader (virulence factors) LT III.A LT19: Diagnostics of infectious diseases LT III.B

09.00 II WG I III.A III.B

09.30 LT12: Bacteria LT II WG I LT16: Host versus invader LT III.A LT20: Interpretation of diagnostic test results LT III.B

10.00 II WG I III.A III.B

10.30 LT13: Viruses LT II WG I LT17: Immune deficiencies and infection risk LT III.A LT21: Essential microorganisms LT III

11.00 II WG I III.A III

11.30 LT14: Fungi and parasites LT II WG I LT18: Pathology of infection LT III Patient demonstration 2 LT III

12.00 II WG I III III

12.30 WG I

13.00 WG I

13.30 WG I

14.00

E-learning module Theme II Laboratory methods

for detection of bacteria COO II WG I

E-learning modules: 2 lessons diagnostics of

infectious diseases (1 teaching, 1 testing) COO III.B

14.30

SSA II. Structure, physiology and virulence

factors of different classes of microorganisms SSA II WG ISSA III.A

SSA III.A SSA and preparing for work group 2 SSA III

15.00 WG I Formative test (BB) II/III

15.30 WG I II/III

16.00 WG I

16.30 WG I

17.00 WG I

17.30 WG I

OPENING ACADEMIC YEAR LINE DAY

LT1: Introduction to G2MD1

LINE DAY


135


08.30Discussion formative test and time for questions

WC II/IIIPRACTICAL BACTERIOLOGY↔

PR III.BLT24: Epidemiology of infectious diseases

LT IV.A PRACTICAL PARASITOLOGY PR III.B

09.00 08.30-10.30: Group C PR III.B IV.A 08.30-10.30: Group D PR III.B

09.30LT22: Antimicrobial therapy

LT III.C WORK GROUP 2 (THEME II / III) WG II / IIILT25: Prevention and control of infectious diseases

LT IV.B PR III.B

10.00 III.C WG II / III IV.B PR III.B

10.30 LT23: Principles of antibiotic pharmacotherapy LT III.C10.30-12.30: Group A

PR III.BPatient demonstration 3

PD IV 10.30-12.30: Group E PR III.B

11.00 III.C PR III.B IV PR III.B

11.30 WG II / III SSA IV.A SSA IV.A PR III.B

12.00 PRACTICAL BACTERIOLOGY PR III.B WG II / III PRACTICAL PARASITOLOGY PR III.B PR III.B

12.30 12.00-14.00: Group B PR III.B WG 12.00-14.00: Group A PR III.B SSA IV.B SSA VI.B

13.00 PR III.B WG PR III.B

13.30 PR III.B 13.30-15.30: Group D PR III.B PR III.B 13.30-15.30: Group F PR III.B

14.00 14.00-16.00: Group F PR III.B PR III.B 14.00-16.00: Group B PR III.B PR III.B

14.30 PR III.B WG II / III PR III.B PR III.B


15.30 PR III.B 15.30-17.30: Group E PR III.B PR III.B 15.30-17.30: Group G PR III.B

16.00 16.00-18.00: Group G PR III.B PR III.B 16.00-18.00: Group C PR III.B PR III.B


17.00 Self study Antibiotics/pharmacotherapy SSA III.C WG II / III PR III.B PR III.B

17.30 TRC antibiotics WG PR III.B Formative test (BB) PR III.B

Week 4 Monday 22 Sept Type Theme Tuesday 23 Sept Type Theme Wednesday 24 Sept Type Theme Thursday 25 Sept Type Theme Friday 26 Sept Type Theme

08.30 WORK GROUP 3 (THEME IV) WG IV LT28: Cells in autoimmunity LT VI

09.00 VGT WG IV VI

09.30 WG IV LT29: Pathology of autoimmunity LT VI

10.00 COMPONENT EXAM G2MD1 T WG IV VI

10.30 USC sportcentrum WG IV LT30: Vasculitis LT VI

11.00 WG IV VI

11.30 WG IV LT31: Systemic lupus erythematodes LT VI

12.00 WG IV VI

12.30 WG IV

13.00 SM1: Seminar diagnostics of infection SM I WG IV

13.30 SM V WG IV

14.00

SM2: Seminar diagnostics of immune

deficiencies and immunopathology SM IIILT26: Mechanisms of allergy

V WG IVSSA VI

SSA VI

14.30 LT V WG IV

15.00 SM3: Seminar health advocate SM IV LT27: Pathology of allergy V WG IV

15.30 LT V WG IV

16.00 Patient demonstration 4 V WG IV

16.30 Preparing for work group 3 WG IV

17.00 SSA V SSA V WG IV

17.30 WG IV

LINE DAY

LINE DAY

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136

Week 5 Time Monday 29 Sept Type Theme Tuesday 30 Sept Type Theme Wednesday 1 Oct Type Theme Thursday 2 Oct Type Theme Friday 3 Oct Type Theme

08.30LT32: HLA and auto-immunity

LT VILT35: Pharmacology: immune-suppression 1

LT VIWORK GROUP 4 THEME V en VI

PR II.B

09.00 VI VI PR II.B

09.30LT33: Infections and auto-immunity

LT VILT36: Pharmacology: immune-supression 2

LT VI WG V

10.00 VI VI WG V

10.30 LT34: Interactive cases LT VI LT37: Academic assignment LT VI PR II.B

11.00 VI VI PR II.B

11.30 Formative test (voting boxes) RC VI Patient demonstration 5 PD VI WG V

12.00 VI WG V

12.30

13.00 PR II.B

13.30 PR II.B

14.00 SSA VI SSA VI Selfstudy pharmacology immunosuppression VI WG V

14.30 WG V

15.00 PR II.B

15.30 PR II.B

16.00 WG V

16.30 WG V

17.00

17.30

Week 6 Time Monday 6 Oct Type Theme Tuesday 7 Oct Type Theme Wednesday 8 Oct Type Theme Thursday 9 Oct Type Theme Friday 10 Oct Type Theme

08.30 LT38: Introduction transplantation WC Question hour Immunology RC all

09.00 LT VII

09.30 LT39: Transplant immunology LT VII Question hour Pathology RC all Selfstudy Selfstudy

10.00 VI

10.30

LT40: Histopathology of transplantation and

rejection LT VI Question hour Infectious Diseases RC all

11.00 VI

11.30 LT41: Islet cell transplantation LT VI Formative test (Voting boxes)

12.00 VI

12.30

13.00

13.30 LT42: Transplantation and infection risk LT VI13.00-16.00 FINAL EXAM

14.00 VI Selfstudy USC sportcentum

14.30 Patient demonstration 6 PD VI

15.00 VI

15.30

(15.30-16.30) replacement missed practical

bacteriology

16.00

16.30

(16.30-17.30) replacement missed practical

parasitology

17.00

17.30

03-okt

LINE DAY

LINE DAY

Mechanisms of Disease 1

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Transcript of Mechanisms of Disease 1