A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary...

Draft xray manuscript Dec 15 2009

A simple, valid numerical score for grading chest X-ray

severity in adult smear-positive pulmonary tuberculosis

Anna RalphMuhammad ArdianAndri Wiguna

Graeme MaguireGovert WaramoriNiels Becker

Glen DrogumullerMike Wilks

Emiliana TjitraSandjaja

Enny KenagalemGysje J. PontororingNicholas M. Anstey

Paul M. Kelly

Word counts

Abstract: 250

Manuscript: 2665

Tables: 4; Figures: 5; Box: 1

References: 39

1


ABSTRACT

BACKGROUND

A standard method for grading radiological severity would be a

valuable tool in clinical trials involving adults with

tuberculosis. We aimed to generate and test a numerical score for

grading chest X-ray (CXR) severity in adults with smear-positive

pulmonary TB.

DESIGN

At a tuberculosis clinic in Papua, Indonesia, serial CXRs were

performed at diagnosis, 2 and 6 months in 115 adults with smear-

positive pulmonary TB. Radiographic findings predictive of 2-month

sputum microscopy status were used to generate a score. Validity

of the score was then assessed in a new dataset of 139 comparable

adults with TB, recruited 4 years later at the same site.

Relationships between the CXR score and other measures of TB

severity were examined.

RESULTS

The estimated proportion of lung affected and presence of

cavitation, but not cavity size or other radiological findings

(e.g. nodules, effusion), were combined to form a score given by

percentage of lung affected plus 40 if cavitation was present. As

well as predicting 2-month outcome, scores were significantly

associated with sputum smear grade at diagnosis (p<0.00005), body

mass index, lung function, haemoglobin, exercise tolerance, and

quality of life (p<0.02 for each). In the validation dataset,

baseline CXR score predicted 2-month smear status significantly

more accurately than did proportion of lung affected alone. In

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both datasets, CXR scores significantly decreased over time

(p<0.0005).

CONCLUSION

This simple method for grading CXR severity in adults with smear-

positive pulmonary TB correlates with baseline clinical and

microbiological severity and response to therapy.

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INTRODUCTION

Sputum smear microscopy, and culture where available, are the

standard modalities for diagnosing and monitoring treatment

response in pulmonary tuberculosis (TB). Chest radiography (CXR)

can provide useful corroborative and additional information

regarding disease extent and progress, but there is no agreed-

upon, validated system for grading the severity of CXR

abnormalities in bacteriologically-proven pulmonary TB. Several

methods were devised for this purpose at the time of early TB

treatment trials, such as those described by the Madras TB

Chemotherapy Centre in 1960,[1] Simon in 1966,[2] and the National

TB and Respiratory Disease Association of the USA in 1969[3] (Box

1). Among recent randomised, controlled trials (RCT) and

observational studies in adults with TB, there is lack of

consistency in grading CXR: previous grading systems,

modifications thereof, or a diversity of other investigator-

generated systems, are used (Table 1).

Problems in CXR reporting arise from the heterogeneous CXR

manifestations of pulmonary TB (e.g. in primary versus post-

primary disease, adults versus children, immunocompetent versus

immunocompromised)[4-6] and to inaccuracies inherent in CXR

performance and interpretation[2] (Box 2), including limited

inter-observer agreement on CXR findings.[7, 8] Despite these

shortcomings, the utility of CXR is well-established in TB

diagnosis and clinical monitoring.

CXR scores have also been developed for the purpose of population

screening,[9-12] but these tools seek to identify the presence of

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TB, rather than measure severity or response to treatment in

established disease. Associations between radiological extent and

other measures such as forced expiratory volume in one second

(FEV1), age or multidrug-resistant (MDR)-TB have previously been

identified,[13, 14] but efforts to generate a standard, simple,

numerical score, validated against TB outcome, in repeated

datasets, is lacking. We therefore aimed to devise a CXR score for

use in adults with smear-positive pulmonary TB, which is simple to

calculate and correlates with bacteriological and clinical

severity markers, for the purpose of grading severity and

monitoring treatment response in the context of TB clinical

trials. We then determined the score’s utility in a separate,

comparable dataset.

METHODS

Study setting

The study was conducted at a community-based TB clinic in Timika,

Papua Province, Indonesia. Timika has population of ~200,000 and

an estimated TB incidence of 311/100 000.[15]

Participants

Adults (>15 years) diagnosed with sputum smear positive pulmonary

TB who gave written informed consent were eligible for enrolment in

the study. Study participants were recruited during 2 time

periods: 2003-4 (training dataset) and 2008-9 (validation

dataset). Other results relating to the first dataset have been

published elsewhere.[16, 17]

Chest radiography

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Standard full-size posteroanterior CXR were performed at the time

of TB diagnosis and 2 and 6 months thereafter, with reports

provided by a clinician at the field site (first dataset: PK,

second dataset: AR) and additionally for the first dataset, by one

of two radiologists (MW or GD). During the first data collection

period, presence or absence of small (1-2 mm) or large (>2 mm)

nodules, patchy or confluent consolidation, cavitation, bronchial

lesions or fibrosis were reported for each of 3 zones (upper, mid

or lower zones) in each lung. The presence of effusion or

lymphadenopathy was reported, the total percentage of each lung

affected by any pathology was estimated, total cavity size in mm

recorded, and effusion volume (% of lung field) was estimated. To

grade percentage of affected lung, visual estimation of the extent

of opacification, cavitation or other pathology as a percentage of

visible lung was made; dense opacification of a zone was graded as

100% of that zone, while patchy opacification within a zone

attracting scores <100% depending on opacification extent. Other

remarks including presence of miliary disease were recorded.

During the second data collection period, a simplified CXR report

method was used (% lung affected, cavitation [0, <4cm, ≥4cm],

effusion [0, <25%, ≥25% of hemithorax], presence of consolidation,

fibrosis, nodules, miliary disease). Reporters were blinded to HIV

status, bacteriological and clinical parameters and treatment

outcome.

Sputum microscopy and clinical evaluations

Baseline sputum microscopy was performed at the onsite laboratory

and repeated at the reference laboratory on samples collected at

0, 2 and 6 months, and density of acid fast bacilli (AFB) was

graded as 1, 2 or 3+ according to standard protocols.[16, 17]6


Baseline and follow-up evaluations included: body mass index

(BMI), FEV1 (spirometry performed using ML3535C, MicroLoop,

MicroMedical), haemoglobin (Hb) measured using point-of-care

HemaCue® or iSTAT® testing, 6-minute walk test (distance walked in

6 minutes on a straight walking track) measured according to

American Thoracic Society guidelines and St George’s Respiratory

Questionnaire (SGRQ) modified to reflect local conditions and

translated into Indonesian language. The SGRQ evaluates quality of

life and disability relating to respiratory impairment. Scores (0

= no impairment) are generated in the domains of respiratory

symptoms, activity impairment, social and psychological impacts of

illness, and overall score.[18] Standard definitions were used for

nutritional category (normal, mild malnutrition, moderate

malnutrition or severe malnutrition) according to BMI,[19]

impairment in lung function (% predicted FEV1 (ref Handojo paper

re normal values and can delete ref 20),[20] and TB treatment

outcome at 6 months (cured, completed, transferred, defaulted,

failed or died).[21]

Outcome measure

The outcome measure used in this study is 2-month sputum AFB

microscopy status. This is recognised as a valid surrogate

endpoint, with 2-month smear positivity predicting unfavourable

outcomes including treatment failure and death,[22-24] and

determining the need for continued intensive-phase therapy versus

switching to continuation-phase therapy.[21]

Data analysis

Statistical calculations were performed using Intercooled Stata

10.1; graphs were created in GraphPad Prism 5. Statistical tests

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were two-sided, with a p-value of <0.05 indicating statistical

significance. Intergroup differences in means or medians were

compared using 2-sample t-tests, Wilcoxon rank sum tests, analysis

of variance or Kruskal-Wallis tests as appropriate. Concordance

for continuous measures was tested using Lin's concordance

correlation coefficient, interpreted in the standard way

(correlation value ≤0.50: very low correlation; 0.51 to 0.79: low;

0.80 to 0.89: moderate; ≥0.90: high) and inter-rater agreement for

binary measures was tested using the kappa statistic, interpreted

according to Altman (kappa ≤0.2: poor, 0.21-0.40: fair; 0.41-0.60:

moderate; 0.61-0.80: good; 0.81-1.00: very good).

Regression models were used to determine relationships between

radiographic findings (radiologist-determined) and outcome (2-

month sputum smear status). Goodness of fit of final models were

assessed using the Hosmer-Lemeshow test. Regression coefficients

provided the weighting for a numerical score. The calculated

numerical score was then assessed for its ability to predict

outcome in the validation dataset, using receiver-operator

characteristics (area under the curve, AUC). Test accuracy was

interpreted according to standard cutoffs: AUC 0.9-1.0 =

excellent, 0.8-0.9 = good, 0.7-0.8 = fair, 0.6-0.7 = poor, 0.5-0.6

= fail.

Ethics

Approval was granted by the ethics committees of the National

Institute of Health Research and Development, Indonesian Ministry

of Health, Jakarta and the Menzies School of Health Research,

Darwin, Australia. Written informed consent was obtained from

participants in Indonesian or an appropriate Papuan language.

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RESULTS

Characteristics of study participants in the two data collection

phases are shown in Table 2. All participants had smear-positive

pulmonary TB (≥2 AFB smear positive sputum samples); the result of

the additional sample provided for microscopy and culture on the

day of treatment commencement is reported here (smear negative in

5.7% and 7.2% of participants in the 2 datasets respectively

despite their prior samples being positive). CXR reports were

available at baseline, 2 and 6 months for 112, 76 and 76 study

participants in the first dataset, and 136, 93 and 76 study

participants in the second dataset (incomplete in the second

dataset since 30 of 139 have not yet completed 6 months) (Table

3). Reasons for missing CXR included patient failure to attend

(died, defaulted or transferred prior to appointment), inability

to obtain CXR (e.g. power failure), CXR date more than 3 weeks

before or after the due follow-up date, or CXR unavailable for

reporting.

Agreement on radiological abnormalities

Agreement between reporters on radiological abnormalities in the

training dataset ranged from poor to moderate only. Concordance

between the clinician and either of the two radiologists was

moderate for percentage of lung affected and cavitation size

(Pearson’s R 0.87 and 0.81 respectively). Inter-rater agreement

was somewhat better for presence of consolidation ( 0.54, moderate

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agreement) than for other pathology types, where agreement was

fair or poor.

Development of score using training dataset

2-month sputum smear status in the initial dataset (n=115) was

significantly predicted in univariate logistic regression models

by the presence of baseline cavitation (odds ratio 3.26, 95% CI

1.11-9.56) and, to a small extent, by the total percentage of lung

affected (odds ratio 1.03, 95% CI 1.01-1.05), but not by

cavitation size, presence or number of nodules, fibrosis,

effusion, bronchial lesions or lymph nodes. Including both

cavitation and percentage of lung affected in the model did not

result in significant improvement in the ability to predict 2-

month sputum smear status.

The relationships between those radiological findings which were

independently predictive of 2-month outcome (cavitation and

percentage of lung affected) and baseline clinical and

bacteriological measures were then examined. Cavitary disease on

CXR at TB diagnosis was significantly associated with higher

baseline AFB density in sputum (i.e. smear microscopy grade)

(p=0.007, test for trend), and people with cavitary disease had

worse lung function, with a mean percent predicted FEV1 of 59.0

(95% CI 54.4-63.6) in cavitary disease versus 68.7 (95% CI 60.6-

76.7) in non-cavitary disease. People with cavitary disease had

slightly lower BMI (18.5, 95% CI 18.0-19.1) compared to those with

non-cavitary disease (19.2 kg/m2, 95% CI 18.5-20.0), but this

difference was not statistically significantly. No significant

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associations were identified between cavitary disease and exercise

tolerance (6-minute walk distance), quality of life (SGRQ total or

individual domain scores) or haemoglobin.

Amount (%) of lung affected significantly predicted all clinical

and laboratory variables. Specifically, greater proportions of

affected lung were significantly associated with decreasing BMI

category (p=0.002, Kruskal-Wallis test), lung function category

(p=0.0005, Kruskal-Wallis test), 6-minute walk distance (0=0.001,

linear regression) and haemoglobin in males (p=0.003, linear

regression), although not in females (p=0.4). Greater proportion

of lung affected on the baseline CXR was also significantly

associated with SGRQ total scores (p<0.0005, linear regression)

and with sputum smear grade at diagnosis (p=0.0005, Kruskal-Wallis

test).

In the logistic regression model including cavitation and

percentage of lung affected as independent variables, regression

coefficients were 0.03167 for proportion of lung affected and

1.26151 for presence / absence of cavitation, indicating a

relative weighting of 40.27 for cavitation (1.26151 ÷ 0.03167),

thereby generating an equation for the weighted score as follows:

CXR score = proportion of total lung affected (%) + 40 if

cavitation present

CXR score results

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CXR score characteristics are shown in Table 3 and Figures 1 to 4.

Scores did not significantly differ according to sex, ethnicity or

smoking status (p>0.05, 2-sample t-tests), and were not

significantly associated with age in univariate or multivariate

analyses. Mean baseline CXR score in people with unfavourable

(smear positive sputum) 2-month outcomes was significantly higher

(88.2; 95% CI 76.5-99.9) than those with a favourable outcome

(56.8; 95% CI 49.7-64.0), but the range of scores in each smear

grade was wide (Figure 1). Scores were also significantly

associated with baseline microscopy grade (Figure 1). CXR scores

were inversely related to BMI, FEV1, Hb and 6-minute walk

distance, were directly related to SGRQ total score, and

significantly decreased over time (Figures 2-4).

Performance of score using validation dataset

The weighted score calculated for the new dataset showed similar

characteristics (Table 3), with a median baseline score of 69, no

significant relationship with study participants’ age, sex,

ethnicity or smoking status, a significant decrease over time

(p<0.0005), and significant positive association with baseline

smear grade (p=0.009, Kruskal-Wallis test). The same relationships

as were found in the initial dataset between CXR score and each of

the clinical / laboratory measures (BMI, Hb, FEV1, SGRQ total

score and 6-minute walk distance) were confirmed; these

relationships remained significant when controlling for age,

ethnicity, sex, gender, smoking status, HIV status and presence of

MDR-TB (p<0.05 in univariate and multivariate analyses).

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Using area under the ROC curve as a measure of test accuracy, the

ability of the weighted score to correctly classify 2-month smear

status as positive or negative was assessed in the validation

dataset, and compared with the diagnostic utility of percentage

lung affected alone. Although the areas under the curve were

relatively modest (weighted score: 0.75; percent lung affected:

0.69), that for the weighted score was significantly greater

(p=0.01, test; Figure 3). The optimal cut point for score (value

furthest from the diagonal) was 71, at which value the sensitivity

for predicting a positive sputum smear status at 2 months was 80%

(95% CI 61.4 - 92.3), and specificity 67.7% (95% CI 57.3 - 77.1).

Comparing the CXR score’s ability to predict 2-month smear

positivity with presence/absence of cavitation, the odds ratio was

higher for CXR score of ≥71 (OR 8.0, 95% CI 2.6-23.8) than for

presence of baseline cavitation (OR 5.6, 95% CI 1.8 - 16.8), but

confidence intervals were wide and overlapping.

DISCUSSION

The need for a universal and standard system for reporting CXR in

pulmonary TB is acknowledged.[25] In order to grade CXR severity

and assess radiological treatment response, we have derived a

simple equation from radiographic parameters from adults with

smear positive pulmonary TB that predicts smear positivity at 2

months and provides a single numerical score for each CXR. The

score shows good correlation with baseline bacteriological and

clinical severity markers, and is sensitive to changes over time.

The score performs better than its individual components: it was

significantly better at predicting outcome than was percentage of

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lung affected alone (p=0.01), and was significantly associated

with a broader range of baseline severity measures (body mass

index, haemoglobin, exercise tolerance, and quality of life;

p<0.02 in each instance) than presence of cavitation alone.

Advantages of this method are that CXR assessment does not require

aids, grids or rulers, and it is derived by fitting a statistical

model to data rather than by assigning points based on assumed

relative importance of radiographic pathologies. It has been

validated in a second dataset, and offers a single, standardized

solution where there are currently multiple methods in use (Table

1).

The proportion of lung affected and cavitation feature as the most

important measures in many methods for grading the CXR in TB (Box

1). Cavitation is well-recognised to correlate with bacillary

load.[26, 27] We confirmed the association between cavitation and

bacteriological measures (baseline and 2-month sputum smear

status), and additionally showed cavitary disease to be predictive

of worse lung function. Proportion of lung affected was associated

with both bacteriological and clinical measures.

The low rates of agreement between reporters on CXR findings

identified in this study are not unusual, with only fair or poor

agreement between radiologists and clinicians also being reported

elsewhere.[7, 8] This emphasizes the importance of using simple

rather than complex scores and ensuring individuals allocating CXR

scores participate in continuing education to maximize agreement.

This score is applicable to adult TB patients with smear positive

pulmonary disease, in a setting with relatively low rates of HIV-

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TB co-infection and MDR-TB. Although the score remained valid in

the newer dataset in which HIV-TB co-infection rates were higher,

it requires further evaluation in populations with high HIV

prevalence, in whom CXR findings characteristic of HIV-TB co-

infection (subtle or absent pathology, non-cavitary disease, lower

lobe infiltrates, hilar lymphadenopathy and pleural effusion)[5,

28] may mean that a differently-weighted score is needed.

The presence of MDR-TB would not be expected to alter radiographic

patterns, other than being associated potentially with higher

scores and smaller incremental improvements over time. Potential

limitations of the study include the use of 2 month smear status

as an outcome measure (rather than a longer-term measure such as

6-month outcome or recurrence) and the inherent problem of limited

inter-rater agreement CXR assessment.

CONCLUSION

In summary, we have derived a simple method for grading CXR

severity in adults with smear-positive pulmonary TB that predicts

baseline clinical and microbiological severity and response to

therapy. This method can be used where a numerical score is

required for the purpose of comparing radiographic severity

between adults with smear positive pulmonary TB, and to monitor an

individual’s improvement over time, such as in clinical trials of

drug efficacy in TB. Finer discriminatory accuracy might be

achieved by collecting more detailed CXR findings (such as cavity

size), although our data did not indicate this. Further validation

of this score is required in other populations, in particular

those with higher HIV-TB co-infection rates.

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COMPETING INTERESTS

We have no competing interests to report.

ACKNOWLEDGEMENTS

We greatly thank the following people for their support and

assistance in this research: National Institute of Health Research

and Development, Jakarta, especially Dr Dina Bisara Lolong and Ibu

Meryani Girsang; Timika District Health Authority, especially Dr M

Okoseray, Pak Penias and Pak E Meokbun; Public Health & Malaria

Control (PHMC) and International SOS, including Dr P. Penttinen,

Mr M. Bangs and Dr M. Stone; PHMC laboratory staff especially Pak

Istanto; Pak J Lempoy and other staff at the Timika TB clinic;

Mimika Community Hospital (RSMM), particularly Dr P. Sugiarto; all

clinical and laboratory staff at the NIHRD-MSHR Timika research

program, including Natalia (Surname), Sri Hasmunik, Mbak Yayuk and

G. Bellatrix; Mr R. Lumb and Dr I. Bastian at IMVS.

This study was funded by the Australian Respiratory Council, the

Royal Australasian College of Physicians (Covance award) and a

Wellcome Trust–National Health and Medical Research Council

(NH&MRC) International Collaborative Research Grant. APR, PMK and

NMA are supported by the Australian National Health & Medical

Research Council. The Timika TB research programme is a

collaboration between the National Institute of Health Research

and Development, Jakarta, Indonesia, and the Menzies School of

Health Research, Darwin, Australia.

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TABLES AND FIGURES

Box 1: Early methods for grading the extent of pulmonary tuberculosis

Prophit Tuberculosis Survey 1948[29]

Radiological lesions were classified according to site and number of lung zones out of 6 (right and left upper, mid and lower zones), or 8 (subdividing upper zones into apical and infraclavicular regions). This was a population X-ray screening survey (not confined to confirmed pulmonary TB cases) but is included here, as subsequent scores used similar methods for defining lung zones.

Tuberculosis Chemotherapy Centre, Madras, 1960[1]

Cavitation assessed as extensive, moderate, slight, nil. Extent of lung involvement assessed as (1) Trivial: minimal lesions regarded as inactive; (2)Slight: minimal lesions regarded as active; (3) Limited: > above but < lung volume equivalent to right upper lobe as seen on PA X-ray; (4) Moderate: > above but ≤ lung volume equivalent to one lung; (5) Extensive: > one whole lung; (6) Gross: very extensive bilateral disease.

Number of lung zones occupied by any (including minimal) pathology: as per Prophit survey method.

Follow-up CXR assessed as showing improvement (slight, moderate, considerable or exceptional) or deterioration (slight, moderate or considerable).

Simon, 1966[2]

Cavities assessed according to number and size, wall thickness, cavity location. Extent assessed as per Tuberculosis Chemotherapy Centre method.

National Tuberculosis and Respiratory Disease Association, 1969[3]

(1) Minimal: slight to moderate density, or no visible radiological pathology,without cavitation. Total extent not to exceed the volume equivalent to the area on one side above the second costochondral junction and the spine of the fourth or body of the fifth thoracic vertebra.(2) Moderately advanced: disseminated lesions of slight to moderate density that may extend throughout the total volume of one lung or the equivalent in both lungs; dense and confluent lesions that are limited in extent to one-

17


third the volume of one lung; total diameter of cavitation not >4cm.(3) Far advanced: Greater than the above.

Snider et al, 1971 [30]

Numerical score (maximum 18) calculated by dividing each lung into thirds, anddetermining for each third the extent of infiltrate (none, ≤ 1/3 of the zone, >1/3 but <2/3, ≥ 2/3 of zone).

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Table 1: CXR grading methods used in recent TB research

Author Study CXR reporting methodRandomised controlled trialsDiacon et al,

2009[31]

TMC207 safety and efficacy

in MDR-TB

CXR categorized according to

cavitation size (≥2cm

unilaterally, ≥2cm

bilaterally, or <2cm), with

randomisation stratified

according to this.

Dorman et al,

2009[32] and

Burman et al,

2006[33]

Substitution of

moxifloxacin for

ethambutol in drug-

susceptible TB

CXR categorized as with or

without cavitation.

Katiyar et al,

2008[34]

Efficacy of high-dose

isoniazid adjuvant to

second-line therapy in

MDR-TB.

Numerical score calculated by

counting the proportion of 3

x 3 cm squares in a grid

superimposed on a CXR

containing a ‘suspicious

active’ lesion (infiltrate or

consolidation cavitary lesion

or nodule with poorly defined

margins).Benator et al

for the

Tuberculosis

Trials

Consortium,

2002[27]

Efficacy of rifapentine

and isoniazid weekly

versus rifampicin and

isoniazid twice weekly in

HIV-negative drug-

susceptible TB

CXR categorized as with or

without cavitation, and as

unilateral or bilateral

disease.

Observational studiesHeo et al,

2009[14]

Study of predictors of

radiographic improvement

in adults with smear

positive or negative

pulmonary TB

CXR lesions: mass-like,

nodular, fibrotic, cavitary,

linear, or miliary;

categorized as single or

multiple lesions. Extent

assessed by indicating

19


percent involvement in each

of four lung zones (right

upper, right lower, left

upper, and left lower), then

averaging these percentages.Mankattitham et

al, 2009[35]

Descriptive study of

characteristics of HIV-

infected TB patients

More than or less than a

third of right or left lung

involved, or abnormalities in

both lungs.Lawson et al,

2008[36]

Descriptive study of

characteristics of adults

with TB +/- HIV

Number of lung zones with

abnormalities (0 to 6);

separate score for cavities

(0=no cavities, 1=<2cm, 2 if

2-4cm, 3 if >4cm).Idh et al,

2008[37]

Investigation of exhaled

nitric oxide levels in

people with TB +/- HIV

Semi quantitative scale from

0 (normal) to 3 (far advanced

tuberculosis) based on

National Tuberculosis

Association of the USA systemThorson et al,

2007[38]

Study of CXR findings in

relation to gender and

symptoms

Miliary pattern, pleuritis,

adenopathy, cavitation,

calcification, fibrosis or a

combination of these.Liam et al,

1998[39]

Investigation of

hypercalcaemia in TB in

relation to radiographic

disease extent

Graded 1 to 6 based on the

method described by Simon.[2]

Box 2: Sources of CXR inaccuracy[2, 12]

20

Observer erroro Failing to see lesiono Misinterpretation of lesion

Radiograph failing to show the lesiono Lesion invisible in standard postero-anterior film:

2-dimensional chest x-rays conceal an estimated20%–30% of the lung field because of overlappingstructures

o Lesion invisible due to poor film quality(incorrect patient positioning, incorrect densityor contrast of the film)


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Table 2: Study participant characteristics

Training dataset Validation dataset

Demographic detailsNumber 115 139Age in years: median

(range)

30 (17 – 69) 27 (15 – 65)

Female gender: no. (%) 33 (28.7) 48 (34.5)Papuan ethnicity: no. (%) 57 (49.6) 66 (47.5)Smokers: n. (%) 38 (33.0) 41 (29.5)HIV positive: no. /

no.tested (%)

5/112 (4.5) 16/121 (13.2)

MDR-TB: no. (%) 2 (1.7) 2 (1.4)Baseline clinical findingsBMI: median (range) kg/m2 18.6 (14.2 – 25.2) 19.0 (12.9 – 32.5)

Haemoglobin: median

(range) g/dL

11.2 (6.8 - 18.0) 12.2 (7.1 – 16.0)

FEV1: median (range) L 1.76 (0.49 – 4.12) 1.70 (0.59 – 3.56)SGRQ total score: median

(range)

45.3 (2.5 – 83.5) 37.8 (5.2 – 91.9)

6 minute walk distance:

median (range) m

405 (185 - 625) 410 (20 – 612)

Sputum AFB smear grade at diagnosis n (%)

0* 6 (5.7) 10 (7.2)Scanty or 1+ 25 (23.6) 65 (45.7)2+ 28 (26.4) 35 (25.2)3+ 47 (44.3) 29 (20.9)2-month smear status n (%)

Positive 25 (21.8) 31 (22.3)Negative 81 (70.4) 95 (68.4)No result available 9 (7.8) 13 (9.3)6-month outcome n (%)

Cured / Completed 88 (76.5) 92 (66.2)Died 3 (2.6) 2 (1.4)Failed 2 (1.7) 1 (0.7)

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Default 13 (11.3) 8 (5.8)Transferred 9 (7.8) 6 (4.3)6 months not yet

completed

0 30 (21.6)

* All study participants had at least 2 prior smear positive sputum samples; some are reported as negative since this result pertains to the additional spot specimen provided at enrolment into the study (see Methods).

Table 3: Chest radiograph results

Training dataset Validation dataset

Number of CXR available for report

Baseline 112 1362 months 76 936 months 76 76*

Baseline radiological findings

Consolidation: no. (%) 106 (94.6) 104 (76.5)Cavitation: no. (%) 71 (63.4) 77 (56.6)Effusion: no. (%) 37 (33.0) 24 (17.3)Miliary: no. (%) 2 (1.7) 5 (3.7)Nodules: no. (%) 83 (72.2) 29 (21.3)Fibrosis: no. (%) 62 (55.3) 10 (7.4)Proportion of lung affected: median

% (range)

35 (0-100) 41.5 (0-100)

CXR weighted score characteristics

Baseline score: median (range) 65 (5-130) 69 (0-140)2 month score: median (range) 35 (0-130) 29 (0-140)6 month score: median (range) 10 (0 – 105) 10 (0-115)

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Median score decrease in 2 months: % 27.3 38.8Median score decrease in 6 months: % 73.1 80.2

Baseline score by smear grade at diagnosis median (range)

0 15 (0.5 – 70) 10 (0-133)Scanty or 1+ 50 (0 – 110) 66 (0-140)2+ 70 (6.5 – 135) 76 (11-140)3+ 80 (10-140) 85 (4-140)

*30 patients still under follow up

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Figure 1: Chest x-ray score at enrolment according to sputum AFB grade at diagnosis and 2 months

*p<0.00005 calculated using one-way analysis of variance for sputum grade at diagnosis; p<0.00005 calculated using 2-sample t-test for sputum status at 2 months. Bars represent mean score.

Figure 2: CXR score according to BMI, percent of predicted FEV1 and haemoglobin at diagnosis

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*All p values calculated from one-way analyses of variance. Bars represent mean score.

Figure 3: CXR score according to SGRQ total score and 6 minute walk distance at TB diagnosis

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*Both p values calculated using one-way analyses of variance. Bars represent mean score.

Figure 4: CXR score at diagnosis, 8 weeks (end of intensive treatment phase) and24 weeks (end of treatment)

Bars represent median CXR scores. Scores decreased significantly over time (p=0.0001 forboth datasets values calculated using Kruskal-Wallis tests of scores by week).

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Figure 5: Receiver-operator characteristics for weighted X-ray score (% lung affected + 40 if cavitation present) (solid red line) compared with percent of lung affected (dashed blue line) as predictors of 2-month smear status (positiveor negative). Optimal cut-point for score (circle) = 71.

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0.00

0.25

0.50

0.75

1.00

Sensitivity

0.00 0.25 0.50 0.75 1.001-Specificity

% Lung affected RO C area: 0.6867CXR Score RO C area: 0.7471

ReferenceOptim al cut-point

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A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary...

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