INT J TUBERC LUNG DIS 14(3):324–331© 2010 The Union

Association of chest radiographic abnormalities with tuberculosis disease in asymptomatic HIV-infected adults

T. Agizew,* M. A. Bachhuber,* S. Nyirenda,* V. Z. S. A. M. Makwaruzi,† Z. Tedla,* R. J. Tallaksen,‡ J. E. Parker,‡ J. J. Mboya,§ T. Samandari*¶

* BOTUSA, Gaborone, † Nyangabgwe Referral Hospital, Francistown, Botswana; ‡ School of Medicine, West Virginia University, Morgantown, West Virginia, USA; § Disease Control Unit, Ministry of Health, Gaborone, Botswana; ¶ Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Correspondence to: Taraz Samandari, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, 1600 Clifton Rd N E, Mailstop E-10, Atlanta, GA 30333, USA. Tel: (+1) 404 639 6014. Fax: (+1) 404 639 1566. e-mail: tsamandari@cdc.govArticle submitted 24 April 2009. Final version accepted 6 October 2009.

S E T T I N G : Francistown and Gaborone, Botswana.

O B J E C T I V E : Chest radiography is used to screen for tu-

berculosis (TB) in asymptomatic persons living with the

h uman immunodefi ciency virus (PLWH) seeking isonia-

zid preventive therapy (IPT). We describe radiographic

features in PLWH in a TB-endemic setting and identify

features associated with TB disease.

D E S I G N : Asymptomatic PLWH seeking IPT under pro-

gram conditions for a clinical trial between 2004 and

2006 received chest radiographs (CXRs) that were read

using the standardized Chest Radiograph Reading and

Recording System (CRRS). Clinical characteristics, in-

cluding TB disease, were compared with the radio-

graphic fi ndings.

R E S U LT S : From 2732 screening CXRs, 183 had one or

more abnormalities and were scored using CRRS, with

42% having infi ltrates (36% upper lobes), 35% paren-

chymal fi brosis and 32% adenopathy. TB disease status

was determined in 129 (70%) PLWH, of whom 22 (17%)

had TB disease. TB disease was associated with upper

lobe infi ltrates (relative risk [RR] 3.0, 95%CI 1.5–6.2)

and mediastinal adenopathy (RR 3.9, 95%CI 1.8–8.4).

The sensitivity and specifi city of either upper lobe infi l-

trates or mediastinal lymphadenopathy for TB disease

were respectively 64% and 82%.

C O N C L U S I O N : A combination of CXR features was

useful for predicting TB disease in asymptomatic PLWH.

CRRS should be used more frequently in similar studies.

K E Y W O R D S : tuberculosis; HIV; screening; chest r adiograph

THE CHEST RADIOGRAPH (CXR) has long been utilized in the screening and diagnosis of tuberculosis (TB), but the current human immunodefi ciency virus (HIV) epidemic complicates its use. The World Health Organization recommends expansion of programs for TB prevention in persons living with HIV infec-tion (PLWH),1 and an essential part of such programs is screening for TB disease to avoid providing single-drug therapy to persons with TB disease. It remains controversial whether CXRs should be required to exclude TB disease in asymptomatic individuals, as radiography may be costly for resource-constrained countries and some studies show the yield to be low.2–5 If CXRs are routinely used in screening asymptom-atic PLWH, as advocated by some,3,6 correlating ra-diographic patterns with active TB disease is a valu-able undertaking.

Radiographic features of TB in PLWH are fre-quently ‘atypical’ (i.e., mid or lower zone infi ltrates, adenopathy, effusions and a paucity of cavitary le-sions), as opposed to ‘typical’ (i.e., upper lobe infi l-

trates and cavitation),7–10 a phenomenon that varies with the degree of immunosuppression.11–15 PLWH are also vulnerable to a number of non-tuberculous acute and chronic pulmonary diseases that may man-ifest as atypical radiographic features.16

TB screening studies in sub-Saharan African set-tings report a TB disease rate of 5–15% among PLWH; however, these studies were reported from mixed populations of symptomatic and asymptomatic PLWH.2,3,17,18 Three previous studies in the United States assessed screening CXRs in asymptomatic PLWH,19–21 but only one documented the spectrum of abnormalities seen.20 To the authors’ knowledge, no study has described CXR fi ndings in an asymp-tomatic HIV-infected African population and corre-lated fi ndings with TB diagnosis. To address this need, screening CXRs and other clinical information were obtained in a large cohort of asymptomatic PLWH during screening for a programmatically based clinical trial of isoniazid preventive therapy (IPT) in Botswana, where TB and HIV are endemic. The CXRs were ex-

S U M M A R Y

CXR in asymptomatic TB-HIV patients 325

amined in detail using the standardized Chest Radio-graph Reading and Recording System (CRRS),22 and then analyzed by TB status and history of TB.

STUDY POPULATION AND METHODS

PLWH seeking IPT through the National IPT Pro-gram who were interested in the IPT Trial were re-ferred to research nurses located at eight local clinics in the two major cities of Gaborone and Francistown. Nearly all candidates referred for evaluation were re-cently diagnosed as HIV-infected and were receiving their initial assessment for HIV care services. As per the screening procedures of the National IPT Pro-gram, the fi rst stage of screening excluded candidates if they had no documentation of HIV infection, ill-ness (e.g., fever, cough, malaise, weight loss or, on physical examination, lymphadenopathy, jaundice or pulmonary disease), TB disease in the past 3 years, or clinical AIDS.23 Details of the screening results are published elsewhere.24

CXRs were obtained under public health program conditions for all asymptomatic candidates not ex-cluded at the fi rst stage of screening. CXRs were in-terpreted by study physicians and later independently reviewed by one of two expert readers, a pulmonary specialist (JEP) or a radiologist (RJT). The expert readers, whose interpretations were considered fi nal for this analysis, were blinded to clinical variables, including TB status and history of TB. A CXR was determined to be normal or abnormal if either expert reader agreed with the study physicians’ interpreta-tion. If one expert disagreed with the study physician, the other expert read the fi lm to break the tie. CXRs were categorized as potentially compatible with TB if they had any of the following fi ndings: cavities, fi bro-sis, infi ltrates, nodules, pleural effusion or thicken-ing, miliary disease, hilar or mediastinal adenopathy or pericardial effusion. CXRs with features poten-tially compatible with TB were then scored using the CRRS.

PLWH with abnormal CXRs were further evalu-ated for TB through a follow-up evaluation, physical examination, a repeat CXR as necessary, and, where possible, sputum smears and cultures. Individuals were categorized as not having TB disease (status ‘Not TB’) if a repeat CXR became normal at the time of the follow-up interview without anti-tuberculosis treatment, if the person had no symptoms of TB for ⩾6 months and never received IPT, had no symptoms of TB for ⩾6 months after stopping IPT, or had an al-ternative diagnosis to explain CXR abnormalities. A TB case (status ‘TB’) was a candidate with an abnor-mal CXR and a positive TB culture, positive smear for acid-fast bacilli, a clinical response to anti-tuberculosis treatment, or initiation of anti-tuberculosis treatment with no alternative diagnosis.

The standard methods used to process smears and

cultures of sputum and blood specimens are cited else-where.25 Tuberculin skin tests (TST) were performed using 5 tuberculin units (TU) of RT23 tuberculin (Statens Serum Institut, Copenhagen, Denmark), and were read by study nurses within 48–72 h.

Data were collected using standardized case report forms and double-entered into a Clindex database (Fortress Medical Systems, Minneapolis, MN, USA). Two-tailed Fisher’s exact test for P and relative risks comparing proportions were performed using SAS (SAS Institute, version 9.1, Cary, NC, USA). P values < 0.05 were considered signifi cant.

The protocol was approved by the Health Research Development Committee in Botswana and the Insti-tutional Review Board at the Centers for Disease Con-trol and Prevention, Atlanta, GA, USA, and written informed consent was obtained from all participants. The clinical trial registration number is NCT00164281 and may be viewed at http://www.clinicaltrials.gov.

RESULTS

Between November 2004 and June 2006, 4331 PLWH were referred for participation in the IPT trial; 37% (n = 1286) were excluded or declined participation in the clinical trial (n = 313) during the fi rst stage of screening (Figure). Most candidates who were ex-cluded had symptomatic illness (57%) and were re-ferred to local clinicians for further evaluation. CXRs were obtained on 2732 asymptomatic PLWH; of these, 11% (302/2732) had abnormal CXRs poten-tially compatible with TB. The overall kappa statistic for agreement between study physicians and expert readers in assignment of normal/abnormal was 0.92, given the very large number of normal CXRs (data not shown). However, 29% (86/295, study physician interpretation was unavailable for seven) of the abnor-mal CXRs were initially read as normal by study phy-sicians and were later determined to be abnormal by both expert readers. Details of the outcomes of these screened candidates have been published elsewhere.25

In the early period of the study, CXRs that were abnormal were returned to PLWH to assist them in seeking medical care. Thus, 64% (194/302) of abnor-mal fi lms were available for scoring using the CRRS. Eleven fi lms (6%) were re-read as normal using the CRRS and were excluded, yielding 183 CRRS forms for analysis. CXR quality was recorded on the CRRS for 98% (180/183) of these radiographs: respectively 71%, 28% and 1% were of high, acceptable and poor but interpretable quality. Of those with an abnormal CXR, candidates whose CXR was scored using the CRRS were more likely to have a positive TST than those whose CXR was not scored using the CRRS (respectively 43% [79/183] vs. 30% [36/119], P = 0.029). No other signifi cant differences were found in baseline characteristics between these groups (data not shown).

326 The International Journal of Tuberculosis and Lung Disease

The demographics and clinical characteristics of these 183 asymptomatic PLWH with abnormal CXRs are given in Table 1: 60% (110/183) were female, with a median age of 34 years (range 18–67). CD4 lymphocyte counts were known in 97% (177/183): their median CD4 lymphocyte count was 222 cells/μl (range 5–2839). Local clinics were the most common source of referral (99/183, 54%). A history of TB was recorded in 24% (34/144) at a median of 7 years be-

fore screening. Follow-up evaluations for TB disease were conducted with 70% (129/183) of these candi-dates, and 17% (22/129) had TB disease, 10 of whom had laboratory evidence (i.e., smear- and/or culture-confi rmed, Figure). Those without TB were followed for a median of 9 months after screening.

Of the 183 PLWH with a CRRS form, 55% (n = 101) had more than one radiographic abnormality. Parenchymal abnormalities were found in 85% (n = 156), of whom 38% (59/156) had multiple parenchy-mal abnormalities (Table 2). Among the parenchy-mal abnormalities, the most common were infi ltrates (42%, n = 77), fi brosis (35%, n = 64) and nodules (27%, n = 49). Pleural abnormalities were found in 15% (n = 28); 36% (10/28) of these had multiple abnormalities in the pleural spaces (Table 3). Costo-phrenic angle obliteration (9%, n = 17) was the most common pleural abnormality, followed by apical pleu-ral thickening (apical cap) (6%, n = 11) and effusion or thickening (5%, n = 10). Abnormal central struc-ture fi ndings were documented in 38% (n = 70) of the PLWH, most commonly either hilar or mediastinal lymphadenopathy (32%, n = 58).

While 12% (22/183) of candidates had TB disease, potential explanations for CXR abnormalities among the rest were history of TB (17%, median 7 years pre-viously), history of smoking (6%), history of chest in-fection other than TB (4%), or history of mine work (1.6%); 59% had no other potential explanation by history. The radiographic fi ndings by known TB status (i.e., TB disease or not TB) are summarized in Table 4. Infi ltrates (relative risk [RR] 2.5, 95% confi dence in-terval [95%CI] 1.1–5.8), upper lobe infi ltrates (RR 3.0, 95%CI 1.5–6.2) and mediastinal adenopathy

Figure Derivation of a cohort of asymptomatic HIV-infected adults who received a score for abnormal CXRs and were as-sessed for tuberculosis, Botswana. * Candidates screened prior to receipt of IPT were found to be ineligible for the following reasons: illness, previous IPT, pregnancy, history of hepatitis, lacking documentation of HIV infection or history of TB in the last 3 years. † CXRs were considered abnormal and potentially compatible with TB if they had any of the following: cavities, fi -brosis, infi ltrates, nodules, pleural effusion or thickening, mili-ary pattern, hilar or mediastinal adenopathy or pericardial effu-sion. ‡ CXRs were scored using the standardized CRRS.22 § CXRs were read at the time of screening by study physicians and were later reviewed by two expert readers for the purpose of scoring with CRRS. ¶ While 10 persons had missing or negative sputum smears or cultures, they responded clinically to anti-tuberculosis treatment; two other individuals initiated anti-tuberculosis treat-ment based on clinician judgment but died before a response to therapy could be assessed. IPT = isoniazid preventive ther-apy; CXR = chest radiograph; TB = tuberculosis; HIV = human immunodefi ciency virus; CRRS = Chest Radiograph Reading and Recording System.

Table 1 Characteristics of asymptomatic HIV-infected adults with abnormal chest radiographs, Botswana (n = 183)

Characteristic n (%)*

Demographics (n = 183) Female 110 (60) Age, years, median [range] 34 [18–67]

Clinical Body mass index <18.5 (n = 133) 38 (29) On antiretroviral medications (n = 181) 8 (4) CD4 lymphocyte count, median, cells/μl (n = 177) 222 Presence of BCG scar (n = 124) 91 (73) TST ⩾5 mm induration (n = 159) 69 (43) TB disease (n = 129) 22 (17)

Referral source (n = 183) Local clinic 99 (54) Voluntary counseling and testing center 57 (31) Other 27 (15)

Exposures History of TB ⩾3 years ago (n =144) 34 (24) Median years since TB 7 History of mine work (n = 126) 10 (8) History of pneumonia or chest infection (n = 132) 12 (9) History of smoking or current smoker (n = 128) 17 (13)

* Not all characteristics were known for all persons living with HIV infection. HIV = human immunodefi ciency virus; BCG = bacille Calmette-Guérin; TST = tuberculin skin test; TB = tuberculosis.

CXR in asymptomatic TB-HIV patients 327

(RR 3.9, 95%CI 1.8–8.4) were signifi cantly associated with TB disease. The sensitivity of either upper lobe infi ltrates or mediastinal lymphadenopathy for TB disease was 64% (14/22), with a specifi city of 82% (88/107, Table 4). Among TB cases, candidates with CD4 cells < 200/μl were more likely to have medias-tinal adenopathy (4/10) than those who had CD4 cells ⩾ 200/μl (0/12, P = 0.029). Such an association was not signifi cant for upper lobe infi ltrates among TB cases (CD4 cells < 200/μl [5/10] vs. ⩾ 200/μl [5/12], P = 1.00).

Signifi cant associations were found between ra-diographic abnormalities and a history of TB (Table 5), including fi brosis (RR 6.2, 95%CI 2.9–13.4), lo-bar volume loss, collapse, or bronchiectasis (RR 2.4, 95%CI 1.3–4.3), apical capping (RR 3.5, 95%CI

2.1–5.9), and hilar elevation (RR 3.0, 95%CI 1.7–5.1). Granulomas, apical pleural thickening, tracheal deviation and mediastinal shift were also associated with a history of TB.

DISCUSSION

Using the validated standardized CRRS, we describe detailed CXR fi ndings in the largest cohort of asymp-tomatic PLWH with abnormal CXRs screened for IPT in sub-Saharan Africa, and correlate these fi nd-ings with TB disease.

The 11% rate of abnormal CXRs observed among screened asymptomatic PLWH falls within the range reported in asymptomatic PLWH from both Bo-tswana and the United States, i.e., 4–14.5%.4,20,21

Table 2 Parenchymal abnormalities in CXRs of asymptomatic HIV-infected adults, Botswana (n = 183)

Totaln (%)

Dominance* Distribution† Lung zone‡

Primaryn (%)

Secondaryn (%)

Bilateraln (%)

Unilateraln (%)

Uppern (%)

Middlen (%)

Lowern (%)

Any 156 (85)§Cavities 14 (8) 10 (71) 4 (29) 4 (29) 10 (71) 9 (50) 6 (33) 3 (17)Fibrosis 64 (35) 59 (92) 5 (8) 20 (32) 42 (68) 56 (69) 15 (19) 10 (12)Infi ltrates 77 (42) 71 (91) 7 (9) 20 (27) 55 (73) 35 (36) 27 (28) 36 (37)Nodules 49 (27) 38 (76) 12 (24) 20 (48) 22 (52) 23 (35) 26 (40) 16 (25)Lobar volume loss, collapse, bronchiectasis 27 (15) — — 6 (22) 21 (78) 22 (81) 0 5 (19)Calcifi ed granulomas 14 (8) — — 5 (45) 6 (55) 9 (56) 5 (31) 2 (13)Non-calcifi ed granulomas 2 (1) — — 0 2 (100) 1 (50) 1 (50) 0

* Only cavities, fi brosis, infi ltrates, and nodules are divided on the Chest Radiograph Reading and Recording System form into primary and secondary domi-nance. Some candidates had both primary and secondary dominance abnormalities, resulting in some sums exceeding the number in the n (%) column.† Distributions of abnormalities were not recorded for some abnormalities, which resulted in the sums of some categories not adding up to the number in the n (%) column.‡ Some PLWH had an abnormality in more than one zone (e.g., infi ltrates in both the upper and middle zones), and so sums may be higher than the value in the n (%) column.§ The difference between the 156 and 183 PLWH with abnormal CXRs are those who had no parenchymal abnormality but only pleural or central structural a bnormalities (Table 3). Percentages shown in this column use 183 as the denominator. CXR = chest radiograph; HIV = human immunodefi ciency virus; PLWH = persons living with HIV.

Table 3 Pleural and central structure abnormalities in CXRs of asymptomatic HIV-infected adults, Botswana (n = 183)

Totaln (%)

Side* Distribution

Rightn (%)

Leftn (%)

Bilateraln (%)

Unilateraln (%)

Pleural abnormality Any 28 (15)† Apical cap 11 (6) 6 (46) 7 (64) 2 (18) 9 (82) Effusion or thickening 10 (5) 4 (40) 6 (60) 0 10 (100) Costophrenic angle obliteration 17 (9) 10 (59) 7 (41) 0 17 (100)

Central abnormality Any 70 (38) — — — — Tracheal deviation 9 (5) 7 (78) 2 (22) — — Hilar elevation 28 (15) 22 (63) 13 (37) 7 (25) 21 (75) Mediastinal shift 7 (4) 4 (57) 3 (43) — — Hilar LAD 50 (27) 32 (52) 29 (48) 11 (22) 39 (78) Mediastinal LAD 12 (7) 6 (46) 7 (64) 1 (8) 11 (92) Either hilar or mediastinal LAD 58 (32) 36 (52) 33 (48) 11 (19) 47 (81) Calcifi ed LAD 8 (4) — — — —

* Some fi ndings are bilateral and were recorded as both right and left; therefore, totals may exceed 100%. † The difference between the 28 and 183 PLWH with abnormal CXRs are those who had no pleural or central struc-tural abnormalities but only parenchymal abnormalities (Table 2). Percentages shown in this column use 183 as the denominator.CXR = chest radiography; HIV = human immunodefi ciency virus; LAD = lymphadenopathy; PLWH = persons living with HIV; HIV = human immunodefi ciency virus.

328 The International Journal of Tuberculosis and Lung Disease

While our study was not designed to determine the etiologies of all these CXR abnormalities, 17% were determined to be caused by TB disease and another 24% had a history that may have explained their ra-diographic abnormalities. The observed associations between a history of TB and fi brosis, granulomas, central abnormalities, apical capping and lobar vol-ume loss, collapse or bronchiectasis are well-known sequelae of TB disease.27 As we found no studies in-vestigating causes of CXR abnormalities in a similar African population for comparison, it is diffi cult to speculate on the etiologies of these abnormalities. It is helpful, however, to consider two studies—one from Rwanda and one from the United States—in which etiologies of abnormal CXRs were sought aggres-sively in either symptomatic PLWH or hospitalized PLWH without pulmonary symptoms. They identi-fi ed TB disease most frequently (23–26%), followed by non-tuberculous mycobacteria, cryptococcosis and Kaposi’s sarcoma.28,29

Parenchymal infi ltrates, particularly in the upper lobes, and mediastinal adenopathy were signifi cantly associated with TB disease in this population of

a symptomatic PLWH: 2.5, 3.0 and 3.9 fold, respec-tively, compared to those with no TB. A Ugandan study found that upper lobe infi ltrates were the most common presentation of TB in symptomatic ambula-tory PLWH.8 However, upper lobe abnormalities have been reported as being less common in PLWH with TB and low CD4 cell counts, which is contrary to our fi nding.12 Our observation of the association between mediastinal adenopathy and TB disease in PLWH with low CD4 counts has been noted by others.13,15

The fi nding that the combination of either upper lobe infi ltrate or mediastinal adenopathy was 64% sensitive and 82% specifi c for TB disease, while im-perfect, is comparable to other reports. Van Cleef et al. reported that in HIV-infected TB patients in Nai-robi, Kenya, a CXR ‘highly consistent with TB’ (i.e., patchy or nodular shadows, cavitations and calcifi ed shadows) was 49% sensitive.30 Cavitary lesions on CXR are usually thought of as highly suggestive of TB, especially when observed in a TB-endemic coun-try. However, when calculated from a 1997 study of symptomatic Botswana patients, the sensitivity and specifi city of cavitation on CXR are respectively 47%

Table 4 Radiographic abnormalities compared with TB disease status at screening of asymptomatic HIV-infected adults, Botswana (TB = 22, not TB =107)

Abnormality*TB

n (%)Not TB n (%) RR (95%CI)

Sensitivity% (95%CI)†

Specifi city% (95%CI)†

PPV% (95%CI)†

NPV% (95%CI)†

Parenchymal Any 22 (100) 89 (83) —‡ 100 (82–100) 17 (11–26) 20 (13–29) 100 (78–100) Cavity 3 (14) 8 (7) 1.7 (0.6–4.8) 14 (4–36) 93 (85–96) 27 (7–61) 84 (76–90) Infi ltrates 15 (68) 44 (41) 2.5 (1.1–5.8)§ 68 (45–85) 59 (49–68) 25 (15–39) 90 (80–96) Upper lobe infi ltrates 10 (45) 18 (17) 3.0 (1.5–6.2)§ 45 (25–67) 83 (74–89) 36 (19–56) 88 (80–93) Mid or lower zone infi ltrates 9 (41) 31 (29) 1.5 (0.7–3.3) 41 (21–63) 71 (61–79) 23 (11–39) 85 (76–92) Fibrosis 7 (32) 40 (37) 0.8 (0.4–1.9) 32 (15–55) 63 (53–72) 15 (7–29) 82 (71–89) Nodules 7 (32) 30 (28) 1.2 (0.5–2.6) 32 (15–55) 72 (62–80) 19 (9–36) 84 (74–90) Lobar volume loss, collapse, or bronchiectasis 2 (9) 20 (18) 0.5 (0.1–2.0) 9 (2–31) 81 (72–88) 9 (2–31) 81 (72–88) Granulomas 1 (5) 9 (8) 0.6 (0.1–3.8) 5 (0–25) 92 (84–96) 10 (1–46) 82 (74–89)

Pleural Any 2 (9) 15 (14) 0.7 (0.2–2.6) 9 (2–31) 86 (78–92) 12 (2–38) 82 (74–100) Apical cap 1 (5) 5 (5) 1.0 (0.2–6.1) 5 (0–25) 95 (89–98) 17 (1–64) 83 (75–89) Effusion or thickening 1 (5) 4 (4) 1.2 (0.2–7.1) 5 (0–25) 96 (90–99) 20 (1–70) 83 (75–89) Costophrenic angle obliteration 1 (5) 9 (8) 0.6 (0.1–3.8) 5 (0–25) 92 (84–96) 10 (1–46) 82 (74–89)

Central Any 10 (45) 42 (39) 1.2 (0.6–2.6) 45 (25–67) 61 (51–70) 19 (10–33) 84 (74–91) Tracheal deviation 1 (5) 5 (5) 1.0 (0.2–6.1) 5 (0–25) 95 (89–98) 17 (1–64) 83 (75–89) Hilar elevation 4 (18) 17 (16) 1.1 (0.4–3.0) 18 (6–41) 84 (75–90) 19 (6–43) 83 (75–90) Mediastinal shift 0 4 (4) — 0 (0–18) 96 (90–99) 0 (0–60) 82 (74–88) Either hilar or mediastinal LAD 9 (41) 35 (33) 1.3 (0.6–2.9) 41 (21–63) 67 (57–76) 20 (10–36) 85 (75–91) Hilar LAD 6 (27) 33 (31) 0.9 (0.4–2.0) 27 (12–50) 69 (59–78) 15 (6–31) 82 (72–89) Mediastinal LAD 4 (18) 3 (3) 3.9 (1.8–8.4)§ 18 (6–41) 97 (91–99) 57 (20–88) 85 (77–91) Calcifi ed LAD 1 (5) 5 (5) 1.0 (0.2–6.1) 5 (0–25) 95 (89–98) 17 (1–64) 83 (75–89)

Combinations Any infi ltrate or any adenopathy 18 (82) 57 (53) 3.2 (1.2–9.0)§ 82 (59–94) 47 (37–57) 24 (15–35) 93 (81–100) Upper lobe infi ltrate or any adenopathy 15 (68) 32 (30) 3.7 (1.6–8.5)§ 68 (45–85) 70 (60–78) 32 (20–47) 91 (83–96) Lower/mid-zone infi ltrate or any LAD 14 (64) 46 (43) 2.0 (0.9–4.5) 64 (41–82) 57 (47–66) 23 (14–36) 88 (78–95) Any infi ltrate or mediastinal LAD 16 (73) 45 (42) 3.0 (1.2–7.1)§ 73 (50–88) 58 (48–67) 26 (16–39) 91 (81–96) Upper lobe infi ltrate or mediastinal LAD 14 (64) 19 (18) 5.1 (2.3–11)§ 64 (41–82) 82 (73–89) 42 (26–61) 92 (84–96) Lower/mid-zone infi ltrate or mediastinal LAD 10 (45) 32 (30) 1.7 (0.8–3.7) 45 (25–67) 70 (60–78) 24 (13–40) 86 (77–92)

* A patient may have more than one of a specifi c abnormality (i.e., multiple cavities), but was only counted once.† Confi dence intervals for single proportions determined using the score method with continuity correction.26

‡ Two-tailed Fisher’s exact test, P = 0.041.§ Statistically signifi cant.TB = tuberculosis; HIV = human immunodefi ciency virus; RR = relative risk; CI = confi dence interval; PPV = positive predictive value; NPV = negative predictive value; LAD = lymphadenopathy.

CXR in asymptomatic TB-HIV patients 329

and 74%.31 Our fi nding that the combination of up-per lobe infi ltrates or mediastinal adenopathy may diagnose TB in asymptomatic PLWH is clinically use-ful, especially when one considers that the sensitivity of a sputum smear is only 50% when properly used.32 Nevertheless, a high index of suspicion should be maintained for any abnormal CXR, as radiographic fi ndings in PLWH with TB disease vary greatly.

Assessment for TB with the CXR is limited by high rates of inter- and even intra-observer variability.33,34 In an attempt to minimize this variability, we used the standardized CRRS which was developed by the late Neil W White.22 It uses principles based on the forms used by the International Union Against Cancer and the International Labour Organization for scoring changes on CXRs in occupational diseases. Although not based on a set of standard CXRs, the scoring sys-tem allowed for accurate descriptions of TB-related abnormalities. The two expert readers reported essen-tially no disagreements on fi ndings or their descrip-tion, and the use of the form allowed accurate tabula-tion of abnormalities. It is possible that the associations we observed were attributable to this standardized scheme; additional validation in fi eld studies such as ours, including the training in CRRS of non-expert physicians, will be needed to increase confi dence in its broader utility.

An important limitation of this study was that 55% of the TB cases were not proven by smear and/or culture and that we were unable to determine the TB status of 30% (54/183) who had abnormal CXRs. This study was conducted using the available stan-dard in Botswana to diagnose TB, which is smear-based but in practice is frequently clinical and radio-logic.35 However, the 107 who did not have TB were observed to be disease-free for a long period and were therefore likely true negatives, given that TB disease tends to progress quickly in PLWH.36,37 Another limi-tation was that 36% of CXRs were unavailable for CRRS scoring. The only baseline characteristic dis-tinguishing between candidates without and those with CRRS scoring was TST positivity. Elsewhere, we have shown that TST positivity was associated with TB disease in this cohort;22 however, as the propor-tion of TB cases in those with and those without CRRS scoring did not differ, it is unlikely that the missing data would affect our conclusions.

In conclusion, we identifi ed a substantial proportion of TB disease in asymptomatic PLWH with abnormal CXRs in Botswana. While a diverse array of radio-logic abnormalities was observed in this population —many of which may have been attributable to a history of either TB or pneumonia—a combination of upper lobe infi ltrates or mediastinal adenopathy was found to be associated with active TB. The CRRS proved highly useful in this study, and we recommend it to others planning screening surveys for pulmonary disease. Finally, until superior techniques for the rapid diagnosis of active TB become available, the CXR will remain a mainstay in screening for and diagnos-ing TB around the world, and additional research into the radiographic patterns and etiologies of ab-normal CXRs in asymptomatic PLWH is needed in TB-endemic settings.

AcknowledgementsThe authors gratefully acknowledge the services of the research nurses, health educators and laboratory technicians, data manager, data clerks, as well as the Botswana volunteers in the IPT trial, for making this study possible. The trial was funded by the CDC, At-lanta, Georgia, USA, and the United States Agency for International Development. The fi ndings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agencies.

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Table 5 Radiographic abnormalities in relation to history of TB in asymptomatic HIV-infected adults, Botswana (n = 144)

Abnormality*

History of TB

(n = 34)n (%)

No historyof TB

(n = 110)n (%) RR (95%CI)

Parenchymal Any 31 (91) 92 (84) 1.8 (0.6–5.3) Cavity 2 (6) 8 (7) 0.8 (0.2–3.0) Infi ltrates 8 (24) 50 (45) 0.5 (0.2–0.9)† Fibrosis 27 (79) 28 (25) 6.2 (2.9–13.4)† Nodules 6 (18) 35 (32) 0.5 (0.2–1.2) Lobar volume loss, collapse, or bronchiectasis 9 (26) 10 (9) 2.4 (1.3–4.3)† Granulomas 10 (29) 2 (2) 4.6 (3.0–7.1)†

Pleural Any 11 (32) 12 (11) 2.5 (1.4–4.4)† Apical cap 7 (21) 3 (3) 3.5 (2.1–5.9)† Effusion or thickening 4 (12) 5 (5) 2.0 (0.9–4.4) Costophrenic angle obliteration 5 (15) 8 (7) 1.7 (0.81–3.7)

Central Any 16 (47) 38 (35) 1.5 (0.8–2.7) Tracheal deviation 5 (15) 1 (1) 4.0 (2.4–6.4)† Hilar elevation 11 (32) 9 (8) 3.0 (1.7–5.1)† Mediastinal shift 5 (15) 1 (1) 4.0 (2.4–6.4)† Either hilar or mediastinal LAD† 11 (32) 33 (30) 1.1 (0.6–2.0) Hilar LAD 10 (29) 28 (25) 1.2 (0.6–2.2) Mediastinal LAD 1 (3) 8 (7) 0.45 (0.1–3.0) Calcifi ed LAD 2 (6) 4 (4) 1.4 (0.45–4.6)

* A patient may have more than one of the particular abnormality (i.e., mul-tiple cavities) but it will only be counted once. Records of a history of TB were not available for 39 persons. † Statistically signifi cant.TB = tuberculosis; HIV = human immunodefi ciency virus; RR = relative risk; CI = confi dence interval; LAD = lymphadenopathy.

330 The International Journal of Tuberculosis and Lung Disease

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CXR in asymptomatic TB-HIV patients 331

C O N T E X T E : Francistown et Gaborone au Botswana. Le

cliché thoracique (CXR) est utilisé pour le dépistage de

la tuberculose (TB) chez les personnes asymptomatiques

infectées par le virus de l’immunodéfi cience humaine

(PLWH) recourant à un traitement préventif de la TB

par l’isoniazide (IPT).

O B J E C T I F : Décrire l’aspect radiologique chez les PLWH

dans un contexte endémique de TB et identifi er les carac-

téristiques en association avec la maladie TB.

S C H É M A : Les CXR ont été pratiqués chez des PLWH

asymptomatiques recourant à l’IPT dans les conditions

du programme dans un essai clinique entre 2004 et 2006.

Les CXR ont été lus en utilisant le système standardisé

« Chest Radiography Reading and Recording System »

(CRRS). Les caractéristiques cliniques, y compris la

maladie TB, ont été comparées avec les observations

radiologiques.

R É S U LTAT S : Une ou plusieurs anomalies étaient présen-

tes dans 183 sur 2732 CXR de dépistage, et elles ont fait

l’objet d’un score selon le CRRS : 42% d’infi ltrats (36%

dans les lobes supérieurs), 35% de fi brose parenchyma-

teuse et 32% d’adénopathies. Le statut en matière de

maladie TB a été déterminé chez 129 PLWH (70%),

parmi lesquels 22 (17%) souffraient de maladie TB. La

maladie TB est en association avec des infi ltrats dans les

lobes supérieurs (risque relatif [RR] 3,0 ; IC95% 1,5–

6,2) et des adénopathies médiastinales (RR 3,9 ; IC95%

1,8–8,4). La sensibilité soit des infi ltrats du lobe supé-

rieur soit des adénopathies médiastinales pour la mala-

die TB a été de 64% et la spécifi cité de 82%.

C O N C L U S I O N : Une combinaison des aspects radiolo-

giques est utile à la prédiction de la maladie TB chez les

PLWH asymptomatiques. Le CRRS devrait être utilisé

plus fréquemment dans les études similaires.

R É S U M É

R E S U M E N

M A R C O D E R E F E R E N C I A : Las ciudades de Francistown

y Gaborone en Botswana. En las personas asintomáticas

con infección por el virus de la inmunodefi ciencia hu-

mana (PLWH) que acuden por tratamiento preventivo

con isoniazida (IPT) se utiliza la radiografía de tórax

(CXR) a fi n de detectar la enfermedad tuberculosa.

O B J E T I V O S : Describir las características radiográfi cas de

PLWH en un entorno con tuberculosis (TB) endémica y

defi nir las características asociadas con esta enfermedad.

M É T O D O S : Se llevó a cabo un estudio clínico de PLWH

asintomáticas que buscaron IPT en el marco del pro-

grama nacional entre el 2004 y el 2006, practicando una

CXR. Se aplicó un sistema normalizado de lectura y re-

gistro de las CXR (CRRS) y se compararon las caracte-

rísticas clínicas, incluida la enfermedad tuberculosa, con

los hallazgos radiográfi cos.

R E S U LTA D O S : De 2732 CXR sistemáticas practicadas,

183 presentaron una o varias imágenes anormales, las

cuales se califi caron mediante el CRRS: en 42% hubo

infi ltrados (36% del lóbulo superior), en 35% imágenes

de fi brosis parenquimatosa y en 32% imágenes ganglio-

nares anormales. Se examinó el estado de la TB en 129

PLWH (70%), de los cuales 22 (17%) presentaron en-

fermedad activa. La enfermedad tuberculosa se asoció

con los infi ltrados del lóbulo superior (riesgo relativo

[RR] 3,0; IC95% 1,5–6,2) y las adenopatías mediasti-

nales (RR 3,9; IC95% 1,8–8,4). Los infi ltrados del ló-

bulo superior y la linfadenopatía mediastinal exhibieron

ambos una sensibilidad de 64% y una especifi cidad de

82% para el diagnóstico de TB.

C O N C L U S I Ó N : La utilización de una combinación de

características radiográfi cas fue útil, para predecir la en-

fermedad tuberculosa en PLWH. El CRRS se debería

utilizar con mayor frecuencia en este tipo de estudios.