HIV/AIDS

MAJOR ARTICLE

Bacille Calmette-Guerin VaccineInduced Disease in HIV-Infected and HIV-Uninfected Children

A. C. Hesseling,1 H. Rabie,1 B. J. Marais,1 M. Manders,3 M. Lips,3 H. S. Schaaf,1 R. P. Gie,1 M. F. Cotton,1 P. D. van Helden,2 R. M. Warren,2 and N. Beyers1
1 Desmond Tutu TB Centre and Department of Pediatrics and Child Health and 2DST/NRF Centre of Excellence in Biomedical Tuberculosis Research/MRC Centre for Molecular and Cellular Biology, Department of Medical Biochemistry, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa; and 3Academic Medical Centre, Amsterdam, The Netherlands

(See the editorial commentary by von Reyn on pages 55961)

Background. Bacille Calmette-Guerin (BCG)a live, attenuated vaccineis routinely given to neonates in settings where tuberculosis is endemic, irrespective of human immunodeciency virus (HIV) exposure. HIVinfected infants and other immunodecient infants are at risk of BCG-related complications. We report the presentation, treatment, and mortality of children who develop BCG disease, with emphasis on HIV-infected children. In addition, we present a revised classication of BCG disease in children and propose standard diagnostic and management guidelines. Methods. This retrospective, hospital-based study was conducted in the Western Cape Province, South Africa. Mycobacterium tuberculosis complex isolates recovered from children aged !13 years during the period of August 2002 through January 2005 were speciated by polymerase chain reaction to conrm Mycobacterium bovis BCG. Clinical data were collected through medical le review. BCG disease was classied according to standard and revised disease classications. Mortality was assessed at the end of the study period. Results. BCG disease was diagnosed in 25 children; 22 (88%) had local disease, and 8 (32%) had distant or disseminated disease; 5 children (20%) had both local and distant or disseminated disease. Seventeen children were HIV infected; 2 children had other immunodeciencies. All 8 children with distant or disseminated disease were immunodecient; 6 were HIV infected. The mortality rate was 75% for children with distant or disseminated disease. Conclusions. BCG vaccination poses a risk to infants perinatally infected with HIV and to other primary immunodecient children. The proposed pediatric BCG disease classication reects clinically relevant disease categories in HIV-infected children. The suggested diagnostic and treatment guidelines should improve existing case management and surveillance. Prospective evaluation of management strategies for BCG disease in HIVinfected and HIV-uninfected children is essential. The World Health Organization currently recommends giving bacille Calmette-Guerin (BCG)a live, atten uated Mycobacterium bovis vaccine strainto all neonates in areas with a high prevalence of tuberculosis, irrespective of HIV exposure, unless the child has symptomatic HIV disease [1]. In South Africa, the present neonatal vaccination policy recommends intradermal administration of the Danish strain BCG [2]. BCG vaccination is associated with injection-site complications, (suppurative) adenitis, and (very rarely) with disseminated disease [3]. Adverse events vary by BCG strain type, physical-chemical property, bacillary load, and administration method and by the hosts immune characteristics [35]. In the era before HIV, the reported frequency of disseminated BCG disease was extremely low (0.192 cases/1 million vaccinated infants) [3, 6], and disease was associated with congenital immunodeciencies [7]. HIV-infected children are at risk of developing BCG disease; this risk is poorly quantied [6, 8]. Apart from the risk of BCG-related disease, there is concern regarding the possible role of neonatal BCG vaccination in accelerating HIV disease progression in HIV-infected infants. The World Health Organization recommends that, where resources permit,

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Received 14 July 2005; accepted 25 September 2005; electronically published 11 January 2006. Reprints or correspondence: Dr. Anneke C. Hesseling, Desmond Tutu TB Centre, Dept. of Pediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg, 7505, South Africa (annekeh@sun.ac.za). Clinical Infectious Diseases 2006; 42:54858 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4204-0017$15.00

548 CID 2006:42 (15 February) HIV/AIDS

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Figure 1. Classication of bacille Calmette-Guerin (BCG) disease in HIV-infected and HIV-uninfected children. Mycobacterium bovis BCG disease conrmed by molecular methods [13] or, alternatively, by culture and biochemical methods [20]. EPI, Expanded Programme on Immunization.

long-term follow-up of BCG-vaccinated, HIV-exposed infants is desirable, to initiate early treatment should disseminated BCG disease occur [1]. Clinical management of BCG disease is difcult in the absence of standard treatment guidelines. Chemotherapy is complicated by the inherent resistance of all M. bovis strains to pyrazinamide, the inherent intermediate resistance of some

BCG strains to isoniazid [9], and the emergence of additional resistance during inappropriate therapy [9, 10]. We report the clinical presentation, treatment, and mortality of children with Danish strain M. bovis BCG disease, with emphasis on HIV-infected children. We present a revised pediatric classication of BCG disease and propose diagnostic and management guidelines for BCG disease in children.
HIV/AIDS CID 2006:42 (15 February) 549

Table 1. Classication of bacille Calmette-Guerin (BCG) disease in 25 children according to the Talbot and revised pediatric disease classications.
Patient group, patient HIV-infected children 1 BCG suppurative axillary adenitis; BCG isolated from pus swab specimen; patient presented 3 months after start of HAART BCG suppurative axillary adenitis and BCG scar ulceration; BCG isolated from FNA and gastric aspirate specimens; CXR revealed perihilar opacication BCG suppurative axillary adenitis; BCG scar ulceration; BCG isolated from FNA specimen BCG injection site abscess and BCG scar ulceration; BCG isolated from gastric aspirate specimens; CXR revealed lobar consolidation BCG axillary adenitis and BCG scar ulceration; BCG isolated from FNA specimen BCG suppurative axillary adenitis; BCG isolated from FNA specimen; patient presented 3 months after start of HAART BCG axillary adenitis; BCG isolated from FNA specimen BCG suppurative axillary adenitis, multiple abscesses on right axilla and shoulder, and BCG scar ulceration; BCG isolated from FNA specimen; patient presented 3 months after start of HAART BCG axillary adenitis; BCG isolated from FNA specimen BCG suppurative axillary adenitis; BCG isolated from FNA specimen; M. tuberculosis isolated from gastric aspirate specimens; CXR revealed mediastinal adenopathy and lobar collapse BCG suppurative axillary adenitis; BCG isolated from pus swab specimen BCG isolated from gastric aspirate specimens; CXR revealed lobar opacication and mediastinal adenopathy BCG axillary adenitis and BCG scar ulceration. BCG isolated from FNA, lymph node biopsy, and gastric aspirate specimens; CXR revealed bronchopneumonic opacication BCG axillary adenitis and scar ulceration; BCG isolated from FNA specimen; patient presented 3 months after start of HAART BCG scar ulceration; BCG isolated from gastric aspirate specimens; CXR revealed mediastinal adenopathy BCG suppurative axillary adenitis, supraclavicular abscess, and extensive local cellulitis; BCG isolated from FNA and pus swab specimen BCG isolated from gastric aspirate specimens; CXR revealed miliary opacication Regional disease Regional disease IRIS Disease description Talbot classication [6] Revised pediatric disease classication

Regional and extra regional localized disease Regional disease Regional and extra regional localized disease Regional disease Regional disease

Regional and distant disease

3 4

Regional disease Local and distant disease

5 6

Regional disease Regional disease IRIS

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7 8

Regional disease Regional and extra regional localized disease

Regional disease Regional disease IRIS

9 10

Regional disease Regional disease

Regional disease Regional and dual disease due to Mycobacterium tuberculosis

11 12

Regional disease Extra regional localized disease Regional and extra regional localized disease

Regional disease Distant disease

13

Regional and distant disease

14

Regional disease

Regional disease IRIS

15 16

Regional and extra regional localized disease Regional and extra regional localized disease Extra regional localized disease

Local and distant disease Regional disease

17 Children with primary immunodeciencies 18

Distant disease

BCG injection site abscess; severe BCG scar ulceration; distant BCG skin nodules present; BCG isolated from tracheal aspirate specimens; CXR revealed Ghon focus with cavitation and bronchopneumonic consolidation BCG isolated from gastric aspirate specimens; CXR revealed mediastinal adenopathy

Regional and disseminated disease

Regional and disseminated disease

19 Immunocompetent children 20

Extra regional localized disease

Distant disease

BCG axillary adenitis and BCG scar ulceration; BCG isolated from FNA specimen

Regional disease

Regional disease (continued)

Table 1. (Continued.)
Patient group, patient 21 22 Disease description BCG suppurative axillary adenitis and BCG scar ulceration; BCG isolated from FNA specimen BCG suppurative axillary adenitis and supraclavicular adenitis; BCG isolated from FNA specimen; M. tuberculosis isolated from pus swab specimen from the ear (mastoiditis) BCG injection site abscess; BCG isolated from pus swab specimen BCG suppurative axillary adenitis; BCG isolated from FNA specimen BCG suppurative axillary adenitis; BCG isolated from pus swab specimen Talbot classication [6] Regional disease Regional and extraregional localized Revised pediatric disease classication Regional disease Regional and dual disease due to M. tuberculosis

23 24 25

Regional disease Regional disease Regional disease

Local disease Regional disease Regional disease

NOTE. Primary immunodeciencies included severe combined immunodeciency (patient 18) and an unknown T cell deciency (patient 19). Patient 19 received subcutaneous vaccination with BCG Tokyo strain as part of a clinical trial. All other patients were documented to have received Danish strain BCG. Immunocompetent children were HIV negative or the child had unconrmed HIV status but the mother tested negative for HIV during pregnancy, and both the child and mother were asymptomatic. Spoligotyping was done to conrm Mycobacterium tuberculosis strain type. In patient 10, the Beijing family strain was recovered from gastric aspirate specimens, and in patient 22, low-copy clade was recovered from pus swabs from the ear; strains were identied from serial isolates recovered at different time points, respectively. BCG isolated dened as isolation of Mycobacterium bovis BCG by culture and conrmed by PCR [18]; M. tuberculosis isolated dened as isolation of M. tuberculosis by culture and conrmed by PCR. CXR, chest radiography; FNA, ne-needle aspirate; IRIS: immune reconstitution inammatory syndrome.

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METHODS Study setting and patients. Participants in this hospitalbased, retrospective study were routinely investigated for suspected mycobacterial disease at the Tygerberg Childrens Hospital, a tertiary referral hospital in the Western Cape Province, South Africa. Investigations included culture of gastric aspirates, ne-needle aspiration of peripheral adenopathy, and other systemic investigations. We reviewed all Mycobacterium tuberculosis complex isolates that were collected from August 2002 through January 2005 from children aged !13 years. HIV testing was routinely performed on clinical grounds or on the basis of maternal HIV status; informed consent was obtained, and pre-and posttest counseling was done. The prevalence of HIV infection among women attending public antenatal care facilities in the province in 2003 was 13.1% (95% CI, 8.5%17.6%). The incidence of tuberculosis in the Cape Metropole area was 638 cases per 100,000 persons in 2003 [11, 12]. Case denitions. Mycobacterial cultures were performed using the MGIT automated broth culture system (BecktonDickinson). M. bovis BCG was differentiated from the other members of the M. tuberculosis complex by standard PCR amplication across the junctions of the region of difference RD1 [13]. Aliquots for PCR analysis were obtained directly from the primary MGIT mycobacterial culture. Stringent protocol for prevention of cross-contamination was followed for mycobacterial culture [14] and PCR [15]. The presence of M. tuberculosis was conrmed by spoligotyping [16]. We included only cases that met the current Expanded Programme on Immunization criteria for local or regional BCG disease (i.e., ipsilateral axillary lymph node enlargement of

15 15 mm, suppurative ipsilateral axillary lymphadenitis, injection site abscess of 10 mm, or a clinically signicant or nonresolving BCG papule) [17] and for which there was proof of BCG dissemination (i.e., isolation of M. bovis BCG from any distant site beyond the ipsilateral regional lymph nodes). Data collection. Clinical information was obtained through review of the medical les using a standard dataextraction tool. Chest radiographs were assessed by 2 pediatric tuberculosis specialists using a standard radiologic classication [18]; the specialists were blinded to BCG disease classication. BCG vaccination was documented from neonatal vaccination records. Children were traced to assess all-cause attributed mortality. HIV infection was diagnosed on the basis of the results of 2 ELISA tests or PCR in children aged !18 months. HIV disease was staged on the basis of the Centers for Disease Control and Prevention criteria for children [19]. BCG disease classication. The classication of BCG disease developed by Talbot et al. [6] was used. In addition, to more accurately reect all relevant disease categories in HIVinfected children, a pediatric classication system was developed; disease categories included local disease, regional disease, distant disease, disseminated disease, and BCG immune reconstitution inammatory syndrome (IRIS) (gure 1). Data management and ethics considerations. Data were analyzed with SPSS, version 11.5 (SPSS). Descriptive analyses were performed using the x2 statistic and Fishers exact test. A P value of .05 was considered to be statistically signicant. Patient condentiality was maintained through anonymous coding of mycobacterial isolates and patients personal information. Informed consent for patient participation was ob-

HIV/AIDS CID 2006:42 (15 February) 551

Table 2.

Summary of clinical and immunologic characteristics of 25 children with bacille Calmette-Guerin (BCG) disease.

Patient group, patient

CD4 HIV Age at percentage CDC disease diagnosis of at time of category at BCG disease, BCG disease a b Sex HIV diagnosis months diagnosis Tuberculin skin test nding Contact with an adult with TB BCG scar present

Revised pediatric disease classication

HIV-infected children F M 7 25 29 29 12 9 16 31 20 11 12 7 29 6 5 5 0 19 NA NA NA NA NA NA ND Mantoux, 11 mm Mantoux, 17 mm ND Mantoux, 6 mm ND ND Mantoux, 0 mm Mantoux, 0 mm Tine, grade 3 Mantoux, 0 mm ND No No Yes No No No No Yes No No Yes No ND No Mantoux, 0 mm Yes Tine grade, 0 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Mantoux, 0 mm No Yes ND No ND No Yes Tine grade, 4 No Mantoux, 0 mm No No Mantoux, 0 mm Yes ND Yes Yes Unknown Regional disease Regional disease IRIS Regional disease IRIS Regional and dual disease due to Mycobacterium tuberculosis Distant disease Regional and distant disease Regional disease IRIS Local and distant disease Unknown Regional disease Distant disease Regional and disseminated disease Distant disease Regional disease Regional disease Regional and dual disease due to M. tuberculosis Local disease Regional disease Unknown Regional disease Unknown Regional disease Unknown Regional disease Unknown Regional disease ND No Yes Regional disease Local and distant disease Mantoux, 0 mm Yes Yes F F F F M M F F F M F M M M M M F M M M M M F 4 NA 6 NA 4 NA 2 NA 3 NA 5 NA 16 NA 5 NA 17 C3 10 C3 8 C3 9 C2 8 C3 20 B3 3 B3 11 C3 3 B1 5 C3 16 C3 11 C3 6 C1 5 C3
d

1 10 3 C2 C2
c

C3

14

Mantoux, 14 mm

Yes

Yes

Regional disease IRIS Regional and distant disease

10

11

12

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552

13

14

15

16

17

Children with primary immunodeciencies

18

19

Immunocompetent children

20

21

22

23

24

25

NOTE. Patient 18 had severe combined immunodeciency, and patient 19 had an undetermined T cell immunodeciency, with a persistently low CD4+ cell count and normal results of investigations for IL-12, TNF and IFN-g. Immunocompetent children were HIV negative or the child had unconrmed HIV status but the mother tested negative for HIV during pregnancy, and both the child and mother were asymptomatic. , CDC, Centers for Disease Control and Prevention; NA, not applicable; ND, not determined; TB, tuberculosis.

Age at the time of diagnosis of culture-positive M. tuberculosis complex infection. Clinical and immunologic disease stage at the time of diagnosis of HIV infection based on CDC criteria [19]. CDC HIV disease staging based on CD4 cell percentage of 15% at the time of diagnosis of HIV disease. CDC HIV disease staging based on absolute CD4 count of 266 cells/mm3 at the time of diagnosis of HIV disease.

Table 3.
Treatment dosage, mg/kg/day

Summary of therapy given to 25 children with bacille Calmette-Guerin (BCG) disease.

Patient group, patient

d

Surgery

Rif

Duration of therapy, a b INH PZA Ethio EMB Oox Cipro months Adherence HAART Outcome (time to death, c days)

Attributed cause of death during hospitalization

HIV-infected children CEB Alive Died (231) Alive Died (8) Died (67)
d

1 ID None
15

25 10 10 Good No No Yes Died (351) Died (12)

d

25 15 10 No PCP 20 20 10 20 Alive Died (3) Died (384) Alive Not recorded Pneumonia 15 NR
!1 13
e

30 20 20 30 20 NR Unknown Good Good Good Good

e

10 10 No Yes No Yes No Yes No

d

10 15 15 20 10 15 20 NR 20 25
13

15 15 15 20
110

15 15 15 Good Poor 9 1
e e

3 9 No therapy NA 4 7 2 7 No therapy NA 4 Good No No Unknown Yes Good No Good Good Good Yes

Unknown

Yes

Septicaemia, dysentery Salmonella dysentery, intracranial hemorrhage Septicaemia Pulmonary hemorrhage

2 None None ID None ID (twice) None None None None ID and CEB None None ID (twice) None 30 20 30 15 15 15 15 15 20 20 20 15 15 20 15 20 20 3 20 20 10 10 NR 15 10 10 10 10

10

Died during therapy (83) Pneumonia, marasmus

11

12

13

Died during therapy (71) Congenital CMV infection, severe neurological impairment Alive Alive Died during therapy (34) Complicated gastroenteritis Died during therapy (19) Marasmus, probable disseminated BCG disease

14

15

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553
None None None ID ID (twice) None CEB ID 10 10 15 15 10 15 10 20 15
110
e

16

17

Children with primary immunodeciency NR NR NR NR 2 Good Good NA NA NA NA 4 Good No therapy NA No therapy NA No therapy NA NA NA NA NA Died during therapy (49) Septicaemia, disseminated BCG disease Alive Alive Alive Alive Died (120) Alive Alive Airway obstruction

18

19

Immunocompetent children No therapy NA No therapy NA

20

21

22

23

24

25

NOTE. Patients 7 an 19 had transient hepatotoxicity which resolved after discontinuation of rifampicin. For patient 4, the diagnosis of BCG disease was made retrospectively, and the patient died before institution of therapy. HAART recipients received HAART at any time before or after the diagnosis of BCG disease. Immunocompetent children were HIV negative or the child had unconrmed HIV status but the mother tested negative for HIV during pregnancy, and both the child and mother were asymptomatic. CEB, complete excision biopsy; Cipro, ciprooxacin; CMV, cytomegalovirus; EMB, ethambutol; Ethio, ethionamide; ID, incision and drainage; INH, isoniazid; NA, not applicable; NR, exact dosage not recorded; Oox, ooxacin; PCP Pneumocystis carinii pneumonia; PZA, pyrazinamide; Rif, rifampicin. ,

Total duration of hospital- or clinic-based directly observed antituberculosis therapy. Good adherence dened as 180% of doses taken, and poor adherence dened as !80% of doses taken. Time from diagnosis of BCG disease to death. Patient was receiving HAART at the time of diagnosis of BCG disease. Patient was still receiving therapy at the end of the study period. Patient was a bone marrow transplant recipient. Patient was receiving hyperimmune globulin.

Figure 2. Guidelines for the diagnosis of bacille Calmette-Guerin (BCG) disease in children. M. bovis, Mycobacterium bovis.

tained from parents or legal guardians. The study was approved by the ethics committee of the Faculty of Health Sciences, Stellenbosch University. RESULTS Overview of cases. There were 466 conrmed cases of M. tuberculosis complex disease in children aged !13 years during the study period. Of these children, 108 (23.2%) were HIV infected, 190 (40.7%) were not HIV infected, and HIV testing was not done for 168 (36.1%). BCG disease was diagnosed in 25 children. Twenty-two children (88%) presented with local or regional disease, and 8 children (32%) presented with distant or disseminated disease; 5 children (20%) had both local/regional and distant/disseminated disease. BCG disease contributed to 25 (5.4%) of 466 cases of conrmed mycobacterial disease among all hospitalized
554 CID 2006:42 (15 February) HIV/AIDS

children and to 17 (15.7%) of 108 cases among HIV-infected children. BCG disease classication. The comparison of BCG disease categories, according to the Talbot classication and the revised pediatric disease classication (as dened in gure 1), is presented in table 1. Local or regional BCG disease was diagnosed by conrmation of M. bovis BCG from ne-needle aspiration or pus swab specimens; distant or disseminated disease was diagnosed by isolation of M. bovis BCG from respiratory isolates in children with respiratory symptoms or from other distant sites; no mycobacterial blood cultures were performed. Distant disease was detected in 3 children in the absence of any local or regional disease. The most important differences noted between the Talbot and revised disease classications were (1) the diagnosis of distant BCG disease on the basis of isolation of M. bovis BCG from gastric and/or tracheal aspirates, (2) the presence of BCG IRIS in HIV-infected children who were receiving HAART, and (3) the occurrence of dual disease with M. tuberculosis and M. bovis BCG reected in the revised but not the Talbot classications. In all children with dual disease, there was clear clinical evidence of regional BCG disease in combination with tuberculosis disease in a remote site, in the presence of bacteriological and molecular conrmation of both organisms from multiple serial isolates. Additional description of cases reects the revised pediatric disease classication only. Clinical and immunologic characteristics. Clinical and immunologic characteristics are shown in table 2. Seventeen (68%) of 25 children had conrmed HIV infection, and there were 2 HIV-uninfected children (8%) with primary immune deciencies (one patient had severe combined immune deciency, and the second had an unidentied T cell deciency). These children were all healthy at birth. All 8 children with distant or disseminated BCG disease had immunodeciencies; 6 were HIV infected. In the 6 children with no known immunodeciencies, 3 were conrmed to be HIV uninfected. HIV status was not conrmed in the remaining 3 children, but the mothers tested HIV negative during pregnancy, and at no stage was there any clinical indication of HIV infection in either the child or the mother. The median age at BCG diagnosis was 8.5 months (range, 3 21 months) in HIV-infected children and 2.7 months (range, 25 months) in children without immunodeciencies. HAART was started in 4 HIV-infected children before the onset of clinical BCG disease; in all of these children, BCG disease presented as acute ipsilateral adenopathy 3 months after the initiation of HAART. These cases were classied as regional BCG disease IRIS. Chemotherapeutic regimens and surgical management. The surgical and medical management and attributed all-cause mortality data are summarized in table 3. Six HIV-infected and

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Figure 3. Preliminary guidelines for the management of bacille Calmette-Guerin (BCG) disease in children. EPI, Expanded Programme on Immunization; IRIS, immune reconstitution inammatory syndrome; M. bovis, Mycobacterium bovis.

4 HIV-uninfected children underwent surgery for axillary and/ or suppurative axillary adenitis. Only 1 surgical complication occurred (a stula in an HIV-uninfected child). Antituberculosis regimens and dosages were not standardized. Pyrazinamide was included in most regimens, because disease due to M. tuberculosis could not be excluded at the time that BCG disease was diagnosed. Mortality. Of the 17 HIV-infected children, 11 (64.8%) died (5 children with distant disease, of whom 4 also had regional disease, and 6 children with regional disease only). The median duration of survival after BCG disease was diagnosed was 67 days (range, 3384 days). Seven HIV-infected children

with BCG disease received HAART; 2 died (28.6%). HAART was signicantly associated with overall survival among HIVinfected children (OR, 0.218; 95% CI, 0.0590.894; P p .035, by Fishers exact test). However, numbers were too small for us to comment on the effect of HAART on survival when patients with BCG IRIS were excluded. Of the 4 HIV-infected children with BCG IRIS, 3 survived. The fourth child, who had HIV disease of Centers for Disease Control and Prevention stage C3, died of bacterial septicemia 351 days after BCG IRIS diagnosis. Of the 8 children with distant or disseminated disease, 6 died during the study period (median duration of survival after BCG
HIV/AIDS CID 2006:42 (15 February) 555

diagnosis, 42 days; range, 8231 days). The 2 children with distant disease who survived included an HIV-infected child with stage B3 HIV disease who started receiving 4 antituberculosis drugs immediately after isolation of BCG from a gastric aspirate specimen; HAART was started 6 weeks later. This child presented with lobar opacication and mediastinal adenopathy on a chest radiograph, despite receiving isoniazid prophylaxis (10 mg/kg/day). At a follow-up visit 6 months later, the chest radiograph ndings were found to have normalized. The second child had an unidentied T cell deciency and presented with persistent low CD4+ T lymphocyte count, septic arthritis, failure to thrive, recurrent airway infections, and distant BCG disease. Investigation for IFN-d, TNF, and IL-12 production and of the IL-12 and IFN-d receptors yielded normal ndings. In addition to monthly hyperimmune globulin therapy, 4-drug antituberculosis therapy was initiated immediately after conrmation of BCG disease. The patient responded well to antituberculosis therapy; mediastinal adenopathy on chest radiography resolved after 4 months. Only 1 child without known immune deciency and with local BCG disease died; the child died at 8 months of age of complications of congenital upper airway obstruction. His mother tested negative for HIV during pregnancy. All other nonimmunodecient children were alive at the end of the study. DISCUSSION To our knowledge, this is the largest study of HIV-infected children with BCG disease reported in the literature. We have demonstrated that neonatal intradermal vaccination with Danish strain BCG poses a risk to infants perinatally infected with HIV, even if the children are asymptomatic when vaccinated. We also describe 2 children with distant and disseminated BCG disease, which was associated with primary immunodeciencies, and 4 HIV-infected children with BCG IRIS. Although hospital-based studies have limitations, these studies are important for the investigation of relatively rare occurrences, such as serious vaccine-related adverse events, especially in the absence of adequate population-based data on risk groups. Our data are strengthened by stringent entry criteria, comprehensive clinical and immunologic data, and the fact that all children were traced to assess attributed mortality. Additional limitations include the studys retrospective nature and the lack of invasive diagnostic procedures, which were not performed in the course of routine clinical care. Detection bias may have favored the selection of HIV-infected children, who were more symptomatic or perceived to be at higher risk and who therefore may have been more readily referred and investigated for BCG disease. On the other hand, HIV-infected children may have been missed because they were not referred or died before presentation. Standard diagnostic guidelines. The importance of the
556 CID 2006:42 (15 February) HIV/AIDS

rapid and accurate diagnosis of BCG disease is emphasized in this study. Fine-needle aspiration was a reliable and minimally invasive tool for the rapid conrmation of local and regional BCG disease. Distant BCG disease was conrmed mainly through examination of gastric aspirate specimens; gastric aspiration is routinely performed in the study setting on the basis of clinical indications. If dissemination is suspected in an immunocompromised child, we recommend that standard investigations include ne-needle aspiration of local and/or regional lesions, chest radiography, and examination of respiratory aspirate specimens. Although we did not routinely perform these tests, mycobacterial blood culture [21, 22], bone marrow biopsy, urine culture, and other systemic investigations are recommended, as clinically indicated, to conrm disseminated disease [6]. On the basis of our results and the literature, we have formulated guidelines for the diagnosis of BCG disease in children (gure 2), with the aim of improving current diagnostic and surveillance strategies. Revised pediatric BCG disease classication. We have documented that BCG has a wide spectrum of disease in HIVinfected children. An important nding is that distant BCG disease may occur in immunocompromised children in the absence of local or regional disease. In these children, a high index of suspicion is required, even if local or regional disease is absent. Our revised BCG disease classication aims to more accurately reect clinically relevant BCG disease categories in HIV-infected children, and it incorporates standard Expanded Programme on Immunization denitions. The revised pediatric disease classication is feasible to implement in routine clinical practice. Distant BCG disease, as dened by our revised disease classication, reects hematogenous and/or distant lymphatic spread, whereas disseminated disease reects the ability to isolate M. bovis BCG from 11 distant site and/or from blood or bone marrow culture. Both of these disease categories have signicant prognostic and therapeutic implications. Furthermore, we recognize that BCG IRIS reects a different disease pathogenesis with improved prognosis. This is supported by the survival of the majority of children with BCG IRIS. Finally, we have allowed for the occurrence of dual disease with M. tuberculosis and M. bovis BCG (e.g., regional BCG disease and pulmonary tuberculosis). This is especially relevant in settings where tuberculosis is highly endemic and affects the decision of whether to initially include pyrazinamide in the chemotherapeutic regimen. Preliminary management guidelines. Preliminary guidelines for the management of BCG disease in children are described in gure 3. There are no conclusive data on the benet of antituberculosis therapy in HIV-uninfected children for local BCG disease, which is usually self-limiting [23]. However, in HIV-infected children, the risk of BCG spread from regional

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to distant sites, coupled with the documented poor outcome, clearly warrant aggressive medical and/or other therapy. On the basis of the observed resistance patterns [9] and the poor outcome noted for children who are receiving limited antituberculosis regimens in this study and in the literature [6, 8, 10], we recommend antituberculosis regimens with at least 4 drugs given at high dosages. Pyrazinamide should be added until tuberculosis is excluded. On the basis of experience with HIVinfected adults with M. bovis disease [24], we believe that a minimum of 9 months therapy is required. Monitoring for drug toxicity and response to therapy are recommended The poor response to therapy observed in HIV-infected children with distant BCG disease may result from a number of factors: the advanced degree of immunosuppression in the majority of subjects, the fact that the majority did not receive HAART, inherent BCG resistance coupled with suboptimal drug dosages in some subjects (despite good adherence to treatment), delayed institution of appropriate antituberculosis therapy, and possible poor absorption of antituberculosis drugs [25]. The survival of the only HIV-infected child with distant BCG disease may be attributed to early initiation of HAART in combination with appropriate antituberculosis therapy. Despite the small number of subjects, we suggest that distant or disseminated BCG disease in HIV-infected children who are not receiving HAART is an indication for expedient initiation of HAART. The value of excision biopsy or therapeutic aspiration for minimizing the focus of potential hematogenous or lymphatic dissemination of BCG in HIV-infected children is unknown and is difcult to assess in this study, because surgical interventions were not performed in a standardized fashion. In summary, we recommend the use of standard diagnostic guidelines for BCG disease in children, and we propose that the clinically relevant revised pediatric BCG disease classication system be used to standardize surveillance and case management in HIV-infected and HIV-uninfected children. Medical and surgical treatment modalities for BCG disease in HIVinfected children should be formally assessed through prospective studies; however, on the basis of the risk of distant or disseminated BCG disease in immunocompromised children, we suggest that, in the interim, the management strategies described above should be adopted. Finally, hospital- and population-based surveillance and prospective follow-up of HIVinfected infants is important for accurate quantication of the risks of BCG disease in HIV-infected children.
Acknowledgments
We would like to thank Wendy Brittle, for performing mycobacterial culture; Colleen Wright, for performing ne-needle aspiration; Monika Esser and Brian Eley, for assistance in immunologic diagnostic evaluation of patients; the TB in the 21st Century Consortium, an international network supported by the Norwegian Research Council, and the Centre for Prevention of Global Infections, University of Oslo, for scientic input; the DST/NRF Centre of Excellence in Biomedical Tuberculosis Research,

for support of laboratory analysis; and Odelia Strauss, for performing spoligotyping. Financial support. Technology and Human Resources for Industry Programme, South Africa. Potential conicts of interest. All authors: no conicts.

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