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Bacille Calmette-Guérin Vaccine—Induced Disease in HIV-Infected and HIV-Uninfected Children

  1. A. C. Hesseling1,
  2. H. Rabie1,
  3. B. J. Marais1,
  4. M. Manders3,
  5. M. Lips1,
  6. H. S. Schaaf1,
  7. R. P. Gie1,
  8. M. F. Cotton1,
  9. P. D. van Helden2,
  10. R. M. Warren2, and
  11. N. Beyers1
  1. 1Desmond Tutu TB Centre and Department of Pediatrics and Child Health, Stellenbosch University, Tygerberg, South Africa
  2. 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
  3. 3Academic Medical Centre, Amsterdam, The Netherlands
  1. 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{at}sun.ac.za).
 
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Abstract

Background. Bacille Calmette-Guérin (BCG)—a live, attenuated vaccine—is routinely given to neonates in settings where tuberculosis is endemic, irrespective of human immunodeficiency virus (HIV) exposure. HIV-infected infants and other immunodeficient 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 classification 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 confirm Mycobacterium bovis BCG. Clinical data were collected through medical file review. BCG disease was classified according to standard and revised disease classifications. 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 immunodeficiencies. All 8 children with distant or disseminated disease were immunodeficient; 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 immunodeficient children. The proposed pediatric BCG disease classification reflects 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 HIV-infected and HIV-uninfected children is essential.

The World Health Organization currently recommends giving bacille Calmette-Guérin (BCG)—a live, attenuated Mycobacterium bovis vaccine strain—to 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 host's immune characteristics [3–5]. In the era before HIV, the reported frequency of disseminated BCG disease was extremely low (0.19–2 cases/1 million vaccinated infants) [3, 6], and disease was associated with congenital immunodeficiencies [7]. HIV-infected children are at risk of developing BCG disease; this risk is poorly quantified [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, 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 difficult 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 classification of BCG disease and propose diagnostic and management guidelines for BCG disease in children.

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Methods

Study setting and patients. Participants in this hospital-based, retrospective study were routinely investigated for suspected mycobacterial disease at the Tygerberg Children's Hospital, a tertiary referral hospital in the Western Cape Province, South Africa. Investigations included culture of gastric aspirates, fine-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 definitions. Mycobacterial cultures were performed using the MGIT automated broth culture system (Beckton-Dickinson). M. bovis BCG was differentiated from the other members of the M. tuberculosis complex by standard PCR amplification 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 confirmed 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 significant 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 files using a standard data-extraction tool. Chest radiographs were assessed by 2 pediatric tuberculosis specialists using a standard radiologic classification [18]; the specialists were blinded to BCG disease classification. 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 classification. The classification of BCG disease developed by Talbot et al. [6] was used. In addition, to more accurately reflect all relevant disease categories in HIV-infected children, a pediatric classification system was developed; disease categories included local disease, regional disease, distant disease, disseminated disease, and BCG immune reconstitution inflammatory syndrome (IRIS) (figure 1).

Figure 1
Figure 1

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

Data management and ethics considerations. Data were analyzed with SPSS, version 11.5 (SPSS). Descriptive analyses were performed using the χ2 statistic and Fisher's exact test. A P value of ⩽.05 was considered to be statistically significant. Patient confidentiality was maintained through anonymous coding of mycobacterial isolates and patients' personal information. Informed consent for patient participation was obtained from parents or legal guardians. The study was approved by the ethics committee of the Faculty of Health Sciences, Stellenbosch University.

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Results

Overview of cases. There were 466 confirmed 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 confirmed mycobacterial disease among all hospitalized children and to 17 (15.7%) of 108 cases among HIV-infected children.

BCG disease classification. The comparison of BCG disease categories, according to the Talbot classification and the revised pediatric disease classification (as defined in figure 1), is presented in table 1. Local or regional BCG disease was diagnosed by confirmation of M. bovis BCG from fine-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.

Figure 2
Figure 2

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

Figure 3
Figure 3

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

Table 1
Table 1

Classification of bacille Calmette-Guérin (BCG) disease in 25 children according to the Talbot and revised pediatric disease classifications.

The most important differences noted between the Talbot and revised disease classifications 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 reflected in the revised but not the Talbot classifications. 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 confirmation of both organisms from multiple serial isolates. Additional description of cases reflects the revised pediatric disease classification only.

Clinical and immunologic characteristics. Clinical and immunologic characteristics are shown in table 2. Seventeen (68%) of 25 children had confirmed HIV infection, and there were 2 HIV-uninfected children (8%) with primary immune deficiencies (one patient had severe combined immune deficiency, and the second had an unidentified T cell deficiency). These children were all healthy at birth. All 8 children with distant or disseminated BCG disease had immunodeficiencies; 6 were HIV infected.

Table 2
Table 2

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

In the 6 children with no known immunodeficiencies, 3 were confirmed to be HIV uninfected. HIV status was not confirmed 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, 2–5 months) in children without immunodeficiencies.

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 classified 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 4 HIV-uninfected children underwent surgery for axillary and/or suppurative axillary adenitis. Only 1 surgical complication occurred (a fistula 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.

Table 3
Table 3

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

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, 3–384 days). Seven HIV-infected children with BCG disease received HAART; 2 died (28.6%). HAART was significantly associated with overall survival among HIV-infected children (OR, 0.218; 95% CI, 0.059–0.894; 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 diagnosis, 42 days; range, 8–231 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 opacification 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 findings were found to have normalized. The second child had an unidentified T cell deficiency and presented with persistent low CD4+ T lymphocyte count, septic arthritis, failure to thrive, recurrent airway infections, and distant BCG disease. Investigation for IFN-δ, TNF, and IL-12 production and of the IL-12 and IFN-δ receptors yielded normal findings. In addition to monthly hyperimmune globulin therapy, 4-drug antituberculosis therapy was initiated immediately after confirmation 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 deficiency 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 nonimmunodeficient children were alive at the end of the study.

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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 immunodeficiencies, 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 study's 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 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 confirmation of local and regional BCG disease. Distant BCG disease was confirmed 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 fine-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 confirm disseminated disease [6]. On the basis of our results and the literature, we have formulated guidelines for the diagnosis of BCG disease in children (figure 2), with the aim of improving current diagnostic and surveillance strategies.

Revised pediatric BCG disease classification. We have documented that BCG has a wide spectrum of disease in HIV-infected children. An important finding 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 classification aims to more accurately reflect clinically relevant BCG disease categories in HIV-infected children, and it incorporates standard Expanded Programme on Immunization definitions. The revised pediatric disease classification is feasible to implement in routine clinical practice.

Distant BCG disease, as defined by our revised disease classification, reflects hematogenous and/or distant lymphatic spread, whereas disseminated disease reflects the ability to isolate M. bovis BCG from >1 distant site and/or from blood or bone marrow culture. Both of these disease categories have significant prognostic and therapeutic implications. Furthermore, we recognize that BCG IRIS reflects 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 figure 3. There are no conclusive data on the benefit 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 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 HIV-infected 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 difficult 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 classification 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 HIV-infected 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 HIV-infected infants is important for accurate quantification of the risks of BCG disease in HIV-infected children.

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Acknowledgments

We would like to thank Wendy Brittle, for performing mycobacterial culture; Colleen Wright, for performing fine-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 scientific 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 conflicts of interest. All authors: no conflicts.

  • Received July 14, 2005.
  • Accepted September 25, 2005.
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References

  1. ↵
    1. World Health Organization
    . BCG vaccine: WHO position paper. Wkly Epidemiol Rec 2004;79:27-38. Available at: http://www.who.int/wer. Accessed 14 September 2005.
    Medline
  2. ↵
    1. Nicol M,
    2. Eley B,
    3. Kibel M,
    4. Hussey G
    . Intradermal BCG vaccination—adverse reactions and their management. S Afr Med J 2002;92:39-42.
    MedlineWeb of Science
  3. ↵
    1. Fine PEM,
    2. Carneiro IAM,
    3. Milstien JB,
    4. Clements CJ
    . Issues relating to the use of BCG immunization programmes—a discussion document. World Health Organization (WHO) document WHO/V&B/99.23. Geneva: WHO; 1999.
    1. Lotte A,
    2. Wasz-Hockert O,
    3. Poisson N,
    4. et al
    . Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc Lung Dis 1988;63:47-59.
    Medline
  5. ↵
    1. Milstien JB,
    2. Gibson JJ
    . Quality control of BCG by WHO: a review of factors that may influence vaccine effectiveness and safety. Bull World Health Organ 1990;68:93-108.
    MedlineWeb of Science
  6. ↵
    1. Talbot EA,
    2. Perkins MD,
    3. Silva SF,
    4. Frothingham R
    . Disseminated bacille Calmette-Guerin disease after vaccination: case report and review. Clin Infect Dis 1997;24:1139-46.
    Abstract/FREE Full Text
  7. ↵
    1. Casanova JL,
    2. Blanche S,
    3. Emile JF,
    4. et al
    . Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study. Pediatrics 1996;98:774-8.
    Abstract/FREE Full Text
  8. ↵
    1. Hesseling AC,
    2. Schaaf HS,
    3. Hanekom WA,
    4. et al
    . Danish bacille Calmette-Guerin vaccine-induced disease in human immunodeficiency virus-infected children. Clin Infect Dis 2003;37:1226-33.
    Abstract/FREE Full Text
  9. ↵
    1. Hesseling AC,
    2. Schaaf HS,
    3. Victor T,
    4. et al
    . Resistant Mycobacterium bovis bacillus Calmette-Guerin disease: implications for management of bacillus Calmette-Guerin disease in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2004;23:476-9.
    CrossRefMedlineWeb of Science
  10. ↵
    1. Sicevic S
    . Generalized BCG tuberculosis with fatal course in two sisters. Acta Paediatr Scand 1972;61:178-84.
    MedlineWeb of Science
  11. ↵
    1. Department of Health
    . National HIV and syphilis antenatal seroprevalence survey 2003. Available at: http://www.doh.gov.za/docs/reports/2003/hiv/p1-23.pdf. Accessed 14 September 2005.
  12. ↵
    1. Cape Town TB Control
    . Progress report 1997–2003. Available at: http://www.hst.org.za/publications/618. Accessed 14 September 2005.
  13. ↵
    1. Talbot EA,
    2. Williams DL,
    3. Frothingham R
    . PCR identification of Mycobacterium bovis BCG. J Clin Microbiol 1997;35:566-9.
    Abstract/FREE Full Text
  14. ↵
    1. Carroll NM,
    2. Richardson M,
    3. van Helden PD
    . Criteria for identification of cross-contamination of cultures of Mycobacterium tuberculosis in routine microbiology laboratories. J Clin Microbiol 2003;41:2269.
    FREE Full Text
  15. ↵
    1. Warren RM,
    2. Victor TC,
    3. Streicher EM,
    4. et al
    . Patients with active tuberculosis often have different strains in the same sputum specimen. Am J Respir Crit Care Med 2004;169:610-4.
    Abstract/FREE Full Text
  16. ↵
    1. Kamerbeek J,
    2. Schouls L,
    3. Kolk A,
    4. et al
    . Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol 1997;35:907-14.
    Abstract/FREE Full Text
  17. ↵
    1. Western Cape Department of Health
    . Intradermal BCG immunization: information for health workers about the use of intradermal BCG (bacille Calmette-Guerin) vaccine against tuberculosis in the Expanded Programme on Immunization in South Africa. Available at: http://www.capegateway.gov.za/eng/your_life/4502. Accessed 14 September 2005.
  18. ↵
    1. Marais BJ,
    2. Gie RP,
    3. Schaaf HS,
    4. et al
    . A proposed radiological classification of childhood intra-thoracic tuberculosis. Pediatr Radiol 2004;34:886-94.
    CrossRefMedlineWeb of Science
  19. ↵
    1. Centers for Disease Control Prevention
    . 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 1994;43(RR-12):1-10. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/0032890.htm.
    Medline
  20. ↵
    1. Sneath PHA,
    2. Holt JG
    1. Wayne LG,
    2. Kubica GP
    . The mycobacteria. In: Sneath PHA, Holt JG, editors. Bergey's manual of systematic bacteriology. Vol. 2. Baltimore: Williams & Wilkins; 1986. p. 1435-57.
  21. ↵
    1. Waddell RD,
    2. Lishimpi K,
    3. von Reyn CF,
    4. et al.,
    5. Dartmouth/UCLMS/UNZA Collaborative Study Group
    . Bacteremia due to Mycobacterium tuberculosis or M. bovis, bacille Calmette-Guerin (BCG) among HIV-positive children and adults in Zambia. AIDS 2001;15:55-60.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Ker CC,
    2. Hung CC,
    3. Huang SY,
    4. et al
    . Comparison of bone marrow studies with blood culture for etiological diagnosis of disseminated mycobacterial and fungal infection in patients with acquired immunodeficiency syndrome. J Microbiol Immunol Infect 2002;35:89-93.
    Medline
  23. ↵
    1. FitzGerald JM
    . Management of adverse reactions to bacille Calmette-Guerin vaccine. Clin Infect Dis 2000;31(Suppl 3):75-6.
    CrossRef
  24. ↵
    1. LoBue PA,
    2. Moser KS
    . Treatment of Mycobacterium bovis infected tuberculosis patients: San Diego County, California, United States, 1994–2003. Int J Tuberc Lung Dis 2005;9:333-8.
    MedlineWeb of Science
  25. ↵
    1. Berning SE,
    2. Huitt GA,
    3. Iseman MD,
    4. Peloquin CA
    . Malabsorption of antituberculous medications by a patient with AIDS. N Engl J Med 1992;327:1817-8.
    MedlineWeb of Science
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  1. Clin Infect Dis. (2006) 42 (4): 548-558. doi: 10.1086/499953
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