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Bacteremia due to Mycobacterium tuberculosis or M. bovis, Bacille Calmette–Guérin (BCG) among HIV-positive children and adults in Zambia

Waddell, Richard D.; Lishimpi, Kennedya; von Reyn, C. Fordham; Chintu, Chifumbea; Baboo, K. S.a; Kreiswirth, Barryb; Talbot, Elizabeth A.c; Karagas, Margaret R.*; and the Dartmouth/UCLMS/UNZA Collaborative Study Group

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From the Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, the aUniversity Teaching Hospital, Lusaka, Zambia, the bPublic Health Research Institute, New York, New York, cDuke University Medical Center, Durham, North Carolina, USA. *See Appendix.

Received: 2 August 2000;

revised: 5 October 2000; accepted: 20 October 2000.

Sponsorship: Supported in part by a grant from The Hitchcock Foundation (250-168).

Requests for reprints to: C. Fordham von Reyn, Infectious Disease Section, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA.

Notes: The work reported in this paper was carried out in partial fulfillment of the requirements for a D.Sc. degree from the Netherlands Institute for Health Sciences (NIHES) at Erasmus University Medical School, Rotterdam.

Presented in part at the Fifth Conference on Retroviruses and Opportunistic Infections Chicago, February 1998, the XII World AIDS Conference, Geneva, June 1998, the 126th Annual Conference of the American Public Health Association, Washington DC, November 1998, and the 11th International Conference on AIDS and STDs in Africa, Lusaka, September 1999.

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Abstract

Background: Among adults with advanced HIV infection in developing countries, bacteremia due to Mycobacterium tuberculosis (MTB) is common and bacteremia due to M. bovis (bacille Calmette–Guérin; BCG) is rare. Comparable data are not available for children with HIV.

Objective: To compare the prevalence of bacteremia due to M. tuberculosis or M. bovis BCG in hospitalized children and adults with HIV infection in a developing country with a high prevalence of tuberculosis and HIV and > 95% BCG immunization coverage.

Design: Descriptive cross-sectional study.

Methods: Prospectively hospitalized patients in Lusaka, Zambia who were suspected to have HIV infection underwent phlebotomy for HIV ELISA, HIV viral load, and lysis-centrifugation blood culture for mycobacteria. Histories were obtained and patients were examined for BCG scars. Mycobacterial isolates were identified using DNA probes for MTB complex (MTBC), multiplex PCR and IS 6110 typing.

Results: The median age of 387 HIV-positive children was 15 months; 98% were BCG immunized. The median age of 344 HIV-positive adults was 32 years; 44% were BCG immunized. Blood cultures were positive for mycobacteria in six children (2%) and 38 adults(11%) (P < 0.001). The six pediatric isolates included five MTBC (40% clustered) and one BCG. The 38 adult isolates included 36 MTBC (16% clustered) and two M. avium complex.

Conclusion: Bacteremia due to MTB is less common among children than adults with advanced HIV infection in Zambia. Bacteremia due to M. bovis BCG is rare even among children with recent BCG immunization and symptomatic HIV infection.

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Introduction

In the pre-HIV era, bacteremia due to Mycobacterium tuberculosis was identified both as a typically asymptomatic feature of primary infection with M. tuberculosis and as the pathophysiologic basis for disseminated or miliary tuberculosis [1,2]. In the HIV era, mycobacteremia has been recognized as a common complication of AIDS, with M. avium predominating in developed countries and M. tuberculosis predominating in developing countries [3,4]. During blood culture studies to determine if M. avium bacteremia occurred among African AIDS patients, unsuspected M. tuberculosis bacteremia was detected in 23% of hospitalized patients with advanced AIDS in Kenya [5]. Subsequent studies have detected rates of M. tuberculosis bacteremia ranging from 10 to 20% among hospitalized or febrile adult patients with HIV infection in developing countries [6–8]. Comparable studies of M. tuberculosis bacteremia have not been conducted in children.

Mycobacteremia due to M. bovis, Bacille Calmette–Guérin (BCG), indicative of disseminated BCG infection, has also been described among persons with HIV infection, principally in case reports involving recently immunized children [9–11]. Although several studies have examined complications of BCG immunization among HIV infected children [12,13], prospective blood culture studies have not been performed to determine the prevalence of disseminated BCG infection among children with HIV infection.

Based on experience in adult patients, it was reasoned that unsuspected cases of disseminated tuberculosis or disseminated BCG might also be occurring in hospitalized children with symptoms of advanced HIV infection. To determine the relative frequencies of M. tuberculosis and BCG bacteremia among children and adults with advanced HIV infection in a developing country, mycobacterial blood cultures were performed on hospitalized children and adults in Lusaka, Zambia.

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Methods

Pediatric patients

Patients aged < 15 years, hospitalized with suspected complications of HIV infection at the University Teaching Hospital (UTH) in Lusaka, were eligible for study. Patients were required to meet the World Health Organization clinical criteria for pediatric AIDS as modified for use in Zambia [14]. After informed consent was obtained from a parent or relative, skin was disinfected with an isopropyl alcohol wipe and then disinfected with povidine-iodine that was allowed to dry for approximately 1 min. Phlebotomy was performed for HIV ELISA, HIV viral load, and mycobacterial blood culture. Patients were examined for a BCG scar over the forearm and available childhood immunization records were reviewed; those with a scar or with documentation of immunization in the absence of a scar were defined as BCG positive. Relatives were questioned about prior treatment for tuberculosis in the patient, the mother, and other household members. Data were not available on concurrent treatment. Outcome of hospitalization was available on a subset of patients.

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Adult patients

Patients age ≥ 15 years hospitalized at UTH with known or suspected HIV infection were eligible for study. After informed consent was obtained, skin was disinfected with an isopropyl alcohol wipe and then disinfected with povidine-iodine that was allowed to dry for approximately 1 min. Phlebotomy was performed for HIV ELISA and mycobacterial blood culture. Patients were examined for a BCG scar over the forearm (younger adults) or deltoid (older adults); those with a visible scar were defined as BCG positive. If they were capable of responding, patients were questioned about prior treatment for tuberculosis and prior chemoprophylaxis with isoniazid. Medical records were also reviewed when available. Data were not available on outcome of hospitalization.

Approval to conduct studies in both adult and pediatric patients was given by the Institutional Review Board at Dartmouth Medical School and the UTH Research and Ethics Committee.

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Laboratory studies

Serum samples were tested for HIV in Zambia using the Murex Wellcozyme Immune Capture ELISA 1.0.2 (Murex Corporation, Dartford, UK) and an aliquot was also shipped to the USA for selective confirmatory testing using the Abbott HIV AB HIV-1 EIA (Abbott Laboratories, Abbott Park, Illinois, USA). For pediatric patients aged < 18 months, HIV status was determined using a qualitative plasma viral load by branched chain DNA assay (Bayer Diagnostics, Emeryville, California, USA) and a qualitative RNA by dried blood spot nucleic acid sequence-based amplification (Organon Teknika, Durham, North Carolina, USA). Western blotting was not performed routinely. Patients aged < 18 months were defined as HIV positive if they had detectable HIV viral load and/or a positive dried blood spot for HIV RNA; patients aged ≥ 18 months were defined as HIV positive if the HIV ELISA assay was positive.

Blood for lysis-centrifugation culture (Isolator; Wampole Laboratories, Cranbury, New Jersey, USA) was collected (1.5 ml for pediatric patients, 10 ml for adults), kept at room temperature, and shipped every 1–2 weeks to the USA for processing using standard methods [15]. We have shown previously that mycobacteria survive for prolonged periods at room temperature in Isolator tubes and that colony forming units (c.f.u.)/ml are higher after a 28 day hold time than at day 0 [16]. Cultures were plated on Middlebrook 7H10 and 7H11 agar and incubated at 35°C for 8 weeks. A subset of 138 pediatric cultures was also plated on Middlebrook 7H11 selective media in an attempt to reduce overgrowth from organisms other than mycobacteria. Cultures positive for bacteria other than mycobacteria or for fungi were considered ‘non-evaluable'. Blood was not cultured routinely for organisms other than mycobacteria, but a subset of organisms from seven non-evaluable pediatric cultures was selected from Middlebrook plates and identified using standard microbiologic methods. Cultures demonstrating mycobacterial growth were identified using DNA probes (Gen-Probe, San Diego, California, USA) for M. avium complex (MAC) and MTB (MTBC). MTBC isolates were tested for M. bovis BCG using the multiplex PCR method described previously [17,18]. All MTBC isolates were analyzed for restriction fragment length polymorphisms using IS 6110 typing [19,20]. The relationship of MTBC isolates to strain W was determined on the basis of a number of genetic markers including the IS 6110, DNA fingerprint pattern, spoligotyping, and the presence of specific IS 6110 insertions in certain chromosomal loci [20].

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Results

Pediatric patients

Between October 1996 and October 1998, blood cultures were obtained from 736 pediatric patients with suspect HIV infection (Table 1). Blood cultures were positive for mycobacteria in six (2%) of 387 HIV-positive children with evaluable blood culture results and one (0.5%) of 196 HIV-negative children (P = 0.43; Fisher's exact test). All mycobacteria were MTBC; one was identified as M. bovis BCG. The child with disseminated BCG was 6 months old and died with a clinical diagnosis of pneumonia 2 days after the blood culture was obtained. IS 6110 typing of five M. tuberculosis isolates showed one cluster of two isolates (two out of five, 40% ‘clustered') and three unique isolates. Of seven cultures positive for non-mycobacteria that were further identified, three were coagulase negative staphylococci and four were potentially pathogenic Gram-negative rods. The use of 7H11 selective media did not reduce plate contamination. Selected demographic data and other patient characteristics are shown in Table 2. Of the 387 evaluable patients, 378 (98%) were BCG positive (15 by scar, 68 by immunization record, and 295 by both measures).

Table 1
Table 1
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Table 2
Table 2
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Of 382 HIV-positive children with available histories, cultures were positive for MTBC in none (0%) of 39 with prior treatment for tuberculosis, and six (2%) of 343 without prior treatment for tuberculosis (P = 1.0). Of the 346 HIV-positive children with available maternal histories, the mothers of 47 children had a history of treatment for tuberculosis. Blood cultures for these children were positive for MTBC in one (2%) compared to four (1%) for children whose mothers did not have a history of treatment for tuberculosis (P = 0.5). Of the 387 HIV-positive children with evaluable blood culture results, 190 (49%) were discharged from hospital in stable or improved condition (two MTBC-positive and 188 MTBC-negative), 138 (36%) died in hospital (one MTBC-positive and 137 MTBC-negative), and for 59 (15%) the outcome status is unknown (three MTBC-positive and 56 MTBC-negative). Eighty-five (22%) received treatment for tuberculosis during hospitalization (two MTBC-positive and 83 MTBC-negative). Viral load data were available for 169 (44%) of 387 HIV-positive children with evaluable blood culture results. Absolute values ranged from 504 123 copies/ml to 2 562 000 copies/ml (median, 262 400 copies/ml; 5.42 log10).

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Adult patients

Between August 1996 and April 1998, blood cultures were obtained on 386 adults patients with suspect HIV infection (Table 1). Blood cultures were positive for mycobacteria in 40 (12%) 344 HIV-positive patients with evaluable blood cultures: 38 were MTBC and two were MAC. None were M. bovis BCG. IS 6110 typing of 38 isolates showed three clusters of two isolates [six out of 38 (16%) clustered] and 32 unique isolates (one related to strain W) [20]. There was no difference in the proportion of BCG-positive versus BCG-negative patients with MTBC bacteremia (42% versus 58’P = 0.81). In a subset of 77 patients for whom data were available, there was no difference in the proportion of MTBC-positive versus MTBC-negative patients with a history of treatment for tuberculosis (86% versus 67%;P = 0.21). The proportion of these 77 patients who had both a history of tuberculosis and a BCG scar was 50% for MTBC-positive patients and 25% for MTBC-negative patients (P = 0.10). Selected demographic data and other patient characteristics are shown in Table 2.

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Comparison of pediatric and adult patients

HIV-positive adult patients were more likely than HIV-positive pediatric patients to have positive blood cultures for MTBC (38/344 versus 6/387;P < 0.001).

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Discussion

We used mycobacterial blood culture techniques to assess the risk of disseminated M. tuberculosis and disseminated BCG among children with HIV. Disseminated tuberculosis was detected in children, but at a significantly lower rate than among adults. There are several possible explanations for this difference. If disseminated tuberculosis in HIV infection results principally from reactivation of latent disease, then rates would be expected to be higher in adults than children, as adults have higher rates of latent infection with M. tuberculosis. If disseminated tuberculosis in HIV infection results principally from new progressive primary infection [4], then rates might be expected to be significant in children, as they are more likely than adults to be naïve to M. tuberculosis. However, recent BCG immunization, almost universal among the children in this study, may provide protection against new primary infection with tuberculosis in children, but may not provide sufficiently durable protection to reduce this risk among adults who were immunized in childhood. Studies in general populations have demonstrated that the efficacy of BCG is greatest against the bacteremic complications of tuberculosis [21] and is greatest in the first few years after immunization. However, further studies are needed to define the relative contributions of recent infection, reactivation and re-infection to the risk of bacteremic tuberculosis, and the role of BCG immunization in preventing this complication.

Higher rates of mycobacteremia among adults might also be due to a greater degree of HIV-related immunodeficiency in the adults in this study. The degree of immunodeficiency due to HIV infection is known to be a powerful predictor of the risk of mycobacteremia [15]. However, neither CD4 cell counts nor functional measures of cellular immunity are available with which to compare this variable in the adults and children in the present study. Another reason that higher rates were detected in adults than children may be that more blood was collected (on average 8.3 ml from adults versus 1.25 ml from children); however, c.f.u./ml were not measured and so whether or not this affected the rate of detection cannot be assessed. We cannot exclude the possibility that detected rates of M. tuberculosis bacteremia in both children and adults might have been higher with immediate specimen processing. We are not aware of previous IS 6110 analysis of MTBC strains isolated from blood. The 16% clustering rate among adults is lower than reported from studies of respiratory isolates, but this may reflect the limited number of isolates analyzed in the present study. One isolate was related to strain W, indicating that this strain may cause infections in areas outside the USA and Asia [20]. Whereas W-like strains have been reported in South Africa [22] strain W or similar strains have not been identified previously in Zambia.

Complications of BCG immunization among children with HIV infection have been assessed in previous studies. The risks of adverse events from BCG immunization depend both on the strain of BCG and the age and immunologic competence of the host. Reports from Zaire, Haiti, and Rwanda indicate that usual doses of BCG vaccine do not result in a significant increase in risk of adenitis in HIV-positive compared to HIV-negative children [23–25]. Because clinical expression of this complication depends on a local cellular immune response, these studies do not permit conclusions on the relative rates of persistent BCG replication in HIV-positive versus HIV-negative vaccine recipients.

The most serious complication of immunization in children with HIV infection, disseminated BCG infection, has been described in numerous case reports with most cases appearing in children less than 2 years of age [11,12,26]. Studies on cohorts of HIV-positive children from Africa have purported to show that disseminated BCG infection does not occur [25,27,28]. However, as disseminated BCG infection may be indistinguishable from terminal AIDS, studies comparing the rates of disseminated BCG in HIV-positive and HIV-negative children cannot be considered valid unless blood cultures have been used or autopsies performed. In a study from France, a cohort of 68 HIV-positive children who received the Pasteur or Merieux (Glaxo) BCG vaccines at age 1–8 weeks were followed clinically with mycobacterial cultures and autopsies. Fatal disseminated BCG was documented in one child at age 36 months and was considered likely in a second child who developed disseminated infection with MTBC at 5 months [29].

To our knowledge, this is the first large cross-sectional study to use blood cultures for the detection of disseminated BCG in HIV-positive children in Africa and the observed prevalence rate was one (0.26%) in 387 patients. This low rate indicates that disseminated BCG is not common among Zambian children with advanced or near-terminal HIV infection who had been immunized at birth with the Glaxo strain of BCG. Although our study was limited to hospitalized children with HIV, there is no reason to believe that the rate of this complication would be higher in outpatients or children who died with AIDS at home. In population-based studies in Europe using clinical features or autopsy rather than blood cultures, the rate of fatal and non-fatal disseminated BCG has been approximately two to four per million vaccinated [30]. Most cases have occurred in children with congenital T cell or mixed immunodeficiency syndromes. Nevertheless, the rate of disseminated BCG infection noted among hospitalized children with advanced HIV infection in Africa remains low when compared to the likely benefits of BCG for HIV-positive infants in developing countries where tuberculosis is endemic. Because most children in this study had been immunized with BCG it was not possible to assess the protective effect of BCG immunization on the risk of disseminated tuberculosis among children. Two previous studies have detected a reduced risk of disseminated tuberculosis among HIV-positive persons with prior BCG immunization [7,31]. The present study, and a study from Tanzania [32], have failed to demonstrate such an association.

In summary, bacteremic tuberculosis occurs in both HIV-infected children and adults in developing countries. The lower rate in HIV-infected children may be a consequence of the protective effects of more recent BCG immunization or to the lower rate of latent tuberculosis in children. Disseminated BCG infection was not identified in adults and was rare in children.

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Acknowledgements

The authors thank the study participants, including the parents or guardians of the pediatric subjects. We also thank Bayer Reference Testing Laboratory for providing branched chain DNA studies, Organon Teknika for providing the NASBA RNA studies, Wampole Laboratories for providing the blood culture tubes and supplies, and the Newborn Screening Program at UMASS Medical Center for performing the DBS testing.

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Appendix
The Dartmouth/UCLMS/UNZA Collaborative Study Group

M.-M. Andrews (Dartmouth Medical School [DMS]), R. D. Arbeit, (VA Medical Center, Boston, MA), B. Cole, (DMS), A. M. Comeau, (University of Massachusetts, Boston, MA), R. Frothingham, (VA Medical Center, Durham, NC), B. Halwiingi, (UNZA/UTH), A. Jaeger, (DMS), W. Kamshasha, (UNZA/UTH), A. D. Lein, (DMS), G. Myunda, (UNZA/UTH), A. Mwinga, (UNZA/UTH), A. N. A. Tosteson, (DMS), S. Tvaroha, (DMS), and W. Wieland-Alter, (DMS). Cited Here...

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Keywords:

Bacille Calmette–Guérin; BCG; HIV; tuberculosis; Zambia

© 2001 Lippincott Williams & Wilkins, Inc.

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