Noel, Francine MD, MSCI*; Wright, Peter F MD†; Bois, Gyrlande MD*; Deschamps, Marie-Marcelle MD*; de Matteis, Patricia MT*; Cassangnol, Rachelle MD*; Thimothee, Maryse MS*; Celestin, Katucia BA*; Vaz, Louise BS†; Bradshaw, John A MD‡; Brignoli, Emilio PhD*; Zhu, Yuwei MD, MS†; Johnson, Warren D MD§; Fitzgerald, Daniel MD§; Pape, Jean W MD*§
Impoverished areas of the world such as Haiti continue to bear the brunt of the HIV-1 epidemic. HIV seroprevalence among women tested at antenatal clinics in Haiti is 3.1%, the highest of any country outside the African continent.1 Sixty-four percent of HIV cases reported in the Caribbean are found in Haiti.2 The rate of mother-to-child transmission (MTCT) in Haiti was estimated to be 30% before interventions were available.3
Numerous studies have documented the natural history of HIV infection in perinatally infected children living in resource-poor countries.4-6 Fewer reports, mostly from Africa, have attempted to document causes of infant mortality associated with HIV; but there remains a paucity of data on the bacterial causes of serious illness and death in HIV-infected children in such settings.7,8
It has already been established that AIDS has important consequences on health and survival rates of children in Haiti.9 Identifying the causes of early infant death in Haiti attributable to HIV infection has been difficult for several reasons including: a high intrinsic infant mortality rate in Haiti (82/1000), a rapid progression of AIDS, with 60% of children with suspected HIV infection dying before 6 months of age, lack of AIDS-defining illnesses in most children,10 and limited availability of laboratory diagnostic techniques.
In 1999, the Haitian Ministry of Health, in collaboration with the Haitian medical community, began a pilot program to reduce the rate of MTCT. The program included limiting unwanted pregnancies in HIV-infected women, providing oral zidovudine (ZDV) short-term prophylaxis for HIV-infected pregnant mothers and infants,11 and offering formula in substitution for breast-feeding.12 The choice of ZDV as a single drug was influenced by concerns about development of resistance to nevirapine, which is an important first-line drug in the national regimen. ZDV, as a single drug, is an alternative option in current WHO recommendations.13,14
The aims of the present study, which was nested within the program to reduce the rate of MTCT, were to identify treatable and preventable infectious causes of morbidity and mortality in children affected by HIV during their first 15 months of life and to define the role of bacterial sepsis in the natural history of AIDS in Haitian children. Despite efforts to limit MTCT, infant morbidity and mortality remained high in children born to HIV-infected mothers. When coupled with effective antiretroviral strategies, the prevention of opportunistic infections should have a major impact on the outcome of children born into a family with HIV.
Enrollment and Routine Assessment
A prospectively observed cohort of 120 children born to HIV-infected mothers between May 2001 and December 2003 were enrolled within 100 days of birth. The study was conducted at GHESKIO Centers, a facility for the diagnosis and care of HIV-infected individuals located in Port-au-Prince, Haiti. Informed consent was obtained from the mother on enrollment in the study. If the parent was illiterate, the consent was read to the parent in Creole in the presence of another witness. If the mother agreed to participate she indicated consent with a fingerprint. The GHESKIO Centers Institutional Review Board (IRB) and the IRBs of Cornell and Vanderbilt Universities approved the study protocol.
The HIV-infected mothers had either: (i) been observed during their pregnancy in an ongoing study of the effectiveness of delivering antiretroviral therapy for preventing MTCT (117 mothers); or (ii) referred with their children for care within 100 days of birth (3 mothers). Mothers less than 16 years of age and or those living outside Port-au-Prince were not included. Mothers who were being observed prenatally were offered antiretroviral therapy with oral ZDV, 300 mg three times daily, beginning at 36 weeks of gestation and continuing through delivery. Infants were started within 72 hours of birth on ZDV, 2 mg/kg every 6 hours for 7 days. Seventy-five of the mother/infants pairs (63%) were reported to be in full compliance with this regimen. No mothers or children received highly active antiretroviral therapy. Deliveries occurred largely in the home with mothers assisted in labor and delivery by people without formal medical or nursing training. Strategies to assure compliance with MTCT antiretroviral therapy and the outcome of those interventions will be described elsewhere.
The choice to breast-feed or formula-feed was made by the mothers after counseling and group sessions with other pregnant women and a psychologist. Formula was provided to mothers who opted for this choice for a 9-month period. The provision of formula was facilitated by weekly visits to the clinic where a supply for the following week was given and safe formula preparation reviewed. At these weekly visits a nurse evaluated the weight and overall appearance of the babies and referred them, if necessary, to the pediatrician.
Formal medical assessments were scheduled in the first week of life and at 1, 2, 3, 4, 6, 9, 12, 15, 18, and 24 months. At each visit, history, weight measurements, and physical examination were performed and socio-demographic, clinical, and outcome data were collected. Additional sick visits were made as necessary. When visits were missed, field workers were sent to encourage the mother to bring her child to the clinic. Children were given all immunizations available on a national level (bacillus Calmette-Guerin (BCG), polio, measles, diphtheria, pertussis, and tetanus). Haemophilus influenzae vaccine was available on a limited basis. Primary prophylaxis for Pneumocystis jiroveci pneumonia (PCP) was offered with trimethoprim sulfamethoxazole (TMP-SMX) for HIV-exposed children from 6 weeks of age until their HIV infection status was established.15 Courses of TMP-SMX, were documented as complete, incomplete, or not done based on physicians' knowledge of compliance with the regimen.
Children who became sick had a diagnostic assessment, which included obtaining a blood culture. Seriously ill infants were referred for care to local hospitals. Full details of diagnosis and care after referrals from GHESKIO are not available. Autopsies were not performed. The physicians caring for the child determined whether an illness compatible with the Centers for Disease Control and Prevention's definition of HIV/AIDS.16
If the child presented with fever (>38°C axillary) hypothermia, lethargy, vomiting or diarrhea, persistent failure to thrive, chronic diarrhea, or clinically diagnosed or suspected tuberculosis infection, blood cultures were obtained before administration of antibiotics. Additional blood cultures were obtained at selected visits on well children. Blood cultures were processed in a BACTEC 9000 MB, Beckton-Dickinson model using BACTEC and BACTEC Myco/F Lytic broths, which allowed detection of both bacterial and mycobacterial species. If growth was detected, Gram and acid-fast stains were done, and the organisms were appropriately subcultured on McConkey, chocolate, and sheep blood agars for bacterial colony growth or Middlebrook 7H9 broth and Lowenstein-Jensen slants for suspected mycobacteria. Mycobacterial speciation was done at Institut Pasteur, Guadeloupe under the directorship of Dr. Nalin Rastogi. The speciation of staphylococcal isolates by the presence of coagulase was confirmed using ID 32 Staph (bioMerieux, Lyon, France) and read in a miniAPI machine (bioMerieux). Antibiotic sensitivity testing was not done.
For purposes of analysis, the isolates were divided into potential pathogens (mycobacteria species Salmonella, Shigella, other enteric pathogens, Staphylococcus aureus, and Candida) and suspected contaminants (staphylococcal species other than aureus, and Corynebacterium). The isolation of an organism was correlated with clinical symptoms consistent with systemic, respiratory, or gastrointestinal disease.
Determination of HIV Status
Children were tested at 3 monthly intervals for the presence of maternally derived antibody to 15 months of age either by one of two rapid latex-agglutination tests, Capillus HIV-1/2 (Trinity Biotech, Wicklow, Ireland), or Determine HIV-1/2 (Abbott Laboratories, Abbott Park, IL), or by ELISA, Murex HIV-1.2.O (Abbott). Equivocal results were confirmed by Western blot, Cambridge Biotech HIV-1 WB (Calypte Biomedical, Rockville, MD).
A nucleic acid sequence-based assay, NASBA (bioMerieux Boxtel, The Netherlands), was performed in the infant's first week of life if a mother had been observed at GHESKIO during her pregnancy or at the first visit if infant was referred postnatally. The test was repeated after 3 months of life. If test results were positive the family was contacted to return for confirmatory testing. An enhanced p24 antigen detection assay was used as complementary assay for confirmation of the nucleic acid amplification in selected patients.17
The criteria for determining HIV status were based on serology, RNA detection, and clinical signs and symptoms compatible with AIDS and are shown in Table 1.
Descriptive and exploratory graphical analyses were used to describe the laboratory test results, and clinical symptoms. χ2 test or Fisher exact test or test for trend was used as appropriate for contingency table analyses. Although many infants were observed beyond 15 months of age all analyses were censored at 15 months with the exception of including later serum specimens that defined seroreversion. The incidence rate of clinically significant organisms was defined as the number of organisms divided by the follow-up time in months assuming Poisson distribution. All data analysis was done using SPSS version 13.0 (Chicago, IL).
Demographics and Follow-up
Enrollment and follow-up are shown in Figure 1. One hundred twenty children were enrolled (53% female) with a median age of 3 days at enrollment (range 0-98 days). One hundred seventeen (97.5%) received BCG within the first 2 weeks of life. Seventy-three (60.8%) children received a complete course of TMP-SMX, 25 (20.8%) children had an incomplete course, 22 (18.3%) children did not receive TMP-SMX. One hundred eighteen (98%) mothers elected to formula-feed their infants. None of the children received treatment with antiretrovirals in the 15 months of postnatal follow-up beyond the perinatal ZDV.
Over the course of follow-up to 15 months, 13 (9.1%) children were lost to follow-up. The most common reason for not being able to return to the clinic was families leaving Port-au-Prince for their rural family homes. Other reasons given were deterioration of health status of the mothers, separation from partner, loss of income, and political instability in the country. Eight mothers are known to have died in the 15 months after the birth of their child.
Determination of HIV Status
Fourteen of 106 (13%) children with sufficient follow-up to determine HIV status were judged to have been infected (Fig. 1). The most consistent means of establishing a diagnosis of HIV were clinical criteria and RNA detection. Because of early deaths of many of the HIV-infected children, serologic confirmation of the diagnosis was much less helpful. Eighty-four patients became seronegative and/or had 2 negative NASBA assays.
The NASBA assay was positive in 4 of 70 tested children within 7 days of birth-a finding indicative of prenatal transmission. The assay was repeated at 3 months of age to detect perinatal transmission. An enhanced p24 assay was run on samples from 7 individuals and was in each case consistent with the other parameters that defined their HIV status.
The administration of antiretroviral therapy to mother and infant decreased the documented rate of transmission from 14% in the untreated group to 8% in the completely treated group and increased the number proven to be uninfected from 50% to 76%. However, neither of these trends was statistically significant in the number studied.
A total of 213 illness visits were recorded for the population being observed to 15 months. The majority of these illnesses could be characterized as systemic, upper respiratory, lower respiratory, or gastrointestinal. Illness in all categories was more frequent in HIV-infected than uninfected children and total and systemic illness had nonoverlapping confidence intervals for the two groups (Table 2). The infants whose HIV status was indeterminate resembled the HIV-infected group in frequency and type of illness (Table 2).
A total of 328 blood cultures were drawn from the 120 study participants in the first 15 months of life. Figure 2 illustrates the results of cultures drawn when the children were symptomatic and those drawn when the children were well. Fourty-eight cultures had a clinically significant organism, of which 38, a remarkable number, were Staphylococcus aureus. Several different assays were used to confirm the identification of the staphylococci as coagulase positive. Blood cultures were more likely to be positive for a significant organism and positive for Staphylococcus aureus if the child was symptomatic (Fig. 2).
Four cultures were positive for mycobacteria species. Cultures from 3 of the 4 children were consistent with BCG and were obtained shortly after BCG vaccine administration. All had chest radiographs performed; one of these radiographs was interpreted as showing tuberculosis. A fourth culture could not be characterized beyond being a mycobacteria species. This child also had a chest radiograph consistent with tuberculosis.
Variables Associated With Bacteremia
The rate of bacteremia was compared between the 14 children with HIV infection and those of indeterminate or uninfected status. The rate of bacteremia was higher in the HIV-infected group than the uninfected group as judged by the nonoverlapping 95% CI (Table 3). Of the 22 children who died within 15 months, 8 had a documented positive blood culture, all of which were Staphylococcus aureus. The rate of bacteremia was also higher in those who died (Table 3).
The use of TMP-SMX as judged by a complete or incomplete course of the drug did not change the rate of bacteremia in the first 6 months of life. Twenty Staphylococcus aureus cultures from the GHESKIO laboratory tested after completion of this study were all sensitive to TMP-SMX.
Skin disease was associated with a higher frequency of isolation of both contaminants and Staphylococcus aureus, but the significant clinical association of Staphylococcus aureus with illness remained even when those with skin disease are excluded.
The infant mortality rate in the first 15 months was very high-22 of 106 (207/1000 live births) with 5 (22%) deaths occurring within 6 weeks and 16 (70%) within 6 months of birth. One additional death occurred in a child over 15 months of age and 1 child died at an unknown age making the total known mortality 24 of 107 (224/1000). The mortality was evenly distributed over the 3 years of enrollment in the study. The most common illness complex leading to death was characterized by the clinical staff as a septic illness with accompanying fever and cough. AIDS was a major contributor to mortality, but a number of deaths could not be directly attributable to AIDS (Fig. 1). The mortality in the indeterminate group was similar in frequency and timing to that of the HIV-infected group.
A decrease in mortality was associated with TMP-SMX administration. Four of 73 who had complete therapy, 6 of 25 who had incomplete therapy, and 13 of 22 not receiving TMP-SMX died, P < 0.01 for trend toward decreased mortality with TMP-SMX treatment. The protective effect of TMP-SMX administration remained after exclusion of 5 infants who died before 6 weeks of age and would not have qualified to receive prophylaxis that is normally begun at 6 weeks of age.
As a partial explanation for their burden of illness, Haitian children born of HIV-infected mothers have a high frequency of bacteremia. Higher rates of bacteremia were associated with HIV infection and mortality. However, of the 23 children who died only 11 were seen within 1 month of death. The explanation is that as their children became chronically ill the parents did not bring them for care and most of the children died at home. Thus we do not have evidence of bacteremia as an immediate cause of death.
Staphylococcus aureus was the predominant pathogen. This is in contrast to the more limited role that staphylococcal bacteremia has until recently played in industrial countries; however, there is now a major resurgence of serious disease caused by Staphylococcus aureus in North America.18 Staphylococcal bacteremia is not unique to Haiti as a number of series from Africa have identified Staphylococcus aureus as a leading organism isolated from the blood.19-21 Several articles have suggested that staphylococcal bacteremia may, in part, be due to the high frequency with which scabies and impetigo interact to cause skin disease in children in developing countries. However, when we controlled for the presence of overt dermatologic conditions the association of Staphylococcus with significant illness remained. It is noted that other reports of causes of bacteremia in developing country settings have found the more predictable pneumococcal disease and Haemophilus influenzae infection.22-25 However, these reports were not specifically from infants of HIV-infected mothers.
The administration of TMP-SMX, although not evaluated in a randomized fashion, was associated with child survival in our study and suggests that organisms sensitive to TMP-SMX, such as P. jiroveci, could be important causes of early mortality. In studies from Africa there is increasing evidence of the role of P. jiroveci infection in mortality in HIV-infected children.26-28 There is also a possibility that TMP-SMX is working through prevention of other bacterial infections, as suggested by observations that TMP-SMX prophylaxis did not decease the observed rate of P. jiroveci infection but did decrease overall mortality in series of HIV-infected children from South Africa29 and Zambia.30 Although the overall rate of bacteremia and of coagulase-positive Staphylococcus was the same regardless of TMP-SMX administration, the use of TMP-SMX may explain the lack of pneumococcal and Haemophilus bacteremia in our series. TMP-SMX is recommended by the World Health Organization for use in developing countries in children born to HIV-infected mothers.15 From our data we would concur with that recommendation.
A concern entering the study was that mycobacterial disease might constitute an important cause of illness in infants born into HIV-infected families either through spread of M. tuberculosis from family members or from disseminated BCG infection.31,32 Three of four isolates of a mycobacterial species from the blood were related to BCG and occurred shortly after BCG vaccination. The significance of the BCG isolates shortly after vaccination, beyond demonstrating systemic spread of the organism, is not clear, though one child had a radiograph consistent with tuberculosis. Others have looked unsuccessfully for mycobacteremia in a BCG-immunized population, and BCG immunization is generally considered safe in HIV-infected children.33,34 As pediatric antiretroviral therapy is initiated in Haiti, tuberculosis is emerging as the primary opportunistic infection35 but this study was too small to directly define the benefit of prophylactic isoniazid in infants born to HIV-infected mothers.
The introduction of MTCT via short-course ZDV in the last month of pregnancy for the mother and for 1 week in the infant appeared to be successful in lowering the rate of MTCT of HIV in the children observed at GHESKIO in Haiti, as has been reported in other countries.11 The precise rate of transmission is still clouded by a small number of children lost to follow-up and a number who died before HIV status could be determined. These points will be further amplified in a separate article describing a larger cohort of HIV-infected mothers and infants.
Despite the introduction of ZDV treatment to limit MTCT and the successful introduction of formula feeding from birth to 9 months of age, overall mortality (217/1000) in children born to HIV-infected mothers remained almost as high as in a study at GHESKIO done before the introduction of ZDV for MTCT.9 In the previous study the mortality rate was 234 of 1000 in children born to HIV-infected mothers compared with 56 of 1000 in children of HIV-uninfected women. In the previous cohort, as in the present study, a clear clinical definition of HIV infection was difficult. Confirmation of these findings has also been seen in Mirebalais, a rural Haitian community, where overall infant mortality is 39 of 1000 but reaches 230 of 1000 in children born of HIV-infected mothers despite MTCT interventions (Ruth Berggren, personal communication).
As in the previous GHESKIO study, the mortality attributed to HIV infection occurred at a very early age and extended to those children who do not fit a virologic, immunologic, or clinical diagnosis of HIV infection by the time of their death.9 This suggests that truly infected children are being missed with present tools, that these children continue to die of exposure to opportunistic infections, or that the social environment in the HIV-infected family complex each may contribute to mortality. Thus, preventing MTCT may not be sufficient to improve child survival. The latter observations have been recently postulated in an article from Zambia.36
Hypotheses for early mortality include rapid progression of the primary HIV disease, intercurrent opportunistic infections, exposure to illnesses such as tuberculosis within the family constellation, and global protein-calorie malnutrition or micronutrient deficiencies. Supplying formula to virtually all children would seem to exclude a strictly nutritional cause for the excess mortality.
The potential now exists in a country like Haiti to take the next steps to fully interrupt mother-to-child HIV transmission. We continue to believe that HIV is a substantial cause of the early childhood mortality seen in Haiti, but recognize that child survival is a composite of adequate nutrition, clean water, maternal care and health, immunization against vaccine- preventable diseases, and a health care system that can respond to illness. Given the difficulties in precisely defining the impact of HIV in this population, it may be that the true impact will only be seen when MTCT is reduced to the very low levels seen in the industrial world (1%-2%)37, full maternal HIV treatment is given a very high priority, and the appropriate vaccines, prophylactic regimens, and treatment for HIV and opportunistic infections are introduced for the children.
The authors acknowledge the contributions of the Elizabeth Glaser Pediatric AIDS Foundation to the conduct of this study. FN is the recipient of an Elizabeth Glaser International Leadership Award.
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© 2006 Lippincott Williams & Wilkins, Inc.