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Epidemiology of Bloodstream Infections in a Bacille Calmette-Guérin-Vaccinated Pediatric Population in Malawi

Identifieur interne : 002F33 ( Istex/Corpus ); précédent : 002F32; suivant : 002F34

Epidemiology of Bloodstream Infections in a Bacille Calmette-Guérin-Vaccinated Pediatric Population in Malawi

Auteurs : Lennox K. Archibald ; Peter N. Kazembe ; Okey Nwanyanwu ; Charles Mwansambo ; L. Barth Reller ; William R. Jarvis

Source :

RBID : ISTEX:901F2C5493D48AEAB8CA41066AAB027BDC9BED22

Abstract

The risk of Mycobacterium bovis bloodstream infection (BSI) in bacille Calmette-Guérin (BCG)-vaccinated children with human immunodeficiency virus (HIV) infection remains uncharacterized. We studied pediatric inpatients during the 1998 dry season in Malawi. After a detailed clinical evaluation, blood was drawn for culture and HIV testing. Of 229 children, 128 (56%) were male, 35 (15.3%) had BSI, and 30% of children aged >1.5 years (median, 2.7 years; range, 1 month–13 years) had HIV infection. The predominant pathogen was non-typhi Salmonella;neither Mycobacterium tuberculosis nor M. bovis was isolated. A diagnosis of malnutrition or sepsis was predictive of BSI; malnutrition alone correlated with both death and BSI. The bloodstream dissemination of M. tuberculosis and M. bovis BCG is uncommon in HIV-infected children vaccinated with BCG. Correlates such as malnutrition or sepsis can provide algorithms for identifying children who need observation or empirical antimicrobial therapy for BSI in the absence of appropriate laboratory testing.

Url:
DOI: 10.1086/376507

Links to Exploration step

ISTEX:901F2C5493D48AEAB8CA41066AAB027BDC9BED22

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<aff id="a4">
<label>4</label>
<institution>United States Agency for International Development</institution>
,
<addr-line>Lilongwe, Malawi</addr-line>
</aff>
</contrib-group>
<author-notes>
<fn id="FN1" fn-type="current-aff">
<label>a</label>
<p>Present affiliations: Regeneration Technologies, Inc., Alachua, Florida (L.K.A.); Office of Health, Population, and Nutrition, US Agency for International Development/ Mozambique, Maputo, Mozambique (O.N.).</p>
</fn>
<corresp id="cor1">Reprints or correspondence: Dr. Lennox K. Archibald, Regeneration Technologies, Inc., 11621 Research Circle, PO Box 2650, Alachua, FL 32616 (
<email>larchibald@rtix.com</email>
).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>15</day>
<month>7</month>
<year>2003</year>
</pub-date>
<volume>188</volume>
<issue>2</issue>
<fpage>202</fpage>
<lpage>208</lpage>
<history>
<date date-type="received">
<day>24</day>
<month>10</month>
<year>2002</year>
</date>
<date date-type="accepted">
<day>24</day>
<month>2</month>
<year>2003</year>
</date>
</history>
<copyright-statement>© 2003 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2003</copyright-year>
<abstract>
<p>The risk of
<italic>Mycobacterium bovis</italic>
bloodstream infection (BSI) in bacille Calmette-Guérin (BCG)-vaccinated children with human immunodeficiency virus (HIV) infection remains uncharacterized. We studied pediatric inpatients during the 1998 dry season in Malawi. After a detailed clinical evaluation, blood was drawn for culture and HIV testing. Of 229 children, 128 (56%) were male, 35 (15.3%) had BSI, and 30% of children aged >1.5 years (median, 2.7 years; range, 1 month–13 years) had HIV infection. The predominant pathogen was non-
<italic>typhi Salmonella;</italic>
neither
<italic>Mycobacterium tuberculosis</italic>
nor
<italic>M. bovis</italic>
was isolated. A diagnosis of malnutrition or sepsis was predictive of BSI; malnutrition alone correlated with both death and BSI. The bloodstream dissemination of
<italic>M. tuberculosis</italic>
and
<italic>M. bovis</italic>
BCG is uncommon in HIV-infected children vaccinated with BCG. Correlates such as malnutrition or sepsis can provide algorithms for identifying children who need observation or empirical antimicrobial therapy for BSI in the absence of appropriate laboratory testing.</p>
</abstract>
</article-meta>
</front>
<body>
<p>In sub-Saharan Africa, bloodstream infections (BSIs) in human immunodeficiency virus type 1 (HIV-1)-infected children are associated with significant mortality [
<xref ref-type="bibr" rid="r1">1</xref>
<xref ref-type="bibr" rid="r5">5</xref>
]. BSI etiologies in pediatric inpatient populations vary across Africa and depend on the region in which the study is conducted, the study population selected, and the microbiological techniques used [
<xref ref-type="bibr" rid="r1">1</xref>
,
<xref ref-type="bibr" rid="r5">5</xref>
<xref ref-type="bibr" rid="r7">7</xref>
]. All published studies, however, have focused solely on isolating bacteria rather than other opportunistic pathogens, such as mycobacteria or fungi. In consequence, the occurrence and clinical features of mycobacteremia and fungemia in HIV-1-infected pediatric patients in sub-Saharan Africa remain uncharacterized.</p>
<p>Although the early detection and treatment of BSI in children may improve patient outcomes, routine screening for BSI among children in less-developed countries, such as Malawi, is not feasible, largely because of the lack of financial and human resources necessary to offer or maintain such services, other priorities for whatever resources are available, and the impracticalities and ethical issues involved in drawing blood from very sick, malnourished, or immunosuppressed children for blood-culture research.</p>
<p>Previous studies of adult inpatient populations in areas of Africa with high endemic rates of HIV-1 infection have documented that all 3 groups of pathogens—mycobacteria, fungi, and bacteria—are important causes of BSI [
<xref ref-type="bibr" rid="r8">8</xref>
<xref ref-type="bibr" rid="r11">11</xref>
]. With increasing rates of HIV-1 infection and concomitant tuberculosis in developing countries, the probable occurrence of mycobacteremia in susceptible pediatric populations needs to be addressed.</p>
<p>In Malawi, newborns receive the bacille Calmette-Guérin (BCG) vaccine at birth. Thus, in 1998, we speculated that Malawian pediatric patients who are infected with HIV-1 might be particularly vulnerable to dissemination of the BCG bacillus strain with which they were vaccinated. In a pilot evaluation study of an improved bloodculture technique that detects mycobacteria and bacteria using just 3–5 mL of blood [
<xref ref-type="bibr" rid="r12">12</xref>
,
<xref ref-type="bibr" rid="r13">13</xref>
], we observed that HIV-1-infected children, all of whom had received BCG vaccination, acquired neither mycobacteremia nor dissemination of
<italic>Mycobacterium bovis</italic>
BCG [
<xref ref-type="bibr" rid="r14">14</xref>
]. We now report the results of a larger and more comprehensive follow-up study that was conducted in an inpatient pediatric population at the same hospital where we conducted our pilot study. The objectives were to estimate the frequency of bacteremia, mycobacteremia, and fungemia; ascertain risk factors for BSI; and confirm whether HIV-1-infected children who received the BCG vaccination are indeed at risk of acquiring
<italic>M. bovis</italic>
BSI caused by dissemination of the BCG strain.</p>
<sec sec-type="materials">
<title>Patients, Materials, and Methods</title>
<p>
<bold>
<italic>Patients and study site.</italic>
</bold>
The study was conducted at Lilongwe Central Hospital (LCH), the largest government regional medical center in central Malawi. LCH has ∼1000 beds and provides services to the patient catchment areas of Lilongwe District (1.4 million citizens) and the Central Region (4.2 million citizens). During July–August 1998 (the study period and height of the Malawi dry season), using a cross-sectional study design, we recruited newly admitted pediatric patients for whom the admitting physician had initiated antimicrobial, antituberculous, or antimalarial therapy. Approval for the study was granted by the Malawian Health Sciences Research Committee in the Malawi Ministry of Health and by the Institutional Review Board at the Centers for Disease Control and Prevention (Atlanta, GA). Patients were enrolled just once in the study. Consent forms were completed for each patient by one or both parents or by guardians, when appropriate. A detailed medical history for each patient was obtained, followed by a physical examination done by one of the principal investigators. Clinical data were entered on a standard assessment form specially designed for the study population. The recorded information for each study patient included age, sex, information on each patient's present and past medical history, presence and duration of acute and chronic symptoms, receipt of antimicrobial therapy before hospital admission, clinical findings on physical examination, and the patient outcome status (survival or death). Symptoms were deemed to be chronic if they had been present for >1 month. If the child was old enough and able to comprehend and answer the questions, the details of the medical history were obtained from him or her. If the child was not old enough to comprehend or was unable to communicate with the person taking the history, the history was obtained from the parents or guardians, when appropriate.</p>
<p>All parents of the patients received HIV-1 pretest counseling. HIV-1 test results were reported to the physician in charge of the patient's inpatient care, and posttest counseling was provided to the parents or guardians of patients with a positive HIV-1 test. The ward was notified as soon as a microorganism was isolated from the blood and again when the microorganism was identified. Physicians and other ward staff were given advice by investigators on antimicrobial regimens, if it was requested. The study was conducted according to the guidelines for the conduct of human clinical research in a country assurance agreed on by the Malawi Ministry of Health, Duke University Medical Center, and the United States Department of Health and Human Services.</p>
<p>
<bold>
<italic>BCG vaccination in Malawi.</italic>
</bold>
The Malawi BCG immunization program recommends the BCG vaccine (Pasteur Merieux Connaught BCG vaccine, derived from strain 1077 and containing 0.4–1.6 × 10
<sup>6</sup>
of culturable particles per newborn dose) for all newborn infants within the first 3 days of life.</p>
<p>
<bold>
<italic>Blood cultures.</italic>
</bold>
After the patient's skin was cleaned with a 2% tincture of iodine and 70% alcohol, 4 mL of venous blood was drawn for culture, blood count, differential, malaria smear, and HIV-1 serological testing. Only 1 set of blood cultures was drawn for each patient before antimicrobial treatment was initiated; 3 mL of blood was inoculated into a single Myco-F-Lytic (MFL; Becton Dickinson Microbiology Systems) blood-culture bottle. MFL blood-culture bottles were incubated at 35°C, examined for growth daily for a week and then once a week for 8 weeks, and processed as described elsewhere [
<xref ref-type="bibr" rid="r9">9</xref>
,
<xref ref-type="bibr" rid="r13">13</xref>
]. Isolates such as
<italic>Bacillus</italic>
species, coagulase-negative
<italic>Staphylococcus</italic>
species, diphtheroids, or
<italic>Micrococcus</italic>
species were deemed to be contaminants [
<xref ref-type="bibr" rid="r15">15</xref>
]. All organisms isolated at the study site were sent to Duke University Medical Center (Durham, NC) for identity confirmation and relevant antimicrobial susceptibility testing.</p>
<p>
<bold>
<italic>HIV-1 testing, malaria smears, and blood counts.</italic>
</bold>
A blood sample of 0.5 mL was put into an EDTA tube for a blood count, differential, and malaria smear, and 0.5 mL was used for HIV-1 antibody serological testing. Thick and thin smears were prepared from the blood of each patient enrolled in the study, stained with a modified Wright stain, and examined microscopically for the presence of
<italic>Plasmodium</italic>
asexual parasites. Serum samples were assayed in batches by ELISA test kits (SUDS HIV 1&2; Murex Diagnostics) for HIV antibodies. Positive HIV-1 ELISA results were repeated for confirmatory results.</p>
<p>
<bold>
<italic>Statistical analysis.</italic>
</bold>
Data from clinical assessment forms and results from blood cultures, malaria smears, and HIV-1 serological testing were entered into a database using Epi Info statistical software (version 6.02; Centers for Disease Control and Prevention) [
<xref ref-type="bibr" rid="r16">16</xref>
]. Categorical variables were compared by χ
<sup>2</sup>
or Fisher's exact test, where appropriate. Continuous variables were compared using Student's
<italic>t</italic>
test.
<italic>P</italic>
= .05 was considered to be statistically significant. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. Multivariate analysis using stepwise logistic regression was done using PC SAS software (SAS Institute) [
<xref ref-type="bibr" rid="r17">17</xref>
]. Continuous variables (e.g., age) were recoded into the appropriate categories to dichotomize for use in multivariate analysis. The regression coefficients and their SDs were used to compute multivariate adjusted odds ratios with 95% CIs.</p>
</sec>
<sec sec-type="results">
<title>Results</title>
<p>
<bold>
<italic>Clinical characteristics of study patients.</italic>
</bold>
During the study period, 229 pediatric patients were enrolled. The median age of these patients was 2.7 years (range, 1 month–13 years); 128 (56%) patients were male. The mean body temperature of patients at admission was 37.7°C (range, 33.9°C–41°C). The median hematocrit level was 35.2% (range, 8.3%–70%); the median white blood cell count was 11,700 cells/mm
<sup>3</sup>
(range, 1000–62,000 cells/mm
<sup>3</sup>
). Of the 229 study patients, 134 (59%) had visible BCG scars or lesions. A complete listing of clinical characteristics of the patients by blood culture status is summarized in
<xref ref-type="fig" rid="t1">table 1</xref>
.</p>
<p>
<bold>
<italic>Blood cultures, HIV-1 testing, malaria smears, and blood counts.</italic>
</bold>
Thirty-five (15.3%) children had positive blood-culture results. Rates of BSI were not significantly greater among the very young: 6 (21%) of 28 infants aged <3 months; 3 (11%) of 28 infants aged 3 to <6 months; 2 (6%) of 34 infants aged 6 months to <1 year; and 24 (18%) of 135 children aged 1–13 years. Organisms isolated from the blood included non-
<italic>typhi Salmonella</italic>
species (
<italic>n</italic>
= 27),
<italic>Escherichia coli</italic>
(
<italic>n</italic>
= 4), an unidentified gram-negative rod (
<italic>n</italic>
= 1),
<italic>Acinetobacter</italic>
species (
<italic>n</italic>
= 1), an unidentified gram-positive bacillus (
<italic>n</italic>
= 1),
<italic>Bacillus cereus</italic>
(
<italic>n</italic>
= 1), and an unidentified fungus (
<italic>n</italic>
= 1).
<italic>Mycobacterium</italic>
species and gram-positive cocci were not isolated from the blood of study infants. Two patients had polymicrobial BSI (i.e., BSI caused by >1 pathogen).</p>
<p>At the initial patient evaluation, physicians made a clinical diagnosis of malaria for 20 (8.7%) study patients. Of these 20 patients, only 2 (10%) had a positive smear. At enrollment, malaria smears were positive for 13 (5.7%) of 229 study patients. Of these, 2 (15%) were diagnosed with malaria. Of the 225 patients tested for HIV-1, 63 (28%) were HIV-1-positive. Of 118 children aged <1.5 years, 30 (25.4%) were HIV-1-positive, potentially secondary to maternal antibodies; 33 (31%) of the children aged ⩽1.5 years were HIV-1-positive.</p>
<p>
<bold>
<italic>Previous antimicrobial use and occurrence of BSI.</italic>
</bold>
Antimicrobials were commonly prescribed for children before their admission to the hospital: 4 (2%) were receiving antituberculous therapy, 52 (23%) were receiving antimalarial therapy, and 88 (38%) were receiving antibacterial therapy. Patients who received antituberculous therapy were significantly more likely than those not receiving such therapy to have a positive blood culture result (
<xref ref-type="fig" rid="t1">table 1</xref>
). However, there was no significant difference in the rate of BSI in those receiving versus those not receiving preadmission antibacterial agents.</p>
<p>
<bold>
<italic>BSI clinical correlates.</italic>
</bold>
By univariate analysis, patients with the following clinical features were significantly more likely to have a BSI than were those without: acute or chronic lethargy, chronic cough, malnutrition, and oral candidiasis (
<xref ref-type="fig" rid="t1">table 1</xref>
). In multivariate analysis, however, 3 clinical features—acute lethargy, malnutrition, and oral candidiasis—were independently associated with the acquisition of a BSI (
<xref ref-type="fig" rid="t2">table 2</xref>
).</p>
<p>
<bold>
<italic>Admission diagnosis correlates.</italic>
</bold>
Patients with positive blood-culture results had varying admission diagnoses, and many had comorbid conditions. Although there were insufficient numbers of cases of BSI to perform valid statistical tests on all presenting symptoms, some diagnoses predominated: pneumonia (93/229 [41%]), malnutrition (19/229 [8.3%]), and sepsis (18/229 [7.9%]). A diagnosis of pneumonia was not associated with the acquisition of a BSI. Conversely, a diagnosis of malnutrition (RR, 3.0; 95% CI, 1.5–6.0;
<italic>P</italic>
<.01) or sepsis (RR, 2.5; 95% CI, 1.2–5.3;
<italic>P</italic>
<.05) was significantly associated with an increased risk of acquiring a BSI. Of 5 children diagnosed with both pneumonia and malnutrition, 2 had BSIs.</p>
<p>
<bold>
<italic>Clinical outcome correlates.</italic>
</bold>
Of the 208 patients for whom outcome was recorded, 7 had been discharged by parents or guardians against medical advice. Of the remaining 201 patients with definite documented outcomes, 22 (10.9%) died. In multivariate analysis, a history of acute decreased feeding, lethargy, or malnutrition remained independently associated with mortality (
<xref ref-type="fig" rid="t2">table 2</xref>
). Although receiving antimalarial treatment before admission was associated with a higher mortality rate according to univariate analysis, this variable was not entered into the logistic regression model, because it is not a physical sign and is subject to recall bias. A positive test for HIV-1 antibodies or a positive blood culture result was not significantly associated with mortality.</p>
</sec>
<sec sec-type="discussion">
<title>Discussion</title>
<p>These data document a BSI rate of ∼15% in febrile or acutely ill pediatric inpatients in a Malawian teaching hospital. Disseminated mycobacterial infection was not seen in our study population, which was composed mostly of BCG-vaccinated children, despite an overall 28% HIV-1 seroprevalence rate for all ages and a 30% HIV-1 seroprevalence rate for children aged >1.5 years. In particular, HIV-1-infected or malnourished children who received BCG vaccination did not appear to acquire disseminated
<italic>M. bovis</italic>
BCG infection. In contrast to studies in Malawi that have highlighted the importance of
<italic>Mycobacterium tuberculosis</italic>
as a cause of BSI in HIV-1-infected adults [
<xref ref-type="bibr" rid="r9">9</xref>
,
<xref ref-type="bibr" rid="r10">10</xref>
], our study suggests that
<italic>M. tuberculosis</italic>
BSIs are relatively uncommon among HIV-1-infected children. However, because our data on disseminated mycobacterial infections were observational, we were not able to ascertain whether the BCG vaccine actually prevented the occurrence of disseminated
<italic>M. tuberculosis</italic>
infections or to establish underlying reasons why disseminated
<italic>M. bovis</italic>
infection did not occur in a BCG-vaccinated, HIV-1-infected pediatric population.</p>
<p>Although published data have suggested that the BCG vaccine is more likely to prevent disseminated forms of tuberculosis in children than pulmonary tuberculosis in adolescents or adults [
<xref ref-type="bibr" rid="r18">18</xref>
], the reasons for the absence of disseminated
<italic>M. bovis</italic>
BCG, a live attenuated mycobacterium, in our study population remain unclear. Disseminated
<italic>M. bovis</italic>
BCG infection after vaccination, which is defined by a positive blood culture for
<italic>M. bovis</italic>
BCG, is a recognized complication in immunosuppressed children [
<xref ref-type="bibr" rid="r19">19</xref>
<xref ref-type="bibr" rid="r21">21</xref>
], especially those with severe hereditary immunodeficiencies [
<xref ref-type="bibr" rid="r22">22</xref>
]. However, the only published study that used blood cultures for the detection of disseminated mycobacteria in an African BCG-vaccinated pediatric population demonstrated a paucity of mycobacterial BSI and disseminated
<italic>M. bovis</italic>
BCG infection [
<xref ref-type="bibr" rid="r23">23</xref>
].</p>
<p>Various concerns have been raised about the safety of vaccinating HIV-1-infected children with the BCG vaccine [
<xref ref-type="bibr" rid="r22">22</xref>
,
<xref ref-type="bibr" rid="r24">24</xref>
,
<xref ref-type="bibr" rid="r25">25</xref>
]. Although tuberculosis is almost synonymous with HIV-1 in developing countries, any implementation of a BCG vaccination program must include an assessment of the potential risks and benefits to patients. The data from our study corroborate the contention that HIV-1 infection or malnutrition does not necessarily predispose BCG-vaccinated pediatric patients to dissemination of the live attenuated vaccine strain of
<italic>M. bovis</italic>
BCG and provide evidence to support the World Health Organization (WHO) recommendation that children in areas with high rates of HIV-1 infection and tuberculosis should be vaccinated with BCG [
<xref ref-type="bibr" rid="r26">26</xref>
,
<xref ref-type="bibr" rid="r27">27</xref>
].</p>
<p>Because all the patients in our study potentially had been immunized with BCG, we were not able to make any objective inferences as to the relative protection afforded by being vaccinated with BCG. This protective effect could be assessed only by prospectively studying parallel populations of pediatric patients with or without BCG vaccination and recording patient outcomes. To date, however, no published studies have used mycobacterial blood-culture results to determine the protective effect of BCG in reducing disseminated disease in children in regions in Africa where HIV-1 is endemic.</p>
<p>Using the frequency of BCG scars or BCG lesions as a rough estimate of the prevalence of BCG vaccination status, we objectively ascertained that at least 59% of our study population had received BCG vaccination prior to enrollment in the study. However, data from the Malawi Ministry of Health (WHO Expanded Programme of Immunisation, Five-Year Plan 2001–2005, Malawi Ministry of Health) have suggested that vaccination coverage in Malawi is much higher (99% in 1996, 95% in 1997, 100% in 1998, 87% in 2000, and 102% in 2001). These figures are based on the estimated number of eligible children against the number of vaccines actually given; the 2001 vaccination rate suggests that children in Malawi could, in fact, be vaccinated more than once. Moreover, because BCG scars may not be readily discernible in children, especially among those whose skin reaction is minimal, we are certain that the BCG vaccination rate among our study patients was much higher than 59%.</p>
<p>Studies in Malawi and other countries in sub-Saharan Africa with high endemic rates of HIV-1 infection have established that mycobacteria, bacteria, and fungi are important causes of BSI in adult inpatient populations [
<xref ref-type="bibr" rid="r8">8</xref>
<xref ref-type="bibr" rid="r11">11</xref>
]. Our data suggest that this pattern of bloodstream pathogens may be different for pediatric inpatient populations in these regions. The 15% BSI rate in our study population is consistent with BSI rates documented by our pilot study [
<xref ref-type="bibr" rid="r14">14</xref>
] and with those for pediatric patient populations in Kenya (16.7%) [
<xref ref-type="bibr" rid="r28">28</xref>
], Malawi (17%) [
<xref ref-type="bibr" rid="r1">1</xref>
], and Rwanda (12.4%) [
<xref ref-type="bibr" rid="r29">29</xref>
]. Although gram-negative enteric pathogens were the predominant cause of BSIs in our patient cohort, regional differences have been documented for the frequency and importance of various organisms that cause BSI in pediatric populations in sub-Saharan Africa [
<xref ref-type="bibr" rid="r1">1</xref>
,
<xref ref-type="bibr" rid="r4">4</xref>
,
<xref ref-type="bibr" rid="r5">5</xref>
,
<xref ref-type="bibr" rid="r30">30</xref>
]. In addition, it is possible that the frequency of these organisms may be dependent on seasons, as has been documented for adult inpatients in the same Malawian study hospital [
<xref ref-type="bibr" rid="r10">10</xref>
] and for pediatric patients in the southern regions of Malawi [
<xref ref-type="bibr" rid="r31">31</xref>
] and in Kenya [
<xref ref-type="bibr" rid="r28">28</xref>
]. Conversely, the results of our pilot study, which surveyed 2 LCH pediatric inpatient populations during each of the seasons in 1998, indicated that gram-negative pathogens are the predominant cause of BSIs in both the wet and dry seasons and that gram-positive organisms, such as
<italic>Staphylococcus aureus</italic>
and
<italic>Streptococcus</italic>
species, are relatively uncommon in this patient population in central Malawi [
<xref ref-type="bibr" rid="r14">14</xref>
]. The possibility of geographic variation is underscored by the results of a prospective review of all positive pediatric blood-culture results from another Malawian hospital over a 1-year period that showed that 24.1% of positive blood cultures were caused by streptococci [
<xref ref-type="bibr" rid="r1">1</xref>
].</p>
<p>In our study population, there appeared to be an overdiagnosis of malaria during the dry season. Community awareness of malaria is high, and the initiation of treatment for malaria is a common first response to unexplained fever. It is possible, therefore, that some of the patients who were diagnosed with malaria but who had negative blood-smear results may have had true malaria cases with smears negative for asexual parasites because of treatment with antimalarials before admission to the hospital. On the other hand, the fact that 11 (85%) of 13 patients with positive malaria smear results were not diagnosed with malaria by their admitting physicians highlights the difficulty in making a diagnosis of malaria versus other etiologies in severely ill pediatric patients.</p>
<p>There are several reasons why only bacteremia, rather then mycobacteremia or fungemia, has been sought or comprehensively studied in pediatric populations in sub-Saharan Africa. First, culturing blood simultaneously for bacteria, mycobacteria, and fungi, using conventional methods, often requires drawing >25 mL of blood from adult patients [
<xref ref-type="bibr" rid="r8">8</xref>
,
<xref ref-type="bibr" rid="r9">9</xref>
]. Drawing such relatively large blood volumes is inappropriate and unethical in infants or children, especially those who are already immunocompromised, malnourished, or severely anemic, as the hematocrit measurements in our study show our study patients to have been. Second, because of cultural reasons, parents may be reluctant for their children to part with the seemingly large volumes of blood that are necessary when culturing for these 3 groups of pathogens. Third, blood may be difficult to obtain aseptically from pediatric populations, especially those with malnutrition or small, fragile veins. Fourth, many less-developed countries do not have the laboratory capacity, infrastructure, or skilled personnel required to provide a microbiology service or to process blood cultures. Fifth, the technician time, laboratory equipment, and materials required to process multiple media and conduct microbiological tests to identify various pathogens may involve prohibitive or unsustainable costs.</p>
<p>Although the present study demonstrated independent clinical indicators associated with acquiring a BSI and with patient outcome, no strong model for a physician-based clinical diagnosis could be ascertained. Acutely decreased feeding, lethargy, and malnutrition were all independent risk factors for mortality. One clinical indicator—malnutrition—was strongly predictive of the presence of a BSI or of death. Our finding of an association between bacteremia with malnutrition rather than with HIV-1 serostatus or proven HIV-1 infection is consistent with the results of studies conducted in Zimbabwe [
<xref ref-type="bibr" rid="r32">32</xref>
] and South Africa [
<xref ref-type="bibr" rid="r33">33</xref>
]. Lethargy, malnutrition, and acutely decreased feeding are general findings that are associated with infectious diseases of many etiologies and are not markers of BSI per se. Moreover, in our study, malnourished children had a >3-fold risk of dying than adequately nourished children with or without an associated BSI. However, in developing countries with little or no laboratory capability, clinical features such as malnutrition, oral candidiasis, lethargy, or acutely decreased feeding might provide usable information and algorithms, at no cost, that could be used to identify critically ill children who are in need of intensive medical care and empirical antimicrobial therapy or to assess those who may most safely be observed without initiating such therapy.</p>
<p>There are limitations to the study and its applicability. The etiology and clinical predictors associated with BSI are highly variable by region. Population and geographic characteristics—such as the rate of HIV-1 and malnutrition, typical childhood illnesses, and seasonality—can affect the types and characteristics of BSI in children. Therefore, the results from our study might not be applicable for treatment and diagnostic algorithms in other regions. In addition, the study covered only a 1-month period, and seasonal variation could have an effect on the validity of the results during the wet season. However, the present study could be used as a model for studies in other populations to establish clinical correlates and BSI etiologies for use in treatment and diagnosis.</p>
<p>In summary, our data suggest that, in a region in central Malawi where HIV-1 is endemic, bloodstream dissemination of
<italic>M. tuberculosis</italic>
and the
<italic>M. bovis</italic>
BCG strain remains uncommon in HIV-1-infected children who received the BCG vaccine, which lends support to the WHO recommendations for the vaccination of pediatric populations in this region against BCG. Gram-negative organisms, particularly non-
<italic>typhi Salmonella</italic>
species and
<italic>E. coli,</italic>
appear to be the predominant bloodstream pathogens in HIV-1-infected children;
<italic>M. tuberculosis</italic>
BSI and fungemia are absent or very uncommon. There are identifiable clinical predictors of BSI that might be considered for the diagnosis and initiation of empirical antimicrobial therapy in the absence of appropriate laboratory testing. Similar studies in different areas among different populations (i.e., adults and children) can provide data that assist physicians in selecting among therapeutic options for BSIs, especially in those who are diagnosed with malnutrition or sepsis.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We are indebted to the nursing and medical staffs in the department of medicine and pediatrics at Lilongwe Central Hospital; the parents and guardians who gave consent for their children to participate in the study and the children themselves; the Malawi Ministry of Health; Celeste M. McKnight, Rachel M Addison, and Terry Byrne, for their technical expertise in the microbiology laboratory; the United States Agency for International Development, Malawi; and Becton Dickinson Microbiology Systems, for providing the BACTEC MFL vials for this project.</p>
</ack>
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<person-group person-group-type="author">
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<lpage>8</lpage>
</nlm-citation>
</ref>
</ref-list>
<fn-group>
<fn fn-type="presented-at">
<p>Presented in part: 36th annual meeting of the Infectious Diseases Society of America, Denver, 12–15 November 1998 (abstract 187).</p>
</fn>
<fn fn-type="financial-disclosure">
<p>Financial support: Hospital Infections Program, Centers for Disease Control and Prevention.</p>
</fn>
<fn fn-type="other">
<p>The use of trade names is for identification only and does not imply endorsement by the Public Health Service or the US Department of Health and Human Services.</p>
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<title>Figures and Tables</title>
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<label>Table 1.</label>
<caption>
<p>Characteristics of study patients, Lilongwe Central Hospital, Malawi, August–September 1998.</p>
</caption>
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<label>Table 2.</label>
<caption>
<p>Independent correlates for bloodstream infections and mortality, Lilongwe Central Hospital, Lilongwe, Malawi, 1998.</p>
</caption>
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<title>Epidemiology of Bloodstream Infections in a Bacille Calmette-Guérin-Vaccinated Pediatric Population in Malawi</title>
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<title>Epidemiology of Bloodstream Infections in a Bacille Calmette-Guérin-Vaccinated Pediatric Population in Malawi</title>
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<name type="personal" displayLabel="corresp">
<namePart type="given">Lennox K.</namePart>
<namePart type="family">Archibald</namePart>
<affiliation>Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation>
<affiliation>E-mail: larchibald@rtix.com</affiliation>
<affiliation>Reprints or correspondence: Dr. Lennox K. Archibald, Regeneration Technologies, Inc., 11621 Research Circle, PO Box 2650, Alachua, FL 32616</affiliation>
<affiliation>E-mail: larchibald@rtix.com</affiliation>
<description>a Present affiliations: Regeneration Technologies, Inc., Alachua, Florida (L.K.A.); Office of Health, Population, and Nutrition, US Agency for International Development/ Mozambique, Maputo, Mozambique (O.N.).</description>
<role>
<roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal">
<namePart type="given">Peter N.</namePart>
<namePart type="family">Kazembe</namePart>
<affiliation>Lilongwe Central Hospital, Lilongwe, Malawi</affiliation>
<role>
<roleTerm type="text">author</roleTerm>
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</name>
<name type="personal">
<namePart type="given">Okey</namePart>
<namePart type="family">Nwanyanwu</namePart>
<affiliation>United States Agency for International Development, Lilongwe, Malawi</affiliation>
<description>a Present affiliations: Regeneration Technologies, Inc., Alachua, Florida (L.K.A.); Office of Health, Population, and Nutrition, US Agency for International Development/ Mozambique, Maputo, Mozambique (O.N.).</description>
<role>
<roleTerm type="text">author</roleTerm>
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<name type="personal">
<namePart type="given">Charles</namePart>
<namePart type="family">Mwansambo</namePart>
<affiliation>Lilongwe Central Hospital, Lilongwe, Malawi</affiliation>
<role>
<roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal">
<namePart type="given">L. Barth</namePart>
<namePart type="family">Reller</namePart>
<affiliation>Clinical Microbiology Laboratory, Duke University Medical Center, Durham, North Carolina</affiliation>
<role>
<roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal">
<namePart type="given">William R.</namePart>
<namePart type="family">Jarvis</namePart>
<affiliation>Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation>
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<dateIssued encoding="w3cdtf">2003-07-15</dateIssued>
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<abstract>The risk of Mycobacterium bovis bloodstream infection (BSI) in bacille Calmette-Guérin (BCG)-vaccinated children with human immunodeficiency virus (HIV) infection remains uncharacterized. We studied pediatric inpatients during the 1998 dry season in Malawi. After a detailed clinical evaluation, blood was drawn for culture and HIV testing. Of 229 children, 128 (56%) were male, 35 (15.3%) had BSI, and 30% of children aged >1.5 years (median, 2.7 years; range, 1 month–13 years) had HIV infection. The predominant pathogen was non-typhi Salmonella;neither Mycobacterium tuberculosis nor M. bovis was isolated. A diagnosis of malnutrition or sepsis was predictive of BSI; malnutrition alone correlated with both death and BSI. The bloodstream dissemination of M. tuberculosis and M. bovis BCG is uncommon in HIV-infected children vaccinated with BCG. Correlates such as malnutrition or sepsis can provide algorithms for identifying children who need observation or empirical antimicrobial therapy for BSI in the absence of appropriate laboratory testing.</abstract>
<note type="footnotes">Present affiliations: Regeneration Technologies, Inc., Alachua, Florida (L.K.A.); Office of Health, Population, and Nutrition, US Agency for International Development/ Mozambique, Maputo, Mozambique (O.N.).</note>
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</subject>
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<topic>Major Articles</topic>
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<identifier type="ISSN">0022-1899</identifier>
<identifier type="eISSN">1537-6613</identifier>
<identifier type="PublisherID">jid</identifier>
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<part>
<date>2003</date>
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<caption>vol.</caption>
<number>188</number>
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<caption>no.</caption>
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