Stephen M. Graham

Epidemics of Invasive Salmonella enterica Serovar Enteritidis and S. enterica Serovar Typhimurium Infection Associated with Multidrug Resistance among Adults and Children in Malawi

BACKGROUND Nontyphoidal salmonellae (NTS) have become the most common cause of bacteremia in tropical Africa, particularly among susceptible children and HIV-infected adults. METHODS We describe 4956 episodes of NTS bacteremia (2439 episodes in adults and 2517 episodes in children) that occurred in Blantyre, Malawi, during the 7-year period 1998-2004. RESULTS A total of 75% of the cases of NTS bacteremia were due to Salmonella enterica serovar Typhimurium, and 21% were due to S. enterica serovar Enteritidis. Epidemic increases in the incidence of NTS bacteremia were seen sequentially, occurring first among cases caused by S. Enteritidis and then among cases caused by S. Typhimurium. Increased incidence of bacteremia was temporally associated with the acquisition of multidrug resistance to ampicillin, cotrimoxazole, and chloramphenicol by each serovar and occurred while the incidence of infection due to other common bloodstream pathogens remained constant. These epidemics were observed among adults and children. A seasonal pattern was also seen, with increased incidence during and after the rainy season. The median age of the patients was 32 years among adults and 22 months among children. Acquisition of multidrug-resistant infection was not associated with an increased case-fatality rate among children (22%), and the case-fatality rate among adults showed a significant trend toward decreasing (from 29% to 20%). CONCLUSIONS These data have important implications for the treatment of severe febrile illness in adults and children in tropical Africa. Further understanding of the molecular basis of these epidemics of multidrug-resistant NTS infection, including ongoing whole-genome sequencing of multidrug-resistant isolates, will yield important tools for the study of NTS pathogenesis, transmission, epidemiology, and prevention.

Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants

A review of the clinical findings in six infants with nutritional vitamin B12 deficiency seen during the last 10 years was undertaken and an attempt made to obtain long-term neurologic follow-up. There was a consistent clinical pattern in vitamin B12-deficient infants; irritability, anorexia, and failure to thrive were associated with marked developmental regression and poor brain growth. Two of the four patients who qualified for long-term review had a poor intellectual outcome. Although early response to treatment is satisfying, the long-term consequences of nutritional vitamin B12 deficiency in infants emphasize the need for prevention or early recognition of this syndrome.

Bacteremia in Malawian Children with Severe Malaria: Prevalence, Etiology, HIV Coinfection, and Outcome

BACKGROUND Previous prospective studies of bacteremia in African children with severe malaria have mainly included children with cerebral malaria, and no study has examined the impact of human immunodeficiency virus (HIV) infection. We examined the prevalence and etiology of bacteremia and the impact of HIV infection on bacteremia in Malawian children with severe malaria, as well as the impact of bacteremia and HIV infection on outcome. METHODS From 1996 until 2005, blood for culture was obtained on admission from all children admitted with severe malaria during the rainy season to the Paediatric Research Ward at the Queen Elizabeth Central Hospital in Blantyre, Malawi. HIV testing was performed prospectively from 2001 to 2005 and retrospectively for those admitted from 1996 to 2000. Multivariate regression analysis examined independent risk factors for bacteremia and death. RESULTS Sixty-four (4.6%) of 1388 children with severe malaria had bacteremia; nontyphoidal Salmonellae (NTS) accounted for 58% of all bacteremias. The prevalence of any bacteremia and of NTS bacteremia was highest in children with severe malarial anemia (11.7% and 7.6%), compared with the prevalence in children with cerebral malaria and severe anemia (4.7% and 3.8%) and in those with cerebral malaria alone (3.0% and 0.9%). HIV infection status was determined in 1119 patients. HIV prevalence was 16% (and was highest in those with severe malaria anemia, at 20.4%), but HIV infection was not significantly associated with bacteremia. Neither bacteremia nor HIV infection was associated with death. CONCLUSIONS Antibiotics are not routinely indicated for children with severe malaria in this region, in which HIV is endemic. However, antibiotic therapy should be used to treat NTS infection if bacteremia is suspected in children with severe malarial anemia.

Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

Lactobacillus GG promotes recovery from acute nonbloody diarrhea in Pakistan.

A prospective, placebo-controlled, triple blind clinical trial was carried out in Pakistan to determine the effect of Lactobacillus GG on the course of acute diarrhea in hospitalized children. Forty children (mean age, 13 months) were enrolled and after rehydration received either oral Lactobacillus GG (n = 21) or placebo (n = 19) twice daily for 2 days, in addition to the usual diet. The clinical course of diarrhea was followed during the treatment period. Features on admission into the study groups were similar and were characterized by severe diarrhea, malnutrition and inappropriate management before presentation. Response was evident on Day 2 when the frequency of both vomiting and diarrhea was less in the Lactobacillus group. In those who had presented with acute nonbloody diarrhea (n = 32), the percentage of children with persistent watery diarrhea at 48 hours was significantly less in the Lactobacillus group: 31% vs. 75% (P < 0.01). No significant difference was observed by 48 hours in those presenting with bloody diarrhea. The relevance of this finding to the management of diarrhea in the tropics is discussed.

The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children

Nontyphoidal strains of Salmonella (NTS) are a common cause of bacteremia among African children. Cell-mediated immune responses control intracellular infection, but they do not protect against extracellular growth of NTS in the blood. We investigated whether antibody protects against NTS bacteremia in Malawian children, because we found this condition mainly occurs before 2 years of age, with relative sparing of infants younger than 4 months old. Sera from all healthy Malawian children tested aged more than 16 months contained anti-Salmonella antibody and successfully killed NTS. Killing was mediated by complement membrane attack complex and not augmented in the presence of blood leukocytes. Sera from most healthy children less than 16 months old lacked NTS-specific antibody, and sera lacking antibody did not kill NTS despite normal complement function. Addition of Salmonella-specific antibody, but not mannose-binding lectin, enabled NTS killing. All NTS strains tested had long-chain lipopolysaccharide and the rck gene, features that resist direct complement-mediated killing. Disruption of lipopolysaccharide biosynthesis enabled killing of NTS by serum lacking Salmonella-specific antibody. We conclude that Salmonella-specific antibody that overcomes the complement resistance of NTS develops by 2 years of life in Malawian children. This finding and the age-incidence of NTS bacteremia suggest that antibody protects against NTS bacteremia and support the development of vaccines against NTS that induce protective antibody.

Bacteremia in febrile Malawian children : Clinical and microbiologic features

Background. There are no published data for the incidence or etiology of childhood bacteremia in Malawi. We describe the clinical and microbiologic features of children admitted to hospital from whom blood cultures yielded bacterial pathogens. Methods. Any neonate or child admitted to the pediatric wards of the Queen Elizabeth Central Hospital had a blood culture taken in the event of fever without obvious clinical explanation. Clinical and microbiologic data were prospectively collected for children with a significant positive culture. Results. Between September, 1996, and August, 1997, we processed 2123 cultures. Of these, 365 (17.2%) grew a pathogen. Non‐typhi salmonellae (NTS) and enteric Gram‐negative bacilli constituted 67.4% of isolates, and Streptococcus pneumoniae constituted 16.4%. More than two‐thirds of NTS episodes coincided with the peak malaria transmission season (January to June); 67% of bacteremic children were malnourished, 28% severely so. Patients with NTS bacteremia were significantly more likely to have coincident malaria and to have splenomegaly and anemia than children with other infecting organisms. The overall mortality was 38% but varied considerably according to age and nutritional status. Prior antibiotic use, coincident malaria or meningitis did not adversely affect outcome. In vitro resistance to the commonly available antibiotics ampicillin and trimethoprim‐sulfamethoxazole was found in 76 and 71% of NTS isolates. Screening tests for penicillin resistance suggested a rate of 21% among pneumococci. Conclusions. Bacteremia is common in hospitalized Malawian children and has a high mortality. There are high rates of resistance to some of the commonly used antibacterial agents.

Clinical presentation and outcome of Pneumocystis carinii pneumonia in Malawian children

BACKGROUND Necropsy studies from Africa have shown that Pneumocystis carinii pneumonia (PCP) is common in infants with HIV infection. We aimed to describe the rate, clinical presentation, and outcome of PCP in young Malawian children with acute severe pneumonia. METHODS Children aged between 2 months and 5 years who were in hospital with a diagnosis of severe pneumonia were admitted to a study ward for clinical monitoring. We carried out blood culture, immunofluorescence on nasopharyngeal aspirate samples to test for PCP, polymerase chain reaction to detect HIV, and chest radiography. FINDINGS 16 cases of PCP were identified among 150 children with radiologically confirmed severe pneumonia. All were HIV-positive and younger than 6 months. 21 children had bacterial pneumonia (including one who was also PCP positive) and 114 were not confirmed. The most common bacterial pathogens among children without PCP were Streptococcus pneumoniae (eight) and non-typhoidal salmonellae (seven). On admission, children with confirmed PCP had a lower mean age, body temperature, and oxygen saturation than children with bacterial pneumonia and were less likely to have a focal abnormality on auscultation. Oxygen requirements were much greater in children with PCP than those with bacterial pneumonias (96 of 105 hospital days vs 15 of 94, p<0.0001). Ten of 16 children with PCP and six of 21 with bacterial pneumonia died (relative risk 2.19 [95% CI 1.0-4.7]). The overall case-fatality rate of severe pneumonia was 22%. In addition to a strong association with PCP, a fatal outcome was significantly and independently associated with HIV infection (2.98 [1.1-7.9]) and with age under 6 months (2.76 [1.0-5.2]). INTERPRETATION PCP is common and contributes to the high mortality from pneumonia in Malawian infants. Clinical features are helpful in diagnosis. The study highlights the impact of HIV infection and difficult issues of management in countries with few resources.

Clinical presentation of non-typhoidal Salmonella bacteraemia in Malawian children.

We report the clinical presentation and outcome of 299 Malawian children with non-typhoidal Salmonella (NTS) bacteraemia and no evidence of focal sepsis, admitted to Queen Elizabeth Central Hospital (QECH), Blantyre, over a 26-month period (February 1996-April 1998). A peak incidence during the rainy season was noted. Salmonella typhimurium (79%) and S. enteritidis (13%) were the commonest isolates. For children aged > 6 months, NTS bacteraemia was significantly associated with malarial parasitaemia (RR 1.5 [1.2, 2.2], P < 0.01) and with severe anaemia (RR 7.2 [3.4, 15.3], P < 0.0001), when compared to other common pathogens causing childhood bacteraemia. Clinical overlap with malaria and anaemia, and the presence of malarial parasitaemia on admission, may delay diagnosis. NTS bacteraemia was commonly diagnosed following blood transfusion. Resistance in vitro to ampicillin (79%), co-trimoxazole (72%) and gentamicin (55%) was very common, and was rare to chloramphenicol (0.3%) which is the antibiotic of choice for NTS sepsis at QECH. Overall mortality was high (23%). Young age and clinical HIV infection were risk factors for mortality. Recurrences of NTS bacteraemia following antibiotic therapy were common among children with clinical HIV infection.

NONTYPHOIDAL SALMONELLA INFECTIONS OF CHILDREN IN TROPICAL AFRICA

“I believe that as soon as haemoculture takes its lawful place in the routine diagnosis, not only of enteric tropical fevers, but also of quinine-resistant fevers of short duration, and that heterogeneous rubbish heap known as P.U.O., paratyphoid C will come to the fore as a frequent and widespread disease, calling for the same general preventive measures currently required for the other better known fevers of the enteric-parenteric group.”