Amanda L. Walsh

Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study

BACKGROUND Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. METHODS Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. FINDINGS We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). INTERPRETATION Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. FUNDING The Policy Research Programme, Department of Health, UK.

Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial

BACKGROUND Steroids are used as adjuvant treatment in childhood pyogenic meningitis to attenuate host inflammatory responses to bacterial invasion. We aimed to assess the effectiveness of dexamethasone in management of acute bacterial meningitis in a developing country. METHODS In a double-blind, placebo controlled trial, we included 598 children with pyogenic meningitis who had been admitted to the childrens wards of the Queen Elizabeth Central Hospital, Blantyre, Malawi. We did physical, neurological, developmental, and hearing assessments at 1 and 6 months after discharge. The primary outcome was overall death. Secondary outcomes included sequelae, in-hospital deaths, and death after discharge. Analysis was done by intention to treat. FINDINGS Of the 598 included children, 307 (51%) were assigned to dexamethasone and 295 (49%) to placebo. 338 (40%) of 598 patients had Streptococcus pneumoniae, 170 (28%) Haemophilus influenzae type b, 66 (11%) Neisseria meningitidis, and 29 (5%) Salmonella spp. 78 (13%) patients had no growth on culture. The number of overall deaths was the same in the two treatment groups (relative risk 1.00 [95% CI 0.8-1.25], p=0.93). At final outcome, sequelae were identified in 84 (28%) of children on steroids and in 81 (28%) on placebo (relative risk 0.99 [95% CI 0.78-1.27], p=0.97). The number of children dying in hospital did not differ between groups. INTERPRETATION Steroids are not an effective adjuvant treatment in children with acute bacterial meningitis in developing countries.

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.

Non-typhoidal salmonella bacteraemia among HIV-infected Malawian adults: high mortality and frequent recrudescence

ObjectiveNon-typhoidal salmonella (NTS) bacteraemia is a common, recurrent illness in HIV-infected African adults. We aimed to describe the presentation and outcome of NTS bacteraemia, the pattern of recurrence, and to determine whether recurrence results from re-infection or recrudescence. DesignOne hundred consecutive adult inpatients with NTS bacteraemia in Blantyre, Malawi, were treated with chloramphenicol. Survivors were prospectively followed to detect bacteraemic recurrence. MethodsIndex and recurrent isolates were typed by antibiogram, pulsed-field gel electrophoresis and plasmid analysis to distinguish recrudescence from re-infection. ResultsInpatient mortality was 47%, and 1-year mortality was 77%. A total of 77 out of 78 cases were HIV positive. Anaemia was associated with inpatient death, and several features of AIDS were associated with poor outpatient survival. Among survivors, 43% (19/44) had a first recurrence of NTS bacteraemia at 23–186 days. Among these, 26% (5/19) developed multiple recurrences up to 245 days. No recurrence was seen after 245 days, despite follow-up for up to 609 days (median 214). Suppurative infections were not found at presentation, and were only seen twice at recurrence. Index and recurrent paired isolates were identical by phenotyping and genotyping, consistent with recrudescence, rather than re-infection. ConclusionNTS bacteraemia has a high mortality (47%) and recurrence (43%) rate in HIV-infected African adults. Recurrence is caused by recrudescence rather than re-infection. As focal infections were rarely found, recrudescence may often be a consequence of intracellular tissue sequestration. There is an urgent need for improved primary treatment and secondary prophylaxis in Africa.

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.

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.

Comparison of Imipenem and Ceftazidime as Therapy for Severe Melioidosis

An open, prospective, randomized, comparative treatment trial was conducted to compare the therapeutic efficacy of high-dose intravenous imipenem and ceftazidime for acute severe melioidosis. Adult Thai patients with suspected acute, severe melioidosis were randomized to receive either imipenem, at a dosage of 50 mg/(kg x d), or ceftazidime, at a dosage of 120 mg/(kg x d), for a minimum of 10 days. The main outcome measures were death or treatment failure. Of the 296 patients enrolled, 214 had culture-confirmed melioidosis, and 132 (61.7%) of them had positive blood cultures. Mortality among patients with melioidosis was 36.9% overall. There were no differences in survival overall (P = .96) or after 48 hours (P = .3). Treatment failure after 48 hours was more common among patients treated with ceftazidime (P = .011). Both treatments were well tolerated. Imipenem is a safe and effective treatment for acute severe melioidosis and may be considered an alternative to ceftazidime.

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.

Quantitation of Bacteria in Bone Marrow from Patients with Typhoid Fever: Relationship between Counts and Clinical Features

ABSTRACT Enteric fever is the only bacterial infection of humans for which bone marrow examination is routinely recommended. A prospective study of the concentrations of bacteria in the bone marrow and their relationship to clinical features was conducted with 120 Vietnamese patients with suspected enteric fever, of whom 89 had confirmed typhoid fever. Ninety-three percent of the Salmonella entericaserovar Typhi samples isolated were resistant to ampicillin, chloramphenicol, and co-trimoxazole. For 81 patients with uncomplicated typhoid and satisfactory bone marrow aspirates, the number of serovar Typhi CFU in bone marrow aspirates was a median value of 9 (interquartile range [IQR], 1 to 85; range, 0.1 to 1,580) compared to 0.3 (IQR, 0.1 to 10; range, 0.1 to 399) CFU/ml in simultaneously sampled blood. The ratio of individual blood counts to bone marrow counts was 10 (IQR, 2.3 to 97.5). The number of bacteria in blood but not bone marrow was correlated inversely with the duration of preceding fever. Thus, with increasing duration of illness the ratio of bone marrow-to-blood bacterial concentrations increased; the median ratio was 4.8 (IQR, 1 to 27.5) during the first week compared with 158 (IQR, 60 to 397) during the third week. After lysing the host cells, the median ratio of viable bone marrow to blood increased, reflecting the higher concentration of intracellular serovar Typhi in the bone marrow. Effective antibiotic pretreatment had a significantly greater effect in reducing blood counts compared to bone marrow counts (P < 0.001). Thus, bacteria in the bone marrow of typhoid patients are less affected by antibiotic treatment than bacteria in the blood. The numbers of bacteria in bone marrow correlated negatively with the white blood cell (R = −0.3, P = 0.006) and platelet counts (R = −0.32, P = 0.01) and positively with fever clearance time after treatment (R = 0.4,P < 0.001). The bacterial load in bone marrow therefore may reflect the clinical course of the infection, and high levels may suppress neutrophil proliferation.

Hepatitis E Outbreak on Cruise Ship

The outbreak was probably foodborne.