Dominique Legros

Intrathecal immune response pattern for improved diagnosis of central nervous system involvement in trypanosomiasis

Diagnosis of central nervous system (CNS) involvement in human African trypanosomiasis is crucial in determination of therapy. Cerebrospinal fluid (CSF) and serum immunoglobulin concentrations, blood-CSF barrier dysfunction, pattern of intrathecal immunoglobulin synthesis, trypanosome-specific antibody synthesis, and CSF lactate concentrations were analyzed in 272 patients with Trypanosoma brucei gambiense infection. As part of the 2- or 3-class immune response, the predominant intrathecal IgM synthesis was the most sensitive (95%) marker for inflammation of the brain. We propose to replace the World Health Organization (WHO) criteria (white blood cell count >5 cells/microL and presence of trypanosomes in CSF) with a new approach for stage determination in trypanosomiasis: CNS involvement is diagnosed only in patients with >20 cells/microL or with intrathecal IgM synthesis, independent of the presence of trypanosomes in CSF. Compared with the use of these new criteria, the WHO criteria incorrectly classified 49 of 234 patients in the meningoencephalitic stage and 7 of 38 patients in the hemolymphatic disease stage. We also show that trypanosomiasis-related immunoglobulin patterns are of value in differential diagnosis.

Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study

BACKGROUND In sub-Saharan Africa in the 1990s, more than 600,000 people had epidemic meningococcal meningitis, of whom 10% died. The current recommended treatment by WHO is short-course long-acting oily chloramphenicol. Continuation of the production of this drug is uncertain, so simple alternatives need to be found. We assessed whether the efficacy of single-dose treatment of ceftriaxone was non-inferior to that of oily chloramphenicol for epidemic meningococcal meningitis. METHODS In 2003, we undertook a randomised, open-label, non-inferiority trial in nine health-care facilities in Niger. Participants with suspected disease who were older than 2 months were randomly assigned to receive either chloramphenicol or ceftriaxone. Primary outcome was treatment failure (defined as death or clinical failure) at 72 h, measured with intention-to-treat and per-protocol analyses. FINDINGS Of 510 individuals with suspected disease, 247 received ceftriaxone, 256 received chloramphenicol, and seven were lost to follow-up. The treatment failure rate at 72 h for the intention-to-treat analysis was 9% (22 patients) for both drug groups (risk difference 0.3%, 90% CI -3.8 to 4.5). Case fatality rates and clinical failure rates were equivalent in both treatment groups (14 [6%] ceftriaxone vs 12 [5%] chloramphenicol). Results were also similar for both treatment groups in individuals with confirmed meningitis caused by Neisseria meningitidis. No adverse side-effects were reported. INTERPRETATION Single-dose ceftriaxone provides an alternative treatment for epidemic meningococcal meningitis--its efficacy, ease of use, and low cost favour its use. National and international health partners should consider ceftriaxone as an alternative first-line treatment to chloramphenicol for epidemic meningococcal meningitis.

Conflict and emerging infectious diseases.

Public health interventions and surveillance and response systems can contribute to disease control.

Adherence to the combination of sulphadoxine-pyrimethamine and artesunate in the Maheba refugee settlement Zambia.

Artemisinin‐based combination therapy (ACT) is one strategy recommended to increase cure rates in malaria and to contain resistance to Plasmodium falciparum. In the Maheba refugee settlement, children aged 5 years or younger with a confirmed diagnosis of uncomplicated falciparum malaria are treated with the combination of sulphadoxine–pyrimethamine (1 day) and artesunate (3 days). To measure treatment adherence, home visits were carried out the day after the last treatment dose. Patients who had any treatment dose left were considered certainly non‐adherent. Other patients’ classification was based on the answers to the questionnaire: patients whose caretakers stated the child had received the treatment regimen exactly as prescribed were considered probably adherent; all other patients were considered probably non‐adherent. Reasons for non‐adherence were assessed. We found 21.2% (95% CI [15.0–28.4]) of the patients to be certainly non‐adherent, 39.4% (95% CI [31.6–47.6]) probably non‐adherent, and 39.4% (95% CI [31.6–47.6]) probably adherent. Insufficient explanation by the dispenser was identified as an important reason for non‐adherence. When considering the use of ACT, the issue of patient adherence remains challenging. However, it should not be used as an argument against the introduction of ACT. For these treatment regimens to remain efficacious on a long‐term basis, specific and locally adapted strategies need to be implemented to ensure completion of the treatment.

Laboratory diagnosis of Ebola hemorrhagic fever during an outbreak in Yambio, Sudan, 2004.

Between the months of April and June 2004, an Ebola hemorrhagic fever (EHF) outbreak was reported in Yambio county, southern Sudan. Blood samples were collected from a total of 36 patients with suspected EHF and were tested by enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G and M antibodies, antigen ELISA, and reverse-transcription polymerase chain reaction (PCR) of a segment of the Ebolavirus (EBOV) polymerase gene. A total of 13 patients were confirmed to be infected with EBOV. In addition, 4 fatal cases were classified as probable cases, because no samples were collected. Another 12 patients were confirmed to have acute measles infection during the same period that EBOV was circulating. Genetic analysis of PCR-positive samples indicated that the virus was similar to but distinct from Sudan EBOV Maleo 1979. In response, case management, social mobilization, and follow-up of contacts were set up as means of surveillance. The outbreak was declared to be over on 7 August 2004.

Nifurtimox plus Eflornithine for late-stage sleeping sickness in Uganda: a case series.

Background We report efficacy and safety outcomes from a prospective case series of 31 late-stage T.b. gambiense sleeping sickness (Human African Trypanosomiasis, HAT) patients treated with a combination of nifurtimox and eflornithine (N+E) in Yumbe, northwest Uganda in 2002–2003, following on a previously reported terminated trial in nearby Omugo, in which 17 patients received the combination under the same conditions. Methodology/Principal findings Eligible sequential late-stage patients received 400 mg/Kg/day eflornithine (Ornidyl, Sanofi-Aventis) for seven days plus 15 mg/Kg/day (20 mg for children <15 years old) nifurtimox (Lampit, Bayer AG) for ten days. Efficacy (primary outcome) was monitored for 24 months post discharge. Clinical and laboratory adverse events (secondary outcome) were monitored during treatment. All 31 patients were discharged alive, but two died post-discharge of non-HAT and non-treatment causes, and one was lost to follow-up. Efficacy ranged from 90.3% to 100.0% according to analysis approach. Five patients experienced major adverse events during treatment, and neutropenia was common (9/31 patients). Conclusions/Significance Combined with the previous group of 17 trial patients, this case series yields a group of 48 patients treated with N+E, among whom no deaths judged to be treatment- or HAT-related, no treatment terminations and no relapses have been noted, a very favourable outcome in the context of late-stage disease. N+E could be the most promising combination regimen available for sleeping sickness, and deserves further evaluation.

Two clusters of human infection with influenza A/H5N1 virus in the Republic of Azerbaijan, February–March 2006

Following the appearance of influenza A/H5 virus infection in several wild and domestic bird species in the Republic of Azerbaijan in February 2006, two clusters of potential human avian influenza due to A/H5N1 (HAI) cases were detected and reported by the Ministry of Health (MoH) to the World Health Organization (WHO) Regional Office for Europe during the first two weeks of March 2006. On 15 March 2006, WHO led an international team, including infection control, clinical management, epidemiology, laboratory, and communications experts, to support the MoH in investigation and response activities. As a result of active surveillance, 22 individuals, including six deaths, were evaluated for HAI and associated risk infections in six districts. The investigations revealed eight cases with influenza A/H5N1 virus infection confirmed by a WHO Collaborating Centre for Influenza and one probable case for which samples were not available. The cases were in two unrelated clusters in Salyan (seven laboratory confirmed cases, including four deaths) and Tarter districts (one confirmed case and one probable case, both fatal). Close contact with and de-feathering of infected wild swans was considered to be the most plausible source of exposure to influenza A/H5N1 virus in the Salyan cluster, although difficulties in eliciting information were encountered during the investigation, because of the illegality of some of the activities that might have led to the exposures (hunting and trading in wild birds and their products). These cases constitute the first outbreak worldwide where wild birds were the most likely source of influenza A/H5N1 virus infection in humans. The rapid mobilisation of resources to contain the spread of influenza A/H5 in the two districts was achieved through collaboration between the MoH, WHO and its international partners. Control activities were supported by the establishment of a field laboratory with real-time polymerase chain reaction (RT-PCR) capacity to detect influenza A/H5 virus. Daily door-to-door surveillance undertaken in the two affected districts made it unlikely that human cases of influenza A/H5N1 virus infection remained undetected.

Meningitis serogroup W135 outbreak, Burkina Faso, 2002.

In 2002, the largest epidemic of Neisseria meningitidis serogroup W135 occurred in Burkina Faso. The highest attack rate was in children <5 years of age. We describe cases from 1 district and evaluate the performance of the Pastorex test, which had good sensitivity (84%) and specificity (89%) compared with culture or PCR.

Mortality Among Displaced Former UNITA Members and Their Families in Angola: A Retrospective Cluster Survey.

Abstract Objective To measure retrospectively mortality among a previously inaccessible population of former UNITA members and their families displaced within Angola, before and after their arrival in resettlement camps after ceasefire of 4 April 2002. Design Three stage cluster sampling for interviews. Recall period for mortality assessment was from 21 June 2001 to 15-31 August 2002. Setting Eleven resettlement camps over four provinces of Angola (Bié, Cuando Cubango, Huila, and Malange) housing 149 000 former UNITA members and their families. Participants 900 consenting family heads of households, or most senior household members, corresponding to an intended sample size of 4500 individuals. Main outcome measures Crude mortality and proportional mortality, overall and by period (monthly, and before and after arrival in camps). Results Final sample included 6599 people. The 390 deaths reported during the recall period corresponded to an average crude mortality of 1.5/10 000/day (95% confidence interval 1.3 to 1.8), and, among children under 5 years old, to 4.1/10 000/day (3.3 to 5.2). Monthly crude mortality rose gradually to a peak in March 2002 and remained above emergency thresholds thereafter. Malnutrition was the leading cause of death (34%), followed by fever or malaria (24%) and war or violence (18%). Most war victims and people who had disappeared were women and children. Conclusions This population of displaced Angolans experienced global and child mortality greatly in excess of normal levels, both before and after the 2002 ceasefire. Malnutrition deaths reflect the extent of the food crisis affecting this population. Timely humanitarian assistance must be made available to all populations in such conflicts.

Systematic screening of cryptococcal antigenemia in HIV-positive adults in Uganda

In sub-Saharan Africa, cryptococcosis is a frequent opportunistic infection and a major cause of death in patients with AIDS. 1,2 The disease is mainly recognized at the neuromeningitis stage and is diagnosed by microscopy and culture of cerebrospinal fluid (CSF). The identification of cryptococcal antigen (CRAG) by latex particle agglutination is highly sensitive, 3,4 and this technique is used routinely in Western countries. We evaluated the prevalence of CRAG in serum samples from adults with clinically advanced HIV infection and the proportion of CRAG-positive patients with neuromeningitis.