Jane Greig

Ebola viral load at diagnosis associates with patient outcome and outbreak evolution

BACKGROUND Ebola virus (EBOV) causes periodic outbreaks of life-threatening EBOV disease in Africa. Historically, these outbreaks have been relatively small and geographically contained; however, the magnitude of the EBOV outbreak that began in 2014 in West Africa has been unprecedented. The aim of this study was to describe the viral kinetics of EBOV during this outbreak and identify factors that contribute to outbreak progression. METHODS From July to December 2014, one laboratory in Sierra Leone processed over 2,700 patient samples for EBOV detection by quantitative PCR (qPCR). Viremia was measured following patient admission. Age, sex, and approximate time of symptom onset were also recorded for each patient. The data was analyzed using various mathematical models to find trends of potential interest. RESULTS The analysis revealed a significant difference (P = 2.7 × 10(-77)) between the initial viremia of survivors (4.02 log10 genome equivalents [GEQ]/ml) and nonsurvivors (6.18 log10 GEQ/ml). At the population level, patient viral loads were higher on average in July than in November, even when accounting for outcome and time since onset of symptoms. This decrease in viral loads temporally correlated with an increase in circulating EBOV-specific IgG antibodies among individuals who were suspected of being infected but shown to be negative for the virus by PCR. CONCLUSIONS Our results indicate that initial viremia is associated with outcome of the individual and outbreak duration; therefore, care must be taken in planning clinical trials and interventions. Additional research in virus adaptation and the impacts of host factors on EBOV transmission and pathogenesis is needed.

Sequential outbreaks due to a new strain of Neisseria meningitidis serogroup C in northern Nigeria, 2013-14

Background Neisseria meningitidis serogroup C (NmC) outbreaks occur infrequently in the African meningitis belt; the most recent report of an outbreak of this serogroup was in Burkina Faso, 1979. Médecins sans Frontières (MSF) has been responding to outbreaks of meningitis in northwest Nigeria since 2007 with no reported cases of serogroup C from 2007-2012. MenAfrivac®, a serogroup A conjugate vaccine, was first used for mass vaccination in northwest Nigeria in late 2012. Reactive vaccination using polysaccharide ACYW135 vaccine was done by MSF in parts of the region in 2008 and 2009; no other vaccination campaigns are known to have occurred in the area during this period. We describe the general characteristics of an outbreak due to a novel strain of NmC in Sokoto State, Nigeria, in 2013, and a smaller outbreak in 2014 in the adjacent state, Kebbi. Methods Information on cases and deaths was collected using a standard line-list during each week of each meningitis outbreak in 2013 and 2014 in northwest Nigeria. Initial serogroup confirmation was by rapid Pastorex agglutination tests. Cerebrospinal fluid (CSF) samples from suspected meningitis patients were sent to the WHO Reference Laboratory in Oslo, where bacterial isolates, serogrouping, antimicrobial sensitivity testing, genotype characterisation and real-time PCR analysis were performed. Results In the most highly affected outbreak areas, all of the 856 and 333 clinically suspected meningitis cases were treated in 2013 and 2014, respectively. Overall attack (AR) and case fatality (CFR) rates were 673/100,000 population and 6.8% in 2013, and 165/100,000 and 10.5% in 2014. Both outbreaks affected small geographical areas of less than 150km2 and populations of less than 210,000, and occurred in neighbouring regions in two adjacent states in the successive years. Initial rapid testing identified NmC as the causative agent. Of the 21 and 17 CSF samples analysed in Oslo, NmC alone was confirmed in 11 and 10 samples in 2013 and 2014, respectively. Samples confirmed as NmC through bacterial culture had sequence type (ST)-10217. Conclusions These are the first recorded outbreaks of NmC in the region since 1979, and the sequence (ST)-10217 has not been identified anywhere else in the world. The outbreaks had similar characteristics to previously recorded NmC outbreaks. Outbreaks of NmC in 2 consecutive years in northern Nigeria indicate a possible emergence of this serogroup. Increased surveillance for multiple serogroups in the region is needed, along with consideration of vaccination with conjugate vaccines rather than for NmA alone.

Association between older age and adverse outcomes on antiretroviral therapy: a cohort analysis of programme data from nine countries.

Context:Recent studies have highlighted the increased risk of adverse outcomes among older patients on antiretroviral therapy (ART). We report on the associations between older age and adverse outcomes in HIV/AIDS antiretroviral programmes across 17 programmes in sub-Saharan Africa. Methods:We included data from nine countries: Central African Republic, Côte d’Ivoire, Democratic Republic of Congo, Ethiopia, Nigeria, Republic of Congo, Uganda, Zambia and Zimbabwe. We describe survival probability for progression to death and loss to follow-up for patients initiating ART aged less than 50 years and at least 50 years. Multivariate Cox proportional hazards models were used to assess the association between age (15–39, 40–49, 50–59, 60–69 and 70–94 years) and adverse outcomes adjusting for confounders identified a priori. Results:Our analysis included 17 561 patients followed for a median of 12 months. The majority (65%) were female and 6672 (38%) were severely immunosuppressed at baseline. Median age at ART initiation was 36.0 years (interquartile range 30.1–42.8); 11.4% of patients were aged at least 50 years. Median gain in CD4 cell count at 6 and 12 months was significantly higher in patients less than 50 years old compared with those at least 50 years (134 vs. 112 cells/&mgr;l at 6 months; 170 vs. 139 cells/&mgr;l at 12 months; both P < 0.001). In multivariate analysis, there was a significant increased risk of mortality beyond 3 months after ART initiation in all age groups of at least 40 years of age compared with less than 40 years [40–49 years adjusted hazard ratios (aHRs) 1.59, P < 0.001; 50–59 years aHR 1.58, P = 0.002; 60–69 years aHR 2.63, P < 0.001; 70–94 years aHR 3.64, P = 0.004). Conclusion:Older age groups represent an important proportion of the overall treatment cohort in these sub-Saharan Africa programmes, and risk of mortality increased as age increased. Future research should be directed at further understanding the reasons for higher mortality, and defining simple interventions that are feasible in highly under-resourced settings to allow for adapted follow-up and care approaches for older age groups.

Impact of Hiv-Associated Conditions on Mortality in People Commencing Anti-Retroviral Therapy in Resource Limited Settings

Objectives To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS). Design, Setting Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010. Subjects, Participants 36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55–2.27). Outcome Measures Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation. Results There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21–5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97–2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74–4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80–3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80–3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi’s sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates. Conclusions A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research.

Incidence of WHO stage 3 and 4 conditions following initiation of Anti-Retroviral Therapy in resource limited settings

Objectives To determine the incidence of WHO clinical stage 3 and 4 conditions during early anti-retroviral therapy (ART) in resource limited settings (RLS). Design/Setting A descriptive analysis of routine program data collected prospectively from 25 Médecins Sans Frontières supported HIV treatment programs in eight countries between 2002 and 2010. Subjects/Participants 35,349 study participants with median follow-up on ART of 1.33 years (IQR 0.51–2.41). Outcome Measures Incidence in 100 person-years of WHO stage 3 or 4 conditions during 5 periods after ART initiation. Diagnoses of conditions were made according to WHO criteria and relied upon clinical assessments supported by basic laboratory investigations. Results The incidence of any WHO clinical stage 3 or 4 condition over 3 years was 40.02 per 100 person-years (31.77 for stage 3 and 8.25 for stage 4). The incidence of stage 3 and 4 conditions fell by over 97% between months 0–3 and months 25–36 (77.81 to 2.40 for stage 3 and 28.70 to 0.64 for stage 4). During months 0–3 pulmonary tuberculosis was the most common condition diagnosed in adults (incidence 22.24 per 100 person-years) and children aged 5–14 years (25.76) and oral candidiasis was the most common in children <5 years (25.79). Overall incidences were higher in Africa compared with Asia (43.98 versus 12.97 for stage 3 and 8.98 versus 7.05 for stage 4 conditions, p<0.001). Pulmonary tuberculosis, weight loss, oral and oesophageal candidiasis, chronic diarrhoea, HIV wasting syndrome and severe bacterial infections were more common in Africa. Extra-pulmonary tuberculosis, non-tuberculous mycobacterial infection, cryptococcosis, penicilliosis and toxoplasmosis were more common in Asia. Conclusions The incidence of WHO stage 3 and 4 conditions during the early period after ART initiation in RLS is high, but greatly reduces over time. This is likely due to both the benefits of ART and deaths of the sickest patients occurring shortly after ART initiation. Access to appropriate disease prevention tools prior to ART, and early initiation of ART, are important for their prevention.

Provision of antiretroviral treatment in conflict settings: the experience of Médecins Sans Frontières

IntroductionMany countries ravaged by conflict have substantial morbidity and mortality attributed to HIV/AIDS yet HIV treatment is uncommonly available. Universal access to HIV care cannot be achieved unless the needs of populations in conflict-affected areas are addressed.MethodsFrom 2003 Médecins Sans Frontières introduced HIV care, including antiretroviral therapy, into 24 programmes in conflict or post-conflict settings, mainly in sub-Saharan Africa. HIV care and treatment activities were usually integrated within other medical activities. Project data collected in the Fuchia software system were analysed and outcomes compared with ART-LINC data. Programme reports and other relevant documents and interviews with local and headquarters staff were used to develop lessons learned.ResultsIn the 22 programmes where ART was initiated, more than 10,500 people were diagnosed with HIV and received medical care, and 4555 commenced antiretroviral therapy, including 348 children. Complete data were available for adults in 20 programmes (n = 4145). At analysis, 2645 (64%) remained on ART, 422 (10%) had died, 466 (11%) lost to follow-up, 417 (10%) transferred to another programme, and 195 (5%) had an unclear outcome. Median 12-month mortality and loss to follow-up were 9% and 11% respectively, and median 6-month CD4 gain was 129 cells/mm 3.Patient outcomes on treatment were comparable to those in stable resource-limited settings, and individuals and communities obtained significant benefits from access to HIV treatment. Programme disruption through instability was uncommon with only one program experiencing interruption to services, and programs were adapted to allow for disruption and population movements. Integration of HIV activities strengthened other health activities contributing to health benefits for all victims of conflict and increasing the potential sustainability for implemented activities.ConclusionsWith commitment, simplified treatment and monitoring, and adaptations for potential instability, HIV treatment can be feasibly and effectively provided in conflict or post-conflict settings.

Prevalence of delayed hypersensitivity to the European standard series in a self-selected population

There are limited reports of the prevalence of positive reactions in healthy adults to patch tests with standard allergens; there are no recent comprehensive studies from Australia. Healthy adult volunteers (n = 219) from the Western Australian community were patch tested using the European standard series of allergens. Seventy‐seven (35%) reacted to at least one allergen, positive patch tests being most prevalent to nickel sulfate (20%), potassium dichromate (9%), cobalt chloride (6%) and fragrance mix (4%). Prevalence of positive patch tests to nickel and chromate was higher than that reported for another healthy population, which may stem from self‐selection of volunteers or geographical differences, including extent of exposure to allergens.

Invasive Meningococcal Meningitis Serogroup C Outbreak in Northwest Nigeria, 2015 - Third Consecutive Outbreak of a New Strain.

BACKGROUND: In northwest Nigeria in 2013 and 2014, two sequential, localized outbreaks of meningitis were caused by a new strain of Neisseria meningitidis serogroup C (NmC). In 2015, an outbreak caused by the same novel NmC strain occurred over a wider geographical area, displaying different characteristics to the previous outbreaks. We describe cases treated by Médecins Sans Frontières (MSF) in the 2015 outbreak. METHODS: From February 10 to June 8, 2015, data on cerebrospinal meningitis (CSM) cases and deaths were recorded on standardized line-lists from case management sites supported by MSF. Cerebrospinal fluid (CSF) samples from suspected cases at the beginning of the outbreak and throughout from suspected cases from new geographical areas were tested using rapid Pastorex® latex agglutination to determine causative serogroup. A subset of CSF samples was also inoculated into Trans-Isolate medium for testing by the WHO Collaborating Centre for Reference and Research on Meningococci, Oslo. Reactive vaccination campaigns with meningococcal ACWY polysaccharide vaccine targeted affected administrative wards. RESULTS: A total of 6394 (65 confirmed and 6329 probable) cases of CSM including 321 deaths (case fatality rate: 5.0%) were recorded. The cumulative attack rate was 282 cases per 100,000 population in the wards affected. The outbreak lasted 17 weeks, affecting 1039 villages in 21 local government areas in three states (Kebbi, Sokoto, Niger). Pastorex® tests were NmC positive for 65 (58%) of 113 CSF samples. Of 31 Trans-Isolate medium samples, 26 (84%) tested positive for NmC (14 through culture and 12 through PCR); all had the same rare PorA type P1.21-15,16 as isolates from the 2013 and 2014 outbreaks. All 14 culture-positive samples yielded isolates of the same genotype (ST-10217 PorA type P1.21-15,16 and FetA type F1-7). More than 222,000 targeted individuals were vaccinated relatively early in the outbreak (administrative coverage estimates 98% and 89% in Kebbi and Sokoto, respectively). CONCLUSIONS: The outbreak was the largest caused by NmC documented in Nigeria. Reactive vaccination in both states may have helped curtail the epidemic. A vaccination campaign against NmC with a long-lasting conjugate vaccine should be considered in the region.

Association of blood lead level with neurological features in 972 children affected by an acute severe lead poisoning outbreak in Zamfara State, northern Nigeria.

Background In 2010, Médecins Sans Frontières (MSF) investigated reports of high mortality in young children in Zamfara State, Nigeria, leading to confirmation of villages with widespread acute severe lead poisoning. In a retrospective analysis, we aimed to determine venous blood lead level (VBLL) thresholds and risk factors for encephalopathy using MSF programmatic data from the first year of the outbreak response. Methods and Findings We included children aged ≤5 years with VBLL ≥45 µg/dL before any chelation and recorded neurological status. Odds ratios (OR) for neurological features were estimated; the final model was adjusted for age and baseline VBLL, using random effects for village of residence. 972 children met inclusion criteria: 885 (91%) had no neurological features; 34 (4%) had severe features; 47 (5%) had reported recent seizures; and six (1%) had other neurological abnormalities. The geometric mean VBLLs for all groups with neurological features were >100 µg/dL vs 65.9 µg/dL for those without neurological features. The adjusted OR for neurological features increased with increasing VBLL: from 2.75, 95%CI 1.27–5.98 (80–99.9 µg/dL) to 22.95, 95%CI 10.54–49.96 (≥120 µg/dL). Neurological features were associated with younger age (OR 4.77 [95% CI 2.50–9.11] for 1–<2 years and 2.69 [95%CI 1.15–6.26] for 2–<3 years, both vs 3–5 years). Severe neurological features were seen at VBLL <105 µg/dL only in those with malaria. Interpretation Increasing VBLL (from ≥80 µg/dL) and age 1–<3 years were strongly associated with neurological features; in those tested for malaria, a positive test was also strongly associated. These factors will help clinicians managing children with lead poisoning in prioritising therapy and developing chelation protocols.

Risk Factors Associated with Default from Multi- and Extensively Drug-Resistant Tuberculosis Treatment, Uzbekistan: A Retrospective Cohort Analysis

Background The Médecins Sans Frontières project of Uzbekistan has provided multidrug-resistant tuberculosis treatment in the Karakalpakstan region since 2003. Rates of default from treatment have been high, despite psychosocial support, increasing particularly since programme scale-up in 2007. We aimed to determine factors associated with default in multi- and extensively drug-resistant tuberculosis patients who started treatment between 2003 and 2008 and thus had finished approximately 2 years of treatment by the end of 2010. Methods A retrospective cohort analysis of multi- and extensively drug-resistant tuberculosis patients enrolled in treatment between 2003 and 2008 compared baseline demographic characteristics and possible risk factors for default. Default was defined as missing ≥60 consecutive days of treatment (all drugs). Data were routinely collected during treatment and entered in a database. Potential risk factors for default were assessed in univariate analysis using chi-square test and in multivariate analysis with logistic regression. Results 20% (142/710) of patients defaulted after a median of 6 months treatment (IQR 2.6–9.9). Factors associated with default included severity of resistance patterns (pre-extensively drug-resistant/extensively drug-resistant tuberculosis adjusted odds ratio 0.52, 95%CI: 0.31–0.86), previous default (2.38, 1.09–5.24) and age >45 years (1.77, 1.10–2.87). The default rate was 14% (42/294) for patients enrolled 2003–2006 and 24% (100/416) for 2007–2008 enrolments (p = 0.001). Conclusions Default from treatment was high and increased with programme scale-up. It is essential to ensure scale-up of treatment is accompanied with scale-up of staff and patient support. A successful first course of tuberculosis treatment is important; patients who had previously defaulted were at increased risk of default and death. The protective effect of severe resistance profiles suggests that understanding disease severity or fear may motivate against default. Targeted health education and support for at-risk patients after 5 months of treatment when many begin to feel better may decrease default.