Protective effect of a first SARS-CoV-2 infection from reinfection: a matched retrospective cohort study using PCR testing data in England.

The duration of immunity after first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the extent to which prior immunity prevents reinfection is uncertain and remains an important question within the context of new variants. This is a retrospective population-based matched observational study where we identified the first polymerase chain reaction (PCR) positive of primary SARS-CoV-2 infection case tests between 1 March 2020 and 30 September 2020. Each case was matched by age, sex, upper tier local authority of residence and testing route to one individual testing negative in the same week (controls) by PCR. After a 90-day pre-follow-up period for cases and controls, any subsequent positive tests up to 31 December 2020 and deaths within 28 days of testing positive were identified, this encompassed an essentially vaccine-free period. We used a conditional logistic regression to analyse the results. There were 517 870 individuals in the matched cohort with 2815 reinfection cases and 12 098 first infections. The protective effect of a prior SARS-CoV-2 PCR-positive episode was 78% (odds ratio (OR) 0.22, 0.21-0.23). Protection rose to 82% (OR 0.18, 0.17-0.19) after a sensitivity analysis excluded 933 individuals with a first test between March and May and a subsequent positive test between June and September 2020. Amongst individuals testing positive by PCR during follow-up, reinfection cases had 77% lower odds of symptoms at the second episode (adjusted OR 0.23, 0.20-0.26) and 45% lower odds of dying in the 28 days after reinfection (adjusted OR 0.55, 0.42-0.71). Prior SARS-CoV-2 infection offered protection against reinfection in this population. There was some evidence that reinfections increased with the alpha variant compared to the wild-type SARS-CoV-2 variant highlighting the importance of continued monitoring as new variants emerge.

Outcomes of visceral leishmaniasis in pregnancy: A retrospective cohort study from South Sudan.

INTRODUCTION: Visceral leishmaniasis (VL) is endemic in South Sudan, where outbreaks occur frequently. Because of changes in the immune system during pregnancy, pregnant women are considered particularly vulnerable for developing complications of VL disease, including opportunistic infections. There is limited evidence available about clinical aspects and treatment outcomes of VL in pregnancy. We describe characteristics, maternal and pregnancy outcomes from a cohort of pregnant women with VL. METHODS: We conducted a retrospective analysis using routine programme data from a MSF health facility in Lankien, Jonglei State, South Sudan, between Oct 2014 and April 2018. Records were extracted of women diagnosed with VL while pregnant, and those symptomatic during pregnancy but diagnosed during the first two weeks postpartum. Records were matched with a random sample of non-pregnant women of reproductive age (15-45 years) with VL from the same period. RESULTS: We included 113 women with VL in pregnancy, and 223 non-pregnant women with VL. Women with VL in pregnancy presented with more severe anaemia, were more likely to need blood transfusion (OR 9.3; 95%CI 2.5-34.2) and were more often prescribed antibiotics (OR 6.0; 95%CI 3.4-10.6), as compared to non-pregnant women with VL. Adverse pregnancy outcomes, including miscarriage and premature delivery, were reported in 20% (16/81) where VL was diagnosed in pregnancy, and 50% 13/26) where VL was diagnosed postpartum. Postpartum haemorrhage was common. Pregnant women were more likely to require extension of treatment to achieve cure (OR 10.0; 95%CI 4.8-20.9), as compared to non-pregnant women with VL. Nevertheless, overall initial cure rates were high (96.5%) and mortality was low (1.8%) in this cohort of pregnant women with VL. CONCLUSION: This is the largest cohort in the literature of VL in pregnancy. Our data suggest that good maternal survival rates are possible in resource-limited settings, despite the high incidence of complications.

What drives mortality among HIV patients in a conflict setting? A prospective cohort study in the Central African Republic.

BACKGROUND: Provision of antiretroviral therapy (ART) during conflict settings is rarely attempted and little is known about the expected patterns of mortality. The Central African Republic (CAR) continues to have a low coverage of ART despite an estimated 110,000 people living with HIV and 5000 AIDS-related deaths in 2018. We present results from a cohort in Zemio, Haut-Mboumou prefecture. This region had the highest prevalence of HIV nationally (14.8% in a 2010 survey), and was subject to repeated attacks by armed groups on civilians during the observed period. METHODS: Conflict from armed groups can impact cohort mortality rates i) directly if HIV patients are victims of armed conflict, or ii) indirectly if population displacement or fear of movement reduces access to ART. Using monthly counts of civilian deaths, injuries and abductions, we estimated the impact of the conflict on patient mortality. We also determined patient-level risk factors for mortality and how the risk of mortality varies with time spent in the cohort. Model-fitting was performed in a Bayesian framework, using logistic regression with terms accounting for temporal autocorrelation. RESULTS: Patients were recruited and observed in the HIV treatment program from October 2011 to May 2017. Overall 1631 patients were enrolled and 1628 were included in the analysis giving 48,430 person-months at risk and 145 deaths. The crude mortality rate after 12 months was 0.92 (95% CI 0.90, 0.93). Our model showed that patient mortality did not increase during periods of heightened conflict; the odds ratios (OR) 95% credible interval (CrI) for i) civilian fatalities and injuries, and ii) civilian abductions on patient mortality both spanned unity. The risk of mortality for individual patients was highest in the second month after entering the cohort, and declined seven-fold over the first 12 months. Male sex was associated with a higher mortality (odds ratio 1.70 [95% CrI 1.20, 2.33]) along with the severity of opportunistic infections (OIs) at baseline (OR 2.52; 95% CrI 2.01, 3.23 for stage 2 OIs compared with stage 1). CONCLUSIONS: Our results show that chronic conflict did not appear to adversely affect rates of mortality in this cohort, and that mortality was driven predominantly by patient-specific risk factors. The risk of mortality and recovery of CD4 T-cell counts observed in this conflict setting are comparable to those in stable resource poor settings, suggesting that conflict should not be a barrier in access to ART.

Real-time analysis of the diphtheria outbreak in forcibly displaced Myanmar nationals in Bangladesh.

BACKGROUND: Between August and December 2017, more than 625,000 Rohingya from Myanmar fled into Bangladesh, settling in informal makeshift camps in Cox's Bazar district and joining 212,000 Rohingya already present. In early November, a diphtheria outbreak hit the camps, with 440 reported cases during the first month. A rise in cases during early December led to a collaboration between teams from Médecins sans Frontières-who were running a provisional diphtheria treatment centre-and the London School of Hygiene and Tropical Medicine with the goal to use transmission dynamic models to forecast the potential scale of the outbreak and the resulting resource needs. METHODS: We first adjusted for delays between symptom onset and case presentation using the observed distribution of reporting delays from previously reported cases. We then fit a compartmental transmission model to the adjusted incidence stratified by age group and location. Model forecasts with a lead time of 2 weeks were issued on 12, 20, 26 and 30 December and communicated to decision-makers. RESULTS: The first forecast estimated that the outbreak would peak on 19 December in Balukhali camp with 303 (95% posterior predictive interval 122-599) cases and would continue to grow in Kutupalong camp, requiring a bed capacity of 316 (95% posterior predictive interval (PPI) 197-499). On 19 December, a total of 54 cases were reported, lower than forecasted. Subsequent forecasts were more accurate: on 20 December, we predicted a total of 912 cases (95% PPI 367-2183) and 136 (95% PPI 55-327) hospitalizations until the end of the year, with 616 cases actually reported during this period. CONCLUSIONS: Real-time modelling enabled feedback of key information about the potential scale of the epidemic, resource needs and mechanisms of transmission to decision-makers at a time when this information was largely unknown. By 20 December, the model generated reliable forecasts and helped support decision-making on operational aspects of the outbreak response, such as hospital bed and staff needs, and with advocacy for control measures. Although modelling is only one component of the evidence base for decision-making in outbreak situations, suitable analysis and forecasting techniques can be used to gain insights into an ongoing outbreak.

Seasonal upsurge of pneumococcal meningitis in the Central African Republic.

A high incidence of bacterial meningitis was observed in the Central African Republic (CAR) from December 2015 to May 2017 in three hospitals in the northwest of the country that are within the African meningitis belt. The majority of cases were caused by Streptococcus pneumoniae (249/328; 75.9%), which occurred disproportionately during the dry season (November-April) with a high case-fatality ratio of 41.6% (95% confidence interval [CI] 33.0, 50.8%). High rates of bacterial meningitis during the dry season in the meningitis belt are typically caused by Neisseria meningitidis (meningococcal meningitis), and our observations suggest that the risk of contracting S. pneumoniae (pneumococcal) meningitis is increased by the same environmental factors. Cases of meningococcal meningitis (67/328; 20.4%) observed over the same period were predominantly type W and had a lower case fatality rate of 9.6% (95% CI 3.6, 21.8%). Due to conflict and difficulties in accessing medical facilities, it is likely that the reported cases represented only a small proportion of the overall burden and that there is high underlying prevalence of S. pneumoniae carriage in the community. Nationwide vaccination campaigns in the CAR against meningitis have been limited to the use of MenAfriVac, which targets only meningococcal meningitis type A. We therefore highlight the need for expanded vaccine coverage to prevent additional causes of seasonal outbreaks.

Accounting for False Positive HIV Tests: Is Visceral Leishmaniasis Responsible?

BACKGROUND: Co-infection with HIV and visceral leishmaniasis is an important consideration in treatment of either disease in endemic areas. Diagnosis of HIV in resource-limited settings relies on rapid diagnostic tests used together in an algorithm. A limitation of the HIV diagnostic algorithm is that it is vulnerable to falsely positive reactions due to cross reactivity. It has been postulated that visceral leishmaniasis (VL) infection can increase this risk of false positive HIV results. This cross sectional study compared the risk of false positive HIV results in VL patients with non-VL individuals. METHODOLOGY/PRINCIPAL FINDINGS: Participants were recruited from 2 sites in Ethiopia. The Ethiopian algorithm of a tiebreaker using 3 rapid diagnostic tests (RDTs) was used to test for HIV. The gold standard test was the Western Blot, with indeterminate results resolved by PCR testing. Every RDT screen positive individual was included for testing with the gold standard along with 10% of all negatives. The final analysis included 89 VL and 405 non-VL patients. HIV prevalence was found to be 12.8% (47/ 367) in the VL group compared to 7.9% (200/2526) in the non-VL group. The RDT algorithm in the VL group yielded 47 positives, 4 false positives, and 38 negatives. The same algorithm for those without VL had 200 positives, 14 false positives, and 191 negatives. Specificity and positive predictive value for the group with VL was less than the non-VL group; however, the difference was not found to be significant (p = 0.52 and p = 0.76, respectively). CONCLUSION: The test algorithm yielded a high number of HIV false positive results. However, we were unable to demonstrate a significant difference between groups with and without VL disease. This suggests that the presence of endemic visceral leishmaniasis alone cannot account for the high number of false positive HIV results in our study.

Adherence to Artemisinin Combination Therapy for the treatment of uncomplicated malaria in the Democratic Republic of the Congo.

Between 2011 and 2013 the number of recorded malaria cases had more than doubled, and between 2009 and 2013 had increased almost 4-fold in MSF-OCA (Médecins sans Frontières - Operational Centre Amsterdam) programmes in the Democratic Republic of the Congo (DRC). The reasons for this rise are unclear. Incorrect intake of Artemisinin Combination Therapy (ACT) could result in failure to treat the infection and potential recurrence. An adherence study was carried out to assess whether patients were completing the full course of ACT. One hundred and eight malaria patients in Shamwana, Katanga province, DRC were visited in their households the day after ACT was supposed to be completed. They were asked a series of questions about ACT administration and the blister pack was observed (if available). Sixty seven (62.0%) patients were considered probably adherent. This did not take into account the patients that vomited or spat their pills or took them at the incorrect time of day, in which case adherence dropped to 46 (42.6%). The most common reason that patients gave for incomplete/incorrect intake was that they were vomiting or felt unwell (10 patients (24.4%), although the reasons were not recorded for 22 (53.7%) patients). This indicates that there may be poor understanding of the importance of completing the treatment or that the side effects of ACT were significant enough to over-ride the pharmacy instructions. Adherence to ACT was poor in this setting. Health education messages emphasising the need to complete ACT even if patients vomit doses, feel unwell or their health conditions improve should be promoted.

Dilution testing using rapid diagnostic tests in a HIV diagnostic algorithm: a novel alternative for confirmation testing in resource limited settings.

BACKGROUND: Current WHO testing guidelines for resource limited settings diagnose HIV on the basis of screening tests without a confirmation test due to cost constraints. This leads to a potential risk of false positive HIV diagnosis. In this paper, we evaluate the dilution test, a novel method for confirmation testing, which is simple, rapid, and low cost. The principle of the dilution test is to alter the sensitivity of a rapid diagnostic test (RDT) by dilution of the sample, in order to screen out the cross reacting antibodies responsible for falsely positive RDT results. METHODS: Participants were recruited from two testing centres in Ethiopia where a tiebreaker algorithm using 3 different RDTs in series is used to diagnose HIV. All samples positive on the initial screening RDT and every 10th negative sample underwent testing with the gold standard and dilution test. Dilution testing was performed using Determine™ rapid diagnostic test at 6 different dilutions. Results were compared to the gold standard of Western Blot; where Western Blot was indeterminate, PCR testing determined the final result. RESULTS: 2895 samples were recruited to the study. 247 were positive for a prevalence of 8.5 % (247/2895). A total of 495 samples underwent dilution testing. The RDT diagnostic algorithm misclassified 18 samples as positive. Dilution at the level of 1/160 was able to correctly identify all these 18 false positives, but at a cost of a single false negative result (sensitivity 99.6 %, 95 % CI 97.8-100; specificity 100 %, 95 % CI: 98.5-100). Concordance between the gold standard and the 1/160 dilution strength was 99.8 %. CONCLUSION: This study provides proof of concept for a new, low cost method of confirming HIV diagnosis in resource-limited settings. It has potential for use as a supplementary test in a confirmatory algorithm, whereby double positive RDT results undergo dilution testing, with positive results confirming HIV infection. Negative results require nucleic acid testing to rule out false negative results due to seroconversion or misclassification by the lower sensitivity dilution test. Further research is needed to determine if these results can be replicated in other settings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01716299 .

Evaluation of HIV testing algorithms in Ethiopia: the role of the tie-breaker algorithm and weakly reacting test lines in contributing to a high rate of false positive HIV diagnoses.

BACKGROUND: In Ethiopia a tiebreaker algorithm using 3 rapid diagnostic tests (RDTs) in series is used to diagnose HIV. Discordant results between the first 2 RDTs are resolved by a third 'tiebreaker' RDT. Médecins Sans Frontières uses an alternate serial algorithm of 2 RDTs followed by a confirmation test for all double positive RDT results. The primary objective was to compare the performance of the tiebreaker algorithm with a serial algorithm, and to evaluate the addition of a confirmation test to both algorithms. A secondary objective looked at the positive predictive value (PPV) of weakly reactive test lines. METHODS: The study was conducted in two HIV testing sites in Ethiopia. Study participants were recruited sequentially until 200 positive samples were reached. Each sample was re-tested in the laboratory on the 3 RDTs and on a simple to use confirmation test, the Orgenics Immunocomb Combfirm® (OIC). The gold standard test was the Western Blot, with indeterminate results resolved by PCR testing. RESULTS: 2620 subjects were included with a HIV prevalence of 7.7%. Each of the 3 RDTs had an individual specificity of at least 99%. The serial algorithm with 2 RDTs had a single false positive result (1 out of 204) to give a PPV of 99.5% (95% CI 97.3%-100%). The tiebreaker algorithm resulted in 16 false positive results (PPV 92.7%, 95% CI: 88.4%-95.8%). Adding the OIC confirmation test to either algorithm eliminated the false positives. All the false positives had at least one weakly reactive test line in the algorithm. The PPV of weakly reacting RDTs was significantly lower than those with strongly positive test lines. CONCLUSION: The risk of false positive HIV diagnosis in a tiebreaker algorithm is significant. We recommend abandoning the tie-breaker algorithm in favour of WHO recommended serial or parallel algorithms, interpreting weakly reactive test lines as indeterminate results requiring further testing except in the setting of blood transfusion, and most importantly, adding a confirmation test to the RDT algorithm. It is now time to focus research efforts on how best to translate this knowledge into practice at the field level. TRIAL REGISTRATION: Clinical Trial registration #: NCT01716299.

Counselling in humanitarian settings: a retrospective analysis of 18 individual-focused non-specialised counselling programmes.

BACKGROUND: Médecins Sans Frontières (MSF) provides individual counselling interventions in medical humanitarian programmes in contexts affected by conflict and violence. Although mental health and psychosocial interventions are a common part of the humanitarian response, little is known about how the profile and outcomes for individuals seeking care differs across contexts. We did a retrospective analysis of routine programme data to determine who accessed MSF counselling services and why, and the individual and programmatic risk factors for poor outcomes. METHODS: We analysed data from 18 mental health projects run by MSF in 2009 in eight countries. Outcome measures were client-rating scores (1-10 scale; 1 worst) for complaint severity and functioning and counsellor assessment. The effect of client and programme factors on outcomes was assessed by multiple regression analysis. Logistic regression was used to assess binary outcome variables. RESULTS: 48704 counselling sessions were held with 14963 individuals. Excluding women-focused projects, 66.8% of patients were women. Mean (SD) age was 33.3 (14.1) years. Anxiety-related complaints were the most common (35.0%), followed by family-related problems (15.7%), mood-related problems (14.1%) and physical complaints (13.7%). Only 2.0% presented with a serious mental health condition. 27.2% did not identify a traumatic precipitating event. 24.6% identified domestic discord or violence and 17.5% psychological violence as the precipitating event. 6244 (43.9%) had only one session. For 91% of 7837 who returned, the counsellor reported the problem had decreased or resolved. The mean (SD) complaint rating improved by 4.7 (2.4) points (p < 0.001) and by 4.2 (2.3, p < 0.001) for functional rating. Risk factors for poorer outcomes were few sessions, non-conflict setting (stable or societal violence settings), serious mental health condition, or attending a large, recently opened project. CONCLUSIONS: The majority of clients accessing counselling services present with anxiety related complaints. Attrition rates were high. Good outcomes were recorded among those who attended for more than one visit. Lessons learned included the importance of adaptation of approach in non-conflict contexts such as societal violence or post-conflict contexts. There is a need for further research to evaluate the intervention against a control group.

Public health surveillance after the 2010 haiti earthquake: the experience of médecins sans frontières.

Background In January 2010, Haiti was struck by a powerful earthquake, killing and wounding hundreds of thousands and leaving millions homeless. In order to better understand the severity of the crisis, and to provide early warning of epidemics or deteriorations in the health status of the population, Médecins Sans Frontières established surveillance for infections of epidemic potential and for death rates and malnutrition prevalence. Methods Trends in infections of epidemic potential were detected through passive surveillance at health facilities serving as sentinel sites. Active community surveillance of death rates and malnutrition prevalence was established through weekly home visits. Results There were 102,054 consultations at the 15 reporting sites during the 26 week period of operation. Acute respiratory infections, acute watery diarrhoea and malaria/fever of unknown origin accounted for the majority of proportional morbidity among the diseases under surveillance. Several alerts were triggered through the detection of immediately notifiable diseases and increasing trends in some conditions. Crude and under-5 death rates, and acute malnutrition prevalence, were below emergency thresholds. Conclusion Disease surveillance after disasters should include an alert and response component, requiring investment of resources in informal networks that improve sensitivity to alerts as well as on the more common systems of data collection, compilation and analysis. Information sharing between partners is necessary to strengthen early warning systems. Community-based surveillance of mortality and malnutrition is feasible but requires careful implementation and validation.

Economic evaluation of infant and adolescent hepatitis B vaccination in the UK.

A Markov model of hepatitis B virus (HBV) disease progression in the UK estimated that 81% of predicted HBV-associated morbidity and mortality could be prevented by universal infant vaccination at a cost of approximately £ 260,000 per QALY gained. Universal adolescent vaccination would be less effective (45% prevented) and less cost-effective (£ 493,000 per QALY gained). Higher HBV incidence rates in males and intermediate/high risk ethnic populations meant it was approximately 3 times more cost-effective to vaccinate these groups. At current vaccine costs a selective infant vaccination programme, based on vaccinating intermediate/high risk ethnic populations would not be considered cost effective. The threshold cost per vaccinated child at which the programme would be considered cost-effective was investigated. Universal infant vaccination would be cost-effective if the average cost of vaccinating each child against HBV, including vaccine and administration costs of all doses, was less than £ 4.09. Given the low cost of vaccination required to make a universal programme cost-effective the most feasible policy in the UK would be to use a suitably priced combined vaccine that included the other antigens in the current infant vaccination schedule.

Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes.

Although genetic variants in tumor necrosis factor (TNF), mannose binding lectin (MBL), and the vitamin D receptor (VDR) have been associated with leprosy clinical outcomes, these findings have not been extensively validated. We used a case-control study design with 933 patients in Nepal, which included 240 patients with type I reversal reaction (RR), and 124 patients with erythema nodosum leprosum (ENL) reactions. We compared genotype frequencies in 933 cases and 101 controls of seven polymorphisms, including a promoter region variant in TNF (G -308A), three polymorphisms in MBL (C154T, G161A and G170A), and three variants in VDR (FokI, BsmI, and TaqI). We observed an association between TNF -308A and protection from leprosy with an odds ratio of 0.52 (95% confidence interval = 0.29-0.95, p = 0.016). MBL polymorphism G161A was associated with protection from lepromatous leprosy (odds ratio = 0.33, 95% confidence interval = 0.12-0.85, p = 0.010). VDR polymorphisms were not associated with leprosy phenotypes. These results confirm previous findings of an association of TNF -308A with protection from leprosy and MBL polymorphisms with protection from lepromatous leprosy. The statistical significance was modest and will require further study for conclusive validation.

Integration of leprosy elimination into primary health care in orissa, India.

BACKGROUND: Leprosy was eliminated as a public health problem (<1 case per 10,000) in India by December 2005. With this target in sight the need for a separate vertical programme was diminished. The second phase of the National Leprosy Eradication Programme was therefore initiated: decentralisation of the vertical programme, integration of leprosy services into the primary health care (PHC) system and development of a surveillance system to monitor programme performance. METHODOLOGY/PRINCIPAL FINDINGS: To study the process of integration a qualitative analysis of issues and perceptions of patients and providers, and a review of leprosy records and registers to evaluate programme performance was carried out in the state of Orissa, India. Program performance indicators such as a low mean defaulter rate of 3.83% and a low-misdiagnosis rate of 4.45% demonstrated no detrimental effect of integration on program success. PHC staff were generally found to be highly knowledgeable of diagnosis and management of leprosy cases due to frequent training and a support network of leprosy experts. However in urban hospitals district-level leprosy experts had assumed leprosy activities. The aim was to aid busy PHC staff but it also compromised their leprosy knowledge and management capacity. Inadequate monitoring of a policy of 'new case validation,' in which MDT was not initiated until primary diagnosis had been verified by a leprosy expert, may have led to approximately 26% of suspect cases awaiting confirmation of diagnosis 1-8 months after their initial PHC visit. CONCLUSIONS/SIGNIFICANCE: This study highlights the need for effective monitoring and evaluation of the integration process. Inadequate monitoring could lead to a reduction in early diagnosis, a delay in initiation of MDT and an increase in disability rates. This in turn could reverse some of the programme's achievements. These findings may help Andhra Pradesh and other states in India to improve their integration process and may also have implications for other disease elimination programmes such as polio and guinea worm (dracunculiasis) as they move closer to their elimination goals.

Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction.

Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-kappaB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29-0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31-0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability.

Cost-effectiveness of antiviral stockpiling and near-patient testing for potential influenza pandemic.

A decision analytical model was developed to investigate the cost-effectiveness of stockpiling antiviral (AV) drugs for a potential influenza pandemic in the United Kingdom and the possible role of near-patient testing in conserving AV drug stocks. Under base-case assumptions (including a fixed stockpile that was smaller than the clinical attack rate), the treat-only option (treating all symptomatic patients with AV drugs) would be considered cost-effective ( pound1,900- pound13,700 per quality-adjusted life year [QALY] gained, depending on the fatality scenario), compared with no intervention (nonintervention but management of cases as they arise). The test-treat option (testing all symptomatic patients but treating those with positive tests results only) would result in moderate gains in QALYs over the treat-only option but at relatively large additional costs. Stockpiling sufficient AV drugs (but not near-patient tests) to treat all patients with clinical cases would be cost-effective, provided AV drugs are effective at preventing deaths from pandemic influenza.

Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy.

BACKGROUND: Leprosy is characterized by a spectrum of clinical manifestations that depend on the type of immune response against the pathogen. Patients may undergo immunological changes known as "reactional states" (reversal reaction and erythema nodosum leprosum) that result in major clinical deterioration. The goal of the present study was to assess the effect of Toll-like receptor 2 (TLR2) polymorphisms on susceptibility to and clinical presentation of leprosy. METHODS: Three polymorphisms in TLR2 (597C-->T, 1350T-->C, and a microsatellite marker) were analyzed in 431 Ethiopian patients with leprosy and 187 control subjects. The polymorphism-associated risk of developing leprosy, lepromatous (vs. tuberculoid) leprosy, and leprosy reactions was assessed by multivariate logistic regression models. RESULTS: The microsatellite and the 597C-->T polymorphisms both influenced susceptibility to reversal reaction. Although the 597T allele had a protective effect (odds ratio [OR], 0.34 [95% confidence interval {CI}, 0.17-0.68]; P= .002 under the dominant model), homozygosity for the 280-bp allelic length of the microsatellite strongly increased the risk of reversal reaction (OR, 5.83 [95% CI, 1.98-17.15]; P= .001 under the recessive model). These associations were consistent among 3 different ethnic groups. CONCLUSIONS: These data suggest a significant role for TLR-2 in the occurrence of leprosy reversal reaction and provide new insights into the immunogenetics of the disease.

Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro.

To induce effector immunity, dendritic cells (DCs) must differentiate into fully mature cells. We show that, after human monocyte-derived DCs were infected with virulent Mycobacterium tuberculosis, up-regulation of cellular-surface maturation markers was minimal and reversible. In the presence of a potent stimulus for maturation (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and prostaglandin E2 [PGE2]), M. tuberculosis inhibited phenotypic DC maturation. M. tuberculosis-infected DCs had an impaired ability to induce allogeneic lymphoproliferation and activated autologous memory CD4+ and CD8+ T cells optimally only in the presence of TNF-alpha, IL-1beta, and PGE2. Thus, virulent M. tuberculosis inhibits phenotypic and functional maturation of human monocyte-derived DCs. This mechanism, which has been described elsewhere for various viruses and for the virulent mycobacterium M. leprae, may be a novel mechanism that this pathogen uses to evade the host's immune response.

A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population.

A major susceptibility locus for leprosy has recently been mapped on chromosome 10 (10p13) by genome-wide linkage analysis. Microsatellite markers from this genome screen that showed suggestive evidence of linkage to leprosy were evaluated in an additional 140 families with affected sib pairs. A second region of linkage has thus been identified on chromosome 20 (20p12). The peak of linkage lies at marker D20S115, which has a significant single-point maximum logarithm of odds score of 3.48 (P=.00003). Transmission disequilibrium testing of the microsatellite markers in 20p12 showed that the marker D20S835 is associated with protection against leprosy (P=.021), which suggests that a locus controlling susceptibility lies close to this marker.

Local nerve damage in leprosy does not lead to an impaired cellular immune response or decreased wound healing in the skin.

This study investigated whether peripheral nerve damage in patients with leprosy impairs local cellular immune responses, thereby reducing wound healing and leading to chronic skin ulceration. Anesthetic and contralateral sensitive skin sites in 42 patients with leprosy were compared for delayed-type hypersensitivity responses to purified protein derivative (PPD) of tuberculin. Leukocyte recruitment, epidermal activation, keratinocyte proliferation, and rates of wound healing after skin biopsy were compared. No significant differences in PPD-induced induration, epidermal activation and thickening or numbers of total T cells, CD8+ T cells, CD1a+ Langerhans cells, and proliferating Ki67+ keratinocytes were observed between anesthetic and sensitive skin sites. Similarly, rates of wound healing over 5 days after skin biopsy did not differ significantly. Thus, local leprosy-associated anesthesia does not appear to contribute to local immune compromise or impaired wound healing. Rather, chronic cutaneous ulceration in leprosy most likely results from repeated trauma associated with loss of sensation.