Longitudinal analysis of post-acute chikungunya-associated arthralgia in children and adults: A prospective cohort study in Managua, Nicaragua (2014-2018).

Chikungunya can result in debilitating arthralgia, often presenting as acute, self-limited pain, but occasionally manifesting chronically. Little is known about differences in chikungunya-associated arthralgia comparing children to adults over time. To characterize long-term chikungunya-associated arthralgia, we recruited 770 patients (105 0-4 years old [y/o], 200 5-9 y/o, 307 10-15 y/o, and 158 16+ y/o) with symptomatic chikungunya virus infections in Managua, Nicaragua, during two consecutive chikungunya epidemics (2014-2015). Participants were assessed at ~15 days and 1, 3, 6, 12, and 18 months post-fever onset. Following clinical guidelines, we defined participants by their last reported instance of arthralgia as acute (≤10 days post-fever onset), interim (>10 and <90 days), or chronic (≥90 days) cases. We observed a high prevalence of arthralgia (80-95%) across all ages over the study period. Overall, the odds of acute arthralgia increased in an age-dependent manner, with the lowest odds of arthralgia in the 0-4 y/o group (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.14-0.51) and the highest odds of arthralgia in the 16+ y/o participants (OR: 4.91, 95% CI: 1.42-30.95) relative to 10-15 y/o participants. Females had higher odds of acute arthralgia than males (OR: 1.63, 95% CI: 1.01-2.65) across all ages. We found that 23-36% of pediatric and 53% of adult participants reported an instance of post-acute arthralgia. Children exhibited the highest prevalence of post-acute polyarthralgia in their legs, followed by the hands and torso - a pattern not seen among adult participants. Further, we observed pediatric chikungunya presenting in two distinct phases: the acute phase and the subsequent interim/chronic phases. Thus, differences in the presentation of arthralgia were observed across age, sex, and disease phase in this longitudinal chikungunya cohort. Our results elucidate the long-term burden of chikungunya-associated arthralgia among pediatric and adult populations.

Characterization of the antispike IgG immune response to COVID-19 vaccines in people with a wide variety of immunodeficiencies.

Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.

Epidemiologic Features of Acute Pediatric Diarrhea in Managua, Nicaragua, from 2011 to 2019.

Diarrhea remains a leading cause of death in children in developing countries, including Nicaragua, but little is known about patterns of diarrhea occurrence in Central America over long periods of time. The purpose of this study was to determine the incidence, risk factors, long-term trends, and seasonality of diarrhea in children age 2 to 14 years in Managua, Nicaragua. From 2011 to 2019, we examined episodes of diarrhea among 6,485 children who participated in a prospective cohort study and presented for care in a primary care facility. We performed a longitudinal analysis considering time-varying variables and the intra-subject correlation of outcomes. In addition, we analyzed the weekly incidence of diarrhea, applying seasonal trend decomposition to extract secular and seasonal patterns. The overall incidence rate of diarrhea was 133.4 episodes per 1,000 person-years (95% CI, 128.3-138.7). We observed a slight increase in the incidence of diarrhea from 2011 to 2019. Younger age was the strongest predictor of the risk of diarrhea, and incidence increased with every additional hour without running water in the household per day. Diarrhea incidence in Managua was seasonal, with high peaks each year between May and July. Despite reductions in childhood mortality since 1990 in Nicaragua, diarrheal morbidity remains a major problem in Managua.

Epidemics of chikungunya, Zika, and COVID-19 reveal bias in case-based mapping.

Accurate tracing of epidemic spread over space enables effective control measures. We examined three metrics of infection and disease in a pediatric cohort (N≈3,000) over two chikungunya and one Zika epidemic, and in a household cohort (N=1,793) over one COVID-19 epidemic in Managua, Nicaragua. We compared spatial incidence rates (cases/total population), infection risks (infections/total population), and disease risks (cases/infected population). We used generalized additive and mixed-effects models, Kulldorf's spatial scan statistic, and intracluster correlation coefficients. Across different analyses and all epidemics, incidence rates considerably underestimated infection and disease risks, producing large and spatially non-uniform biases distinct from biases due to incomplete case ascertainment. Infection and disease risks exhibited distinct spatial patterns, and incidence clusters inconsistently identified areas of either risk. While incidence rates are commonly used to infer infection and disease risk in a population, we find that this can induce substantial biases and adversely impact policies to control epidemics.

Surveillance and Epidemiology of Dengue in Medellín, Colombia from 2009 to 2017.

Dengue is the most prevalent arthropod-borne viral disease in humans, primarily transmitted by the Aedes aegypti mosquito. We conducted a descriptive analysis of dengue cases from 2009 to 2017 in Medellín, Colombia, using data available from the Secretariat of Health. We analyzed the burden of outbreak years on the healthcare system, risk of cases exhibiting severe illness, potential disease surveillance problems, gender and age as risk factors, and spatiotemporal patterns of disease occurrence. Our data consisted of 50,083 cases, separated based on whether they were diagnostic test negative, diagnostic test positive (primarily IgM ELISA), clinically confirmed, epidemiologically linked, or probable. We used dengue incidence to analyze epidemiological trends between our study years, related to human movement patterns, between gender and age-groups, and spatiotemporally. We used risk to analyze the severity of dengue cases between the study years. We identified human movement could contributed to dengue spread, and male individuals (incidence rate: 0.86; 95% CI: 0.76-0.96) and individuals younger than 15 years (incidence rate: 1.24; 95% CI: 1.13-1.34) have higher incidence of dengue and located critical parts of the city where dengue incidence was high. Analysis was limited by participant diagnostic information, data concerning circulating strains, and a lack of phylogenetic information. Understanding the characteristics of dengue is a fundamental part of improving the health outcomes of at-risk populations. This analysis will be useful to support studies and initiatives to counteract dengue and provide context to the surveillance data collected by the health authorities in Medellín.

Age-dependent manifestations and case definitions of paediatric Zika: a prospective cohort study.

BACKGROUND: Paedeatric Zika remains an understudied topic. WHO and the Pan American Health Organization (PAHO) Zika case definitions have not been assessed in children. We aimed to characterise clinical profiles and evaluate the diagnostic performance of the WHO and PAHO case definitions in a large cohort of paediatric Zika cases. METHODS: From January, 2016 to February, 2017, encompassing the major 2016 Zika epidemic, participants in the Pediatric Dengue Cohort Study (PDCS) in Managua, Nicaragua, were encouraged to visit the study health centre at first indication of any illness. PDCS participants were aged 2-14 years, healthy at enrolment, and recruited before the initiation of the present study. Molecular and serological assays were used to test participants exhibiting any of four broad clinical profiles suspected of resulting from a symptomatic Zika virus infection. These clinical profiles were: fever and at least two of headache, retro-orbital pain, myalgia, arthralgia, rash, haemorrhagic manifestations, and leukopenia; fever and at least two of nausea or vomiting, rash, aches and pains, positive tourniquet test, leukopenia, and any dengue warning sign; undifferentiated fever without evident cause, with or without any other clinical finding; and afebrile rash with or without any other clinical finding. We characterised acute clinical findings (signs, symptoms, and complete blood counts) in both Zika cases and non-Zika cases. FINDINGS: We prospectively followed a cohort of about 3700 children, of which 1110 were deemed eligible for inclusion. Four participants with laboratory-confirmed Zika (three co-infections with dengue virus, one missing complete blood count data) and two participants who were non-Zika cases (missing complete blood count data) were excluded from analysis. We analysed 556 laboratory-confirmed Zika and 548 non-Zika cases. The WHO case definition captured 176 confirmed Zika cases, and the PAHO definition 109 confirmed Zika cases, who presented with the most clinical findings and a dengue-like clinical profile. The remaining two thirds of Zika cases, principally characterised by undifferentiated fever or afebrile rash, were missed. Among Zika cases, rash (n=440)-particularly generalised erythematous rash (n=334)-fever (n=333), leukopenia (n=217), and headache (n=203) were most common and peaked within 3 days of illness onset. The most common Zika presentation over the first week of illness was rash only (n=80). The sensitivity of Zika case definitions increased across paediatric age (from 11·3% to 56·1% for the WHO case definition and from 6·0% to 36·6% for the PAHO case definition), as the prevalence of most clinical findings (particularly arthralgia) increased with age, irrespective of previous dengue virus infection. Consequently, Zika manifested differently across paediatric age; older Zika cases presented with a dengue-like clinical profile while younger Zika cases presented with undifferentiated fever or afebrile rash. INTERPRETATION: We provide the most thorough description of paediatric Zika to date. Most paediatric Zika cases go undetected under the WHO and PAHO case definitions, suggesting that current standards for Zika case ascertainment require revision. Zika manifests with mild but differing clinical profiles across paediatric age, presenting major challenges to diagnosis, surveillance, and efforts to control future Zika epidemics. FUNDING: US National Institutes of Health.

Epidemiological Evidence for Lineage-Specific Differences in the Risk of Inapparent Chikungunya Virus Infection.

In late 2013, chikungunya virus (CHIKV) was introduced into the Americas, leading to widespread epidemics. A large epidemic caused by the Asian chikungunya virus (CHIKV) lineage occurred in Managua, Nicaragua, in 2015. Literature reviews commonly state that the proportion of inapparent CHIKV infections ranges from 3 to 28%. This study estimates the ratio of symptomatic to asymptomatic CHIKV infections and identifies risk factors of infection. In October to November 2015, 60 symptomatic CHIKV-infected children were enrolled as index cases and prospectively monitored, alongside 236 household contacts, in an index cluster study. Samples were collected upon enrollment and on day 14 or 35 and tested by real-time reverse transcription-PCR (rRT-PCR), IgM capture enzyme-linked immunosorbent assays (IgM-ELISAs), and inhibition ELISAs to detect pre- and postenrollment CHIKV infections. Of 236 household contacts, 55 (23%) had experienced previous or very recent infections, 41 (17%) had active infections at enrollment, and 21 (9%) experienced incident infections. Vehicle ownership (multivariable-adjusted risk ratio [aRR], 1.58) increased the risk of CHIKV infection, whereas ≥4 municipal trash collections/week (aRR, 0.38) and having externally piped water (aRR, 0.52) protected against CHIKV infection. Among 63 active and incident infections, 31 (49% [95% confidence interval {CI}, 36%, 62%]) were asymptomatic, yielding a ratio of symptomatic to asymptomatic infections of 1:0.97 (95% CI, 1:0.56, 1:1.60). Although our estimate is outside the 3% to 28% range reported previously, Bayesian and simulation analyses, informed by a systematic literature search, suggested that the proportion of inapparent CHIKV infections is lineage dependent and that more inapparent infections are associated with the Asian lineage than the East/Central/South African (ECSA) lineage. Overall, these data substantially improve knowledge regarding chikungunya epidemics.IMPORTANCE Chikungunya virus (CHIKV) is an understudied threat to human health. During the 2015 chikungunya epidemic in Managua, Nicaragua, we estimated the ratio of symptomatic to asymptomatic CHIKV infections, which is important for understanding transmission dynamics and the public health impact of CHIKV. This index cluster study identified and monitored persons at risk of infection, enabling capture of asymptomatic infections. We estimated that 31 (49%) of 63 at-risk participants had asymptomatic CHIKV infections, which is significantly outside the 3% to 28% range reported in literature reviews. However, recent seroprevalence studies, including two large pediatric cohort studies in the same setting, had also found percentages of inapparent infections outside the 3% to 28% range. Bayesian and simulation analyses, informed by a systematic literature search, revealed that the percentage of inapparent infections in epidemic settings varies by CHIKV phylogenetic lineage. Our study quantifies and provides the first epidemiological evidence that chikungunya epidemic characteristics are strongly influenced by CHIKV lineage.

Seroprevalence, risk factor, and spatial analyses of Zika virus infection after the 2016 epidemic in Managua, Nicaragua.

In 2015, a Zika epidemic in Brazil began spreading throughout the Americas. Zika virus (ZIKV) entered Managua, Nicaragua, in January 2016 and caused an epidemic that peaked in July-September 2016. ZIKV seropositivity was estimated among participants of pediatric (n = 3,740) and household (n = 2,147) cohort studies, including an adult-only subset from the household cohort (n = 1,074), in Managua. Seropositivity was based on a highly sensitive and specific assay, the Zika NS1 blockade-of-binding ELISA, which can be used in dengue-endemic populations. Overall seropositivity for the pediatric (ages 2-14), household (ages 2-80), and adult (ages 15-80) cohorts was 36, 46, and 56%, respectively. Trend, risk factor, and contour mapping analyses demonstrated that ZIKV seroprevalence increased nonlinearly with age and that body surface area was statistically associated with increasing seroprevalence in children. ZIKV seropositivity was higher in females than in males across almost all ages, with adjusted prevalence ratios in children and adults of 1.11 (95% CI: 1.02-1.21) and 1.14 (95% CI: 1.01-1.28), respectively. No household-level risk factors were statistically significant in multivariate analyses. A spatial analysis revealed a 10-15% difference in the risk of ZIKV infections across our 3-km-wide study site, suggesting that ZIKV infection risk varies at small spatial scales. To our knowledge, this is the largest ZIKV seroprevalence study reported in the Americas, and the only one in Central America and in children to date. It reveals a high level of immunity against ZIKV in Managua as a result of the 2016 epidemic, making a second large Zika epidemic unlikely in the near future.

Spores and soil from six sides: interdisciplinarity and the environmental biology of anthrax (Bacillus anthracis).

Environmentally transmitted diseases are comparatively poorly understood and managed, and their ecology is particularly understudied. Here we identify challenges of studying environmental transmission and persistence with a six-sided interdisciplinary review of the biology of anthrax (Bacillus anthracis). Anthrax is a zoonotic disease capable of maintaining infectious spore banks in soil for decades (or even potentially centuries), and the mechanisms of its environmental persistence have been the topic of significant research and controversy. Where anthrax is endemic, it plays an important ecological role, shaping the dynamics of entire herbivore communities. The complex eco-epidemiology of anthrax, and the mysterious biology of Bacillus anthracis during its environmental stage, have necessitated an interdisciplinary approach to pathogen research. Here, we illustrate different disciplinary perspectives through key advances made by researchers working in Etosha National Park, a long-term ecological research site in Namibia that has exemplified the complexities of the enzootic process of anthrax over decades of surveillance. In Etosha, the role of scavengers and alternative routes (waterborne transmission and flies) has proved unimportant relative to the long-term persistence of anthrax spores in soil and their infection of herbivore hosts. Carcass deposition facilitates green-ups of vegetation to attract herbivores, potentially facilitated by the role of anthrax spores in the rhizosphere. The underlying seasonal pattern of vegetation, and herbivores' immune and behavioural responses to anthrax risk, interact to produce regular 'anthrax seasons' that appear to be a stable feature of the Etosha ecosystem. Through the lens of microbiologists, geneticists, immunologists, ecologists, epidemiologists, and clinicians, we discuss how anthrax dynamics are shaped at the smallest scale by population genetics and interactions within the bacterial communities up to the broadest scales of ecosystem structure. We illustrate the benefits and challenges of this interdisciplinary approach to disease ecology, and suggest ways anthrax might offer insights into the biology of other important pathogens. Bacillus anthracis, and the more recently emerged Bacillus cereus biovar anthracis, share key features with other environmentally transmitted pathogens, including several zoonoses and panzootics of special interest for global health and conservation efforts. Understanding the dynamics of anthrax, and developing interdisciplinary research programs that explore environmental persistence, is a critical step forward for understanding these emerging threats.

Increasing Campylobacter Infections, Outbreaks, and Antimicrobial Resistance in the United States, 2004-2012.

BACKGROUND: Campylobacteriosis, a leading cause of foodborne illness in the United States, was not nationally notifiable until 2015. Data describing national patterns and trends are limited. We describe the epidemiology of Campylobacter infections in the United States during 2004-2012. METHODS: We summarized laboratory-confirmed campylobacteriosis data from the Nationally Notifiable Disease Surveillance System, National Outbreak Reporting System, National Antimicrobial Resistance Monitoring System, and Foodborne Diseases Active Surveillance Network. RESULTS: During 2004-2012, 303520 culture-confirmed campylobacteriosis cases were reported. Average annual incidence rate (IR) was 11.4 cases/100000 persons, with substantial variation by state (range, 3.1-47.6 cases/100000 persons). IRs among patients aged 0-4 years were more than double overall IRs. IRs were highest among males in all age groups. IRs in western states and rural counties were higher (16.2/100000 and 14.2/100000, respectively) than southern states and metropolitan counties (6.8/100000 and 11.0/100000, respectively). Annual IRs increased 21% from 10.5/100000 during 2004-2006 to 12.7/100000 during 2010-2012, with the greatest increases among persons aged >60 years (40%) and in southern states (32%). The annual median number of Campylobacter outbreaks increased from 28 in 2004-2006 to 56 in 2010-2012; in total, 347 were reported. Antimicrobial susceptibility testing of isolates from 4793 domestic and 1070 travel-associated infections revealed that, comparing 2004-2009 to 2010-2012, ciprofloxacin resistance increased among domestic infections (12.8% vs 16.1%). CONCLUSIONS: During 2004-2012, incidence of campylobacteriosis, outbreaks, and clinically significant antimicrobial resistance increased. Marked demographic and geographic differences exist. Our findings underscore the importance of national surveillance and understanding of risk factors to guide and target control measures.