Anicteric Leptospirosis-Associated Meningitis in a Tropical Urban Environment, Brazil.

While studying aseptic meningitis in Salvador, Brazil, we diagnosed anicteric leptospirosis in 1.7% (5/295) of patients hospitalized for aseptic meningitis. Leptospirosis-associated meningitis patients had lower mean cerebrospinal fluid cell counts and protein than other-cause aseptic meningitis (p<0.05). Clinicians must consider leptospirosis-associated meningitis in appropriate clinical-epidemiologic contexts.

Progress Toward Rubella Elimination - Western Pacific Region, 2000-2019.

Rubella is the leading vaccine-preventable cause of birth defects. Rubella typically manifests as a mild febrile rash illness; however, infection during pregnancy, particularly during the first trimester, can result in miscarriage, fetal death, or a constellation of malformations known as congenital rubella syndrome (CRS), commonly including one or more visual, auditory, or cardiac defects (1). In 2012, the Regional Committee of the World Health Organization (WHO) Western Pacific Region (WPR)* committed to accelerate rubella control, and in 2017, resolved that all countries or areas (countries) in WPR should aim for rubella elimination† as soon as possible (2,3). WPR countries are capitalizing on measles elimination activities, using a combined measles and rubella vaccine, case-based surveillance for febrile rash illness, and integrated diagnostic testing for measles and rubella. This report summarizes progress toward rubella elimination and CRS prevention in WPR during 2000-2019. Coverage with a first dose of rubella-containing vaccine (RCV1) increased from 11% in 2000 to 96% in 2019. During 1970-2019, approximately 84 million persons were vaccinated through 62 supplementary immunization activities (SIAs) conducted in 27 countries. Reported rubella incidence increased from 35.5 to 71.3 cases per million population among reporting countries during 2000-2008, decreased to 2.1 in 2017, and then increased to 18.4 in 2019 as a result of outbreaks in China and Japan. Strong sustainable immunization programs, closing of existing immunity gaps, and maintenance of high-quality surveillance to respond rapidly to and contain outbreaks are needed in every WPR country to achieve rubella elimination in the region.

Increase in Infant Measles Deaths During a Nationwide Measles Outbreak-Mongolia, 2015-2016.

BACKGROUND: Surveillance data from a large measles outbreak in Mongolia suggested increased case fatality ratio (CFR) in the second of 2 waves. To confirm the increase in CFR and identify risk factors for measles death, we enhanced mortality ascertainment and conducted a case-control study among infants hospitalized for measles. METHODS: We linked national vital records with surveillance data of clinically or laboratory-confirmed infant (aged <12 months) measles cases with rash onset during March-September 2015 (wave 1) and October 2015-June 2016 (wave 2). We abstracted medical charts of 95 fatal cases and 273 nonfatal cases hospitalized for measles, matched by age and sex. We calculated adjusted matched odds ratios (amORs) and 95% confidence intervals (CIs) for risk factors. RESULTS: Infant measles deaths increased from 3 among 2224 cases (CFR: 0.13%) in wave 1 to 113 among 4884 cases (CFR: 2.31%) in wave 2 (P < .001). Inpatient admission, 7-21 days before measles rash onset, for pneumonia or influenza (amOR: 4.5; CI, 2.6-8.0), but not other diagnoses, was significantly associated with death. DISCUSSION: Measles infection among children hospitalized with respiratory infections likely increased deaths due to measles during wave 2. Preventing measles virus nosocomial transmission likely decreases measles mortality.

Correction: Cathelicidin Insufficiency in Patients with Fatal Leptospirosis.

[This corrects the article DOI: 10.1371/journal.ppat.1005943.].

Healthcare-Associated Measles After a Nationwide Outbreak in Mongolia.

Measles virus is highly infectious and can spread rapidly where vaccine coverage is low and isolation precautions suboptimal. We describe healthcare-associated measles transmission during the 2015-2016 measles outbreak in Mongolia, describe infection prevention gaps, and outline preventive strategies.

Cathelicidin Insufficiency in Patients with Fatal Leptospirosis.

Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10-50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.

Progress Toward Measles Elimination - Western Pacific Region, 2013-2017.

In 2005, the Regional Committee for the World Health Organization (WHO) Western Pacific Region (WPR)* established a goal for measles elimination† by 2012 (1). To achieve this goal, the 37 WPR countries and areas implemented the recommended strategies in the WPR Plan of Action for Measles Elimination (2) and the Field Guidelines for Measles Elimination (3). The strategies include 1) achieving and maintaining ≥95% coverage with 2 doses of measles-containing vaccine (MCV) through routine immunization services and supplementary immunization activities (SIAs), when required; 2) conducting high-quality case-based measles surveillance, including timely and accurate testing of specimens to confirm or discard suspected cases and detect measles virus for genotyping and molecular analysis; and 3) establishing and maintaining measles outbreak preparedness to ensure rapid response and appropriate case management. This report updates the previous report (4) and describes progress toward measles elimination in WPR during 2013-2017. During 2013-2016, estimated regional coverage with the first MCV dose (MCV1) decreased from 97% to 96%, and coverage with the routine second MCV dose (MCV2) increased from 91% to 93%. Eighteen (50%) countries achieved ≥95% MCV1 coverage in 2016. Seven (39%) of 18 nationwide SIAs during 2013-2017 reported achieving ≥95% administrative coverage. After a record low of 5.9 cases per million population in 2012, measles incidence increased during 2013-2016 to a high of 68.9 in 2014, because of outbreaks in the Philippines and Vietnam, as well as increased incidence in China, and then declined to 5.2 in 2017. To achieve measles elimination in WPR, additional measures are needed to strengthen immunization programs to achieve high population immunity, maintain high-quality surveillance for rapid case detection and confirmation, and ensure outbreak preparedness and prompt response to contain outbreaks.

Risk Factors for Measles Virus Infection Among Adults During a Large Outbreak in Postelimination Era in Mongolia, 2015.

Background: In 2015, a large nationwide measles outbreak occurred in Mongolia, with very high incidence in the capital city of Ulaanbaatar and among young adults. Methods: We conducted an outbreak investigation including a matched case-control study of risk factors for laboratory-confirmed measles among young adults living in Ulaanbaatar. Young adults with laboratory-confirmed measles, living in the capital city of Ulaanbaatar, were matched with 2-3 neighborhood controls. Conditional logistic regression was used to estimate adjusted matched odds ratios (aMORs) for risk factors, with 95% confidence intervals. Results: During March 1-September 30, 2015, 20 077 suspected measles cases were reported; 14 010 cases were confirmed. Independent risk factors for measles included being unvaccinated (adjusted matched odds ratio [aMOR] 2.0, P < .01), being a high school graduate without college education (aMOR 2.6, P < .01), remaining in Ulaanbaatar during the outbreak (aMOR 2.5, P < .01), exposure to an inpatient healthcare facility (aMOR 4.5 P < .01), and being born outside of Ulaanbaatar (aMOR 1.8, P = .02). Conclusions: This large, nationwide outbreak shortly after verification of elimination had high incidence among young adults, particularly those born outside the national capital. In addition, findings indicated that nosocomial transmission within health facilities helped amplify the outbreak.

Use of a Diagonal Approach to Health System Strengthening and Measles Elimination after a Large Nationwide Outbreak in Mongolia.

Measles is a highly transmissible infectious disease that causes serious illness and death worldwide. Efforts to eliminate measles through achieving high immunization coverage, well-performing surveillance systems, and rapid and effective outbreak response mechanisms while strategically engaging and strengthening health systems have been termed a diagonal approach. In March 2015, a large nationwide measles epidemic occurred in Mongolia, 1 year after verification of measles elimination in this country. A multidisciplinary team conducted an outbreak investigation that included a broad health system assessment, organized around the Global Health Security Agenda framework of Prevent-Detect-Respond, to provide recommendations for evidence-based interventions to interrupt the epidemic and strengthen the overall health system to prevent future outbreaks of measles and other epidemic-prone infectious threats. This investigation demonstrated the value of evaluating elements of the broader health system in investigating measles outbreaks and the need for using a diagonal approach to achieving sustainable measles elimination.

Multistate Outbreak of Respiratory Infections Among Unaccompanied Children, June 2014-July 2014.

BACKGROUND: From January 2014-July 2014, more than 46 000 unaccompanied children (UC) from Central America crossed the US-Mexico border. In June-July, UC aged 9-17 years in 4 shelters and 1 processing center in 4 states were hospitalized with acute respiratory illness. We conducted a multistate investigation to interrupt disease transmission. METHODS: Medical charts were abstracted for hospitalized UC. Nonhospitalized UC with influenza-like illness were interviewed, and nasopharyngeal and oropharyngeal swabs were collected to detect respiratory pathogens. Nasopharyngeal swabs were used to assess pneumococcal colonization in symptomatic and asymptomatic UC. Pneumococcal blood isolates from hospitalized UC and nasopharyngeal isolates were characterized by serotyping and whole-genome sequencing. RESULTS: Among 15 hospitalized UC, 4 (44%) of 9 tested positive for influenza viruses, and 6 (43%) of 14 with blood cultures grew pneumococcus, all serotype 5. Among 48 nonhospitalized children with influenza-like illness, 1 or more respiratory pathogens were identified in 46 (96%). Among 774 nonhospitalized UC, 185 (24%) yielded pneumococcus, and 70 (38%) were serotype 5. UC transferring through the processing center were more likely to be colonized with serotype 5 (odds ratio, 3.8; 95% confidence interval, 2.1-6.9). Analysis of core pneumococcal genomes detected 2 related, yet independent, clusters. No pneumococcus cases were reported after pneumococcal and influenza immunization campaigns. CONCLUSIONS: This respiratory disease outbreak was due to multiple pathogens, including Streptococcus pneumoniae serotype 5 and influenza viruses. Pneumococcal and influenza vaccinations prevented further transmission. Future efforts to prevent similar outbreaks will benefit from use of both vaccines.

Secondary Infections with Ebola Virus in Rural Communities, Liberia and Guinea, 2014-2015.

Persons who died of Ebola virus disease at home in rural communities in Liberia and Guinea resulted in more secondary infections than persons admitted to Ebola treatment units. Intensified monitoring of contacts of persons who died of this disease in the community is an evidence-based approach to reduce virus transmission in rural communities.

Decreased Ebola Transmission after Rapid Response to Outbreaks in Remote Areas, Liberia, 2014.

We measured the reproduction number before and after interventions were implemented to reduce Ebola transmission in 9 outbreaks in Liberia during 2014. We evaluated risk factors for secondary cases and the association between patient admission to an Ebola treatment unit (ETU) and survival. The reproduction number declined 94% from 1.7 (95% CI 1.1-2.6) to 0.1 (95% CI 0.02-0.6) after interventions began. The risk for secondary infections was 90% lower for patients admitted to an ETU (risk ratio 0.1, 95% CI 0.04-0.3) than for those who died in the community. The case-fatality rate was 68% (95% CI 60-74), and ETU admission was associated with a 50% reduction in death (hazard ratio 0.5, 95% CI 0.4-0.8). Isolation and treatment of Ebola patients had the dual benefit of interrupting community transmission and improving survival.

Progress toward polio eradication - worldwide, 2014-2015.

In 1988, the World Health Assembly of the World Health Organization (WHO) resolved to eradicate polio worldwide. Wild poliovirus (WPV) transmission has been interrupted in all but three countries (Afghanistan, Nigeria, and Pakistan). No WPV type 2 cases have been detected worldwide since 1999, and the last WPV type 3 case was detected in Nigeria in November 2012; since 2012, only WPV type 1 has been detected. Circulating vaccine-derived poliovirus (cVDPV), usually type 2, continues to cause cases of paralytic polio in communities with low population immunity. In 2012, the World Health Assembly declared global polio eradication "a programmatic emergency for global public health", and in 2014, WHO declared the international spread of WPV to previously polio-free countries to be "a public health emergency of international concern". This report summarizes global progress toward polio eradication during 2014-2015 and updates previous reports. In 2014, a total of 359 WPV cases were reported in nine countries worldwide. Although reported WPV cases increased in Pakistan and Afghanistan, cases in Nigeria decreased substantially in 2014, and encouraging progress toward global WPV transmission interruption has occurred. Overcoming ongoing challenges to interruption of WPV transmission globally will require sustained programmatic enhancements, including improving the quality of supplementary immunization activities (SIAs) to interrupt transmission in Afghanistan and Pakistan and to prevent WPV exportation to polio-free countries.

Implementation of Ebola case-finding using a village chieftaincy taskforce in a remote outbreak - Liberia, 2014.

On October 16, 2014, a woman aged 48 years traveled from Monrovia, Liberia, to the Kayah region of Rivercess County, a remote, resource-poor, and sparsely populated region of Liberia, and died on October 21 with symptoms compatible with Ebola virus disease (Ebola). She was buried in accordance with local tradition, which included grooming, touching, and kissing the body by family and other community members while it was being prepared for burial. During October 24-November 12, eight persons with probable and 13 with confirmed Ebola epidemiologically linked to the deceased woman had onset of symptoms. Nineteen of the 21 persons lived in five nearby villages in Kayah region; two, both with probable cases, lived in neighboring Grand Bassa County (Figure). Four of the confirmed cases in Kayah were linked by time and location, although the source case could not be determined because the patients had more than one exposure.

Rapid response to Ebola outbreaks in remote areas - Liberia, July-November 2014.

West Africa is experiencing its first epidemic of Ebola virus disease (Ebola). As of February 9, Liberia has reported 8,864 Ebola cases, of which 3,147 were laboratory-confirmed. Beginning in August 2014, the Liberia Ministry of Health and Social Welfare (MOHSW), supported by CDC, the World Health Organization (WHO), and others, began systematically investigating and responding to Ebola outbreaks in remote areas. Because many of these areas lacked mobile telephone service, easy road access, and basic infrastructure, flexible and targeted interventions often were required. Development of a national strategy for the Rapid Isolation and Treatment of Ebola (RITE) began in early October. The strategy focuses on enhancing capacity of county health teams (CHT) to investigate outbreaks in remote areas and lead tailored responses through effective and efficient coordination of technical and operational assistance from the MOHSW central level and international partners. To measure improvements in response indicators and outcomes over time, data from investigations of 12 of 15 outbreaks in remote areas with illness onset dates of index cases during July 16-November 20, 2014, were analyzed. The times to initial outbreak alerts and durations of the outbreaks declined over that period while the proportions of patients who were isolated and treated increased. At the same time, the case-fatality rate in each outbreak declined. Implementation of strategies, such as RITE, to rapidly respond to rural outbreaks of Ebola through coordinated and tailored responses can successfully reduce transmission and improve outcomes.

Breakthrough Measles among Vaccinated Adults Born during the Post-Soviet Transition Period in Mongolia.

Mongolia experienced a nationwide measles outbreak during 1 March 2015-31 December 2016, with 49,077 cases reported to the WHO; many were among vaccinated young adults, suggesting a possible role of vaccine failure. Advanced laboratory methods, coupled with detailed epidemiological investigations, can help classify cases as vaccine failure, failure to vaccinate, or both. In this report, we conducted a study of cases to identify risk factors for breakthrough infection for a subset of laboratory-confirmed measles cases. Of the 193 cases analyzed, only 19 (9.8%) reported measles vaccination history, and 170 (88%) were uncertain. Measles-specific IgG avidity testing classified 120 (62%) cases as low IgG avidity, indicating no prior exposure to measles. Ten of these cases with low IgG avidity had a history of measles vaccination, indicating primary vaccine failure. Overall, sixty cases (31%) had high IgG avidity, indicating breakthrough infection after prior exposure to measles antigen through vaccination or natural infection, but the IgG avidity results were highly age-dependent. This study found that among young children aged 9 months-5 years, breakthrough infection was rare (4/82, 5%); however, among young adults aged 15-25 years, breakthrough infection due to secondary vaccine failure (SVF) occurred on a large scale during this outbreak, accounting for the majority of cases (42/69 cases, 61%). The study found that large-scale secondary vaccine failure occurred in Mongolia, which highlights the potential for sustained outbreaks in post-elimination settings due to "hidden" cohorts of young adults who may have experienced waning immunity. This phenomenon may have implications for the sustainability of measles elimination in countries that remain vulnerable to the importation of the virus from areas where it is still endemic. Until global measles elimination is achieved, enhanced surveillance and preparedness for future outbreaks in post- or peri-elimination countries may be required.

Infant feeding practices were not associated with breast milk HIV-1 RNA levels in a randomized clinical trial in Botswana.

Exclusive breastfeeding has been associated with a reduced risk of late vertical HIV transmission as compared to an infant diet composed of breast milk mixed with supplemental foods or liquids. Hypothesized mechanisms include increased infectivity of breast milk from mothers who practice mixed breastfeeding (MBF), or mechanisms such as increased gastrointestinal permeability in the infant caused by mixed feeding. It has been proposed that MBF may result in subclinical mastitis and higher breast milk HIV titers. However, little is known about the relationship between feeding strategy and breast milk viral load. We measured the HIV-1 concentration in breast milk in a sub-cohort of women enrolled in a mother-to-child HIV transmission prevention trial (the "Mashi" study). We report no observed relationship between MBF and measured breast milk viral RNA load. Our findings suggest that the increased transmission risk associated with higher breast milk HIV-1 RNA during MBF is unlikely.

Surveillance for leptospirosis in the Americas, 1996-2005: a review of data from ministries of health.

OBJECTIVE: To characterize current leptospirosis reporting practices in the Americas. METHODS: Information was collected from the official websites of national ministries of health from the Americas region and two international organizations; personal communications; and three international morbidity databases. For all sources other than the morbidity databases, the review was limited to official reports citing clinically suspected and laboratory confirmed leptospirosis cases or deaths during the period 1996-2005. RESULTS: A total of 73 out of 1 644 reports met the selection criteria and were included in the analysis. Published leptospirosis data were available from half of the countries/sovereign territories (24 out of 48), and 18 of them had mandatory notification policies for leptospirosis. The sum of the median number of leptospirosis cases notified annually by the 24 countries/territories was 4 713.5, but just three countries (Brazil, Costa Rica, and Cuba) accounted for 83.1% (3 9cas20 es) of the notifications. Eight (16.7%) countries reported deaths due to leptospirosis. The sum of the median number of deaths reported annually for the eight countries was 380, but 349 (91.8%) were reported by Brazil. CONCLUSIONS: Notification practices in the Americas for leptospirosis are limited. Therefore, the numbers of cases and deaths reported are not representative for the region. The lack of leptospirosis data for many countries/territories may reflect weaknesses in certain aspects of national surveillance systems, including mandatory reporting policies, clinical laboratory infrastructure for performing case confirmation, and capacity to collect reported cases. Improved surveillance of leptospirosis cases and deaths in the Americas is needed to allow monitoring of regional epidemiological patterns and to estimate the burden of this important disease.

Linking rattiness, geography and environmental degradation to spillover Leptospira infections in marginalised urban settings: An eco-epidemiological community-based cohort study in Brazil.

Background: Zoonotic spillover from animal reservoirs is responsible for a significant global public health burden, but the processes that promote spillover events are poorly understood in complex urban settings. Endemic transmission of Leptospira, the agent of leptospirosis, in marginalised urban communities occurs through human exposure to an environment contaminated by bacteria shed in the urine of the rat reservoir. However, it is unclear to what extent transmission is driven by variation in the distribution of rats or by the dispersal of bacteria in rainwater runoff and overflow from open sewer systems. Methods: We conducted an eco-epidemiological study in a high-risk community in Salvador, Brazil, by prospectively following a cohort of 1401 residents to ascertain serological evidence for leptospiral infections. A concurrent rat ecology study was used to collect information on the fine-scale spatial distribution of 'rattiness', our proxy for rat abundance and exposure of interest. We developed and applied a novel geostatistical framework for joint spatial modelling of multiple indices of disease reservoir abundance and human infection risk. Results: The estimated infection rate was 51.4 (95%CI 40.4, 64.2) infections per 1000 follow-up events. Infection risk increased with age until 30 years of age and was associated with male gender. Rattiness was positively associated with infection risk for residents across the entire study area, but this effect was stronger in higher elevation areas (OR 3.27 95% CI 1.68, 19.07) than in lower elevation areas (OR 1.14 95% CI 1.05, 1.53). Conclusions: These findings suggest that, while frequent flooding events may disperse bacteria in regions of low elevation, environmental risk in higher elevation areas is more localised and directly driven by the distribution of local rat populations. The modelling framework developed may have broad applications in delineating complex animal-environment-human interactions during zoonotic spillover and identifying opportunities for public health intervention. Funding: This work was supported by the Oswaldo Cruz Foundation and Secretariat of Health Surveillance, Brazilian Ministry of Health, the National Institutes of Health of the United States (grant numbers F31 AI114245, R01 AI052473, U01 AI088752, R01 TW009504 and R25 TW009338); the Wellcome Trust (102330/Z/13/Z), and by the Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB/JCB0020/2016). MTE was supported by a Medical Research UK doctorate studentship. FBS participated in this study under a FAPESB doctorate scholarship.

Assessing the burden of congenital rubella syndrome in China and evaluating mitigation strategies: a metapopulation modelling study.

BACKGROUND: A rubella vaccine was licensed in China in 1993 and added to the Expanded Programme on Immunization in 2008, but a national cross-sectional serological survey during 2014 indicates that many adolescents remain susceptible. Maternal infections during the first trimester often cause miscarriages, stillbirths, and, among livebirths, congenital rubella syndrome. We aimed to evaluate possible supplemental immunisation activities (SIAs) to accelerate elimination of rubella and congenital rubella syndrome. METHODS: We analysed residual samples from the national serological survey done in 2014, data from monthly rubella surveillance reports from 2005 and 2016, and additional publications through a systematic review. Using an age-structured population model with provincial strata, we calculated the reproduction numbers and evaluated the gradient of the metapopulation effective reproduction number with respect to potential supplemental immunisation rates. We corroborated these analytical results and estimated times-to-elimination by simulating SIAs among adolescents (ages 10-19 years) and young adults (ages 20-29 years) using a model with regional strata. We estimated the incidence of rubella and burden of congenital rubella syndrome by simulating transmission in a relatively small population lacking only spatial structure. FINDINGS: By 2014, childhood immunisation had reduced rubella's reproduction number from 7·6 to 1·2 and SIAs among adolescents were the optimal elimination strategy. We found that less than 10% of rubella infections were reported; that although some women with symptomatic first-trimester infections might have elected to terminate their pregnancies, 700 children could have been born with congenital rubella syndrome during 2014; and that timely SIAs would avert outbreaks that, as susceptible adolescents reached reproductive age, could greatly increase the burden of this syndrome. INTERPRETATION: Our findings suggest that SIAs among adolescents would most effectively reduce congenital rubella syndrome as well as eliminate rubella, owing both to fewer infections in the immunised population and absence of infections that those immunised would otherwise have caused. Metapopulation models with realistic mixing are uniquely capable of assessing such indirect effects. FUNDING: WHO and National Science Foundation.