Guilherme S. Ribeiro

Impact of Environment and Social Gradient on Leptospira Infection in Urban Slums

Background Leptospirosis has become an urban health problem as slum settlements have expanded worldwide. Efforts to identify interventions for urban leptospirosis have been hampered by the lack of population-based information on Leptospira transmission determinants. The aim of the study was to estimate the prevalence of Leptospira infection and identify risk factors for infection in the urban slum setting. Methods and Findings We performed a community-based survey of 3,171 slum residents from Salvador, Brazil. Leptospira agglutinating antibodies were measured as a marker for prior infection. Poisson regression models evaluated the association between the presence of Leptospira antibodies and environmental attributes obtained from Geographical Information System surveys and indicators of socioeconomic status and exposures for individuals. Overall prevalence of Leptospira antibodies was 15.4% (95% confidence interval [CI], 14.0–16.8). Households of subjects with Leptospira antibodies clustered in squatter areas at the bottom of valleys. The risk of acquiring Leptospira antibodies was associated with household environmental factors such as residence in flood-risk regions with open sewers (prevalence ratio [PR] 1.42, 95% CI 1.14–1.75) and proximity to accumulated refuse (1.43, 1.04–1.88), sighting rats (1.32, 1.10–1.58), and the presence of chickens (1.26, 1.05–1.51). Furthermore, low income and black race (1.25, 1.03–1.50) were independent risk factors. An increase of US

Zika virus: History, emergence, biology, and prospects for control

1 per day in per capita household income was associated with an 11% (95% CI 5%–18%) decrease in infection risk. Conclusions Deficiencies in the sanitation infrastructure where slum inhabitants reside were found to be environmental sources of Leptospira transmission. Even after controlling for environmental factors, differences in socioeconomic status contributed to the risk of Leptospira infection, indicating that effective prevention of leptospirosis may need to address the social factors that produce unequal health outcomes among slum residents, in addition to improving sanitation.

Outbreak of Exanthematous Illness Associated with Zika, Chikungunya, and Dengue Viruses, Salvador, Brazil

Zika virus (ZIKV), a previously obscure flavivirus closely related to dengue, West Nile, Japanese encephalitis and yellow fever viruses, has emerged explosively since 2007 to cause a series of epidemics in Micronesia, the South Pacific, and most recently the Americas. After its putative evolution in sub-Saharan Africa, ZIKV spread in the distant past to Asia and has probably emerged on multiple occasions into urban transmission cycles involving Aedes (Stegomyia) spp. mosquitoes and human amplification hosts, accompanied by a relatively mild dengue-like illness. The unprecedented numbers of people infected during recent outbreaks in the South Pacific and the Americas may have resulted in enough ZIKV infections to notice relatively rare congenital microcephaly and Guillain-Barré syndromes. Another hypothesis is that phenotypic changes in Asian lineage ZIKV strains led to these disease outcomes. Here, we review potential strategies to control the ongoing outbreak through vector-centric approaches as well as the prospects for the development of vaccines and therapeutics.

Prevention of Haemophilus influenzae Type b (Hib) Meningitis and Emergence of Serotype Replacement with Type a Strains after Introduction of Hib Immunization in Brazil

To the Editor: Zika virus (ZIKV) has been recognized as an emerging mosquito-borne flavivirus since outbreaks were reported from Yap Island in 2007 (1), French Polynesia in 2013 (2), and Cook Island and New Caledonia in 2014 (3). It has joined dengue virus (DENV) and chikungunya virus (CHIKV) as global public health threats (4). ZIKV infection typically causes a self-limited dengue-like illness characterized by exanthema, low-grade fever, conjunctivitis, and arthralgia, and an increase in rates of Guillain-Barre syndrome have been observed during ZIKV outbreaks (5). In Brazil, clusters of cases of acute exanthematous illness have been reported from various regions since late 2014, and in April 2015, ZIKV was identified as the etiologic agent (6). In May 2015, the Brazilian Ministry of Health recognized circulation of ZIKV in Brazil. We report epidemiologic findings for an ongoing outbreak of acute exanthematous illness in the population of Salvador, the third largest city in Brazil. The Salvador Epidemiologic Surveillance Office (ESO) was first alerted to cases of an acute exanthematous illness early in 2015. Reporting of cases increased during March, and in April the ESO established 10 public emergency health centers in Salvador as sentinel units for systematic surveillance of patients with acute exanthematous illness of unknown cause. The units searched retrospectively for suspected cases by review of medical charts of patients treated since February 15, continued with prospective case detection, and submitted weekly reports of identified cases to the ESO. During February 15−June 25, a total of 14,835 cases of an indeterminate acute exanthematous illness were reported from the 12 sanitary districts in Salvador. The overall attack rate was 5.5 cases/1,000 persons (4.6 cases/1,000 men and 6.3 cases/1,000 women, 8.2 cases/1,000 children 40 years of age). The epidemic curve peaked in the first week of May, which was 1 week after molecular diagnosis of ZIKV in 8 patients residing ≈50 km from Salvador and during a period of intense media coverage of the outbreak (Figure) (6). Reporting of suspected dengue cases in Salvador did not vary substantially from that in other years and was >5 times lower: 2,630 cases, of which 165/366 (45.1%) were positive for dengue IgM, 20/590 (3.4%) positive for dengue virus nonstructural protein 1, and 1/11 (9.1%) positive for dengue virus by reverse transcription PCR (Figure). During the same period, 58 cases of suspected chikungunya were reported and 24 patients with suspected Guillain-Barre syndrome were hospitalized. Figure Reported cases of indeterminate acute exanthematous illness and suspected dengue fever in Salvador, Brazil, by date of medical care, February 15−June 25, 2015. Letters indicate specific events. A) February 15: systematic reporting of cases of ... The median age of case-patients was 26 years (interquartile range 11–39 years), but all age groups were affected, which is a pattern typical of spread of new microorganisms (or subtypes) in a susceptible population. Median duration of symptoms at time of medical attention was 1 day (interquartile range 0–3 days). All patients had exanthema and most (12,711/14,093 [90.2%]) had pruritus. Fever (4,841/13,786, 35.1%), arthralgia (278/1,048 [26.5%]), headache (3,446/13,503 [25.6%]), and myalgia (223/1,033 [21.6%]) were less common. Serum samples from some patients were examined for rubella IgM (2/200, 1.0% positive), rubella IgG (15/18, 83.3% positive), measles IgM (0/11, 0% positive), dengue nonstructural protein 1 (3/185, 1.6% positive), dengue IgM (17/80, 21.3% positive), parvovirus B19 IgM (0/1, 0% positive), and parvovirus B19 IgG (1/1, 100% positive). Reverse transcription PCR was performed on 58 serum samples stored at −20°C and confirmed ZIKV in 3 (5.2%) samples, CHIKV in 3 (5.2%) samples, DENV type 3 in 1 (1.7%) sample, and DENV type 4 in 1 (1.7%) sample. Identification of ZIKV, CHIKV and DENV as etiologic agents of acute exanthematous illness suggests that these 3 Aedes spp. mosquito−transmitted viruses were co-circulating in Salvador and highlights the challenge in clinically differentiating these infections during outbreaks. Although we were not able to determine the specific incidence of each virus, the low frequency of fever and arthralgia, which are indicators of dengue and chikungunya, point to ZIKV as the probable cause of several of the reported cases. Furthermore, laboratory-confirmed cases of infection with ZIKV were simultaneously identified in other cities within metropolitan Salvador (6,7) and in other states in Brazil (8). Low diagnosis of ZIKV infection is likely because viremia levels among infected patients appear to be low (9). The spread of ZIKV represents an additional challenge for public health systems, particularly because of the risk for concurrent transmission of DENV and CHIKV by the same vectors, Ae. aegypti and Ae. albopictus mosquitoes, which are abundant throughout tropical and subtropical regions. To date, the largest outbreak of chikungunya in Brazil occurred in 2014 in Feira de Santana, Bahia, ≈100 km from Salvador, where dengue is also prevalent (10). This report illustrates the potential for explosive simultaneous outbreaks of ZIKV, CHIKV, and DENV in the Western Hemisphere and the increasing public health effects of Aedes spp. mosquitoes as vectors. The apparent increase in reports of Guillain-Barre syndrome during the outbreak deserves further investigation to elucidate whether this syndrome is associated with ZIKV infection. Public health authorities in Brazil and neighboring countries should plan accordingly.

Eschar-associated Spotted Fever Rickettsiosis, Bahia, Brazil

Surveillance for Haemophilus influenzae meningitis cases was performed in Salvador, Brazil, before and after introduction of H. influenzae type b (Hib) immunization. The incidence of Hib meningitis decreased 69% during the 1-year period after initiation of Hib immunization (from 2.62 to 0.81 cases/100,000 person-years; P<.001). In contrast, the incidence for H. influenzae type a meningitis increased 8-fold (from 0.02 to 0.16 cases/100,000 person-years; P=.008). Pulsed-field gel electrophoretic analysis demonstrated that H. influenzae type a isolates belonged to 2 clonally related groups, both of which were found before Hib immunization commenced. Therefore, Hib immunization contributed to an increased risk for H. influenzae type a meningitis through selection of circulating H. influenzae type a clones. The risk attributable to serotype replacement is small in comparison to the large reduction in Hib meningitis due to immunization. However, these findings highlight the need to maintain surveillance as the use of conjugate vaccines expands worldwide.

Prospective Study of Leptospirosis Transmission in an Urban Slum Community: Role of Poor Environment in Repeated Exposures to the Leptospira Agent

In Brazil, Brazilian spotted fever was once considered the only tick-borne rickettsial disease. We report eschar-associated rickettsial disease that occurred after a tick bite. The etiologic agent is most related to Rickettsia parkeri, R. africae, and R. sibirica and probably widely distributed from São Paulo to Bahia in the Atlantic Forest.

Time Lags between Exanthematous Illness Attributed to Zika Virus, Guillain-Barré Syndrome, and Microcephaly, Salvador, Brazil.

Background Leptospirosis has emerged as an urban health problem as slum settlements have rapidly spread worldwide and created conditions for rat-borne transmission. Prospective studies have not been performed to determine the disease burden, identify risk factors for infection and provide information needed to guide interventions in these marginalized communities. Methodology/Principal Findings We enrolled and followed a cohort of 2,003 residents from a slum community in the city of Salvador, Brazil. Baseline and one-year serosurveys were performed to identify primary and secondary Leptospira infections, defined as respectively, seroconversion and four-fold rise in microscopic agglutination titers. We used multinomial logistic regression models to evaluate risk exposures for acquiring primary and secondary infection. A total of 51 Leptospira infections were identified among 1,585 (79%) participants who completed the one-year follow-up protocol. The crude infection rate was 37.8 per 1,000 person-years. The secondary infection rate was 2.3 times higher than that of primary infection rate (71.7 and 31.1 infections per 1,000 person-years, respectively). Male gender (OR 2.88; 95% CI 1.40–5.91) and lower per capita household income (OR 0.54; 95% CI, 0.30–0.98 for an increase of

Emergence of Congenital Zika Syndrome: Viewpoint From the Front Lines

1 per person per day) were independent risk factors for primary infection. In contrast, the 15–34 year age group (OR 10.82, 95% CI 1.38–85.08), and proximity of residence to an open sewer (OR 0.95; 0.91–0.99 for an increase of 1 m distance) were significant risk factors for secondary infection. Conclusions/Significance This study found that slum residents had high risk (>3% per year) for acquiring a Leptospira infection. Re-infection is a frequent event and occurs in regions of slum settlements that are in proximity to open sewers. Effective prevention of leptospirosis will therefore require interventions that address the infrastructure deficiencies that contribute to repeated exposures among slum inhabitants.

Variation in aedes aegypti mosquito competence for zika virus transmission

There is strong evidence of a temporal relationship between virus infection in pregnant women and birth outcome.

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

Zika, a mosquito-borne flavivirus discovered in Uganda in 1947, remained obscure until its emergence in Micronesia in 2007. Six years later, it arrived in French Polynesia and other islands in the South Pacific (1). The virus was first detected in Brazil in early 2015 and has now spread throughout South and Central America and the Caribbean (2). Infection often remains unrecognized because it either is asymptomatic (75% to 80%) or has a nonspecific presentation of rash and fever. The first suggestion that Zika virus causes more than a self-limited illness was during the French Polynesian outbreak, when incidence of Guillain-Barr syndrome increased 20-fold (3). Likewise, a cluster of cases of this syndrome was identified in Brazil after the introduction of Zika virus (4). From July to September 2015, several months after the introduction of Zika virus into northeastern Brazil, obstetricians noticed an increased number of fetuses with congenital malformations during ultrasound screening. By October, the number of newborns with microcephaly had increased significantly in this area, according to birth registry data from previous years. Microcephaly had now increased in other regions along with the spread of Zika virus. To date, more than 4000 cases have been reported (Figures 1 and 2). Figure 1. Distribution of incident cases of microcephaly among Brazilian newborns, according to epidemiologic week and geographic region from 15 November 2015 to 16 January 2016. From the Brazilian Ministry of Health. Figure 2. Cumulative cases of microcephaly according to federal state from 15 November 2015 to 16 January 2016. From the Brazilian Ministry of Health. That Zika virus is the cause of the large number of microcephaly cases identified during the epidemic remains presumptive (5). Brazilian researchers first noted the viruss potential association with microcephaly when they investigated a newborn with this condition, who died soon after birth and was found to have detectable virus in tissues. Subsequently, Zika virus RNA was detected in additional cases of fetuses and stillbirths with congenital malformations (68). To date, the strongest evidence of the correlation between Zika virus and microcephaly is a circumstantial link between the spatial and temporal patterns of these infections and the appearance of microcephaly. In addition, this condition was retrospectively identified in infants born during the 2013 outbreak in French Polynesia. Despite these observations, investigators have not determined a definitive association between Zika virus and microcephaly cases in the Brazilian outbreak, most of which have been live-born infants. Our investigation is still in progress; however, we have gained insight into the scope and severity of microcephaly due to presumed congenital Zika syndrome (CZS), as well as challenges in confirming this association. Microcephaly is characterized by severe manifestations, such as marked cerebral atrophy and ventriculomegaly, extensive intracranial calcifications, simplified gyral patterns, dysgenesis of the corpus collosum, and cerebellar hypoplasia (Figure 3). Furthermore, CZS manifestations that extend beyond the central nervous system have been observed, including auditory impairment as well as ocular manifestations (9), such as focal pigment mottling and chorioretinal atrophy, which are distinct from other congenital conditions. Similar ocular lesions have been anecdotally identified in normocephalic newborns, suggesting that the overall burden may not be restricted to microcephaly cases. Figure 3. Computed tomography, reconstructed in the coronal oblique plane, of a newborn with microcephaly. Craniofacial dysmorphism, subcortical and basal ganglia calcifications, simplified gyral pattern, ventriculomegaly, and dysgenesis of the corpus callosum are seen. Although the apparent increase in microcephaly supports the assertion that Zika virus causes a distinct congenital syndrome, diagnostic limitations suggest caution in assuming a causal relationship. We have detected Zika virus RNA in only a fraction of microcephaly cases. Increased case ascertainment of microcephaly due to other causes has probably occurred contemporaneously. The inability to detect Zika virus in newborns with microcephaly may reflect compartmentalization of virus in tissues not sampled at the time of birth. Alternatively, intrauterine infections may be self-limited and Zika virus often cleared by birth. Screening approaches are essential for pregnant women who reside in impoverished regions where Zika virus has been recently introduced and who do not have access to ultrasonography and amniocentesis. Although detection is hampered by the extensive antigenic cross-reactivity with dengue and other circulating flaviviruses, a serologic test for prior intrauterine exposure to the virus in newborns is critically needednot only for diagnosis in pregnant women and newborns but also to identify individuals who have been infected with Zika virus and are presumably immune to reinfection. A more accurate IgG assay is essential to stratify risk in women of childbearing age and to facilitate targeted prenatal screening. Molecular detection is unlikely to be available in many regions, and infections are asymptomatic. Potential explanations for the recent explosion of Zika virus in the Pacific islands and the Americas and its continued spread are unclear but include recent genetic/phenotypic virus changes before or coincident with its disbursement beyond Asia. This could involve selection for enhanced infection of mosquito vectors, such as Aedes aegypti. Such vector-adaptive selection of more transmissible chikungunya virus strains has occurred since 2005. Other possibilities include selection for higher levels of human viremia in the urban cycle, which could increase the efficiency of transmission as well as enhance fetal infection. A simpler explanation is that the outbreaks began when, by chance, the virus was introduced into naive populations at the right time and place for initiation of the humanmosquito cycle. If the virus is able to establish endemic or enzootic circulation (as has been suggested as occurring in Asia on the basis of seroprevalence data) stable herd immunity may prevent future epidemics, as well as CZS in Brazil. Further, genetic, pathogenesis, and vector infection studies with diverse virus strains combined with improved surveillance and better, more affordable diagnostics that can be deployed even in remote, resource-limited settings, are needed to evaluate these hypotheses. Unfortunately, the immediate prospects for controlling the magnitude and spread of the current Zika virus epidemic are not promising. Until a vaccine is available, mosquito control and education of at-risk populations to reduce contact with the vector are the only short-term approaches available. These methods have had limited success for dengue and chikungunya viruses. Although recent advances in flavivirus vaccines may guide relatively rapid development of a Zika vaccine, availability is still probably years away. Treatment with a monoclonal antibody could also be developed quickly on the basis of promising past results with flaviviruses. However, systematic investigations of pregnant women and newborns will still be needed to determine the risk for transplacental infection and development of severe congenital sequelae that can, in turn, guide effective diagnostic and prevention efforts.