The American Journal of Tropical Medicine and Hygiene - Current Issue

Detection of acute HIV infection is a unique problem that fourth-generation HIV assays were expected to alleviate. In this commentary, we draw attention to the limitations and challenges with use of currently available rapid antigen–antibody (Ag/Ab) combination tests for detection of acute HIV infection in sub-Saharan Africa. Laboratory-based HIV-1 Ag/Ab immunoassays are complex, requiring specialized equipment and handling that are currently not affordable in many settings in Africa. The point-of-care Ag/Ab platform on the other hand is easier to deploy and potentially more accessible in resource-limited settings. However, available fourth-generation HIV-1 rapid diagnostic tests have demonstrated poor performance characteristics in field studies where non-B subtypes of HIV-1 dominate. The potential for point-of-care HIV-1 Ag/Ab diagnostics to significantly improve detection of acute HIV infection remains yet to be realized in sub-Saharan Africa. Assay platforms need to be optimized to identify local circulating subtypes, and optimal algorithms need to be determined.

Early trials of killed, whole-cell typhoid vaccine indicated a paradoxical, positive effect on malaria infections. British soldiers in India in 1898 reported > 90% decrease in malaria recurrences after receiving an investigational typhoid vaccine despite no intention or expectation to observe such an outcome. In the 1940s, multiple doses of intravenous typhoid vaccine appeared to control parasitemia and limit reinfection in three syphilis patients purposefully infected with Plasmodium vivax. Several modern vaccines (against human papillomavirus, hepatitis B virus, and malaria) use a detoxified lipid A derived from Salmonella as an immune adjuvant. Early typhoid vaccines could have plausibly functioned as an innate immune stimulus, leading to some protection against malaria.

Providencia alcalifaciens is a member of the family Enterobacteriaceae that has been commonly implicated as a causative agent of diarrheal infection in humans and animals. Recent outbreaks of P. alcalifaciens in both developing and developed countries have raised public health concerns. Several studies have suggested that P. alcalifaciens can cause diarrhea by invading the intestinal mucosa, although its pathogenicity has not been well established. Often routine laboratory investigations that seek etiological agents of diarrhea do not actively pursue P. alcalifaciens detection. Therefore, routine laboratory diagnosis should be given more attention for better understanding the epidemiology and pathogenicity of P. alcalifaciens.

Despite being preventable, foodborne diseases remain a global health challenge. Poor food hygiene practices such as improper handling of kitchen utensils are among the major causes of diarrhea transmission. A formative study was conducted in Malawi to inform an intervention design to promote complementary food hygiene practices. An assessment of contextual and psychosocial factors for behavior change was conducted using Risk, Attitude, Norms, Ability, and Self-regulation model. We conducted 323 household surveys with caregivers of children aged 6 to 24 months. Analysis of variance was used to estimate difference between doers and non-doers of three targeted behaviors: washing utensils with soap, keeping utensils on a raised place, and handwashing with soap. Analysis of variance analyses revealed that literacy level, ownership of animals, and presence of handwashing facility and dish racks were contextual factors predicting storage of utensils on an elevated place and handwashing frequencies. Psychosocial factors, such as time spent to wash utensils with soap, distance to the handwashing facility, and cost for soap, had an influence on washing utensils and handwashing practices. Perceived vulnerability determined effective handwashing and storage of utensils. Perceived social norms and ability estimates were favorable for the three targeted behaviors. Promotion of already existing targeted beneficial behaviors should be encouraged among caregivers. Risk perceptions on storage of utensils and handwashing practices should be increased with motivational exercises such as paint games. Caregivers’ technical know-how of local dish rack and tippy tap construction is essential.

Diarrheal disease is a leading cause of childhood morbidity and mortality worldwide, but particularly in low-income countries in sub-Saharan Africa and South Asia. The Global Enteric Multicenter Study (GEMS) examined the infectious etiologies as well as associated demographics, socioeconomic markers, health-care–seeking behaviors, and handwashing practices of the households of children with diarrhea and their age- and gender-matched controls in seven countries over a 3-year period (December 2007–December 2010). Stool studies to determine diarrheal etiologies and anthropometry were performed at baseline and at 60-day follow-up visits, along with surveys to record demographics and living conditions of the children. We performed secondary analyses of the GEMS data derived from the Bangladesh portion of the study in children with diarrhea associated with viral enteropathogens and explored pathogen-specific features of disease burden. Rotavirus and norovirus were the most prevalent pathogens (39.3% and 35%, respectively). Disease due to rotavirus and adenovirus was more common in infants than in older children (P < 0.001 and P = 0.001, respectively). Height for age decreased from baseline to follow-up in children with diarrhea associated with rotavirus, norovirus, and adenovirus (P < 0.001). Based on these analyses, preventive measures targeted at rotavirus, norovirus, and adenovirus will be expected to have meaningful clinical impact. Cost of treatment was highest for rotavirus as well, making it an obvious target for intervention. Association of specific viruses with stunting is particularly notable, as stunting is an attributable risk factor for poor cognitive development and future productivity and economic potential.

Acute diarrhea is an important public health issue. Here, we focused on the differences of enteropathogens in acute diarrhea between urban and rural areas in southeast China. Laboratory- and sentinel-based surveillance of acute diarrhea (≥ 3 loose or liquid stools/24 hours) was conducted at 16 hospitals. Fecal specimens were tested for bacterial (Aeromonas sp., Campylobacter sp., diarrheagenic Escherichia coli, Plesiomonas shigelloides, non-typhoidal Salmonella, Shigella sp., Vibrio sp., and Yersinia sp.) and viral (adenovirus, astrovirus, Norovirus, Rotavirus, and Sapovirus) pathogens. Descriptive statistics were used. Between January 1, 2010, and December 31, 2014, 4,548 outpatients with acute diarrhea were enrolled (urban, n = 3,220; rural, n = 1,328). Pathogens were identified in 2,074 (45.6%) patients. Norovirus (25.7%), Vibrio parahaemolyticus (10.2%), enteroaggregative Escherichia coli (EAEC) (8.8%), group A Rotavirus (7.0%), and enterotoxigenic Escherichia coli (ETEC) (5.6%) were the most common pathogens. Enteropathogens were less common in urban than in rural areas (42.0% versus 54.4%, P < 0.001). In urban areas, EAEC and ETEC were more common in high-income than in middle-income regions. Interventions targeting the most common enteropathogens can substantially reduce the burden of acute diarrhea in southeast China.

Acute respiratory distress syndrome (ARDS) is seldom described as a complication of typhoid fever (TF). Only 13 cases have hitherto been reported in the English and non-English literature since 1990. We report an 8-year-old boy with TF after return from India who developed pediatric ARDS (pARDS) despite adequate antibiotic treatment. Among patients with available information including this case, we noted that most not born or raised in a TF-endemic country (4/6) compared with none (0/6) of the domestic cases in a TF-endemic country developed ARDS within 48 hours of starting the antibiotic treatment. Our case raises important questions regarding the frequency, pathophysiology, and appropriate management of ARDS and pARDS in patients with TF.

Melioidosis is a bacterial infection caused by exposure to water or soil that contains Burkholderia pseudomallei (Bp). Burkholderia pseudomallei is endemic to many tropical and subtropical areas of the world. In 2013, the first case of melioidosis was recognized in Yap, the Federated States of Micronesia. Six additional cases were identified in the subsequent 3 years. An investigation was initiated to understand the epidemiology of melioidosis in Yap. Serum from family and community members of the identified cases were tested for antibodies to Bp. Archived serum from a 2007 Zika serosurvey were also tested for antibodies to Bp. Sequencing of bacterial isolates was performed to understand bacterial phylogeny. Soil and water were tested for the presence of Bp in the environment by culture and PCR. None of the affected patients had a history of travel to melioidosis-endemic countries. Two of the 34 (5.8%) samples from the field investigation and 67 (11.7%) of the historical samples demonstrated serologic evidence of prior Bp exposure. No Bp were detected from 30 soil or water samples. Genotype analysis showed highly related Bp isolates that were unique to Yap. Melioidosis is likely to be endemic to Yap; however, it has only recently been recognized by the clinical community in country. Further investigation is needed to understand the local sites that harbor Bp and represent the highest risk to the community.

Although the in-hospital mortality of Australian patients with melioidosis continues to decline, the ensuing clinical course of survivors is poorly described. Between January 1, 1998, and January 31, 2019, 228 patients in Cairns, tropical Australia, survived their hospitalization with melioidosis; however, 52 (23%) subsequently died. Death occurred at a median of 3.8 years after discharge, with patients dying at a mean age of 59 years. Only 1/27 (4%) without predisposing conditions for melioidosis died during follow-up, versus 51/201 (25%) with these comorbidities (P = 0.01). Death during follow-up was more likely in patients with chronic lung disease (OR [95% CI]: 4.05 (1.84–8.93, P = 0.001) and chronic kidney disease (OR [95% CI]: 2.87 [1.33–6.20], P = 0.007), and was most commonly due to infection and macrovascular disease. A significant proportion of Australians surviving hospitalization with melioidosis will die soon after discharge, usually prematurely and frequently from preventable conditions. A more holistic approach is required to their care.

Rickettsia monacensis and Orientia tsutsugamushi are bacteria of the family Rickettsiaceae, which causes fever, rash, and eschar formation; outdoor activities are a risk factor for Rickettsiaceae infection. A 75-year-old woman presented with fever, rash, and eschar and was confirmed as being scrub typhus based on a nested-polymerase chain reaction (N-PCR) test for a 56-kDa gene of O. tsutsugamushi; the genome was identified as the Boryong genotype. In addition, a pan-Rickettsia real-time PCR test was positive and a N-PCR test using a Rickettsia-specific partial outer membrane protein A (rOmpA) confirmed R. monacensis. This is the first case wherein a patient suspected of having scrub typhus owing to the presence of rash and eschar was also found to be coinfected with O. tsutsugamushi and R. monacensis based on molecular testing.

Rocky Mountain spotted fever (RMSF) has been reported in Colombia since 1937. Most recent outbreaks were in 2006–2008, followed by the absence of recognized cases. This report describes new clinical cases of RMSF and epidemiologic investigations. Medical records were reviewed, and fieldwork, serological and molecular diagnostic testing, and bacterial isolation were performed. Fever, hypotension, abdominal discomfort, and rash accompanied by thrombocytopenia and leukopenia were the most characteristic manifestations. Two convalescent sera from the index case and sera from two dogs revealed high anti-spotted fever group Rickettsia antibody titers. Rickettsia rickettsii was isolated from case 4. Cases 2 and 3 were identified by epidemiological connection with the index case. Thus, a new cluster of cases of RMSF was identified in Antioquia, Colombia, with the occurrence of fatal cases, which indicates the active circulation of the bacteria and a potential risk for the population.

In this study, we investigated the diagnostic utility of the cytokine profile of the cerebrospinal fluid (CSF) and enzyme-linked immunospot (ELISPOT) assays of patients with suspected tuberculous meningitis (TBM). We prospectively enrolled adult patients with suspected TBM, and CSF specimens were analyzed for 18 cytokines/chemokines and soluble programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1). Enzyme-linked immunospot assays were performed on mononuclear cells from the CSF (CSF-MCs) and peripheral blood (PBMCs). A total of 87 patients with meningitis, including 42 TBM-suspected patients and 45 non-TBM patients, were enrolled. Excluding the 32 patients with possible TBM, 10 patients with TBM and 45 patients with non-TBM were finally analyzed. Levels of adenosine deaminase (ADA), interleukin 12 subunit β (IL-12p40), IL-13, macrophage inflammatory protein α (MIP-1α), and soluble PD-1 and PD-L1 in the CSF were significantly higher in the TBM group than in the non-TBM group (P < 0.05). The optimal cutoff values for the sensitivities and specificities of the test methods for diagnosing TBM with small samples of 10 cases of definite or probable TBM were as follows: ADA > 6.95 U/L, 70% and 81%; IL-12p40 > 52.04 pg/mL, 80% and 73%; IL-13 > 0.44 pg/mL, 90% and 47%; MIP-1α > 8.83 pg/mL, 80% and 62%; soluble PD-1 > 35.87 pg/mL, 80% and 63%; soluble PD-L1 > 24.19 pg/mL, 80% and 61%; CSF-MC ELISPOT > 13.5 spots/250,000 CSF-MC, 30% and 91%; and PBMC ELISPOT > 14 spots/250,000 PBMCs, 50% and 78%, respectively. Therefore, CSF IL-12p40, IL-13, MIP-1α, and soluble PD-1 and PD-L1 concentrations appear to be useful adjuncts for diagnosing TBM.

Statins have anti-inflammatory and immunomodulatory properties that may affect the development of tuberculosis (TB). We assessed the association between use of statins and the risk of active TB by propensity score matching. Furthermore, we analyzed the impact of statins on TB in patients according to the presence or absence of diabetes. The study was based on the National Health Insurance database and its subset database of the “medical checkup” population of South Korea. We identified 123,468 statin users and 439,546 non–statin users. After propensity score matching, 28,018 statin users and the same number of non–statin users were finally analyzed. The development of active TB was monitored in these matched pairs over 11 years. In the propensity score–matching analysis, the number of active TB cases was 30 in 30,303 person-years (0.99 per 1,000 person-years; 95% CI, 0.64–1.35) in the statin users and 235 in 167,857 person-years (1.40 per 1,000 person-years; 95% CI, 1.22–1.58) in the non–statin users. Statin users had a significantly lower risk of TB than non–statin users: hazard ratio (HR) 0.67 (95% CI, 0.46–0.98) (P = 0.04). A subgroup analysis showed that statin use reduced the risk of TB in subjects without diabetes, but not in patients with diabetes: HRs were, respectively, 0.28 (95% CI, 0.13–0.60) (P = 0.001) and 1.05 (95% CI, 0.66–1.67) (P = 0.84). There is epidemiologic evidence that statin decreases the risk of active TB. However, the protective effect of statins against TB is attenuated by diabetes.

Most deaths in tuberculous meningitis occur in the early part of the illness. We assessed the determinants of early deaths, occurring within 2 months of intensive therapy. We prospectively included consecutive newly diagnosed adults with HIV-negative tuberculous meningitis. Patients were given WHO-recommended antituberculosis treatment and were followed up for 9 months. We enrolled 152 patients. A total of 26 deaths were recorded during 2 months. The logistic regression analysis revealed that papilledema (P = 0.029, odds ratio (OR) = 4.8 [1.2–19.8]), increasing age (P = 0.001, OR = 1.07 [1.03–1.1]), stage-III disease (Glasgow coma scale score ≤ 10; P = 0.01, OR = 4.2 [1.4–12.3]), and hydrocephalus (P = 0.003, OR = 8.4 [2.1–33.6]) were independently associated with death. In addition, cerebral infarcts (P = 0.012, OR = 5.6 [1.5–21.3]), paraparesis (P = 0.004, OR = 8.8 [2.02–38.1]), and age (P = 0.005, OR = 1.05 [1.02–1.09]) were associated with poor functional outcome. In conclusion, disease severity predicts early deaths in tuberculous meningitis.

The Asian tiger mosquito, Aedes albopictus, transmits several arboviruses of public health importance, including chikungunya and dengue. Since its introduction to the United States in 1985, the species has invaded more than 40 states, including temperate areas not previously at risk of Aedes-transmitted arboviruses. Mathematical models incorporate climatic variables in predictions of site-specific Ae. albopictus abundances to identify human populations at risk of disease. However, these models rely on coarse resolutions of environmental data that may not accurately represent the climatic profile experienced by mosquitoes in the field, particularly in climatically heterogeneous urban areas. In this study, we pair field surveys of larval and adult Ae. albopictus mosquitoes with site-specific microclimate data across a range of land use types to investigate the relationships between microclimate, density of larval habitat, and adult mosquito abundance and determine whether these relationships change across an urban gradient. We find no evidence for a difference in larval habitat density or adult abundance between rural, suburban, and urban land classes. Adult abundance increases with increasing larval habitat density, which itself is dependent on microclimate. Adult abundance is strongly explained by microclimate variables, demonstrating that theoretically derived, laboratory-parameterized relationships in ectotherm physiology apply to the field. Our results support the continued use of temperature-dependent models to predict Ae. albopictus abundance in urban areas.

Seasonal variation in the proportion of the population using an insecticide-treated net (ITN) is well documented and is widely believed to be dependent on mosquito abundance and heat, driven by rainfall and temperature. However, seasonal variation in ITN use has not been quantified controlling for ITN access. Demographic and Health Survey and Malaria Indicator Survey datasets, their georeferenced data, and public rainfall and climate layers were pooled for 21 countries. Nine rainfall typologies were developed from rainfall patterns in Köppen climate zones. For each typology, the odds of ITN use among individuals with access to an ITN within their households (“ITN use given access”) were estimated for each month of the year, controlling for region, wealth quintile, residence, year, temperature, and malaria parasitemia level. Seasonality of ITN use given access was observed over all nine rainfall typologies and was most pronounced in arid climates and less pronounced where rainfall was relatively constant throughout the year. Peak ITN use occurred 1–3 months after peak rainfall and corresponded with peak malaria incidence and average malaria transmission season. The observed lags between peak rainfall and peak ITN use given access suggest that net use is triggered by mosquito density. In equatorial areas, ITN use is likely to be high year-round, given the presence of mosquitoes and an associated year-round perceived malaria risk. These results can be used to inform behavior change interventions to improve ITN use in specific times of the year and to inform geospatial models of the impact of ITNs on transmission.

Trypanosoma cruzi is the etiologic agent of Chagas disease (CD), which can result in severe cardiomyopathy. Trypanosoma cruzi is endemic to the Americas, and of particular importance in Latin America. In the United States and other non-endemic countries, rising case numbers have also been observed. The currently used drugs are benznidazole (BNZ) and nifurtimox, which have limited efficacy during chronic infection. We repurposed itraconazole (ICZ), originally an antifungal, in combination with amiodarone (AMD), an antiarrhythmic, with the goal of interfering with T. cruzi infection. Human pluripotent stem cells (hiPSCs) were differentiated into cardiomyocytes (hiPSC-CMs). Vero cells or hiPSC-CMs were infected with T. cruzi trypomastigotes of the II or I strain in the presence of ICZ and/or AMD. After 48 hours, cells were Giemsa stained, and infection and multiplication were evaluated microscopically. Trypanosoma cruzi infection and multiplication were evalutated also by electron microscopy. BNZ was used as a reference compound. Cell metabolism in the presence of test substances was assessed. Itraconazole and AMD showed strain- and dose-dependent interference with T. cruzi infection and multiplication in Vero cells or hiPSC-CMs. Combinations of ICZ and AMD were more effective against T. cruzi than the single substances, or BNZ, without affecting host cell metabolism, and better preserving host cell integrity during infection. Our in vitro data in hiPSC-CMs suggest that a combination of ICZ and AMD might serve as a treatment option for CD in patients, but that different responses due to T. cruzi strain differences have to be taken into account.

Mucosal leishmaniasis (ML) is characterized by high production of inflammatory cytokines. Administration of pentoxifylline (PTX), an inhibitor of TNF-alpha, with pentavalent antimony (Sbv), has been successfully used as alternative treatment for refractory ML. Our study aims to investigate the in situ cellular response underlying the effectiveness of this therapy, by evaluating the intensity of the inflammatory infiltrate, cellular composition, and expression of cytokines and granzyme A in lesions from ML before and after treatment with Sbv alone or in combination with PTX. Our data showed no differences in the intensity of inflammatory infiltrate comparing before and after treatment, and comparing between different treatments. However, although the number and frequency of CD4+ and CD8+ cells were not different before and after treatments or comparing different treatments, frequency of CD68+ cells decreased after treatment with Sbv + PTX, but not with Sbv. This was due to a reduction in CD68+ TNF-alpha+ and not in CD68+ IL-10+ cells. The frequency of TNF-alpha+ cells was correlated with the intensity of the inflammatory infiltrate before treatment, but this correlation was lost after treatment with Sbv + PTX. Although the total expression of granzyme A did not significantly change after treatments, a clear trend of decrease was observed after treatment with Sbv + PTX. Interestingly, patients who took longer to heal, regardless of the treatment, displayed a higher frequency of granzyme A+ cells. Our data suggest that treatment with Sbv + PTX acts in CD68+ cells reducing the expression of TNF-alpha but not IL-10, resulting in more efficient modulation of the inflammatory response, accelerating the healing process.