The American Journal of Tropical Medicine and Hygiene - Current Issue

Little is known about the specific causes of neonatal and under-five childhood death in high-mortality geographic regions due to a lack of primary data and dependence on inaccurate tools, such as verbal autopsy. To meet the ambitious new Sustainable Development Goal 3.2 to eliminate preventable child mortality in every country, better approaches are needed to precisely determine specific causes of death so that prevention and treatment interventions can be strengthened and focused. Minimally invasive tissue sampling (MITS) is a technique that uses needle-based postmortem sampling, followed by advanced histopathology and microbiology to definitely determine cause of death. The Bill & Melinda Gates Foundation is supporting a new surveillance system called the Child Health and Mortality Prevention Surveillance network, which will determine cause of death using MITS in combination with other information, and yield cause-specific population-based mortality rates, eventually in up to 12–15 sites in sub-Saharan Africa and south Asia. However, the Gates Foundation funding alone is not enough. We call on governments, other funders, and international stakeholders to expand the use of pathology-based cause of death determination to provide the information needed to end preventable childhood mortality.

Although there has been rapid growth in global health educational experiences over the last two decades, the flow of learners remains overwhelmingly one directional; providers from high-resourced settings travel to limited-resourced environments to participate in clinical care, education, and/or research. Increasingly, there has been a call to promote parity in partnerships, including the development of bidirectional exchanges, where trainees from each institution travel to the partner’s setting to learn from and teach each other. As global health educators and steering committee members of the Association of Pediatric Program Directors Global Health Pediatric Education Group, we endorse the belief that we must move away from merely sending learners to international partner sites and instead become true global health partners offering equitable educational experiences. In this article, we summarize the benefits, review common challenges, and highlight solutions to hosting and providing meaningful global health experiences for learners from limited-resourced partner institutions to academic health centers in the United States.

Clinical trials are challenging endeavors. Planning and implementing an investigational vaccine trial in Liberia, in the midst of an Ebola virus disease (EVD) epidemic that World Health Organization classified a public health emergency of international concern, presented extraordinary challenges. Normally, years of preparation and a litany of tasks lay the groundwork for a successful, randomized, blinded, placebo-controlled trial focused on safety and efficacy. Difficult research settings, unpredictable events, and other unique circumstances can add complexity. The setting in Liberia was especially problematic due to an infrastructure still badly damaged following a lengthy civil war and a very fragile health-care system that was further devastated by the EVD outbreak. The Partnership for Research on Vaccines in Liberia I EVD vaccine trial was planned and implemented in less than 3 months by a Liberian and U.S. research partnership, and its Phase II substudy was fully enrolled 3 months later. Contrasting conventional wisdom with trial outcomes offers an opportunity to compare early assumptions, barriers encountered, and adaptive strategies used, with end results. Understanding what was learned can inform future trial responses when disease outbreaks, especially in resource-poor locations with minimal infrastructure, pose a significant threat to public health.

More than 700,000 cases of Zika virus (ZIKAV) disease have been officially reported to the Pan American Health Organization (PAHO) from 48 countries and territories of the Americas. The response led by the PAHO and partners suggests major lessons of this outbreak. A seemingly innocuous pathogen became the new villain, causing fear, economic losses and, most importantly, debilitating birth defects and neurological problems, reaffirming the well-known war principle of never to underestimate one's opponent. The ZIKAV tested public health capacities under the International Health Regulations, highlighting the need for continued investment in health security. Last but not least, the lack of appropriate tools was another reminder of the pressing need for innovative solutions to persistent problems. Latin America and the Caribbean have approximately 500 million persons living in areas at risk for transmission of ZIKAV. The fight against ZIKAV is not a 100-m race, but rather a marathon in which science and public health need to work hand in hand for the benefit of our peoples.

Rickettsia australis, the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia. Changing human population demographics, climate change, and increased understanding of expanding vector distribution indicate QTT is an emerging public health threat. This review summarizes the epidemiology, pathogenesis, clinical features, treatment principles, and future directions of this disease. Increased recognition of QTT will enable consideration of and prompt treatment of R. australis infection by clinicians in Australia.

We investigated the 47-kDa outer membrane protein (OMP), which is a periplasmic serine protease and an antigenic major surface protein of Orientia tsutsugamushi, as a vaccine candidate. We developed a conventional subunit vaccine expressing recombinant 47-kDa OMP (rec47) and a DNA vaccine (p47). In mouse immunization experiments, intranasal immunization with rec47 alone or with rec47 plus heat-labile enterotoxin B subunit from Escherichia coli or plus cholera toxin (CT) as adjuvants induced a higher amount of rec47-specific antibodies than intramuscular immunization with p47 alone or with p47 plus pBOOST2-samIRF7/3 (pB) as adjuvant. Moreover, the combination of rec47 and CT induced a strong cellular immune response to 47-kDa OMP, as demonstrated by a spleen cell proliferation assay, and also induced Th1- and Th2-type cytokine production, as demonstrated by a cytokine enzyme-linked immunosorbent assay. Intranasal immunization with rec47 plus CT was the most effective method for the induction of humoral and cell-mediated immune responses. Furthermore, relatively strong protection against homologous O. tsutsugamushi strain Boryong challenge was observed in mice immunized with rec47 plus CT. Therefore, 47-kDa OMP is an attractive candidate for developing a prophylactic vaccine against scrub typhus by O. tsutsugamushi infection.

Talaromyces marneffei is a dimorphic fungus endemic mainly in southeast and south Asia. It causes severe mycosis, usually in immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection. Concomitant infection with T. marneffei and other opportunistic pathogens is plausible because the majority of T. marneffei infections occur in patients with advanced HIV infection. Nonetheless, coinfection in the same site has rarely been reported, and poses a considerable diagnostic and therapeutic challenge. We report the case of an HIV-infected Japanese patient who had lived in Thailand for 6 years. The patient developed T. marneffei and Mycobacterium tuberculosis coinfection, and both pathogens were isolated from the same sites: a blood specimen and a lymph node aspirate. Clinicians should be aware of concomitant infection with T. marneffei and other pathogens in patients with advanced HIV disease who are living in or who have visited endemic areas.

Histoplasmosis is one of the most common and deadly opportunistic infections among persons living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome in Latin America, but due to limited diagnostic capacity in this region, few data on the burden and clinical characteristics of this disease exist. Between 2005 and 2009, we enrolled patients ≥ 18 years of age with suspected histoplasmosis at a hospital-based HIV clinic in Guatemala City. A case of suspected histoplasmosis was defined as a person presenting with at least three of five clinical or radiologic criteria. A confirmed case of histoplasmosis was defined as a person with a positive culture or urine antigen test for Histoplasma capsulatum. Demographic and clinical data were also collected and analyzed. Of 263 enrolled as suspected cases of histoplasmosis, 101 (38.4%) were confirmed cases. Median time to diagnosis was 15 days after presentation (interquartile range [IQR] = 5–23). Crude overall mortality was 43.6%; median survival time was 19 days (IQR = 4–69). Mycobacterial infection was diagnosed in 70 (26.6%) cases; 26 (25.7%) histoplasmosis cases were coinfected with mycobacteria. High mortality and short survival time after initial symptoms were observed in patients with histoplasmosis. Mycobacterial coinfection diagnoses were frequent, highlighting the importance of pursuing diagnoses for both diseases.

To identify regional differences in the distribution of opportunistic infections (OIs) among human immunodeficiency virus (HIV)-infected patients in Asia, the medical records of antiretroviral therapy (ART)-naïve patients who attended the following tertiary hospitals from 2003 to 2011 were reviewed: Nagoya Medical Center (NMC, Nagoya, Japan), Lampang Hospital (LPH, Lampang, northern Thailand), Bach Mai Hospital (BMH, Hanoi, northern Vietnam), and Philippine General Hospital (PGH, Manila, Philippines). Logistic regression analyses were performed to identify associations between country of origin and risk of major OIs. In total, 1,505 patients were included: NMC, N = 365; LPH, N = 442; BMH, N = 384; and PGH, N = 314. The median age was 32 years, and 73.3% of all patients were male. The median CD4 count was 200 cells/μL. Most patients at NMC and PGH were men who have sex with men. Injection drug users were most common at BMH (35.7%). Mycobacterium tuberculosis (TB) was most common at PGH (N = 75) but was rare at NMC (N = 4). Pneumocystis pneumonia (PCP) prevalence was highest at NMC (N = 74) and lowest at BMH (N = 13). Multivariable logistic regression showed increased odds of TB at PGH (adjusted odds ratio [aOR] = 42.2, 95% confidence interval [CI] = 14.6–122.1), BMH (aOR = 12.6, CI = 3.9–40.3), and LPH (aOR = 6.6, CI = 2.1–21.1) but decreased odds of PCP at BMH (aOR = 0.1, CI = 0.04–0.2) and LPH (aOR = 0.2, CI = 0.1–0.4) compared with those at NMC. The cryptococcosis risk was increased at LPH (aOR = 6.2, CI = 0.9–41.0) compared with that at NMC. Cytomegalovirus (CMV) retinitis prevalences were similar in all countries. OI prevalence remained high among ART-naïve patients in our cohort. The risks of TB, PCP, and cryptococcosis, but not CMV retinitis, differed between countries. Improved early HIV detection is warranted.

Nontuberculous mycobacteria (NTM) cause significant pulmonary infections in humans. Researchers have reported an association between interferon-gamma receptor-1 (IFN-γR1 or IFNGR1) deficiency and susceptibility to NTM, but the relevance of polymorphism within these genes is not yet clear. In this study, a single nucleotide polymorphism (SNP), T to C, at position-56 in NTM patients with pulmonary disease was investigated. Molecular identification of Mycobacterium isolates was performed with hsp65 genes using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Then, the host genomic DNA from confirmed NTM patients (N = 80) and control subjects (N = 80) were screened for SNPs of IFNGR1 (T-56C) by PCR-RFLP. The results indicated that NTM patients had higher TC (26/80; 32.5%) or CC (46/80; 57.5%) genotypes in comparison with control groups (TC genotypes [22/80, 27.5%]; CC genotypes [6/80, 7.5%]) (P < 0.05). In this regard, all the patients infected with rapid-growing Mycobacterium (RGM, i.e., Mycobacterium chelonae and Mycobacterium fortuitum) had CC genotypes (100%). In contrary, only 50.7% (35/69) of infected patients with slow-growing Mycobacterium (i.e., Mycobacterium simiae, Mycobacterium kansasii, and Mycobacterium avium-intracellulare) had CC genotypes. Thus, patients with CC mutation in IFNGR1 at position-56 are more likely to develop RGM infection. In overall, there is a significant association between SNP of IFNGR1 at position-56 and susceptibility to NTM infection. Based on these data, we propose SNP of IFNGR1 at position-56 as a suitable “biomarker” for identifying populations at higher risk of infection.

Burkholderia pseudomallei is the causative agent of melioidosis, a serious infection associated with high mortality and relapse. Current antimicrobial therapy using ceftazidime (CAZ) is often ineffective. Inhibitors of LpxC, the enzyme responsible for lipid A biosynthesis, have potential antimicrobial activity against several Gram-negative bacteria in vivo, but their activity against B. pseudomallei is unclear. Herein, we investigated the susceptibility of B. pseudomallei clinical isolates to LpxC-4, an LpxC inhibitor, and LpxC-4 in combination with CAZ. Time-kill assays for bactericidal activity were conducted for B. pseudomallei K96243, revealing growth inhibition and bactericidal effect at LpxC-4 concentrations of 2 μg/mL and 4 μg/mL, respectively. No significant synergistic effect was observed with the combination of LpxC-4 and CAZ. LpxC-4 susceptibility was tested on three groups of clinical isolates:1) CAZ- and trimethoprim–sulfamethoxazole (SXT)–susceptible (N = 71), 2) CAZ-resistant (N = 14), and 3) SXT-resistant (N = 23) isolates, by broth microdilution. The minimum concentration of LpxC-4 required to inhibit the growth of 90% of organisms was 2 μg/mL for all isolates. The median minimum inhibitory concentration of both the CAZ/SXT-susceptible and CAZ-resistant groups was 1 μg/mL (interquartile range [IQR] = 1–2 μg/mL), compared with 2 μg/mL (IQR = 2–4 μg/mL) for the SXT-resistant group. Cell morphology was observed after drug exposure by immunofluorescent staining, and a change from rod-shaped to cell wall–defective spherical cells was observed in surviving bacteria. LpxC-4 is a potent bactericidal agent against B. pseudomallei and warrants further testing as a new antibiotic to treat melioidosis.

Pneumonia is the leading cause of death in children. The objectives were to evaluate the microbiological agents linked with hypoxemia in hospitalized children with pneumonia from developing countries, to identify predictors of hypoxemia, and to characterize factors associated with in-hospital mortality. A multicenter, observational study was conducted in five hospitals, from India (Lucknow, Vadu), Madagascar (Antananarivo), Mali (Bamako), and Paraguay (San Lorenzo). Children aged 2–60 months with radiologically confirmed pneumonia were enrolled prospectively. Respiratory and whole blood specimens were collected, identifying viruses and bacteria by real-time multiplex polymerase chain reaction (PCR). Microbiological agents linked with hypoxemia at admission (oxygen saturation < 90%) were analyzed by multivariate logistic regression, and factors associated with 14-day in-hospital mortality were assessed by bivariate Cox regression. Overall, 405 pneumonia cases (3,338 hospitalization days) were analyzed; 13 patients died within 14 days of hospitalization. Hypoxemia prevalence was 17.3%. Detection of human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) in respiratory samples was independently associated with increased risk of hypoxemia (adjusted odds ratio [aOR] = 2.4, 95% confidence interval [95% CI] = 1.0–5.8 and aOR = 2.5, 95% CI = 1.1–5.3, respectively). Lower chest indrawing and cyanosis were predictive of hypoxemia (positive likelihood ratios = 2.3 and 2.4, respectively). Predictors of death were Streptococcus pneumoniae detection by blood PCR (crude hazard ratio [cHR] = 4.6, 95% CI = 1.5–14.0), procalcitonin ≥ 50 ng/mL (cHR = 22.4, 95% CI = 7.3–68.5) and hypoxemia (cHR = 4.8, 95% CI = 1.6–14.4). These findings were consistent on bivariate analysis. hMPV and RSV in respiratory samples were linked with hypoxemia, and S. pneumoniae in blood was associated with increased risk of death among hospitalized children with pneumonia in developing countries.

We conducted an observational study to describe the characteristics of infective endocarditis (IE) in French West Indies (FWI) and to identify variables associated with in-hospital case fatality. The records of the patients admitted for IE to the University Hospital of Martinique between 2000 and 2012 were collected using an electronic case report form. Only Duke-Li definite cases were considered for this analysis. Variables associated with in-hospital mortality were tested using univariate logistic regression analysis. The analysis included 201 patients (median age 58 years, sex ratio: two males to one female). There was no previously known heart disease in 45.8%, a prosthetic valve in 21.4%, and previously known native valve disease in 32.8% of the cases. Community-acquired IE represented 59.7% of all cases, health-care-associated IE represented 38.3% and injection-drug-use-acquired IE represented 1.5%. Locations of IE were distributed as follows: 42.3% were mitral valve IE, 34.8% were aortic valve IE, and 7% were right-sided IE. Microorganisms recovered from blood cultures included 30.4% streptococci, 28.9% staphylococci, and 5% enterococci. Blood cultures were negative in 20.9% of the cases. Surgical treatment was performed in 53% of the patients. In-hospital case fatality rate was 19%. Advanced age, Staphylococcus aureus IE, and health-care-associated IE were associated with in-hospital case fatality. The epidemiological and microbiological profile of IE in FWI is in between those observed in developed countries and developing countries: patients were younger, blood cultures were more frequently negative, and IE due to group D streptococci and enterococci were less common than in industrialized countries.

We herein report a case of suspected Borrelia miyamotoi disease in Hokkaido, Japan. The patient complained of lassitude, arthralgia, and high fever after a tick bite. Furthermore, at the time of consultation, the patient exhibited momentary loss of consciousness and low blood pressure. Laboratory tests revealed elevation of liver enzymes, thrombocytopenia, and increased C-reactive protein. Seroconversion to B. miyamotoi glycerophosphoryl diester phosphodiesterase antigen suggested the patient was infected with a relapsing fever group Borrelia species.

In tropical and subtropical settings, the epidemiology of viral acute respiratory tract infections varies widely between countries. We determined the etiology, seasonality, and clinical presentation of viral acute respiratory tract infections among outpatients in southern Sri Lanka. From March 2013 to January 2015, we enrolled outpatients presenting with influenza-like illness (ILI). Nasal/nasopharyngeal samples were tested in duplicate using antigen-based rapid influenza testing and multiplex polymerase chain reaction (PCR) for respiratory viruses. Monthly proportion positive was calculated for each virus. Bivariable and multivariable logistic regression were used to identify associations between sociodemographic/clinical information and viral detection. Of 571 subjects, most (470, 82.3%) were ≥ 5 years of age and 53.1% were male. A respiratory virus was detected by PCR in 63.6% (N = 363). Common viral etiologies included influenza (223, 39%), human enterovirus/rhinovirus (HEV/HRV, 14.5%), respiratory syncytial virus (RSV, 4.2%), and human metapneumovirus (hMPV, 3.9%). Both ILI and influenza showed clear seasonal variation, with peaks from March to June each year. RSV and hMPV activity peaked from May to July, whereas HEV/HRV was seen year-round. Patients with respiratory viruses detected were more likely to report pain with breathing (odds ratio [OR] = 2.60, P = 0.003), anorexia (OR = 2.29, P < 0.001), and fatigue (OR = 2.00, P = 0.002) compared with patients with no respiratory viruses detected. ILI showed clear seasonal variation in southern Sri Lanka, with most activity during March to June; peak activity was largely due to influenza. Targeted infection prevention activities such as influenza vaccination in January–February may have a large public health impact in this region.

Worldwide, virus infections are responsible for many diseases in terms of morbidity and mortality. Vaccinations and therapies are only available for relatively few virus infections and not always where they are needed. However, knowledge of transmission routes can prevent virus infection. In the context of this study, we measured the effects of a secondary school education module, named Viruskenner, on knowledge, attitude, and risk behavior as these relate to virus infections. A nonrandomized intervention study was conducted between April and August 2015 to assess the effect of this 2-month education module on knowledge, attitude, and behavior of 684 secondary school students in the Netherlands, Suriname, and Indonesia. For the Netherlands, a control group of a further 184 students was added. Factor analysis was performed on questions pertaining to attitude and behavior. Comparative analyses between pre- and posttest per country were done using multiple linear regression, independent sample T-tests, and one-way analysis of variance. These showed a significant increase in knowledge about virus infections and the prevention of infectious diseases among the Dutch and Surinamese groups, whereas a trend of increased knowledge was evident among the Indonesian participants. The Dutch control group showed an overall decrease in knowledge. Regression analyses showed that there was a significant interaction effect between participation and time on knowledge, attitude, and awareness and behavior and risk infection. Attitudes improved significantly in the intervention group. Pearson correlation coefficients between knowledge, attitude, and behavior were found to be positive.

Rift Valley Fever (RVF) is a climate-related arboviral infection of animals and humans. Climate is thought to represent a threat toward emerging risk areas for RVF epidemics globally. The objective of this study was to evaluate influence of climate on distribution of suitable breeding habitats for Culex pipiens complex, potential mosquito vector responsible for transmission and distribution of disease epidemics risk areas in Tanzania. We used ecological niche models to estimate potential distribution of disease risk areas based on vectors and disease co-occurrence data approach. Climatic variables for the current and future scenarios were used as model inputs. Changes in mosquito vectors’ habitat suitability in relation to disease risk areas were estimated. We used partial receiver operating characteristic and the area under the curves approach to evaluate model predictive performance and significance. Habitat suitability for Cx. pipiens complex indicated broad-scale potential for change and shift in the distribution of the vectors and disease for both 2020 and 2050 climatic scenarios. Risk areas indicated more intensification in the areas surrounding Lake Victoria and northeastern part of the country through 2050 climate scenario. Models show higher probability of emerging risk areas spreading toward the western parts of Tanzania from northeastern areas and decrease in the southern part of the country. Results presented here identified sites for consideration to guide surveillance and control interventions to reduce risk of RVF disease epidemics in Tanzania. A collaborative approach is recommended to develop and adapt climate-related disease control and prevention strategies.

Rift Valley fever virus (RVFV) causes severe disease in both animals and humans, resulting in significant economic and public health damages. The objective of this study was to measure RVFV seroprevalence in six coastal Kenyan villages between 2009 and 2011, and characterize individual-, household-, and community-level risk factors for prior RVFV exposure. Sera were tested for anti-RVFV IgG via enzyme-linked immunosorbent assay. Overall, 51 (1.8%; confidence interval [CI95] 1.3–2.3) of 2,871 samples were seropositive for RVFV. Seroprevalence differed significantly among villages, and was highest in Jego Village (18/300; 6.0%; CI95 3.6–9.3) and lowest in Magodzoni (0/248). Adults were more likely to be seropositive than children (P < 0.001). Seropositive subjects were less likely to own land or a motor vehicle (P < 0.01), suggesting exposure is associated with lower socioeconomic standing (P = 0.03). RVFV exposure appears to be low in coastal Kenya, although with some variability among villages.