The American Journal of Tropical Medicine and Hygiene - Current Issue

Gains in reducing childhood disease burden rely heavily on effective means of preventing environmental exposures. For many environmental health interventions, such as point-of-use water treatment, sanitation, or cookstoves, exposures are strongly influenced by user behaviors and the degree to which participants adhere to the prescribed preventive measures. In this commentary, we articulate the need for increased attention on user behaviors—critically, the careful measurement and inclusion of compliance—to strengthen exposure assessment and health impact trials in environmental health intervention research. We focus here on water, sanitation, and hygiene interventions to illustrate the problem with the understanding that this issue extends to other environmental health interventions.

A panel of experts from the Infectious Disease Society of America and The American Society of Tropical Medicine and Hygiene recently published guidelines for management of neurocysticercosis, showing that clinical manifestations as well as the stage of involution and the anatomical location of parasites must be taken into account before the start of a rational therapy. Soon thereafter, isolated opinions attempted to discredit these guidelines, arguing insufficient or inadequate evidence and suggesting that they should not be followed worldwide. In view of these conflicting reports, it is appropriate to review the origin and evolution of the controversy on the medical treatment of neurocysticercosis.

Dengue virus (DENV) causes asymptomatic to severe life-threatening infections and affects millions of people worldwide. Autophagy, a cellular degradative pathway, has both proviral and antiviral functions. Dengue virus triggers the autophagy pathway for the successful replication of its genome. However, the exact mechanism and the viral factors involved in activating this pathway remain unclear. This review summarizes the existing knowledge on the mechanism of autophagy induction and its significance during DENV infection.

Isolated renal mucormycosis in immunocompetent hosts is a rare entity. We present the largest case series of isolated renal mucormycosis in immunocompetent hosts. Retrospective data of isolated renal mucormycosis from March 2012 to June 2017 was reviewed. Fifteen patients of isolated renal mucormycosis were identified. Contrast-enhanced computed tomography scan showed enlarged globular kidneys with decreased or patchy enhancement, perinephric stranding and thickened Gerota’s fascia in all patients. Ten patients with unilateral involvement underwent nephrectomy and two of four patients with bilateral renal mucormycosis underwent bilateral nephrectomy. Two patients were managed with intravenous antifungal therapy alone. Overall, the mortality rate in our series was 40% (6/15). Isolated renal mucormycosis in healthy immunocompetent hosts is an emerging new entity. Prompt diagnosis based on the characteristic clinical and radiological picture and starting high-dose antifungal therapy at least 24 hours before surgical debridement offer the best chance of survival in these patients.

American cutaneous leishmaniasis (ACL) is a common and important vector-borne parasitic zoonosis in Panamá. Here, we study Leishmania spp. infection rates and blood-feeding patterns among common sand flies in Trinidad de Las Minas, a rural community with hyperendemic ACL transmission, and where a deltamethrin fogging trial was performed. Sand flies were collected from April 2010 to June 2011 with light traps installed inside and in the peridomicile of 24 houses. We restricted our analysis to the most abundant species at the study site: Lutzomyia trapidoi, Lutzomyia gomezi, Lutzomyia panamensis, Lutzomyia triramula, and Lutzomyia dysponeta. We detected Leishmania spp. infection in sand flies by polymerase chain reaction (PCR) amplification of the internal transcribed spacer region 1 (ITS-1) in pooled females (1–10 females per pool). Host species of engorged sand flies were identified using a cytochrome b PCR. From 455 sand fly pools analyzed, 255 pools were positive for Leishmania spp., with an estimated infection rate (confidence interval) of 0.096 [0.080–0.115] before the deltamethrin fogging which slightly, but not significantly (P > 0.05), increased to 0.116 [0.098–0.136] after the deltamethrin fogging. Blood meal analysis suggested that pigs, goats, and birds were the most common sand fly blood sources, followed by humans and domestic dogs. DNA sequencing from a subsample of ITS-1 positive pools suggests that Leishmania panamensis, Leishmania naiffi, and other Leishmania spp. were the parasite species infecting the most common vectors at the study site. Our data confirm an association between sand fly species, humans, domestic dogs, and pigs and Leishmania spp. parasites in rural Panamá.

We analyzed the association between insulin-like growth factor-I (IGF-I) and the pathogenesis of anemia during active visceral leishmaniasis (VL). Serum levels of IGF-I, IGF-binding protein 3 (IGFBP3), and cytokines were measured in samples from individuals with active VL and cured VL, asymptomatic Leishmania-infected, and noninfected individuals. Then, we extended our analysis to VL dogs to evaluate hematimetric parameters, bone marrow alterations, and cytokine and IGF-I expression. We identified a positive correlation between lower IGF-I and IGFBP3 levels in active VL patients and lower hemoglobin levels. In infected dogs, there was a positive correlation between lower IGF-I expression in the bone marrow and lower peripheral blood hematocrit and hemoglobin levels. There was no correlation between decreased IGF-I level/expression and any measured cytokine serum levels in either host. The data suggest that low IGF-I expression is associated with pathogenesis of anemia in active VL, primarily in severe cases, by mechanisms other than alterations in cytokine production.

B-cells have a spectrum of functions ranging from antibody production to antigen presentation and have additional vital roles in immune mechanisms. There is rudimentary knowledge about the role of B-cells in intracellular infections with contradictory findings. We explored the role of B-cell dysfunctions in visceral leishmaniasis (VL) pathogenesis in terms of the phenotypic and functional properties of B-cells during the course of disease. This study was performed on blood and splenic aspirates (SA) of VL cases pre- and post-treatment. Whole blood was used for flow cytometric studies for determining the profiles of B-cells at different time-points of treatment. Peripheral blood mononuclear cells were used for magnetic purification of B-cells, for transcriptional studies by real-time polymerase chain reaction (RT-PCR). Serum/plasma was used for direct agglutination test for determining parasite-specific antibodies and SA were used for scoring the presence of parasite by microscopic examination. Flow cytometric studies depicted decreased B-cell percentages during the entire course of disease and attainment of exhaustive phenotype with tissue-like memory cell markers, indicative of B-cell dysfunctions in VL. In addition, B-cells had compromised abilities of antigen processing and presentation and altered levels of B-lymphocyte–induced maturation protein-1 (Blimp-1). Blimp-1 expression goes hand in hand with B-cell maturation antigen and transmembrane activator and calcium modulator (TACI) and cyclophilin ligand interactor, suggestive of its role in promoting plasma cell survival and antibody production. Elevated level of VL-specific antibody titre was directly correlated with exhausted phenotype and also with disease severity during VL. This study indicated for impaired B-cell functions during chronic infection which may lead to pathological consequences in human VL.

The standard in vitro cultivation procedure for Plasmodium falciparum requires gas exchange and a microaerophilic atmosphere. A novel system using a commercially available cell culture device (Petaka G3™; Celartia Ltd., Powell, OH) was assessed for long-term cultivation of a P. falciparum reference laboratory clone in normal air. Parasite growth during 30 days was similar, or better, in Petaka G3 than that in the standard cultivation method with gas exchange in a CO2 incubator. The successful cultivation of P. falciparum in the Petaka G3 device suggests that low O2 content available in hemoglobin and dissolved gas in the blood is sufficient for long-term cultivation. This finding may open the way to novel methods to cultivate and adapt P. falciparum field isolates to in vitro conditions with more ease.

In this study, we reviewed imported malaria cases observed at the National Center for Global Health and Medicine, Tokyo, between 2005 and 2016, to comprehend their demographic and clinical characteristics. Data on 169 cases were used to analyze demographic information; data on 146 cases were used for the analysis of clinical information. The median patients’ age was 34 years, and 79.3% of them were male. The proportion of non-Japanese patients increased and surpassed that of Japanese patients after 2015. In 82.2% of the cases, the region of acquisition was Africa, and Plasmodium falciparum was the dominant species (74.0%) followed by Plasmodium vivax (15.4%). We observed 19 (18.4%, 19/103) severe falciparum malaria cases. Mefloquine was the most commonly used drug for treatment until the early 2010s; atovaquone/proguanil was the most commonly used after its licensure in 2013. Although none of the patients died, four recrudescence episodes after artemether/lumefantrine (A/L) treatment and one relapse episode were observed. Overall, malaria was diagnosed on median day 4 of illness, and, thereon, treatment was initiated without delay. Diagnosis on day 5 or later was significantly associated with severe disease in Japanese cases (odds ratio = 4.1; 95% CI = 1.2–14.3). We observed a dominance of falciparum malaria, an increase in the number of non-Japanese cases, late treatment failure after A/L treatment, a low relapse rate, and an association between delayed malaria diagnosis and higher disease severity. Pretravel care and early diagnosis are necessary to reduce malaria-related mortality and morbidity in settings such as ours.

We aimed to identify clinical and laboratory predictors of mortality in children from a malaria-endemic area of Papua New Guinea hospitalized for severe illness. Children aged 0.5–10 years presenting with any WHO-defined feature of severe malarial illness were eligible for recruitment. Each child was assessed with a detailed clinical examination, blood film microscopy, malaria rapid diagnostic testing (RDT), a full blood examination, and blood glucose and lactate concentrations. Clinical care was coordinated by local medical staff in accordance with national guidelines. Daily study assessments were conducted until death or discharge. Other biochemical tests and malaria polymerase chain reaction (PCR) tests were performed subsequently. Logistic regression identified independent predictors of death. Of 787 evaluable children with severe illness, 336 had confirmed severe malaria (microscopy and PCR positive) and 58 (6.6%) died during hospitalization. The independent predictors of mortality were hyperlactatemia (adjusted odds ratio [95% CI]: 2.85 [1.24–6.41], P = 0.01), malnutrition (2.92 [1.36–6.23], P = 0.005), renal impairment (3.85 [1.53–9.24], P = 0.002), plasma albumin (0.93 [0.88–0.98] for a 1 g/L increase, P = 0.004), and Blantyre coma score (BCS) ≤ 2 (10.3 [4.77–23.0] versus a normal BCS, P < 0.0001). Confirmed severe malaria (0.11 [0.03–0.30] versus non-malarial severe illness, P < 0.0001) was independently associated with lower mortality. Although established risk factors were evident, malaria was inversely associated with mortality. This highlights the importance of accurate diagnosis through blood film microscopy, RDTs, and, if available, PCR to both guide management and provide valid epidemiological data.

We attempted to identify Plasmodium falciparum histidine–rich protein 2/3 (pfhrp2/3) deletions among rapid diagnostic test (RDT)–negative but PCR- or microscopy-positive P. falciparum–infected individuals in areas of low transmission (Choma District, 2009–2011) and high transmission (Nchelenge District, 2015–2017) in Zambia. Through community-based surveys, 5,167 participants were screened at 1,147 households by P. falciparum histidine-rich protein 2 (PfHRP2)-based RDTs. Slides were made and dried blood spots were obtained for molecular analysis. Of 28 samples with detectable P. falciparum DNA, none from Nchelenge District were pfhrp2/3 negative. All eight samples from Choma District had detectable pfhrp3 genes, but pfhrp2 was undetectable in three. DNA concentrations of pfhrp2-negative samples were low (< 0.001 ng/μL). These findings suggest that PfHRP2-based RDTs remain effective tools for malaria diagnosis in Nchelenge District, but further study is warranted to understand the potential for pfhrp2/3 deletions in southern Zambia where malaria transmission declined over the past decade.

During the building of the Thai–Burma railway in 1943 Australian and British prisoners of war died at high rates from tropical infections and nutritional deficiencies. Mortality records from “F” Force (n = 7,000) showed nearly half (44%) of the soldiers perished in a single year, yet only 4% of these deaths were primarily attributed to malaria, with another 7% where malaria was listed as a major contributing cause. Case fatality rates were < 1%, with nearly all soldiers chronically infected with Plasmodium vivax > Plasmodium falciparum. Separate labor camp point prevalence malaria rates by microscopy ranged from 28% to 69% (median 54%) despite intermittent quinine suppression. During complex public health emergencies, malaria mortality may be disguised by its combination with other common infections and nutritional deficiencies.

The U.S. President’s Malaria Initiative–funded MalariaCare project implemented an external quality assurance scheme to support malaria diagnostics and case management across a spectrum of health facilities in participating African countries. A component of this program was a 5-day, malaria diagnostic competency assessment (MDCA) course for health facility laboratory staff conducting malaria microscopy. The MDCA course provided a method to quantify participant skill levels in microscopic examination of malaria across three major diagnosis areas: parasite detection, species identification, and parasite quantification. A total of 817 central-, regional-, and peripheral-level microscopists from 45 MDCA courses across nine African countries were included in the analysis. Differences in mean scores with respect to daily marginal performance were positive and statistically significant (P < 0.001) for each challenge type across all participants combined. From pretest to assessment day 4, mean scores for parasite detection, species identification, and parasite quantification increased by 19.1, 34.9, and 38.2 percentage points, respectively. In addition, sensitivity and specificity increased by 20.8 and 13.8 percentage points, respectively, by assessment day 4. Furthermore, the ability of MDCA participants to accurately report Plasmodium falciparum species when present increased from 44.5% at pretest to 67.1% by assessment day 4. The MDCA course rapidly improved the microscopy performance of participants over a short period of time. Because of its rigor, the MDCA course could serve as a mechanism for measuring laboratory staff performance against country-specific minimum competency standards and could easily be adapted to serve as a national certification course.

Between 2012 and 2017, the U.S. President’s Malaria Initiative–funded MalariaCare project supported national malaria control programs in sub-Saharan Africa to implement a case management quality assurance (QA) system for malaria and other febrile illnesses. A major component of the system was outreach training and supportive supervision (OTSS), whereby trained government health personnel visited health facilities to observe health-care practices using a standard checklist, to provide individualized feedback to staff, and to develop health facility–wide action plans based on observation and review of facility registers. Based on MalariaCare’s experience, facilitating visits to more than 5,600 health facilities in nine countries, we found that programs seeking to implement similar supportive supervision schemes should consider ensuring the following: 1) develop a practical checklist that balances information gathering and mentorship; 2) establish basic competency criteria for supervisors and periodically assess supervisor performance in the field; 3) conduct both technical skills training and supervision skills training; 4) establish criteria for selecting facilities to conduct OTSS and determine the appropriate frequency of visits; and 5) use electronic data collection systems where possible. Cost will also be a significant consideration: the average cost per OTSS visit ranged from $44 to $333. Significant variation in costs was due to factors such as travel time, allowances for government personnel, length of the visit, and involvement of central level officials. Because the cost of conducting supportive supervision prohibits regularly visiting all health facilities, internal QA measures could also be considered as alternative or complementary activities to supportive supervision.

Although light microscopy is the reference standard for diagnosing malaria, maintaining skills over time can be challenging. Between 2015 and 2017, the U.S. President’s Malaria Initiative–funded MalariaCare project supported outreach training and supportive supervision (OTSS) visits at 1,037 health facilities in seven African countries to improve performance in microscopy slide preparation, staining, and reading. During these visits, supervisors observed and provided feedback to health-care workers (HCWs) performing malaria microscopy using a 30-step checklist. Of the steps observed in facilities with at least three visits, the proportion of HCWs that performed each step correctly at baseline ranged from 63.2% to 94.2%. The change in the proportion of HCWs performing steps correctly by the third visit ranged from 16.7 to 23.6 percentage points (n = 916 observations). To assess the overall improvement, facility scores were calculated based on the steps performed correctly during each visit. The mean score at baseline was 85.7%, demonstrating a high level of performance before OTSS. Regression analysis predicted an improvement in facility scores of 3.6 percentage points (P < 0.001) after three visits across all countries. In reference-level facilities with consistently high performance on microscopy procedures and parasite detection, quality assurance (QA) mechanisms could prioritize more advanced skills, such as proficiency testing for parasite counting and species identification. However, in settings with high staff turnover and declining use of microscopy in favor of rapid diagnostic tests, additional supervision visits and/or additional QA measures may be required to improve and maintain performance.