The American Journal of Tropical Medicine and Hygiene - Current Issue

Despite myriad improvements in the care of COVID-19 patients, atypical manifestations are least appreciated during the current pandemic. Because COVID-19 is primarily manifesting as an acute respiratory illness with interstitial and alveolar pneumonia, the possibility of viral invasions into the other organs cannot be disregarded. Acute kidney injury (AKI) has been associated with various viral infections including dengue, chikungunya, Zika, and HIV. The prevalence and risks of AKI during the course of COVID-19 have been described in few studies. However, the existing literature demonstrate great disparity across findings amid variations in methodology and population. This article underscores the propensity of AKI among COVID-19 patients, limitations of the exiting evidence, and importance of timely identification during the case management. The prevalence of AKI is variable across the studies ranging from 4.7% to 81%. Evidence suggest old age, comorbidities, ventilator support, use of vasopressors, black race, severe infection, and elevated levels of baseline serum creatinine and d-dimers are independent risk factors of COVID-19 associated with AKI. COVID-19 patients with AKI also showed unsatisfactory renal recovery and higher mortality rate as compared with patients without AKI. These findings underscore that AKI frequently occurs during the course of COVID-19 infection and requires early stratification and management.

COVID-19 is a highly contagious disease that has affected all African countries including the Democratic Republic of Congo (DRC). Formidable challenges limit precautionary measures which were instituted by the government to curb the pandemic. Insufficient COVID-19 testing laboratories, limited medical and personal protective equipment, and an inadequate number of health workers leave the country ill-equipped in the fight against the pandemic. Lack of assistance from the government to those who lost their jobs due to lockdown forced these individuals to go outside to find provisions, thus increasing the spread of the virus. Moreover, the fragile healthcare system is overburdened by civil conflicts and other epidemics and endemics amid the COVID-19 pandemic. The conflicts have led to thousands of deaths and hundreds of thousands of displacements and deprived many people of basic health services. The 11th outbreak of Ebola has been increasing at an alarming pace, and it is expected to soar because of a shortfall of funds and insufficient numbers of health workers. The DRC with the cooperation of regional powers needs to address these challenges in a manner similar to that used in the previous Ebola epidemics. Moreover, the government should have a balance in shifting the available resources between COVID-19 and other diseases. Until a vaccine is available, the DRC needs to be prudent when lifting restrictions to prevent explosion of new cases.

Modern clinical trials have suggested that anemia protects against malaria mortality. Military records of the Second World War in Asia were examined to see if there was support for this hypothesis. When relatively well-nourished Imperial Japanese Navy sailors captured on Nauru (n = 799) were imprisoned on the Fauro Islands, 26% died from falciparum malaria. Similarly treated but very malnourished colocated Imperial Army soldiers experienced low stable malaria mortality. One-fifth of previously healthy Australian Army soldiers (n = 252) retreating from New Britain died largely because of malaria in April 1942. Malnourished prisoners of war, who were as a group very anemic, both Australian Army soldiers in Thailand and Japanese Army soldiers in Papua New Guinea, had high malaria rates but very low (< 3%) mortality rates. Malaria immunity does not adequately explain this dichotomy, suggesting that severe nutritional deprivation may be protective against malaria mortality possibly because of iron-deficiency anemia.

Immune correlates of protection against clinical malaria are difficult to ascertain in low-transmission areas because of the limited number of malaria cases. We collected blood samples from 5,753 individuals in a Kenyan highland area, ascertained malaria incidence in this population over the next 6 years, and then compared antibody responses to 11 Plasmodium falciparum vaccine candidate antigens in individuals who did versus did not develop clinical malaria in a nested case–control study (154 cases and 462 controls). Individuals were matched by age and village. Antigens tested included circumsporozoite protein (CSP), liver-stage antigen (LSA)-1, apical membrane antigen-1 FVO and 3D7 strains, erythrocyte-binding antigen-175, erythrocyte-binding protein-2, merozoite surface protein (MSP)-1 FVO and 3D7 strains, MSP-3, and glutamate-rich protein (GLURP) N-terminal non-repetitive (R0) and C-terminal repetitive (R2) regions. After adjustment for potential confounding factors, the presence of antibodies to LSA-1, GLURP-R2, or GLURP-R0 was associated with decreased odds of developing clinical malaria (odds ratio [OR], [95% CI] 0.56 [0.36–0.89], 0.56 [0.36–0.87], and 0.77 [0.43–1.02], respectively). Levels of antibodies to LSA-1, GLURP-R2, and CSP were associated with decreased odds of developing clinical malaria (OR [95% CI]; 0.61 [0.41–0.89], 0.60 [0.43–0.84], and 0.49 [0.24–0.99], for every 10-fold increase in antibody levels, respectively). The presence of antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 combined best-predicted protection from clinical malaria. Antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 are associated with protection against clinical malaria in a low-transmission setting. Vaccines containing these antigens should be evaluated in low malaria transmission areas.

In epidemic-prone areas of the western highlands, the Kenya Ministry of Health conducted campaigns of indoor residual spraying (IRS) of households, followed by mass distribution of insecticide-treated bed nets (ITNs), as part of the National Malaria Strategy. We previously reported that in the highland areas of Kipsamoite and Kapsisiywa, widespread IRS coverage in 2007, after lower but substantial coverage in 2005 and 2006, contributed to possible local interruption of malaria transmission between 2007 and 2008. Indoor residual spraying campaigns in the area ended in 2010, succeeded by a mass ITN distribution campaign in 2011 and 2012 targeting universal coverage. Insecticide-treated bed net use in the area increased from 17.1% pre-campaign in 2011 to 51.7% post-campaign in 2012, but decreased to 35.8% in 2013. The ITN campaign did not reduce malaria incidence in the population as a whole (odds ratio [OR] after ITN distribution versus before, 1.29, 95% CI: 1.00–1.66, P = 0.049). However, in 2011–2013, individuals who stated that they slept under ITNs as compared with those who did not had a decrease in malaria incidence that approached statistical significance (OR 0.74, 95% CI: 0.52–1.04, P = 0.08). Mass ITN distribution after previous annual IRS campaigns was insufficient to further reduce malaria transmission in this area of low and highly seasonal transmission possibly because of low ITN use despite the mass campaign.

Prevalence and levels of antibodies to multiple Plasmodium falciparum antigens show promise as tools for estimating malaria exposure. In a highland area of Kenya with unstable transmission, we assessed the presence and levels of antibodies to 12 pre-erythrocytic and blood-stage P. falciparum antigens by multiplex cytometric bead assay or ELISA in 604 individuals in August 2007, with follow-up testing in this cohort in April 2008, April 2009, and May 2010. Four hundred individuals were tested at all four time points. During this period, the only substantial malaria incidence occurred from April to August 2009. Antibody prevalence in adults was high at all time points (> 70%) for apical membrane antigen 1, erythrocyte-binding antigen 175, erythrocyte-binding protein-2, glutamate rich protein (GLURP)-R2, merozoite surface protein (MSP) 1 (19), MSP-1 (42), and liver-stage antigen-1; moderate (30–70%) for GLURP-R0, MSP-3, and thrombospondin-related adhesive protein; and low (< 30%) for SE and circumsporozoite protein (CSP). Changes in community-wide malaria exposure were best reflected in decreasing antibody levels overtime for highly immunogenic antigens, and in antibody seroprevalence overtime for the less-immunogenic antigens. Over the 3 years, antibody levels to all antigens except CSP and schizont extract (SE) decreased in an age-dependent manner. Prevalence and levels of antibodies to all antigens except CSP and SE increased with age. Increases in antibody prevalence and levels to CSP and SE coincided with increases in community-wide malaria incidence. Antibody levels to multiple P. falciparum antigens decrease in the absence of consistent transmission. Multiplex assays that assess both the presence and level of antibodies to multiple pre-erythrocytic and blood-stage P. falciparum antigens may provide the most useful estimates of past and recent malaria transmission in areas of unstable transmission and could be useful tools in malaria control and elimination campaigns.

The use of spatial data in malaria elimination strategies is important to understand whether targeted interventions against malaria can be used, particularly in areas with limited resources. We previously documented consistent areas of increased malaria incidence in the epidemic-prone area of Kipsamoite in highland Kenya from 2001 to 2004. In this area and a neighboring subcounty (Kapsisiywa), malaria incidence decreased substantially in 2005, going from peak incidence of 31.7 per 1,000 persons in June 2004 to peak incidence of 7.4 per 1,000 persons in May 2005. Subsequently, the use of indoor residual spraying and artemisinin combination therapy malaria treatment led to a possible interruption of malaria transmission for a 13-month period from 2007 to 2008, after which the incidence returned to very low levels until an epidemic in April–July 2013. In the present study, we used novel kernel density estimation methods to determine whether areas of increased malaria incidence were consistent in six periods of peak incidence from 2003 to 2013, and to assess patterns of incidence in the period before versus. after the period of possible interruption. Areas of highest incidence differed during peak malaria transmission periods over the years 2003–2013, and differed before and after the potential malaria interruption. In this epidemic-prone region with very low malaria transmission, consistent malaria “hotspots” identified in a time of higher transmission are no longer present. Ongoing assessment of spatial malaria epidemiology to identify and target current areas of elevated malaria risk may be important in campaigns to control or eliminate malaria in epidemic-prone areas.

Although Plasmodium falciparum continues to be the main target for malaria elimination, other Plasmodium species persist in Africa. Their clinical diagnosis is uncommon, whereas rapid diagnostic tests (RDTs), the most widely used malaria diagnostic tools, are only able to distinguish between P. falciparum and non-falciparum species, the latter as “pan-species.” Blood samples from health facilities were collected in southern Nigeria (Lagos and Calabar) in 2017 (October–December) and Calabar only in 2018 (October–November), and analyzed by several methods, namely, microscopy, quantitative real-time PCR (qPCR), and peptide serology targeting candidate antigens (Plasmodium malariae apical membrane antigen, P. malariae lactose dehydrogenase, and P. malariae circumsporozoite surface protein). Both microscopy and qPCR diagnostic approaches detected comparable proportions (∼80%) of all RDT-positive samples infected with the dominant P. falciparum malaria parasite. However, higher proportions of non-falciparum species were detected by qPCR than microscopy, 10% against 3% infections for P. malariae and 3% against 0% for Plasmodium ovale, respectively. No Plasmodium vivax infection was detected. Infection rates for P. malariae varied between age-groups, with the highest rates in individuals aged > 5 years. Plasmodium malariae–specific seroprevalence rates fluctuated in those aged < 10 years but generally reached the peak around 20 years of age for all peptides. The heterogeneity and rates of these non-falciparum species call for increased specific diagnosis and targeting by elimination strategies.

Chloroquine remains the first-line treatment for uncomplicated malaria in Haiti, and until recently, sulfadoxine–pyrimethamine was the second-line treatment. A few studies have reported the presence of molecular markers for resistance in Plasmodium falciparum parasites, and in vivo therapeutic efficacy studies (TESs) have been limited. Recognizing the history of antimalarial resistance around the globe and the challenges of implementing TESs in low-endemic areas, the Ministry of Health established a surveillance program to detect molecular markers of antimalarial resistance in Haiti. Sentinel sites were purposefully selected in each of Haiti’s 10 administrative departments; an 11th site was selected in Grand’Anse, the department with the highest number of reported cases. Factors considered for site selection included the number of malaria cases identified, observed skills of laboratory technicians conducting rapid diagnostic tests (RDTs), stock and storage conditions of RDTs, accuracy of data reporting to the national surveillance system, and motivation to participate. Epidemiologic data from 2,437 patients who tested positive for malaria from March 2016 to December 2018 and consented to provide samples for molecular sequencing are presented here. Of these, 936 (38.4%) patients reported self-treatment with any medication since the onset of their illness before diagnosis; overall, 69 (2.8%) patients reported taking an antimalarial. Ten patients (0.4%) reported travel away from their home for at least one night in the month before diagnosis. Establishing a molecular surveillance program for antimalarial drug resistance proved practical and feasible in a resource-limited setting and will provide the evidence needed to make informed treatment policy decisions at the national level.

Artemether–lumefantrine (AL) is a first-line agent for uncomplicated malaria caused by Plasmodium falciparum. The WHO recommends periodic therapeutic efficacy studies of antimalarial drugs for the detection of malaria parasite drug resistance and to inform national malaria treatment policies. We conducted a therapeutic efficacy study of AL in a high malaria transmission region of northern Zambia from December 2014 to July 2015. One hundred children of ages 6 to 59 months presenting to a rural health clinic with uncomplicated falciparum malaria were admitted for treatment with AL (standard 6-dose regimen) and followed weekly for 5 weeks. Parasite counts were taken every 6 hours during treatment to assess parasite clearance. Recurrent episodes during follow-up (n = 14) were genotyped to distinguish recrudescence from reinfection and to identify drug resistance single nucleotide polymorphisms (SNPs) and multidrug resistance protein 1 (mdr1) copy number variation. Day 7 lumefantrine concentrations were measured for correspondence with posttreatment reinfection. All children who completed the parasite clearance portion of the study (n = 94) were microscopy-negative by 72 hours. The median parasite elimination half-life was 2.7 hours (interquartile range: 2.1–3.3). Genotype-corrected therapeutic efficacy was 98.8% (95% CI: 97.6–100). Purported artemisinin and lumefantrine drug resistance SNPs in atp6, 3D7_1451200, and mdr1 were detected but did not correlate with parasite recurrence, nor did day 7 lumefantrine concentrations. In summary, AL was highly effective for the treatment of uncomplicated falciparum malaria in northern Zambia during the study period. The high incidence of recurrent parasitemia was consistent with reinfection due to high, perennial malaria transmission.

Independent evaluations of XEh Rapid®, an IgG4-based rapid dipstick test, were performed to assess its diagnostic performance to detect amebic liver abscess (ALA) using 405 samples at seven laboratories in four countries. The test showed high diagnostic specificity (97–100%) when tested with samples from healthy individuals (n = 100) and patients with other diseases (n = 151). The diagnostic sensitivity was tested with a total of 154 samples, and the results were variable. It was high in three laboratories (89–94%), and moderate (72%) and low (38%) in two other laboratories. Challenges and issues faced in the evaluation process are discussed. Nevertheless, XEh Rapid is promising to be developed into a point-of-care test in particular for resource-limited settings, and thus merits further confirmation of its diagnostic sensitivity.

Peripheral blood mononuclear cells (PBMC) from patients with ocular toxoplasmosis were challenged with total antigens from Toxoplasma gondii lysate (TATL) in a cytokine release assay (CRA), run during the inactive period of the disease. Increased interferon gamma (IFN-γ) levels were detected after PBMC stimulation with either ME49 reference strain (P = 0.0015) or local TgCkAr-11-9 isolate (P = 0.0012), as compared with those recorded under basal conditions. TATL from TgCkAr11-9 isolate induced a higher release of IFN-γ than ME49 strain in CRA from all tested patients (P = 0.02). The median value of IFN-γ release on TgCkAr-11-9 stimulation (26.03 pg/mL) allowed the classification of patients into high– or low–/non–IFN-γ releasers. Clinical correlations were established with both groups. The results obtained in this study suggest the need to include local strains when performing CRA with TATL.

Human African trypanosomiasis (HAT) remains a serious public health problem with diagnostic and treatment challenges in many African countries. The absence of a gold-standard biomarker has been a major difficulty for accurate disease staging and treatment follow-up. We therefore attempted to develop a simple, affordable, and noninvasive biomarker for HAT diagnosis and staging. Simultaneous actigraphy and polysomnography as well as cerebrospinal fluid (CSF) white blood cell (WBC) count, trypanosome presence, and C-X-C motif ligand (CXCL)-10 cytokine levels were performed in 20 HAT patients and nine healthy individuals (controls) using standard procedures. The International HIV Dementia Scale (IHDS) was scored in some patients as a surrogate for clinical assessment. From actigraphic parameters, we developed a novel sleep score and used it to determine correlations with other HAT markers, and compared their performance in differentiating between patients and controls and between HAT stages. The novel actigraphy sleep score (ASS) had the following ranges: 0–25 (healthy controls), 67–103 (HAT stage I), 111–126 (HAT intermediate), and 133–250 (HAT stage II). Compared with controls, stage I patients displayed a 7-fold increase in the ASS (P < 0.01), intermediate stage patients a 10-fold increase (P < 0.001), and HAT stage II patients an almost 20-fold increase (P < 0.001). CXCL-10 showed high interindividual differences. White blood cell counts were only marked in HAT stage II patients with a high interindividual variability. The International HIV Dementia Scale score negatively correlated with the ASS. We report the development and better performance of a new biomarker, ASS, for HAT diagnosis, disease staging, and monitoring that needs to be confirmed in large cohort studies.

We report a case of visceral leishmaniasis (VL)/HIV coinfection in a patient undergoing regular antiretroviral therapy and treatment with thalidomide for erythema nodosum leprosum. He presented at a health service with high fever, chills, asthenia, pale skin, lower limb edema, hepatomegaly, and splenomegaly. Visceral leishmaniasis was confirmed by direct examination, and serological and molecular tests. Serum levels of Th1/Th2 cytokines were measured. The patient began treatment with liposomal amphotericin B, with good clinical response; however, VL recurred 6 months later. Treatment was reinitiated, maintaining secondary prophylaxis with liposomal amphotericin B. The patient showed clinical improvement with important recovery of CD4+ T-lymphocyte count.