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A fecal survey in Tamil Nadu, India, revealed 2 persons passed schistosome eggs, later identified as Schistosoma incognitum, a parasite of pigs, dogs, and rats. We investigated those cases and reviewed autochthonous schistosomiasis cases from India and Nepal. Whether the 2 new cases represent true infection or spurious passage is undetermined.
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Heces , Schistosoma , Esquistosomiasis , Animales , India/epidemiología , Humanos , Schistosoma/aislamiento & purificación , Esquistosomiasis/epidemiología , Esquistosomiasis/parasitología , Heces/parasitología , Masculino , Femenino , Perros , Adulto , Porcinos , Ratas/parasitología , Nepal/epidemiología , Persona de Mediana Edad , Sur de AsiaRESUMEN
We describe a case of a 2-year-old child who expelled a single adult female Ascaris lumbricoides worm. The patient is from a rural county in Mississippi, USA, with no reported travel outside of the United States. The caregivers in the home practice good sanitation. Exposure to domestic pigs is the likely source of infection.
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Ascariasis , Porcinos , Adulto , Animales , Humanos , Femenino , Preescolar , Mississippi/epidemiología , Ascariasis/diagnóstico , Ascariasis/epidemiología , Ascaris lumbricoides , Sus scrofa , ViajeRESUMEN
Human infections with the protozoan Lophomonas have been increasingly reported in the medical literature over the past three decades. Initial reports were based on microscopic identification of the purported pathogen in respiratory specimens. Later, a polymerase chain reaction (PCR) was developed to detect Lophomonas blattarum, following which there has been a significant increase in reports. In this minireview, we thoroughly examine the published reports of Lophomonas infection to evaluate its potential role as a human pathogen. We examined the published images and videos of purported Lophomonas, compared its morphology and motility characteristics with host bronchial ciliated epithelial cells and true L. blattarum derived from cockroaches, analyzed the published PCR that is being used for its diagnosis, and reviewed the clinical data of patients reported in the English and Chinese literature. From our analysis, we conclude that the images and videos from human specimens do not represent true Lophomonas and are predominantly misidentified ciliated epithelial cells. Additionally, we note that there is insufficient clinical evidence to attribute the cases to Lophomonas infection, as the clinical manifestations are non-specific, possibly caused by other infections and comorbidities, and there is no associated tissue pathology attributable to Lophomonas. Finally, our analysis reveals that the published PCR is not specific to Lophomonas and can amplify DNA from commensal trichomonads. Based on this thorough review, we emphasize the need for rigorous scientific scrutiny before a microorganism is acknowledged as a novel human pathogen and discuss the potential harms of misdiagnoses for patient care and scientific literature.
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Parabasalidea , Infecciones por Protozoos , Humanos , Infecciones por Protozoos/diagnóstico , Errores DiagnósticosRESUMEN
The Strongyloides genus of parasitic nematodes have a fascinating life cycle and biology, but are also important pathogens of people and a World Health Organization-defined neglected tropical disease. Here, a community of Strongyloides researchers have posed thirteen major questions about Strongyloides biology and infection that sets a Strongyloides research agenda for the future. This article is part of the Theo Murphy meeting issue 'Strongyloides: omics to worm-free populations'.
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Estadios del Ciclo de Vida , Strongyloides , Animales , HumanosRESUMEN
Strongyloidiasis is a World Health Organization neglected tropical disease usually caused by Strongyloides stercoralis, a parasitic worm with a complex life cycle. Globally, 300-600 million people are infected through contact with fecally contaminated soil. An autoinfective component of the life cycle can lead to chronic infection that may be asymptomatic or cause long-term symptoms, including malnourishment in children. Low larval output can limit the sensitivity of detection in stool, with serology being effective but less sensitive in immunocompromise. Host immunosuppression can trigger catastrophic, fatal hyperinfection/dissemination, where large numbers of larvae pierce the bowel wall and disseminate throughout the organs. Stable disease is effectively treated by single-dose ivermectin, with disease in immunocompromised patients treated with multiple doses. Strategies for management include raising awareness, clarifying zoonotic potential, the development and use of effective diagnostic tests for epidemiological studies and individual diagnosis, and the implementation of treatment programs with research into therapeutic alternatives and medication safety.
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Strongyloides stercoralis , Estrongiloidiasis , Animales , Niño , Humanos , Estrongiloidiasis/diagnóstico , Estrongiloidiasis/tratamiento farmacológico , Estrongiloidiasis/parasitología , Ivermectina/farmacología , Ivermectina/uso terapéutico , Huésped Inmunocomprometido , Terapia de InmunosupresiónRESUMEN
Recent reports of hookworm infection in Alabama, USA, has prompted surveillance in Mississippi, given the states' similar environmental conditions. We collected stool specimens from 277 children in Rankin County, Mississippi. Kato-Katz microscopic smear, agar plate culture, and quantitative PCR indicated no soil-transmitted helminths. Nevertheless, further surveillance in other high-risk Mississippi counties is warranted.
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Helmintos , Suelo , Niño , Animales , Humanos , Suelo/parasitología , Mississippi/epidemiología , Heces/parasitología , Prevalencia , Helmintos/genéticaRESUMEN
The taxonomy of medically important parasites continues to evolve. This minireview provides an update of additions and updates in the field of human parasitology from June 2020 through June 2022. A list of previously reported nomenclatural changes that have not been broadly adapted by the medical community is also included.
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Cryptosporidium , Parásitos , Animales , Humanos , ParasitologíaRESUMEN
A previously described universal parasite diagnostic (nUPDx) based on PCR amplification of the 18S rDNA and deep-amplicon sequencing, can detect human blood parasites with a sensitivity comparable to real-time PCR. To date, the efficacy of this assay has only been assessed on human blood. This study assessed the utility of nUPDx for the detection of parasitic infections in animals using blood, tissues, and other biological sample types from mammals, birds, and reptiles, known to be infected with helminth, apicomplexan, or pentastomid parasites (confirmed by microscopy or PCR), as well as negative samples. nUPDx confirmed apicomplexan and/or nematode infections in 24 of 32 parasite-positive mammals, while also identifying several undetected coinfections. nUPDx detected infections in 6 of 13 positive bird and 1 of 2 positive reptile samples. When applied to 10 whole parasite specimens (worms and arthropods), nUPDx identified all to the genus or family level, and detected one incorrect identification made by morphology. Babesia sp. infections were detected in 5 of the 13 samples that were negative by other diagnostic approaches. While nUPDx did not detect PCR/microscopy-confirmed trichomonads or amoebae in cloacal swabs/tissue from 8 birds and 2 reptiles due to primer template mismatches, 4 previously undetected apicomplexans were detected in these samples. Future efforts to improve the utility of the assay should focus on validation against a larger panel of tissue types and animal species. Overall, nUPDx shows promise for use in both veterinary diagnostics and wildlife surveillance, especially because species-specific PCRs can miss unknown or unexpected pathogens.
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BACKGROUND: Long-term persistence of Ebola virus (EBOV) in immunologically privileged sites has been implicated in recent outbreaks of Ebola virus disease (EVD) in Guinea and the Democratic Republic of Congo. This study was designed to understand how the acute course of EVD, convalescence, and host immune and genetic factors may play a role in prolonged viral persistence in semen. METHODS: A cohort of 131 male EVD survivors in Liberia were enrolled in a case-case study. "Early clearers" were defined as those with 2 consecutive negative EBOV semen test results by real-time reverse-transcription polymerase chain reaction (rRT-PCR) ≥2 weeks apart within 1 year after discharge from the Ebola treatment unit or acute EVD. "Late clearers" had detectable EBOV RNA by rRT-PCR >1 year after discharge from the Ebola treatment unit or acute EVD. Retrospective histories of their EVD clinical course were collected by questionnaire, followed by complete physical examinations and blood work. RESULTS: Compared with early clearers, late clearers were older (median, 42.5 years; P < .001) and experienced fewer severe clinical symptoms (median 2, P = .006). Late clearers had more lens opacifications (odds ratio, 3.9 [95% confidence interval, 1.1-13.3]; P = .03), after accounting for age, higher total serum immunoglobulin G3 (IgG3) titers (P = .005), and increased expression of the HLA-C*03:04 allele (0.14 [.02-.70]; P = .007). CONCLUSIONS: Older age, decreased illness severity, elevated total serum IgG3 and HLA-C*03:04 allele expression may be risk factors for the persistence of EBOV in the semen of EVD survivors. EBOV persistence in semen may also be associated with its persistence in other immunologically protected sites, such as the eye.
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Ebolavirus , Fiebre Hemorrágica Ebola , Humanos , Masculino , Ebolavirus/genética , Fiebre Hemorrágica Ebola/epidemiología , Semen , Liberia/epidemiología , Estudios Retrospectivos , Antígenos HLA-C , Sobrevivientes , Factores de RiesgoRESUMEN
Advances in laboratory techniques have revolutionized parasitology diagnostics over the past several decades. Widespread implementation of rapid antigen detection tests has greatly expanded access to tests for global parasitic threats such as malaria, while next-generation amplification and sequencing methods allow for sensitive and specific detection of human and animal parasites in complex specimen matrices. Recently, the introduction of multiplex panels for human gastrointestinal infections has enhanced the identification of common intestinal protozoa in feces along with bacterial and viral pathogens. Despite the benefits provided by novel diagnostics, increased reliance on nonmicroscopy-based methods has contributed to the progressive, widespread loss of morphology expertise for parasite identification. Loss of microscopy and morphology skills has the potential to negatively impact patient care, public health, and epidemiology. Molecular- and antigen-based diagnostics are not available for all parasites and may not be suitable for all specimen types and clinical settings. Furthermore, inadequate morphology experience may lead to missed and inaccurate diagnoses and erroneous descriptions of new human parasitic diseases. This commentary highlights the need to maintain expert microscopy and morphological parasitology diagnostic skills within the medical and scientific community. We proposed that light microscopy remains an important part of training and practice in the diagnosis of parasitic diseases and that efforts should be made to train the next generation of morphological parasitologists before the requisite knowledge, skills, and capacity for this complex and important mode of diagnosis are lost. In summary, the widespread, progressive loss of morphology expertise for parasite identification negatively impacts patient care, public health, and epidemiology.
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Parásitos , Enfermedades Parasitarias , Animales , Humanos , Enfermedades Parasitarias/diagnóstico , Enfermedades Parasitarias/parasitología , Parásitos/genética , Microscopía/métodos , Heces/parasitología , BacteriasRESUMEN
We report an imported case of myositis caused by a rare parasite, Haycocknema perplexum, in Australia in a 37-year-old man who had progressive facial, axial, and limb weakness, dysphagia, dysphonia, increased levels of creatine kinase and hepatic aminotransferases, and peripheral eosinophilia for 8 years. He was given extended, high-dose albendazole.
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Miositis , Nematodos , Animales , Masculino , Humanos , Estados Unidos , Adulto , Albendazol , Miositis/parasitología , Creatina Quinasa , TransaminasasRESUMEN
Strongyloidiasis is the infection caused by soil-transmitted nematodes of Strongyloides species, infecting humans and some animals. Strongyloides stercoralis is the species with most clinical and epidemiological relevance in humans and dogs, due to its high prevalence and its capacity of inducing a life-threatening hyperinfection. Diagnosis of strongyloidiasis is challenging, due to the absence of a single reference standard test with high sensitivity and specificity, which also hampers the estimation of the accuracy of other diagnostic tests. In this chapter, we review the deployment and performance of the parasitological, immunological, molecular tests for the diagnosis of strongyloidiasis in humans and in dogs. Further, we comment the available evidence from genotyping studies that have addressed the zoonotic potential of S. stercoralis. Finally, we discuss the use of different diagnostic methods in relation to the purpose (i.e., screening, individual diagnosis, inclusion in a clinical trial) and the setting (endemic/non-endemic areas) and report the accuracy figures reported by systematic reviews on either parasitological, serological or molecular techniques published in literature.
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Strongyloides stercoralis , Estrongiloidiasis , Animales , Perros , Humanos , Mascotas , Prevalencia , Estrongiloidiasis/diagnóstico , Estrongiloidiasis/epidemiología , Estrongiloidiasis/veterinariaAsunto(s)
Infecciones por Enoplida , Refugiados , Bélgica , Niño , Infecciones por Enoplida/diagnóstico , Familia , HumanosRESUMEN
The serologic diagnosis of chronic Chagas disease, caused by infection with the parasite Trypanosoma cruzi, is challenging and lacks a gold-standard assay. To overcome the problem, CDC uses an algorithm that uses two tests on different platforms and applies a third test as a tiebreaker. The Ortho T. cruzi ELISA Test System from Ortho Diagnostics was cleared by FDA for clinical diagnosis usage. We evaluated this test against the CDC algorithm for chronic Chagas disease. We tested several sets of serum specimens: 104 specimens tested positive for T. cruzi specific antibody and 283 (including 30 specimens positive for antibody to Leishmania spp.) tested negative based on the current CDC chronic T. cruzi infection diagnostic testing algorithm. Concordance of the Ortho T. cruzi ELISA Test System with the CDC algorithm result was 90% (95% CI 87 to 93%) overall and 92% (95% CI 89 to 95%) when excluding Leishmania spp. antibody positive specimens. The cross-reactivity of the Ortho T. cruzi ELISA Test System was 37% to Leishmania spp. serologically positive specimens, 1% to specimens from patients diagnosed with other parasitic infections, and 0% against specimens from a US noninfected population. In conclusion, the Ortho T. cruzi ELISA Test System compares well against the CDC diagnostic algorithm for chronic Chagas disease. The availability of this FDA-cleared assay will improve the chronic Chagas disease diagnosis.
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Enfermedad de Chagas , Leishmania , Trypanosoma cruzi , Anticuerpos Antiprotozoarios , Enfermedad de Chagas/parasitología , Ensayo de Inmunoadsorción Enzimática , HumanosRESUMEN
â¢Neglected tropical diseases (NTDs) represent a threat to the health, wellbeing and economic prosperity of billions of people worldwide, often causing serious disease or death. â¢Commonly considered diseases of low and middle-income nations, the presence of NTDs in high income countries such as Australia is often overlooked. â¢Seven of the 20 recognised NTDs are endemic in Australia: scabies, soil-transmitted helminths and strongyloidiasis, echinococcosis, Buruli ulcer, leprosy, trachoma, and snakebite envenoming. â¢Dengue, while not currently endemic, poses a risk of establishment in Australia. There are occasional outbreaks of dengue fever, with local transmission, due to introductions in travellers from endemic regions. â¢Similarly, the risk of introduction of other NTDs from neighbouring countries is a concern. Many NTDs are only seen in Australia in individuals travelling from endemic areas, but they need to be recognised in health settings as the potential consequences of infection can be severe. â¢In this review, we consider the status of NTDs in Australia, explore the risk of introducing and contracting these infections, and emphasise the negative impact they have on the health of Australians, especially Aboriginal and Torres Strait Islander peoples.
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Lepra , Escabiosis , Australia/epidemiología , Humanos , Nativos de Hawái y Otras Islas del Pacífico , Enfermedades Desatendidas/epidemiologíaRESUMEN
BACKGROUND: Strongyloides stercoralis is considered to be historically endemic in Appalachia and the American South, but recent surveillance data, especially data evaluating strongyloidiasis associated with hospitalization, are lacking in most parts of the United States. METHODS: We performed a population-based retrospective analysis on strongyloidiasis using the National Inpatient Sample from 2003 to 2018. Geographic distribution of strongyloidiasis associated hospitalization was assessed. Logistic regression was used to identify risk factors associated with strongyloidiasis. RESULTS: We identified 6931 hospitalizations associated with strongyloidiasis during the study period (11.8 per million hospitalizations). The rate of strongyloidiasis was highest in the Northeast US region, including the Middle Atlantic division (47.1 cases per million population; adjusted odds ratio, 2.00 [95% confidence interval: 1.58-2.53]), and the East South Central division (27.5 cases per million; adjusted odds ratio, 2.77 [2.02-3.80]). Older age, male sex, nonwhite race/ethnicity (particularly Hispanic and Asian), nonprivate insurance, and residence in neighborhoods with low median income were also associated with strongyloidiasis. Immunocompromising conditions, particularly human immunodeficiency virus infection, were present in 41.3% of hospitalizations with strongyloidiasis. In-hospital death occurred in 7.8% of patients with strongyloidiasis-associated hospitalization. CONCLUSIONS: Strongyloidiasis-associated hospitalization is rare in the United States but can be associated with increased mortality rate/mortality risk . It occurs more frequently in poor and marginalized populations. Immunocompromised conditions were common among hospitalized patients with strongyloidiasis. Enhanced surveillance efforts are needed to inform health policies for improving the health of at-risk populations.
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Strongyloides stercoralis , Estrongiloidiasis , Animales , Estados Unidos/epidemiología , Humanos , Masculino , Estrongiloidiasis/epidemiología , Estudios Retrospectivos , Mortalidad Hospitalaria , HospitalizaciónRESUMEN
Non-typhoidal Salmonella associated with multidrug resistance cause invasive disease in sub-Saharan Africa. Specific lineages of serovars Typhimurium and Enteritidis have been implicated. Here we characterized the genomic diversity of 100 clinical non-typhoidal Salmonella collected from 93 patients in 2001 from the eastern, and in 2006-2018 from the western regions of The Gambia respectively. A total of 93 isolates (64 invasive, 23 gastroenteritis and six other sites) representing a single infection episode were phenotypically tested for antimicrobial susceptibility using the Kirby-Bauer disc diffusion technique. Whole genome sequencing of 100 isolates was performed using Illumina, and the reads were assembled and analysed using SPAdes. The Salmonella in Silico Typing Resource (SISTR) was used for serotyping. SNP differences among the 93 isolates were determined using Roary, and phylogenetic analysis was performed in the context of 495 African strains from the European Nucleotide Archive. Salmonella serovars Typhimurium (26/64; 30.6â%) and Enteritidis (13/64; 20.3â%) were associated with invasive disease, whilst other serovars were mainly responsible for gastroenteritis (17/23; 73.9â%). The presence of three major serovar Enteritidis clades was confirmed, including the invasive West African clade, which made up more than half (11/16; 68.8â%) of the genomes. Multidrug resistance was confined among the serovar Enteritidis West African clade. The presence of this epidemic virulent clade has potential for spread of resistance and thus important implications for systematic patient management. Surveillance and epidemiological investigations to inform control are warranted.
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Gastroenteritis , Infecciones por Salmonella , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana/genética , Gambia/epidemiología , Gastroenteritis/epidemiología , Genómica , Humanos , Filogenia , Infecciones por Salmonella/tratamiento farmacológico , Infecciones por Salmonella/epidemiología , Salmonella typhimurium/genéticaRESUMEN
Soil-transmitted helminths (STH) are important and widespread intestinal pathogens of humans and animals. It is presently unknown which inactivating procedures may be universally effective for safe transport, preservation, and disinfection of STH-contaminated specimens, and this lack of knowledge may expose laboratory staff to higher risk of laboratory-acquired infections (LAI's). There are limited data on the efficacy of commonly used disinfectants and fecal fixatives for inactivating the eggs of STH. This work tested five disinfectants for surface cleanup, four storage temperature conditions, and six transport/storage fixatives, to inactivate eggs of three species of STH of animal origin (Ascaris suum "roundworm," Trichuris vulpis "whipworm" and Ancylostoma caninum "hookworm") as surrogates for human STH. Among disinfectants, exposure to 10% povidone-iodine for ≥5 min inactivated 100% of the three species tested, while 5 min exposure to 95% ethanol inactivated T. vulpis and A. caninum eggs. All of the fixatives tested had inactivation effects on A. caninum hookworm eggs within 24 h of exposure, except potassium dichromate, which required 48 h. 95% ethanol for ≥48 h inactivated eggs from all three STH species. Freezing at ≤-20°C for ≥24 h inactivated eggs of T. vulpis and A. caninum, but only freezing at -80°C for ≥24 h inactivated >99% eggs, including A. suum. This work provides an evidence base for health and safety guidelines and mitigation strategies for the handling, storage, and disposal of stool samples containing STH eggs in laboratory, health care, childcare, or veterinary settings. IMPORTANCE This study systematically evaluates common laboratory disinfectants and storage conditions for their effectiveness in inactivating the infective stages of soil-transmitted helminths (STH). Animal-infecting proxy species were chosen to represent three major groups of STH that infect humans: roundworms, whipworms, and hookworms. Previously published work in this area typically focuses on a particular inactivation method, either for a single STH species, or on a subset of closely related species. Because prediagnostic fecal specimens must be regarded as potentially infectious with a mix of species, such information may be of limited utility in a working laboratory. We provide a straightforward summary of storage and disinfection methods that can achieve complete inactivation across a range of STH species, which represents a significant advance for clinical, veterinary and research laboratory biosafety.
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Antiinfecciosos Locales/farmacología , Desinfectantes/farmacología , Desinfección/métodos , Helmintos/efectos de los fármacos , Infecciones por Uncinaria/prevención & control , Ancylostoma/efectos de los fármacos , Ancylostoma/embriología , Ancylostomatoidea/efectos de los fármacos , Animales , Ascaris suum/efectos de los fármacos , Ascaris suum/embriología , Contención de Riesgos Biológicos/métodos , Etanol/farmacología , Heces/parasitología , Humanos , Óvulo/efectos de los fármacos , Povidona Yodada/farmacología , Suelo/parasitología , Manejo de Especímenes , Trichuris/efectos de los fármacos , Trichuris/embriologíaRESUMEN
Strongyloidiasis represents a major medical and veterinary helminthic disease. Human infection is caused by Strongyloides stercoralis, Strongyloides fuelleborni fuelleborni and Strongyloides fuelleborni kellyi, with S.stercoralis accounting for the majority of cases. Strongyloides f. fuelleborni likely represents a zoonosis acquired from non-human primates (NHPs), while no animal reservoir for S. f. kellyi infection has been found. Whether S. stercoralis represents a zoonosis acquired from dogs and cats remains unanswered. Over the past two decades various tools have been applied to genotype Strongyloides spp. The most commonly sequenced markers have been the hyper-variable regions I and IV of the 18S rRNA gene and selected portions of the cytochrome c oxidase subunit I gene. These markers have been sequenced and compared in Strongyloides from multiple hosts and geographical regions. More recently, a machine learning algorithm multi-locus sequence typing approach has been applied using these markers, while others have applied whole genome sequencing. Genotyping of Strongyloides from dogs, cats, NHPs and humans has identified that S. stercoralis likely originated in dogs and adapted to human hosts. It has also been demonstrated that S. stercoralis is distinct from S. f. fuelleborni and S. f. kellyi. Two distinct genetic clades of S. stercoralis exist, one restricted to dogs and another infecting humans, NHPs, dogs and cats. Genotyping of S. f. fuelleborni has identified two separate clades, one associated with African isolates and another Indochinese peninsular clade. This review summarises the history and development of genotyping tools for Strongyloides spp. It describes the findings of major studies to date in the context of the epidemiology and evolutionary biology of these helminths, with a specific focus on human-infecting species.
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Enfermedades de los Gatos , Enfermedades de los Perros , Strongyloides stercoralis , Estrongiloidiasis , Animales , Gatos , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/parasitología , Perros , Heces/parasitología , Genética de Población , Genotipo , Tipificación de Secuencias Multilocus , Filogenia , Primates/genética , Salud Pública , Strongyloides stercoralis/genética , Estrongiloidiasis/epidemiología , Estrongiloidiasis/parasitología , Estrongiloidiasis/veterinaria , Zoonosis/parasitologíaRESUMEN
BACKGROUND: The specific roles that gut microbiota, known pathogens, and host energy-regulating hormones play in the pathogenesis of non-edematous severe acute malnutrition (marasmus SAM) and moderate acute malnutrition (MAM) during outpatient nutritional rehabilitation are yet to be explored. METHODS: We applied an ensemble of sample-specific (intra- and inter-modality) association networks to gain deeper insights into the pathogenesis of acute malnutrition and its severity among children under 5 years of age in rural Gambia, where marasmus SAM is most prevalent. FINDINGS: Children with marasmus SAM have distinct microbiome characteristics and biologically-relevant multimodal biomarkers not observed among children with moderate acute malnutrition. Marasmus SAM was characterized by lower microbial richness and biomass, significant enrichments in Enterobacteriaceae, altered interactions between specific Enterobacteriaceae and key energy regulating hormones and their receptors. INTERPRETATION: Our findings suggest that marasmus SAM is characterized by the collapse of a complex system with nested interactions and key associations between the gut microbiome, enteric pathogens, and energy regulating hormones. Further exploration of these systems will help inform innovative preventive and therapeutic interventions. FUNDING: The work was supported by the UK Medical Research Council (MRC; MC-A760-5QX00) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement; Bill and Melinda Gates Foundation (OPP 1066932) and the National Institute of Medical Research (NIMR), UK. This network analysis was supported by NIH U54GH009824 [CLD] and NSF OCE-1558453 [CLD].