Impact of Strongyloides stercoralis infection on complement activation in Type 2 diabetes mellitus: Insights from a clinical and anthelmintic intervention study.

BACKGROUND: Numerous studies indicate a potential protective role of helminths in diabetes mellitus (DM) progression. The complement system, vital for host defense, plays a crucial role in tissue homeostasis and immune surveillance. Dysregulated complement activation is implicated in diabetic complications. We aimed to investigate the influence of the helminth, Strongyloides stercoralis (Ss) on complement activation in individuals with type 2 DM (T2D). METHODOLOGY: We assessed circulating levels of complement proteins (C1q, C2, C3, C4, C4b, C5, C5a, and MBL (Lectin)) and their regulatory components (Factor B, Factor D, Factor H, and Factor I) in individuals with T2D with (n = 60) or without concomitant Ss infection (n = 58). Additionally, we evaluated the impact of anthelmintic therapy on these parameters after 6 months in Ss-infected individuals (n = 60). RESULTS: Ss+DM+ individuals demonstrated reduced levels of complement proteins (C1q, C4b, MBL (Lectin), C3, C5a, and C3b/iC3b) and complement regulatory proteins (Factor B and Factor D) compared to Ss-DM+ individuals. Following anthelmintic therapy, there was a partial reversal of these levels in Ss+DM+ individuals. CONCLUSION: Our findings indicate that Ss infection reduces complement activation, potentially mitigating inflammatory processes in individuals with T2D. The study underscores the complex interplay between helminth infections, complement regulation, and diabetes mellitus, offering insights into potential therapeutic avenues.

High Efficacy of Ivermectin for Strongyloidiasis Treatment.

Infection with Strongyloides stercoralis is often asymptomatic but can be life-threatening in immunocompromised patients, which can be prevented by ivermectin (IVM) treatment. The efficacy of IVM has been reported to have lessened over time in some regions as a consequence of prolonged use and mass treatment campaigns. Ivermectin has been used in Thailand for more than a decade; therefore, we investigated the efficacy of a single dose (200 µg/kg) of IVM against in asymptomatic strongyloidiasis in northeastern Thailand. Fecal samples were collected before and 2 weeks after treatment and were analyzed for the presence of Strongyloides using a modified agar plate culture and the formalin-ethyl acetate concentration technique. Our results showed that single-dose IVM treatment successfully eliminated S. stercoralis infection in asymptomatic individuals in the endemic area with a 100% cure rate, indicating the high efficacy of IVM treatment in strongyloidiasis in northeast Thailand.

Strongyloidiasis in Auckland: A ten-year retrospective study of diagnosis, treatment and outcomes of a predominantly Polynesian and Fijian migrant cohort.

BACKGROUND: Strongyloides stercoralis is not endemic in Aotearoa New Zealand (AoNZ). However, approximately one third of Auckland residents are born in endemic countries. This study aimed to describe the epidemiology and management of strongyloidiasis in Auckland, with a focus on migrants from Pacific Island Countries and Territories. METHODS: This study retrospectively reviewed clinical, laboratory and pharmacy records data for all people diagnosed with strongyloidiasis in the Auckland region between July 2012 and June 2022. People with negative Strongyloides serology were included to estimate seropositivity rate by country of birth. FINDINGS: Over ten years, 691 people were diagnosed with strongyloidiasis. Most diagnoses were made by serology alone (622, 90%). The median age was 63 years (range 15-92), 500 (72%) were male, and the majority were born in Polynesia (350, 51%), Fiji (130, 19%) or were of Pasifika ethnicity (an additional 7%). Twelve participants (1.7%) had severe strongyloidiasis at diagnosis. The total proportion treated with ivermectin was only 70% (484/691), with no differences between immunocompromised and immunocompetent participants, nor by ethnicity. The outcome of treatment (based on a combination of serology and/or eosinophilia and/or stool microscopy) could only be determined in 50% of the treated cohort. One participant failed treatment with ivermectin, experiencing recurrent strongyloidiasis, and another participant died in association with severe strongyloidiasis. The rate of 'positive' Strongyloides serology was highest among participants born in Samoa (48%), Fiji (39%), and Southeast Asian countries (34%). INTERPRETATION: Strongyloidiasis was common and under-treated in Auckland during the study period. Clinicians should have a low threshold for considering strongyloidiasis in migrants from endemic countries, including Polynesia and Fiji.

Case Report: Disseminated Paracoccidioidomycosis and Strongyloides Hyperinfection in a Patient with Human T-Lymphotropic Virus Type 1/2 Infection.

Co-occurrence of paracoccidioidomycosis and strongyloidiasis in immunosuppressed patients, particularly those infected with human T-lymphotropic virus type 1/2, is infrequent. We describe the case of a Peruvian farmer from the central jungle with human T-lymphotropic virus type 1/2 infection, with 2 months of illness characterized by respiratory and gastrointestinal symptoms associated with fever, weight loss, and enlarged lymph nodes. Strongyloides stercoralis and Paracoccidioides brasiliensis were isolated in sputum and bronchoalveolar lavage samples, respectively. The clinical evolution was favorable after the patient received ivermectin and amphotericin B. We hypothesize that autoinfestation by S. stercoralis in human T-lymphotropic virus type 1/2-infected patients may contribute to the disseminated presentation of Paracoccidioides spp. Understanding epidemiological context is crucial for suspecting opportunistic regional infections, particularly those that may coexist in immunosuppressed patients.

Discovery and Structure-Activity Relationships of Novel ssDAF-12 Receptor Modulators.

The nuclear receptor ssDAF-12 has been recognized as the key molecular player regulating the life cycle of the nematode parasite Strongyloides stercoralis. ssDAF-12 ligands permit the receptor to function as an on/off switch modulating infection, making it vulnerable to therapeutic intervention. In this study, we report the design and synthesis of a set of novel dafachronic acid derivatives, which were used to outline the first structure-activity relationship targeting the ssDAF-12 receptor and to unveil hidden properties shared by the molecular shape of steroidal ligands that are relevant to the receptor binding and modulation. Moreover, biological results led to the discovery of sulfonamide 3 as a submicromolar ssDAF-12 agonist endowed with a high receptor selectivity, no toxicity, and improved properties, as well as to the identification of unprecedented ssDAF-12 antagonists that can be exploited in the search for novel chemical tools and alternative therapeutic approaches for treating parasitism such as Strongyloidiasis.

Strongyloidiasis.

Strongyloidiasis is a neglected tropical disease caused primarily by the roundworm Strongyloides stercoralis. Strongyloidiasis is most prevalent in Southeast Asia and the Western Pacific. Although cases have been documented worldwide, global prevalence is largely unknown due to limited surveillance. Infection of the definitive human host occurs via direct skin penetration of the infective filariform larvae. Parasitic females reside in the small intestine and reproduce via parthenogenesis, where eggs hatch inside the host before rhabditiform larvae are excreted in faeces to begin the single generation free-living life cycle. Rhabditiform larvae can also develop directly into infectious filariform larvae in the gut and cause autoinfection. Although many are asymptomatic, infected individuals may report a range of non-specific gastrointestinal, respiratory or skin symptoms. Autoinfection may cause hyperinfection and disseminated strongyloidiasis in immunocompromised individuals, which is often fatal. Diagnosis requires direct examination of larvae in clinical specimens, positive serology or nucleic acid detection. However, there is a lack of standardization of techniques for all diagnostic types. Ivermectin is the treatment of choice. Control and elimination of strongyloidiasis will require a multifaceted, integrated approach, including highly sensitive and standardized diagnostics, active surveillance, health information, education and communication strategies, improved water, sanitation and hygiene, access to efficacious treatment, vaccine development and better integration and acknowledgement in current helminth control programmes.

Identification and treatment of Strongyloides stercoralis infection in a Boston Terrier dog from south-eastern Australia.

Strongyloides stercoralis, the causative agent of strongyloidiasis, is a potentially zoonotic intestinal nematode endemic to northern Australia. Strongyloidiasis is typically observed in immunocompromised hosts and is characterised by gastrointestinal signs, respiratory symptoms and a failure to thrive. In immunocompromised hosts, hyperinfection syndrome and disseminated infections can prove life-threatening. A 24-month-old Boston Terrier dog was referred for investigation of chronic small and large intestinal watery hematochezic diarrhoea, emaciation and hematemesis. Small intestinal histology identified a nematode despite consecutive negative faecal flotations. A real-time polymerase chain reaction and Baermann test subsequently confirmed infection with S. stercoralis. The dog had received an oral parasiticide comprising milbemycin oxime and afoxolaner every month for the 11 months prior to this diagnosis. Despite fenbendazole being reported as successful in the treatment of canine strongyloidiasis, a course of fenbendazole failed to clear the infection. Eradication of S. stercoralis infection was confirmed after the administration of off-label ivermectin fortnightly for 12 doses. Attention should be paid to this nematode as the failure of routine copromicroscopic methods to diagnose S. stercoralis infections can result in misdiagnosis, mistreatment and progression of the disease. Off-label ivermectin may be an alternative to fenbendazole for the treatment of Strongyloides spp. infection in dogs.

Efficacy and safety of moxidectin compared with ivermectin against Strongyloides stercoralis infection in adults in Laos and Cambodia: a randomised, double-blind, non-inferiority, phase 2b/3 trial.

BACKGROUND: Infection with the soil-transmitted helminth Strongyloides stercoralis affects up to 600 million people globally, most of whom live in rural areas with poor sanitation. If untreated, infection leads to long-lasting morbidity and might even be life-threatening. Moxidectin might be a promising alternative to ivermectin, the only currently recommended single-dose treatment. We aimed to assess whether moxidectin is non-inferior in terms of efficacy and safety compared with ivermectin. METHODS: In this randomised, double-blind, parallel-group, non-inferiority, phase 2b/3 trial in communities in Laos and Cambodia, adults aged 18-65 years were screened for the presence of S stercoralis larvae in their stool via sextuplicate quantitative Baermann assays. Using computer-generated group allocation (block randomisation stratified by infection intensity), parasitologically (two or more positive Baermann assays) and clinically eligible participants were randomly assigned (1:1) to receive single oral doses of either moxidectin (8 mg) and ivermectin-matched placebo, or ivermectin (200 µg/kg bodyweight) and moxidectin-matched placebo. The primary endpoint was cure rate assessed at 14-21 days after treatment, using the available-case population analysed according to intention-to-treat principles. Moxidectin was considered non-inferior to ivermectin if the lower limit of the two-sided 95% CI of the difference was greater than the non-inferiority margin of -10 percentage points. Safety endpoints were assessed before treatment, and at 2-3 h, 24 h, and 14-21 days after treatment. This trial is registered at ClinicalTrials.gov, NCT04056325 and NCT04848688. FINDINGS: Between Dec 6, 2020, and May 21, 2022, 4291 participants were screened, 726 of whom were enrolled and randomly assigned to moxidectin (n=363) or ivermectin (n=363). For the participants with primary outcome data, we observed a cure rate of 93·6% (95% CI 90·5 to 96·0; 324 of 346 participants) in the moxidectin group and 95·7% (93·0 to 97·6; 335 of 350 participants) in the ivermectin group, resulting in a between-group difference of -2·1 percentage points (95% CI -5·5 to 1·3). The most common adverse events were abdominal pain (32 [9%] of 363 with moxidectin vs 34 [9%] of 363 with ivermectin) and headache (25 [7%] vs 30 [8%]), which were predominantly mild and transient. INTERPRETATION: Moxidectin was non-inferior to ivermectin in terms of efficacy in the treatment of strongyloidiasis. Additionally, both drugs had a similar safety profile. The fixed dose and lower cost of moxidectin compared with ivermectin make it a valuable alternative for people with strongyloidiasis. FUNDING: Swiss National Science Foundation.

Progress towards the implementation of control programmes for strongyloidiasis in endemic areas: estimation of number of adults in need of ivermectin for strongyloidiasis.

The World Health Organization has started a process to issue guidelines for the control of strongyloidiasis. The guidelines might recommend to implement preventive chemotherapy (PC) at community level (i.e. to all individuals above 5 years of age), over a defined prevalence threshold. We previously estimated the number of school-age children (SAC) who would need PC. Here we estimate the number of people above 15 years of age who might be included in PC for strongyloidiasis. Based on previous Strongyloides prevalence estimates and on countries' age distribution, we retrieved the number of adults in need of PC. We then subtracted the number of people already involved in ivermectin mass distribution for the elimination of onchocerciasis and lymphatic filariasis and people living in countries where Loa loa is endemic. The number of adults to be involved in PC was estimated at 905.4 (95% confidence interval (CI): 520.6-1177.2), 660.2 (95% CI: 512.7-1214.9), and 512.1 (95% CI: 276-719.4) million people, when the strongyloidiasis prevalence threshold for implementing PC was set to 10%, 15% and 20%, respectively. Estimates at country level are also provided.These estimates might help endemic countries wishing to implement PC for strongyloidiasis to allocate resources to include adults in addition to SAC in control programmes. This article is part of the Theo Murphy meeting issue 'Strongyloides: omics to worm-free populations'.

A severe case of hyperinfection by Strongyloides stercoralis in a pet dog from Romania.

Strongyloides stercoralis is a zoonotic soil-transmitted nematode affecting mainly humans and dogs but identified also in non-human primates, cats and wild carnivores. It has a cosmopolitan distribution being endemic in tropical and subtropical areas. In Romania, the infection was reported on several occasions in dogs with low prevalence (3.5% -3.8%), assessed by coproscopy and it was confirmed in human patients with no travel history. A 2-year-old male Boston Terrier dog presented to a private clinic due to severe digestive problems, in July 2022. The animal had a long history of health problems. The dog was in a very bad clinical condition with severe abdominal pain, bloody diarrhea, and weight loss. Coproparasitological examinations using the saline flotation method and the modified Baermann's technique were done, both being negative. In addition, an intestinal biopsy was performed during the second endoscopy. Nematodes were collected and identified morphologically and molecularly confirmed. Histology revealed severe inflammation of the duodenal mucosa with areas of edema, necrosis, and hemorrhage, and in the intestinal glands, there were numerous nematodes suggesting a parasitic infection by Strongyloides spp. PCR followed by sequencing confirmed the infection with S. stercoralis. The dog was treated with a combination of oral fenbendazole and milbemycin oxime for 5 months. No relapse was observed 3 months after negativity was attained. This case describes a severe clinical infection by Strongyloides stercoralis in a domestic dog from Romania and the recovery after long-term treatment.

Human strongyloidiasis: complexities and pathways forward.

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.

First identification of Strongyloides stercoralis infection in a pet dog in Argentina, using integrated diagnostic approaches.

BACKGROUND: Strongyloides stercoralis is a soil-transmitted intestinal nematode with a complex life cycle that primarily affects humans, non-human primates, dogs, and occasionally cats. This study presents, to the best of our knowledge, the first case of S. stercoralis infection and its genotyping in a domestic dog from Argentina. METHODS: The patient was a female wired-haired Teckel dog exhibiting recurrent coughing. Coproparasitological analysis using the Baermann technique revealed the presence of rhabditiform larvae morphologically compatible with S. stercoralis. To confirm this finding, molecular diagnosis (18S ribosomal RNA) and analysis of the cox1 gene were performed. RESULTS: We identified a haplotype (HP20) that has previously only been related to S. stercoralis infection in dogs, but was found in the present study to be highly related to the haplotype (HP16) of a zoonotic variant and divergent from those previously described from human patients in Argentina. Furthermore, unlike in human cases following treatment with ivermectin, the dog was negative after moxidectin treatment according to polymerase chain reaction of the sampled faeces. CONCLUSIONS: This case report shows the importance of further investigation into potential transmission events and prevalences of S. stercoralis in dogs and humans in South America. The results reported here should also encourage future work that examines different scenarios of infection with S. stercoralis in dogs and humans with the aim of integrating clinical management, diagnosis, treatment and follow-up strategies in the quest for new approaches for the treatment of this disease in animals and humans. The findings support the adoption of a One Health approach, which recognizes the interconnectedness between animal and human health, in addressing parasitic infections such as strongyloidiasis.

Implementation and Outcomes of an Empiric Ivermectin Strongyloides Treatment Protocol for Patients Receiving High-Dose Corticosteroids for Severe COVID-19.

Strongyloides stercoralis is a parasitic roundworm that is present worldwide and can cause lifelong, often asymptomatic, infection. Immunosuppression, particularly by corticosteroids, is a risk factor for hyperinfection syndrome and disseminated strongyloidiasis-severe disease states that can lead to septic shock and death. Our institution implemented a strongyloidiasis screening and empiric ivermectin treatment protocol for inpatients receiving high-dose corticosteroids for severe COVID-19. Among 487 COVID-19 admissions treated with high-dose corticosteroids from June 10, 2020 to March 31, 2021, 61% of those with demographics at risk for Strongyloides exposure were screened for Strongyloides and treated empirically with ivermectin. Adherence to the protocol declined over time during the study period. The empiric ivermectin protocol appeared safe, but more research is needed to determine the effect on hyperinfection and/or disseminated strongyloidiasis risk and mortality rate, as well as to improve institutional adherence to the protocol.

Disseminated Strongyloides stercoralis infection in the setting of Escherichia coli meningitis and bacteraemia in a patient living with HIV on high-dose corticosteroid therapy.

Strongyloidiasis, a helminth infection caused by Strongyloides stercoralis, can be complicated by hyperinfection, especially in the setting of immunosuppression; however, many patients go undiagnosed. One clue to diagnosis is unexplained gram-negative bacteraemia or meningitis in patients who are immunosuppressed. Serology can be helpful but may be negative in these patients who are immunocompromised.We present the case of a white cisgender man from Central America in his 40s, living with HIV, with a CD4 count of 77 cells/µL. He was diagnosed with Strongyloides hyperinfection after an increase in his steroid dose. He also had Escherichia coli meningitis and bacteraemia. Strongyloidiasis was diagnosed by stool microscopy despite a negative serology test.This case highlights the challenges in diagnosing strongyloidiasis in the setting of immunosuppression. A high index of clinical suspicion is warranted for patients living with HIV on high-dose corticosteroids. Up to three stool microscopy studies for Strongyloides should be sent in addition to serology.

Recurrent Klebsiella bacteremia due to chronic strongyloidiasis in the context of cirrhotic hepatopulmonary syndrome.

A woman in her 50s with a medical history of cirrhosis, alcohol use disorder, primary biliary cholangitis and extended spectrum beta lactamase (ESBL) Klebsiella presented with weakness, cough and abdominal pain with positive blood cultures for ESBL Klebsiella, and was treated with intravenous meropenem and patient symptoms improved. Testing for Strongyloides antibodies was positive, so she was treated with ivermectin. Strongyloidiasis-associated Gram-negative rod (GNR) bacteremia are rare conditions; however, it is important to consider an underlying strongyloidiasis in recurrent GNR bacteremia to prevent recurrent hospitalisation and morbidity.

MANAGEMENT OF A FATAL OUTBREAK OF STRONGYLOIDIASIS IN A CAPTIVE POPULATION OF PANTHER CHAMELEONS (FURCIFER PARDALIS) WITH IVERMECTIN.

An outbreak of the nematode Strongyloides sp. occurred in a population of 18 male and 29 female panther chameleons (Furcifer pardalis) at the Singapore Zoo. The parasite was first detected in one individual during routine microscopic examination of feces using the direct examination and magnesium sulfate flotation methods. The parasite was later found to have a closest match (98.96%) with Strongyloides sp. Okayama by DNA sequencing. Over a period of 6 mon, 97.9% (46/47) of the panther chameleons tested positive for the parasite, and 25.5% (12/47) of the animals died due to the disease. All the animals that died were female. Of the positive tests, magnesium sulfate flotation identified the parasite 98.1% (105/107) of the time, compared to direct fecal microscopy, which identified the parasite only 43.9% (47/107) of the time. Parasite eggs were detected in 100% (105/105) of the positive magnesium sulfate flotation tests but only 66.0% (31/47) of the positive direct fecal microscopy tests. Parasite larvae were detected in 61.7% (29/47) of the positive direct fecal microscopy tests but only 9.5% (10/105) of the magnesium sulfate flotation tests. Treatments with fenbendazole and pyrantel pamoate at published doses were ineffective at eliminating the parasite. Ivermectin (0.2 mg/kg PO q2wk for two doses) was successful at treating the parasite, with all animals testing negative for the parasite at the end of the treatment course without any observed adverse reactions. However, complete eradication of the parasite could not be achieved, as Strongyloides sp. could still be detected in the population on routine coproscopy intermittently over 3 yr. There were no further mortalities due to the disease with prompt treatment with ivermectin. Strongyloidiasis may cause high morbidity in panther chameleons, but severe disease leading to mortality can be prevented with the use of ivermectin.

Impact of preventive chemotherapy on Strongyloides stercoralis: A systematic review and meta-analysis.

BACKGROUND: Strongyloides stercoralis is a neglected soil-transmitted helminth (STH) that leads to significant morbidity in endemic populations. Infection with this helminth has recently been recognised by the World Health Organization (WHO) as a major global health problem to be addressed with ivermectin preventive chemotherapy, and therefore, there is now, the need to develop guidelines for strongyloidiasis control that can be implemented by endemic countries. This study aimed to evaluate the impact of ivermectin preventive chemotherapy (PC) on S. stercoralis prevalence in endemic areas to generate evidence that can inform global health policy. METHODOLOGY/PRINCIPAL FINDINGS: This study was a systematic review and meta-analysis. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS for literature published between 1990 and 2022 and reporting prevalence of S. stercoralis before and after PC with ivermectin, administered either at school or at community level. The search strategy identified 933 records, eight of which were included in the meta-analysis. Data extraction and quality assessment were carried out by two authors. Meta-analysis of studies based on fecal testing demonstrated a significant reduction of S. stercoralis prevalence after PC: prevalence Risk Ratio (RR) 0.18 (95% CI 0.14-0.23), I2 = 0. A similar trend was observed in studies that used serology for diagnosis: RR 0.35 (95% CI 0.26-0.48), I2 = 4.25%. A sensitivity analysis was carried out for fecal tests where low quality studies were removed, confirming a post-intervention reduction in prevalence. The impact of PC could not be evaluated at different time points or comparing annual vs biannual administration due to insufficient data. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate a significant decrease of S. stercoralis prevalence in areas where ivermectin PC has taken place, supporting the use of ivermectin PC in endemic areas.