The majority of the 30-100 million people infected with Strongyloides stercoralis, a soil transmitted intestinal nematode, have subclinical (or asymptomatic) infections. These infections are commonly ...chronic and longstanding because of the autoinfective process associated with its unique life cycle. A change in immune status can increase parasite numbers, leading to hyperinfection syndrome, dissemination, and death if unrecognized. Corticosteroid use and HTLV-1 infection are most commonly associated with the hyperinfection syndrome. Strongyloides adult parasites reside in the small intestine and induce immune responses both local and systemic that remain poorly characterized. Definitive diagnosis of S. stercoralis infection is based on stool examinations for larvae, but newer diagnostics - including new immunoassays and molecular tests - will assume primacy in the next few years. Although good treatment options exist for infection and control of this infection might be possible, S. stercoralis remains largely neglected.
Most of the 30 to 100 million people infected with Strongyloides stercoralis have subclinical (or asymptomatic) infections. These infections are commonly chronic and longstanding. A change in immune ...status can increase parasite numbers, leading to hyperinfection syndrome, dissemination, and death if unrecognized. The use of corticosteroids and HTLV-1 infection are most commonly associated with the hyperinfection syndrome. Strongyloides adult parasites reside in the small intestine and induce immune responses that are like other nematodes. Definitive diagnosis of S stercoralis infection is based on stool examinations for larvae. S stercoralis remains largely neglected.
Over 2 billion people worldwide are infected with helminths (worms). Similarly, infection with Mycobacterium tuberculosis (Mtb) occurs in over a third of the world's population, often with a great ...degree of geographical overlap with helminth infection. Interestingly, the responses induced by the extracellular helminths and those induced by the intracellular Mtb are often mutually antagonistic and, as a consequence, can result in impaired (or cross-regulated) host responses to either of the infecting pathogens. In this review, we outline the nature of the immune responses induced by infections with helminths and tuberculosis (TB) and then provide data from both experimental models and human studies that illustrate how the immune response engendered by helminth parasites modulates Mtb-specific responses in helminth–TB coinfection
This review discusses the latest approaches to the diagnosis and treatment of patients with strongyloidiasis, with an emphasis on infection in the immunocompromised host and the risk for disseminated ...strongyloidiasis.
The differences in acute, chronic, accelerated autoinfection, and disseminated disease in Strongyloides stercoralis infection are explored with particular emphasis on early diagnosis, treatment, and prevention. The goals of treatment are investigated for the different infection states. Predisposing risks for dissemination are delineated, and the roles played for newer diagnostics in the identification of at-risk individuals are detailed.
The use of newer diagnostic tests and broader screening of immunocompromised patients from Strongyloides-endemic areas is of paramount importance, particularly if prevention of life-threatening dissemination is the goal.
Strongyloides stercoralis (Ss) is the etiological agent of strongyloidiasis, a neglected tropical disease of global concern. Laboratory diagnosis of strongyloidiasis is most often based on detection ...of antibodies against antigens in an enzyme linked immunosorbent assay (ELISA). Herein, we report a preliminary validation study of newly developed IgG4- and/or IgG- based ELISAs to detect strongyloidiasis (Strongy Detect, InBios) incorporating a cocktail of 2 previously described recombinant antigens, Ss-NIE and Ss-IR.
The sensitivity and specificity were determined by using the assay in 150 cryopreserved serum samples from humans known to be Ss infected (n = 74), helminth uninfected (n = 47), or infected with a helminth other than Ss n = 29). The treatment associated dynamics of antibody detection were then assessed using 35 paired samples obtained before and after definitive therapy.
The IgG and IgG4 assays were 99% and 96% sensitive, respectively, and 99% and 100% specific, respectively. Neither the IgG or IgG4 assay showed cross reactions with sera from those infected with other helminths. Although ELISA values did decline post-treatment few returned to levels below the cutoff for infection.
Strongy Detect is the most sensitive and specific commercialized immunoassay for detection of strongyloidiasis. The assay remains positive for greater than a year post-treatment.
The diagnosis of Strongyloides stercoralis (S. stercoralis) infection is hampered by the suboptimal sensitivity of fecal-based tests. Serological methods are believed to be more sensitive, although ...assessing their accuracy is difficult because of the lack of sensitivity of a fecal-based reference ("gold") standard.
The sensitivity and specificity of 5 serologic tests for S. stercoralis (in-house IFAT, NIE-ELISA and NIE-LIPS and the commercially available Bordier-ELISA and IVD-ELISA) were assessed on 399 cryopreserved serum samples. Accuracy was measured using fecal results as the primary reference standard, but also using a composite reference standard (based on a combination of tests).
According to the latter standard, the most sensitive test was IFAT, with 94.6% sensitivity (91.2-96.9), followed by IVD-ELISA (92.3%, 87.7-96.9). The most specific test was NIE-LIPS, with specificity 99.6% (98.9-100), followed by IVD-ELISA (97.4%, 95.5-99.3). NIE-LIPS did not cross-react with any of the specimens from subjects with other parasitic infections. NIE-LIPS and the two commercial ELISAs approach 100% specificity at a cut off level that maintains ≥70% sensitivity.
NIE-LIPS is the most accurate serologic test for the diagnosis of S. stercoralis infection. IFAT and each of the ELISA tests are sufficiently accurate, above a given cut off, for diagnosis, prevalence studies and inclusion in clinical trials.
Summary Background Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective ...against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. Methods After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Donéguébougou and surrounding villages in Mali. We recruited 18–35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 105 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov , number NCT01988636. Findings Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three 7% people in the vaccine group vs four 9% in the placebo group) followed by fatigue (one 2% person in the placebo group), fever (one 2% person in the placebo group), and myalgia (one 2% person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313–0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528–0·918) by proportional analysis (p=0·006). Interpretation PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season. Funding US National Institutes of Health Intramural Research Program, Sanaria.
Abstract
Background
Interleukin-10 (IL-10) has been implicated as the major cytokine responsible for the modulation of parasite-specific responses in filarial infections; however, the role of other ...IL-10 superfamily members in filarial infection is less well studied.
Methods
Peripheral blood mononuclear cells from loiasis patients were stimulated with or without filarial antigen. Cytokine production was quantified using a Luminex platform and T-cell expression patterns were assessed by flow cytometry.
Results
All patients produced significant levels of IL-10, IL-13, IL-5, IL-4, and IL-9 in response to filarial antigen, indicating a common infection-driven response. When comparing microfilaria (mf)-positive and mf-negative patients, there were no significant differences in spontaneous cytokine nor in parasite-driven IL-10, IL-22, or IL-28a production. In marked contrast, mf-positive individuals had significantly increased filarial antigen-driven IL-24 and IL-19 compared to mf-negative subjects. mf-positive patients also demonstrated significantly higher frequencies of T cells producing IL-19 in comparison to mf-negative patients. T-cell expression of IL-19 and IL-24 was positively regulated by IL-10 and IL-1β. IL-24 production was also regulated by IL-37.
Conclusion
These data provide an important link between IL-10 and its related family members IL-19 and IL-24 in the modulation of the immune response in human filarial infections.
Clinical Trials Registration
NCT00001230.
IL-19 and IL-24 are differentially regulated and expressed in Loa loa infection. Parasite-antigen driven IL-19 and IL-24 production appears to be related to microfilarial positivity and IL-37, IL-10, and IL-1β are important regulators of IL-24 and IL-19 production in loiasis.
...adult subjects in endemic areas with chronic helminth infection show impaired cellular responses that may alter the responses to Mtb antigens and possibly contribute to a higher incidence of ...active TB disease 12. ...subjects with latent TB and filarial coinfection have been shown to exhibit decreased toll-like receptor 2 (TLR2) and toll-like receptor 9 (TLR9) expression, which was reversed after successful antifilarial chemotherapy 30.\n Using the diagnostic tools available to these investigators, the rates of acquisition of parasitic infection by infants enrolled in this study were very low, suggesting that helminth-induced T cell priming at birth may have long-lasting consequences for immunologic memory.
Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ∼40 million have lymphedema and/or other pathologic manifestations including ...hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, tropical pulmonary eosinophilia, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites, the host inflammatory response to the parasites and their secreted antigens, the host inflammatory response to the endosymbiont
Wolbachia
, and those seen as a consequence of secondary bacterial or fungal infections. Inflammatory damage induced by filarial parasites appears to be multifactorial, with endogenous parasite products,
Wolbachia
, and host immunity all playing important roles. This review will initially examine the prototypical immune responses engendered by the parasite and delineate the regulatory mechanisms elicited to prevent immune-mediated pathology. This will be followed by a discussion of the proposed mechanisms underlying pathogenesis, with the central theme being that pathogenesis is a two-step process—the first initiated by the parasite and host innate immune system and the second propagated mainly by the host's adaptive immune system and by other factors (including secondary infections).
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