PhD defence Dora Buonfrate

Supervisors

• Prof. dr. Emmanuel Bottieau (ITM)

• Prof. dr. Erika Vlieghe (University of Antwerp, University Hospital Antwerp)

Abstract

Strongyloides stercoralis is a soil-transmitted helminth which can cause a fatal syndrome in immunosuppressed individuals. The parasitic infection is mostly present in disadvantaged areas of the world, characterized by poor sanitation and lack of adequate sewage disposal, causing the contamination of the soil with human stool. In such settings, Strongyloides larvae are dispersed in the environment through human faeces and moult in the soil into an infective stage. The infective larvae can penetrate human skin and start the parasitic cycle. Peculiar to S. stercoralis, an auto-infective cycle in humans, which leads to a chronic, long-life (if not treated) infection. Due to auto-infection, we can diagnose strongyloidiasis in people who left an endemic area even decades ago. In some individuals, the infection may not cause evident signs or symptoms, but there is still the risk of developing the life-threatening form of infection later on in life, in case of emergence of an immunosuppressant condition or treatment. Other people do present unrelenting or fluctuating signs and symptoms mostly affecting the skin, the intestine and the respiratory tract, and might seek clinical care for these. Unfortunately, the infection is often misdiagnosed because health care providers are seldom aware of this condition (which is precisely included in the WHO list of Neglected Tropical Diseases), and proper diagnostic tests might not be prescribed. Microscopic examination of stool samples, which is traditionally used to detect intestinal parasites, has low sensitivity for this infection, thus it might be falsely negative. In fact, there is no diagnostic gold standard. This issue has hampered for long time both individual management of the infection and estimates of global prevalence (causing part of the neglect of strongyloidiasis). Also, the dose of ivermectin to be administered for chronic infection was undefined for long time.

Main objective of this doctoral work was to address the main critical aspects of strongyloidiasis in the non-endemic setting, covering a wide spectrum of areas, from epidemiology to clinical presentation, diagnosis, treatment and follow up. Specific objectives were: 

• To estimate the prevalence of strongyloidiasis at global level and in different populations in a non-endemic area (Northern Italy)

• To review the clinical presentation and laboratory profile of infected individuals

• To assess the accuracy of diagnostic tests for the diagnosis and post-treatment follow up

• To assess the efficacy of different doses of ivermectin for the treatment of chronic strongyloidiasis

The objectives are addressed here with a collection of published papers, ranging from narrative and systematic reviews, case-control studies, original diagnostic studies and a randomized controlled trial.

The first chapter is a narrative review, describing the main characteristics of strongyloidiasis in the non-endemic setting. It reports the state-of-the-art and the grey areas on this topic before the following studies were carried out, and thus serves as an introduction to the whole work. In the second chapter, I deal with epidemiological aspects. Global prevalence of strongyloidiasis was estimated using a mathematical model, and resulted in 613.9 (95% CI: 313.1–910.1) million people infected worldwide, figures much larger than previous estimated (about 30-100 million people). This partly explains the neglect of this infection, whose prevalence was dramatically underestimated for years. The chapter also reports the results of a screening survey carried out in Northern Italy. Among Italians born before 1960, 8% (97/1,137) of those with eosinophilia were positive for strongyloidiasis, compared to 1% (13/1,178) of those with normal eosinophil count (adjusted odds ratio (aOR) 8.2; 95% confidence interval (CI): 4.5–14.8). Among immigrants, the infection was found in 17% (36/214) of individuals with eosinophilia and in 2% (3/172) of those with normal eosinophil count (aOR 9.6; 95% CI: 2.9–32.4). These results demonstrate that eosinophilia is an important diagnostic clue, both for migrants and for Italians. The third chapter deals with clinical presentation and laboratory profile of chronic infection, and is composed by a systematic review with meta-analysis, whose main results are: a) About 50% people with chronic infection complain symptoms, mostly abdominal pain in 51.9% (95%CI 50.2-53.6) individuals, diarrhea in 43.6% (95%CI 41.7-45.6), itching in 36.3% (95%CI 34.5-37.9), skin rash/urticaria in 30.4% (95%CI 28.8-32.0), respiratory symptoms in 29.6% (95%CI 27.7-31.4), and nausea/vomiting in 8.1% (95%CI 6.4-9.9). b) About 77% infected people might have eosinophilia at presentation. c) both symptoms and eosinophilia tend to clear after treatment. This demonstrates that strongyloidiasis deserves attention also in absence of immunocompromise, as it can cause relevant disturbances that can be solved with treatment.

The collection of papers composing the fourth chapter address the diagnostic area. In a narrative review I comment the advantages and disadvantages of the available diagnostic tests for strongyloidiasis, pointing out that the use of highly sensitive diagnostic tests (that is the case of serological assays) is of primary importance. In a systematic review with meta-analysis I demonstrate that the sensitivity of real-time PCR for S. stercoralis is unsatisfactory (64.4, 95% CI 46.2±77.7); hence, once again, serology is preferred as screening tool. Finally, in an original diagnostic study, I demonstrate that serology can be used for post-treatment monitoring, although time to seroconversion can take up to 12 months. However, if a quantitative result is available, the decrease of antibody titre can be used in a shorter period of time to evaluate response to treatment.

Finally, the last chapter is composed by a multicenter randomized controlled trial (“Strong Treat” study) comparing a single dose versus multiple doses of 200 µg/kg of ivermectin for the treatment of chronic uncomplicated strongyloidiasis. The study showed that a single dose is as effective as multiple doses and better tolerated.