Abstract
Strongyloides colitis is a gastrointestinal manifestation of the parasitic infection, Strongyloides stercoralis, which may be misdiagnosed and treated as ulcerative colitis (UC) in patients presenting in non-endemic regions. Treatment of Strongyloides colitis as UC can lead to a lethal hyperinfection syndrome. Therefore, prior to commencing immunosuppressive treatment of UC, it is essential to use diagnostic markers to differentiate the two etiologies. In this case series, we discuss two migrant patients who were previously diagnosed with UC and treated accordingly who presented to our clinic for further investigation of suspected parasitic infection.
Introduction
Strongyloidiasis is a soil-transmitted helminthiasis endemic to the tropics and sub-tropics. The unique auto-infective nature of Strongyloides stercoralis allows persistence of the infection for decades following migration or exposure. 1 Symptomatic infections occur in approximately half of those with disease, which manifests as chronic gastrointestinal symptoms including abdominal pain and diarrhea, in addition to recurrent Löffler-like syndrome, larva currens, and/or pruritus ani. 2 Due to the worm’s residence in the proximal small bowel, Strongyloides spp.-induced abdominal discomfort is often epigastric in nature. 2 Chronic reflux symptoms refractory to acid suppression using proton-pump inhibitors in a person born or raised in equatorial parts of the planet should alert clinicians to the possibility of strongyloidiasis. 2 Similarly, the sensation of formication or crawling on or under the skin is also frequently present in strongyloidiasis, the diagnosis of which should be excluded in those with compatible epidemiologic risk and such symptoms. The lifecycle of S. stercoralis begins when human skin contacts infectious larvae found in sand or soil. 2 The infectious larvae penetrate the intact skin, and after migrating though the tissue, including an obligatory lung migration phase after which they are coughed and swallowed, the larvae mature into adults in the small bowel in the human. 2 Then, the autoinfection cycle can take place when the larvae re-penetrate the peri-anal skin or small bowel. 2 Due to the autoinfection cycle, Strongyloides spp. is a lifelong infection unless clinically diagnosed and treated. 2
Rarity of ulcerative colitis in equatorial regions
Ulcerative colitis (UC) is one of two main etiologies comprising inflammatory bowel disease (IBD), with Crohn’s disease representing the other. IBD is traditionally regarded as a disease of high-income countries but a rapid rise in incidence has been reported in South America, Asia, and Africa. 3 A recent systematic analysis of the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2018, found a direct correlation between the prevalence of IBD and a country’s socio-demographic index (SDI), with higher IBD prevalence in countries of higher SDI. 3 Consistent with this correlation, epidemiological studies have demonstrated that prevalence and incidence rates of UC are greater in the northern hemisphere compared with countries within the equatorial region.4–10 In India, the prevalence of UC was noted to be 44.3 cases per 100,000 population, while the incidence was 6.02 cases per 100,000 per year. 11 This is significantly lower than the prevalence and incidence of UC in the South Asian population of North America or the United Kingdom, where the prevalence rates are estimated to be 144–243 cases per 100,000 population and incidence rates of 7.9–20.2 per 100,000 population per year. 11 Interestingly, studies have also demonstrated that individuals are at increased risk of developing IBD if they migrate from equatorial countries to countries in the northern hemisphere, such as the United Kingdom and countries of North America.12–14
These epidemiological findings further support the hypothesis that environmental factors play a role in prevalence rates of UC. Onset of UC peaks in December in northern hemispheres, a time of the year when there is minimal endogenous production of vitamin D. 13 A putative pathophysiological explanation for these epidemiological trends is the association between higher serum vitamin D levels with a decreased risk of IBD and symptom severity.14,15 In addition to environmental changes, dietary changes may also influence the rise in prevalence rates when individuals shift from equatorial regions to the northern hemisphere. In many Asian countries, fermented foods are considered an integral component of the diet. Fermentation using lactic acid bacteria was primarily developed as a means for food preservation in many regions, a process that ultimately also influences the composition of intestinal flora. 16 The use of fermentation inherently produces probiotic-rich foods, which have a role in altering intestinal microbiota and strengthening the intestinal mucosal barrier, which plays a critical role in the pathogenesis of UC. 16
Case 1
A 36-year-old male born in Guyana, living in Canada and previously diagnosed with UC via colonic tissue biopsies and stable on 5-ASA and azathioprine with prior courses of prednisone, visited Jamaica for 1 week. Five days after returning to Canada, he developed an asymptomatic serpiginous facial rash noted to migrate every few weeks (Figure 1). He was systemically well and reported his UC to be stable. He was seen by his family doctor and referred to dermatology. Given the history of a migrating serpiginous rash after a trip to Jamaica, cutaneous larva migrans was high on the differential. The dermatologist requested Strongyloides spp. serology and stool for microscopic ova and parasite (O&P) testing, and promptly referred the patient to our tropical disease unit (TDU) for further assessment and management.
Larva currens on the (a) jaw and (b) cheek in a 36-year-old Guyanese-born male (case 1).
When the patient was initially seen at our tropical disease clinic, the facial rash was still present. The rash was reportedly non-pruritic, and the patient noted that every few weeks the rash would migrate to a different position on his face. He did not notice rapid migration of the serpiginous tract. He denied additional skin symptoms including anal pruritis. Review of systems was negative, and he continued to report stability of his UC symptoms. On examination, he was well and afebrile with normal vital signs. He had a serpiginous erythematous rash, approximately 4 cm in length on his left forehead that was non-migratory in clinic. All other systems examined were unremarkable. Initial testing for serum antibodies to Strongyloides spp., processed as per routine protocol at the Public Health Ontario Laboratory (PHOL), was negative with an optical density of 0.03 (non-reactive < 0.2). Complete blood count (CBC) obtained 1 month prior to his appointment, demonstrated a normal white blood cell count and an eosinophil count of 0.2 × 109/L (normal < 0.4 × 109/L). Stool O&P examination was pending at the time of his initial consultation in the TDU.
Given that the patient was raised in Guyana and that his previous travel history included Mexico, India, Cuba, and the recent trip to Jamaica, he was at high risk of Strongyloides spp. infection. 1 Although his rash had classic features of larva currens, except for the rate of migration, his initial Strongyloides spp. serology was negative. However, it was important to note that his serology sample was obtained while he was on 5-ASA and the immunosuppressant azathioprine. Since the clinical suspicion for strongyloidiasis was high, repeat serology was sent to the U.S. Centers for Disease Control and Prevention (CDC) for further testing. Re-review of previously collected colonic tissue biopsies was requested to investigate for histopathological signs of strongyloidiasis, including skip pattern of inflammation, distal attenuation of disease, preservation of crypt architecture, eosinophil-rich lamina propria infiltrates, and sub-mucosal involvement. In addition, blood work was ordered to monitor eosinophil count and determine human T-cell lymphotropic virus type 1 or 2 (HTLV-1/2) status, given his country of origin and the potential to produce falsely negative Strongyloides spp. serology results in the context of HTLV-1/2 infection. 17
At the follow-up visit 2 months later, the patient remained clinically well and his symptoms were unchanged. Repeat eosinophil count was 0.1, HTLV1/2 serology was negative, and stool O&P microscopic examination was negative. In addition, serologies for schistosomiasis, filariasis, hepatitis B, hepatitis C, and HIV were negative. Antibodies to Strongyloides spp. by the CDC enzyme immunoassay (EIA) was detected at an optical density of 2.08 (reactive > 1.70). Re-examination of colonic tissue biopsies demonstrated evidence of architectural distortion, mucin depletion, basal plasmacytosis, and focal cryptitis most consistent with IBD with no specific features of Strongyloides colitis.
Given the reactive Strongyloides spp. serology, patient epidemiology, and the facial rash that was near-pathognomonic for larva currens, he was treated with two doses of ivermectin at 200 μg/kg per dose, 2 weeks apart. At his follow-up visit 1 month after treatment completion, he reported complete resolution of his facial rash and continued stability of his UC symptoms. At follow-up approximately 1 year after treatment with ivermectin, he continued to remain symptom-free with regards to his facial rash, and his UC remained unremarkable. Repeat Strongyloides spp. serology using the CDC assay was non-reactive at an optical density of 1.12 (non-reactive < 1.70), demonstrating expected seroreversion, and eosinophil count remained normal at 0.1 × 109/L (reference range < 0.4 × 109/L). Further management of the patient’s UC was left to his gastroenterologist.
Case 2
A 64-year-old woman was referred to our unit for treatment of S. stercoralis infection, following identification of rhabditiform larvae on routine microscopic stool O&P examination. At consultation, the patient was clinically well. Aside from minimal abdominal discomfort, review of systems was unremarkable. She reported regular bowel movements without diarrhea or hematochezia. She denied skin or respiratory symptoms. Past medical history was notable for a diagnosis of UC 10 years prior to referral via colonic biopsies, with recommendation for follow-up colonoscopies every 3–5 years. Her only medication was 5-ASA, which she had been taking for a few years. Beyond the abnormal stool O&P, another notable laboratory finding was moderate peripheral eosinophilia of 1.18 × 109/L (reference < 0.4 × 109/L) from a CBC 6 months prior.
Given the patient’s birth country of Nigeria and notable travel throughout the Caribbean over the prior decades, including to high-risk destinations for strongyloidiasis, such as Antigua, Barbados, Curacao, the Dominican Republic, Jamaica, Haiti, and Puerto Rico, the timing of her exposure to Strongyloides spp. was unclear. Thus, a review of the previously obtained colonic tissue was requested to exclude signs of Strongyloides spp.-induced colitis. Routine blood work was performed and a pre-treatment Strongyloides spp. Serology was requested along with screening for HTLV-1/2. The patient was treated with two doses of ivermectin at 200 μg/kg 2 weeks apart.
Pre-treatment Strongyloides spp. serology was reactive with an optical density (OD) of 2.39 (non-reactive < 0.2), and eosinophilia persisted at 1.8 × 109/L. HTLV-1/2 testing was negative. Re-examination of colonic tissue demonstrated features consistent with Strongyloides colitis including distal attenuation of disease with sparing of the sigmoid colon and rectum, preservation of crypt architecture and goblet cell mucin, and eosinophilic infiltrates of the lamina propria. The patient’s 5-ASA was held in light of the new findings. At 2 weeks post-treatment, the patient remained clinically well, with reduction in her eosinophil count to 0.4 × 109/L, and at 9 months after ivermectin treatment, she reported feeling very well, with complete resolution of her UC symptoms. Post-treatment, Strongyloides spp. serology revealed seroreduction to an OD of 0.65 (non-reactive < 0.2).
Discussion
Due to the rarity of Strongyloides spp. in non-endemic regions and similarity of predominant gastrointestinal symptoms, chronic Strongyloides spp. infection can be attributed to etiologies such as gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and occasionally IBD, particularly UC. 2 Inadvertently treating Strongyloides colitis as UC with corticosteroids and immunomodulators can induce a Strongyloides spp. hyperinfection syndrome, which can be fatal.1–3 Therefore, clinical expertise is important to keep strongyloidiasis on the differential diagnosis so that it is recognized in migrants entering non-endemic areas like Canada. The possibility that strongyloidiasis is acquired after IBD diagnosis also exists. However, exclusion of strongyloidiasis in patients with epidemiologic risk before diagnosing UC, and before initiating immunosuppressive medications is recommended. By doing so, harmful effects on the patient such as potentially lethal hyperinfection syndrome can be avoided. There is also a possibility of the recurrence of strongyloidiasis when starting immunosuppressive treatment after the treatment of strongyloidiasis. A previous case study has demonstrated relapse of Strongyloides spp. infection after ongoing immunosuppression for another clinical condition. 18 Therefore, secondary prophylaxis could be considered when treating a patient for strongyloidiasis who also has ongoing immunosuppressive treatments, particularly in the context of HTLV-1 coinfection. 18
Histopathological clues to strongyloidiasis are as described above and also include universal rectal sparing, skip pattern of inflammation, and frequent involvement of the submucosa. The mimicry of strongyloidiasis as IBD, specifically UC, makes accurate diagnosis and management of the parasite challenging in patients presenting without other pertinent positives or a recent travel history to an endemic region. Endemic regions for strongyloidiasis include tropical and subtropical areas of Africa, Asia, South America, and temperate areas of the Mediterranean. 19 As such, strongyloidiasis may be overlooked in the differential diagnosis for patients presenting in non-endemic regions such as Canada. With a high index of suspicion, close follow-up of symptoms that should resolve with UC-targeted medications, and reliance on histopathological features, clinicians are better positioned to differentiate these two distinct causes of colitis.
Ruling out strongyloidiasis before ruling in UC or other autoimmune diseases in patients from the tropics
With UC being more prevalent in North America, migrants and travelers from tropical and subtropical regions presenting with gastrointestinal symptoms have been misdiagnosed accordingly. Instead, such travelers and migrants have been later found to have persistent strongyloidiasis infections, with an acute activation of the S. stercoralis parasite (Table 1). As previously illuminated, Strongyloides colitis shares several morphological features on histopathology with UC, which often leads to diagnostic errors; understanding the aforementioned morphologic features of colitis due to strongyloidiasis – as well as being able to detect the presence of larvae in mucosa and submucosa – are critical for rendering a correct histopathological diagnosis. 20 It is important that clinicians have a low index of clinical suspicion and consider strongyloidiasis on the differential diagnosis for patients returning from endemic countries with chronic gastrointestinal symptoms given its rarity and similar histological appearance to UC. Several cases, primarily from the United States of America and Brazil, report fatal or near fatal hyperinfection of strongyloidiasis as a result of iatrogenic immunosuppression for UC treatment (Table 1). Clinical findings can also help to distinguish the two diseases. Rash, respiratory involvement, ova and larvae noted on microscopic examination of the stool, exacerbation of symptoms with steroid treatment, and peripheral eosinophilia support Strongyloides spp. infection rather than UC.20,21 There are features unique to a strongyloidiasis infection, such as larva currens, the rapidly migrating cutaneous manifestation of the parasite, which can be used to distinguish colitis attributed to Strongyloides spp. from UC. Published literature supports that larva currens is a strong diagnostic marker that can be used to differentiate UC from reactivation of chronic Strongyloides spp. infection (Table 2).
A summary of published cases of Strongyloides colitis in non-endemic areas.
N/A, not available; IBD, inflammatory bowel disease.
Strongyloidiasis should be a differential diagnosis for IBD since iatrogenic immunosuppression to treat IBD can lead to fatal hyperinfection of strongyloidiasis.
A summary of published cases of larva currens in non-endemic areas.
N/A, not available.
Larva currens is a cutaneous manifestation of the helminth Strongyloides stercoralis. The infection is primarily endemic in rural and beach areas of the tropics and sub-tropics. 1
Conclusion
We report two cases that highlight the importance of considering travel and migration history when diagnosing and managing patients presenting with common gastrointestinal symptomatology. The mimicry of S. stercoralis infection to IBD, specifically UC, makes accurate diagnosis and management of the parasitic infection challenging in patients presenting without other pertinent positives or a recent travel history to an endemic region. As such, parasitic infections such as strongyloidiasis may be overlooked in the differential diagnosis for patients presenting in non-endemic regions. With a high index of suspicion, rapid identification of the cutaneous presentation of Strongyloides spp., and use of histopathological features, clinicians can readily differentiate these two distinct causes of colitis.
