Diagnostic challenge of Strongyloides stercoralis hyperinfection syndrome: a case report Anja Šterbenc1, Barbara Šoba1, Urška Glinšek Biškup1, Miša Fister2, Urša Mikuž2, Marko Noč2, Boštjan Luzar3 ✉ 1Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 2Ljubljana University Medical Center, Ljubljana, Slovenia. 3Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 79 2022;31:79-81 doi: 10.15570/actaapa.2022.11 Introduction Strongyloides stercoralis is an intestinal nematode that causes chronic, mostly asymptomatic infections. However, fulminant fa- tal illness with parasite dissemination may occur in individuals with compromised immunity, especially those receiving corticos- teroids (1). Although S. stercoralis is considered to be a disease of tropical and subtropical areas, its prevalence has also been in- creasing in temperate regions, including various European coun- tries (2). Unfortunately, the signs and symptoms of hyperinfection syndrome vary widely and may be atypical in immunosuppressed patients (1). Patients with Strongyloides hyperinfection syndrome tend to present with acute respiratory distress and a Gram-nega- tive sepsis/bacteremia (3). Rarely, dermatological manifestations such as periumbilical petechiae or purpura may be the first signs of hyperinfection syndrome (4). Case report A 62-year-old Caucasian female was admitted to the intensive care unit (ICU) with acute respiratory failure. Her medical history was significant for diabetes mellitus type 2, arterial hypertension, dys- lipidaemia, hypothyroidism, past hepatitis B (HBV) infection and a heart transplantation 2.5 months prior. Approximately 1.5 months after transplantation, the patient was hospitalized due to in- creased troponin levels and segmental contraction abnormalities on echocardiogram. Transplant rejection was suspected and meth- ylprednisolone dosage was increased. Follow-up echocardiogram showed no improvement, with serum troponin levels stagnating at around 800 ng/l; however, histopathological examination of the heart biopsy sample excluded organ rejection. The patient sub- sequently developed a macular rash, clinically suspected of urti- carial exanthema, which resolved after antihistaminic treatment; however, abdominal petechiae quickly followed (Fig. 1). Abstract Strongyloides stercoralis causes chronic, mostly asymptomatic infections but hyperinfection syndrome may occur in immunosup- pressed patients, especially in those receiving corticosteroids. We report a case of S. stercoralis hyperinfection syndrome in a solid organ transplant recipient that occurred approximately 2.5 months after heart transplantation. The patient presented to the inten- sive care unit with acute respiratory distress, bacteremia, and petechial rash on abdomen and toe. Microbiology testing of respira- tory samples excluded infection with Pneumocystis jirovecii, respiratory viruses, pathogenic bacteria and fungi. No eosinophilia was found. Histopathological examination of the skin biopsy of the petechial rash provided the first indication of the diagnosis, revealing the presence of isolated filariform S. stercoralis larvae in the dermis. Subsequent microbiology testing confirmed the diagnosis. This case highlights the role of histopathological examination of a skin rash in diagnosing patients with atypical clinical presentation of Strongyloides hyperinfection syndrome. Keywords: Strongyloides stercoralis, transplant, hyperinfection syndrome, petechiae, skin Acta Dermatovenerologica Alpina, Pannonica et Adriatica Acta Dermatovenerol APA Received: 12 April 2022 | Returned for modification: 10 May 2022 | Accepted: 11 May 2022 ✉ Corresponding author: bostjan.luzar@mf.uni-lj.si Figure 1 | Periumbilical petechiae (A) and petechial rash on toes (B). 80 Acta Dermatovenerol APA | 2022;31:79-81A. Šterbenc et al. Three days prior to ICU admission, the patient’s pulmonary function deteriorated, requiring supplemental oxygen therapy. Due to increased beta-D-glucan (83.4 pg/ml) and diffuse bilateral ground-glass opacities on chest CT scan, Pneumocystis jirovecii pneumonia (PCP) was initially suspected. Extensive microbiol- ogy testing excluded PCP and respiratory infection with atypical bacteria, fungi and respiratory viruses (including SARS-CoV-2). Extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae was isolated from blood cultures, urine and bron- choalveolar lavage samples, for which she received antibiotic treatment with meropenem. Nevertheless, the patient became hy- potensive and her pulmonary function continued to deteriorate, necessitating transfer to ICU and intubation. On admission to ICU, her leukocytes were 10^9/l and no eosin- ophilia was found. Despite continuously increased beta-D-glucan levels (highest value = 267.8 pg/ml), diagnosis of invasive asper- gillosis was deemed unlikely due to negative results for galacto- mannan, PCR for Aspergillus spp. and lack of growth on culture. Hemorrhagic fever with renal syndrome was also suspected due to an ongoing hantaviral outbreak in Slovenia and the presence of petechial rash; however, hantavirus serology and PCR testing were negative. The diagnosis of strongyloidiasis was first sus- pected by the dermopathologist, who identified the presence of isolated scattered filariform S. stercoralis larvae within the dermis from the excisional skin biopsy of the petechial rash (Fig. 2). On receiving the pathologist’s report, serology testing for S. stercoralis was immediately performed using S. ratti ELISA (Bor- dier Affinity Products SA, Crissier, Switzerland), which confirmed the presence of anti-Strongyloides IgG. Additionally, real-time PCR and microscopic examination of various samples were performed (Table 1). The diagnosis of Strongyloides hyperinfection syndrome was thus established and ivermectin (200 μg/kg per day) was im- mediately administered; however, the patient’s condition contin- ued to deteriorate. She developed irreversible shock and died 2 days later. The transplant center was immediately contacted and it was confirmed that the donor was not infected with S. stercoralis. Discussion Strongyloides stercoralis is a common human parasite with wide- spread global distribution. The infection is usually acquired by walking barefoot on contaminated soil in endemic countries in tropical and subtropical climates (2). Nevertheless, infection rates are also on the rise in many countries with a temperate climate, with several reports of the emergence of the disease in areas that are considered to be non-endemic for the disease (5). To date, the prevalence of Strongyloides infection in Slovenia has not been sys- tematically investigated but some reports are available for neigh- boring countries. For example, in northern Italy, 8% (97/1,137) and 1% (13/1,178) of individuals with and without eosinophilia, respectively, had a positive serology test result for Strongyloides, while even higher rates were observed among immigrants (17% and 2%, respectively) (6). In addition, the Balkans, the region from which immigrants in Slovenia most commonly originate, is also considered to be an endemic region for strongyloidiasis, with an estimated seroprevalence of 7.3% among Bosnian farmers, schoolchildren and miners (7). A more recent study evaluating the prevalence of Strongyloides infection and hyperinfection syn- drome among renal allograft recipients in Central Europe identi- fied serologic evidence of infection in 3% of tested patients (8). Due to the exclusion of Strongyloides infection in the donor and positive serology for Strongyloides in our patient, it is highly likely that the infection occurred before the patient underwent organ transplantation. Unfortunately, determining the exact origin of infection may be challenging since chronic infection may asymp- tomatically persist for up to 50 years (9). In addition to infection with human T-cell lymphotropic virus-1 (HTLV-1) and hematological malignancies, treatment with corti- costeroids is the main trigger predisposing to the development of S. stercoralis hyperinfection syndrome (2, 10), which occurs due to an increase in the parasite load followed by increased penetration of the bowel mucosa by infective larvae. Whereas hyperinfection is defined as the presence of numerous migrating Strongyloides larvae in organs normally involved in the pulmonary autoinfec- tion cycle (i.e., lungs and gastrointestinal tract), dissemination implies migration of larvae to organs that are not ordinarily in- volved in the classic pulmonary life cycle of the nematode, in- cluding the skin, mesenteric lymph nodes, gallbladder, liver, dia- Table 1 | Microbiology testing results for Strongyloides. Days since ICU admission Sample type Microscopic examination Real-time PCR 2 BAL* Negative Positive 6 Endotracheal aspirate Positive Positive 7 Stool Negative Positive ICU = intensive care unit, BAL = bronchoalveolar lavage, PCR = polymerase chain reaction. * tested in retrograde, the sample was initially submitted for P. jirovecii PCR testing. Figure 2 | Cutaneous strongyloidiasis. (A) A low power magnification reveals unremarkable epidermis, areas of erythrocyte extavasation in the dermis and scat- tered larvae in the reticular dermis (arrow). (B) Higher magnification depicting larvae. A mild perivascular lymphocytic infiltrate can also be appreciated. 81 Acta Dermatovenerol APA | 2022;31:79-81 Strongyloides hyperinfection syndrome phragm, heart, pancreas, skeletal muscle, kidneys, ovaries, and brain (3, 11). Interestingly, Strongyloides hyperinfection syndrome can develop in patients receiving high-dose, low-dose and even locally injected corticosteroids (10). Due to the high fatality rate (up to 80%), timely recognition of the infection is of utmost im- portance (12). Ideally, treatment with ivermectin or albendazole should be initiated before the induction of immunosuppressive treatment; however, prophylactic anthelmintic therapy is also possible for those who are immunocompromised at the time of strongyloidiasis diagnosis (1). Dermatologic manifestations of Strongyloides hyperinfection syndrome include intensely itchy migratory serpiginous rash, petechiae and purpura that usually develop on the abdomen, proximal thighs and buttocks (1). Periumbilical purpura (the “thumb print sign”) is considered to be a rare but pathognomonic feature of hyperinfection syndrome, caused by migration of lar- vae through vessels into the dermis (13). Unfortunately, the signs and symptoms of hyperinfection syndrome in our patient were somewhat atypical. Initially, a macular exanthema that resolved after antihistaminic treatment was observed, followed quickly by petechial rash without classical periumbilical purpura or linear streaks (Fig. 1), not raising the suspicion of strongyloidiasis. In ad- dition, parasitic infestation was also not immediately suspected due to normal eosinophil counts. Strongyloidiasis is approximate- ly nine-times more common in individuals with eosinophilia than in those with normal eosinophils (5); however, lack of eosinophil- ia on presentation, especially if the patient is immunosuppressed, should not be considered a reliable marker for excluding under- lying chronic strongyloidiasis (14). In fact, eosinophilia may be present in only 16.4% of patients with parasite dissemination (5). The lack of familiarity with strongyloidiasis by health care provid- ers (especially in non-endemic countries) is another concerning issue that delays appropriate management. As shown previously (5), in approximately 12% of severe strongyloidiasis cases the cor- rect diagnosis was only made post mortem. Lastly, this case report also raises the question of pre-trans- plant screening for Strongyloides of allograft recipients. A sys- tematic review of case reports on severe strongyloidiasis showed that pre-transplant serological screening was mentioned in only 10% (3/29 cases of solid organ/bone marrow transplantations) (5). While pre-transplant screening for strongyloidiasis is rec- ommended in some endemic countries and/or populations with particularly high potential for exposure to Strongyloides (15), such protocols have not yet been uniformly adopted in non-endemic areas. Rarely, infection can also be transmitted through cadaveric transplant allografts (1). Hence, in order to minimize post-trans- plant infectious complications, recipient and donor screening should be implemented in transplantation programs in Central Europe, especially because Strongyloides infection rates are in- creasing due to migration and travel to endemic regions (8). To conclude, asymptomatic S. stercoralis infections should be considered even in individuals residing in non-endemic regions (especially if they are receiving corticosteroids) and regardless of their eosinophil count. Histopathological examination of perium- bilical rash may aid in establishing a correct diagnosis, particular- ly in patients with atypical dermatological presentations. Because of the increasing prevalence of strongyloidiasis in Europe and the proportion of immunosuppressed patients, pre-transplant screen- ing may be warranted in donors and organ recipients. 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