Disseminated Strongyloidiasis Following Chemoradiotherapy for Lung Cancer in a Patient Living in a Non-endemic Area in Japan

Abstract

We herein report a case of disseminated strongyloidiasis in a 64-year-old man with human T-lymphotropic virus type 1 infection who developed the condition after undergoing chemoradiotherapy for lung cancer. Treatment included daily ivermectin, which eradicated Strongyloides stercoralis after 7 days but was interrupted after 14 days due to the development of skin rashes. After excluding ivermectin as the cause of the drug eruption, intermittent ivermectin was continued monthly for six months, with no recurrence of strongyloidiasis or bacteremia. This case highlights the importance of obtaining a comprehensive patient history and making an early diagnosis to improve the outcomes of disseminated strongyloidiasis.

Introduction

Strongyloidiasis is a soil-transmitted helminthiasis that is endemic to the tropics and subtropics. An estimated 30 to 100 million people are infected with Strongyloides stercoralis worldwide, which is designated as a neglected tropical disease by the World Health Organization (1). S. stercoralis causes chronic infections with no or mild symptoms in immunocompetent individuals. However, hyperinfection and disseminated strongyloidiasis in immunocompromised individuals can be fatal. In Japan, the number of patients with strongyloidiasis is expected to be decreasing, and most patients have been reported from Okinawa and Kagoshima Prefectures located in the southern part of Japan (2).

We herein report a case of human T-lymphotropic virus type 1 (HTLV-1)-associated disseminated strongyloidiasis in a patient that occurred after chemoradiotherapy for lung cancer at a hospital in Aichi Prefecture, a non-strongyloidiasis-endemic area.

Case Report

A 64-year-old man collapsed on the street and was transported to our hospital in Aichi Prefecture by emergency services. He had been diagnosed with T2bN2M0 Stage IIIA lung squamous cell carcinoma of the left upper lobe four months before the visit and had received four courses of weekly carboplatin and paclitaxel and radiotherapy three months before the visit. The patient had shown a partial response two months previously and been followed up thereafter. His medical history other than lung cancer included interstitial pneumonia, bronchial asthma, chronic obstructive pulmonary disease, diabetes mellitus, and colonic diverticulum. His regular medications included fluticasone furoate/umeclidinium bromide/vilanterol inhalation, ambroxol, codeine phosphate, and dapagliflozin.

Upon an examination, his vital signs were as follows: body temperature, 37.0°C; blood pressure, 78/53 mmHg; pulse rate, 109 beats/min; peripheral oxygen saturation, 96% (room air); and respiratory rate, 16 breaths/min. The patient also showed impaired consciousness, with a Glasgow Coma Scale score of E2 V2M4. Fine crackles were heard in both lower lungs, tenderness was observed in the abdomen, and purpura was observed from the lower abdomen to both groin areas. No other notable physical findings were noted. Laboratory test results were as follows: white blood cell count, 19,600/μL (neutrophil percentage, 94.2%; eosinophil percentage, 0%); hemoglobin (Hb) level, 13.1 g/dL; platelet count, 12.6×10⁴/μL; aspartate transaminase level, 115 U/L; alanine transaminase level, 81 U/L; lactate dehydrogenase level, 604 U/L; alkaline phosphatase level, 589 U/L; gamma-glutamyl transferase level, 214 U/L; creatinine level, 0.34 mg/dL; C-reactive protein level, 0.37 mg/dL; and HbA1c, 6.5%. A urinalysis revealed no evidence of pyuria or bacteriuria. Thoracic and abdominal contrast-enhanced computed tomography (CT) revealed a new small cavity in the right upper lobe (Fig. 1A), ground-glass opacities with airway dissemination in the left upper lobe, and wall edema of the ascending colon to the descending colon (Fig. 1B). No exacerbation of the lung cancer was observed. The patient was initially treated for septic shock and bacterial pneumonia with extracellular fluid hydration, noradrenaline, and meropenem (1 g every 8 h).

Figure 1.

Contrast-enhanced computed tomography on admission. A small new cavitary lesion is observed in the right upper lobe (A, arrow), and the wall of the ascending to descending colon is thickened (B, arrows).

On the day after admission, two sets of blood culture samples collected on admission revealed Enterococcus faecium. Vancomycin was added and then de-escalated to ampicillin-sulbactam after antimicrobial susceptibility testing was performed. Although the blood cultures obtained on day 5 of hospitalization were negative, with his consciousness gradually improving, an intermittent fever persisted on day 9, and the noradrenaline dose could not be tapered. On day 13, the patient experienced melena and underwent esophagogastroduodenoscopy, which revealed duodenal mucosal edema. Colonoscopy performed on day 16 revealed erythematous mucosa scattered from the cecum to the descending colon.

A histopathological examination of the duodenal mucosa showed infiltration of plasma cells, eosinophils, and worms presumed to be S. stercoralis into the glandular lumen (Fig. 2A). A histopathological examination of the colon revealed Strongyloides within the crypts and stroma of the lamina propria (Fig. 2B). Direct microscopy of the sputum (Fig. 3A) and stool (Fig. 3B) with saline wet mounts showed numerous motile filariform and rhabditiform larvae of S. stercoralis, respectively. The agar plate culture method using sputum showed a bacterial colony distribution along the worm migration tracks (Fig. 3C). Screening for antiparasitic antibodies was positive for Strongyloides and Clonorchis. An enzyme-linked immunosorbent assay performed at Miyazaki University showed positive results for Strongyloides-specific antibodies, but only slightly above the cutoff. An additional investigation of his medical history revealed that the patient had been born and raised on Okinoerabujima Island, one of the Amami Islands in Kagoshima Prefecture, and had moved to Aichi Prefecture in elementary school. He often walked barefoot in school and in the field. He had also tested positive for HTLV-1 antibodies in a previous laboratory test.

Figure 2.

Histopathological findings. Histopathology with Hematoxylin and Eosin staining of the duodenum (A, ×100) and colonic mucosa (B, ×200). Worms presumed to be Strongyloides stercoralis in the glandular lumen (A, arrows), infiltration of eosinophils (B, arrowheads), and S. stercoralis (B, arrow) within the stroma of the lamina propria.

Figure 3.

Direct microscopy and agar plate culture. Direct microscopy of sputum showing motile filariform larva (A, ×400). A width/length ratio of 4.1% suggests that it is an autoinfective third-stage filariform larva. Direct microscopy of stool samples showing numerous motile rhabditiform larvae with a width/length ratio of 6.7% (B, ×100). The agar plate culture method using sputum showed bacterial colony distribution along worm migration tracks (C).

The patient was diagnosed with disseminated strongyloidiasis, and oral ivermectin was initiated at a dose of 15 mg daily, corresponding to 200 μg/kg/day on day 19 (later reduced to 12 mg daily owing to weight loss) (Fig. 4). Ampicillin-sulbactam was discontinued on the same day; however, a fever was observed the next day, and the blood culture was repeated. Ampicillin-sulbactam was resumed because Escherichia coli was detected in the recollected blood culture specimen. Noradrenaline was tapered after initiating ivermectin, and the disappearance of worms from sputum and stool was confirmed by direct microscopy and agar culture on day 25 of hospitalization, i.e. on day 7 of ivermectin initiation. On day 32 (day 14 after ivermectin initiation), the patient presented with systemic erythema. The ampicillin-sulbactam was changed to ceftriaxone, and ivermectin was discontinued, leading to the disappearance of erythema. An additional single dose of ivermectin was administered on day 44, and the patient was discharged. Because the rash did not recur after re-administration of ivermectin, the previous erythema was likely a drug eruption associated with ampicillin-sulbactam administration. After discharge, ivermectin 12 mg was administered once a month for 6 months, and there has been no recurrence of strongyloidiasis or bacteremia since then.

Figure 4.

Clinical course after ivermectin administration. A/S, ampicillin-sulbactam; CTRX: ceftriaxone, E. coli: Escherichia coli. *Direct microscopy of sputum nine days after ivermectin administration shows one immobile larva.

Discussion

In Japan, most cases of strongyloidiasis occur in Okinawa and the Amami Islands (Kagoshima Prefecture) in the southern region of the country (3). A study using the agar plate culture method on stool samples conducted at Ryukyu University Hospital between 2004 and 2006 reported a prevalence of 3.4% for S. stercoralis. All patients were ≥40 years old, with approximately 90% ≥60 years old (4). In addition, a chart review of 70 patients diagnosed with disseminated strongyloidiasis between 1975 and 2017 revealed a median age of 61 years old, and all patients were born before 1964. Of the 39 patients tested for HTLV-1, 36 (92.3%) tested positive (5). The patient in this case was born in 1956 and shared demographic and clinical characteristics similar to those reported in these studies.

In individuals infected with S. stercoralis, immunosuppression can lead to an increased number of worms due to enhanced autoinfection, resulting in a hyperinfection state. This condition may progress to bacteremia or bacterial meningitis (6). There is no consensus on the definition of disseminated strongyloidiasis. Some use the term to describe the stage in which hyperinfection is accompanied by complications, such as bacteremia or meningitis. Others reserve it for cases in which S. stercoralis itself invades organs outside the gastrointestinal tract and lungs (7), which is a part of its traditional life cycle. In this case, purpura was observed in the lower abdomen. Although a skin biopsy was not performed to confirm the diagnosis, this finding suggested cutaneous infiltration by larvae (8). Therefore, the term “disseminated strongyloidiasis” was used. Our patient had a small cavitary lesion in the right lung, suggestive of pulmonary abscess. Although a previous study reported no cavitary lesions in 9 patients with severe strongyloidiasis who underwent CT imaging (9), another study reported pulmonary abscesses in 3 of 20 patients with strongyloidiasis (10). Therefore, this finding is consistent with radiological changes associated with strongyloidiasis.

Risk factors for hyperinfection include the use of immunosuppressive agents, such as corticosteroids and cyclosporine, as well as underlying conditions, such as HTLV-1 infection, hematologic malignancies, and post-solid organ or hematopoietic stem cell transplantation (11). Additionally, cases of hyperinfection have been reported following a 5-day course of dexamethasone and baricitinib for coronavirus disease 2019 (12), indicating that even relatively short-term corticosteroid therapy warrants caution. In the present case, the hyperinfection state was exacerbated by chemotherapy for lung cancer in the context of HTLV-1 positivity. As dexamethasone was administered as an antiemetic on the days of chemotherapy, it remains unclear whether the chemotherapy regimen itself is an independent risk factor for hyperinfection. If this case had occurred in an area endemic for strongyloidiasis, the presence of consecutive episodes of Enterococcus and E. coli bacteremia over a short period, purpura, and a history of HTLV-1 antibody positivity might have led to an earlier suspicion of disseminated strongyloidiasis.

Treatment for strongyloidiasis involves oral administration of ivermectin. For chronic strongyloidiasis, ivermectin is administered at a dose of 200 μg/kg/day, either as a single daily dose for 1-2 days (13) or as 2 doses given 2 weeks apart (6). Japanese guidelines (6) recommend administering ivermectin at a dose of 200 μg/kg/day once daily for at least 4 doses at 1- to 2-week intervals for disseminated strongyloidiasis until S. stercoralis is no longer detectable. In cases of pulmonary involvement, continuous daily administration is recommended until S. stercoralis disappears from stool and sputum samples, typically for 7-14 days. The U.S. Centers for Disease Control and Prevention (CDC) recommends administering ivermectin at a dose of 200 μg/kg/day once daily until S. stercoralis is undetectable in both stool and sputum for 2 consecutive weeks (13).

Although whether direct microscopy or the agar plate culture method should be used to confirm negativity for S. stercoralis is unknown, the agar plate culture method, which is considered to have better sensitivity, should be preferred. However, as seen in the present case, viable larvae were detected by direct microscopy on day 5 after initiating ivermectin treatment, despite a negative result with the agar plate culture method. This may be attributable to the low parasite load in the specimen and heterogeneous distribution of larvae within the sample. In our patient, a larva was again detected in sputum by direct microscopy on day 9 after ivermectin initiation; however, the larva was immobile, and the agar plate culture on the same day was negative. Therefore, it was considered to be a dead larva. It is presumed that the reduction in parasitic burden in the lungs due to ivermectin treatment led to the intermittent appearance of larvae in sputum.

Owing to concerns regarding drug eruption, ivermectin was discontinued after 14 consecutive days of administration. At this point, the treatment duration recommended by the Japanese guidelines was complete; however, since S. stercoralis negativity was confirmed in the sample collected on day 7 after initiating ivermectin treatment, an additional week of treatment would have been required to fulfill the duration recommended by the CDC. Particularly in cases of HTLV-1 positivity, several reports have indicated poor responsiveness to ivermectin treatment (14-16); therefore, we decided not to reduce the treatment intensity. We extrapolated the thiabendazole suppressive therapy studied in patients undergoing renal transplantation (17) and practiced intermittent ivermectin treatment for six months. Retrospectively, an additional one-week course of daily ivermectin administration might have been a reasonable treatment option. The intermittent ivermectin regimen used in this case was not generalizable as a standard approach.

The fatality rate of disseminated strongyloidiasis has been reported to be ＞85% in studies conducted overseas (11,18) and 56.3% in reports from Japan (5), highlighting the importance of prevention. Methods for preventing disseminated strongyloidiasis include either the “test and treat” approach or empiric therapy for chronic infections conducted prior to the initiation of immunosuppressive therapy. In the “test and treat” approach, stool ova and parasites (O&P) testing, preferably combined with the agar plate culture method when available, and serological testing are performed. Stool O&P testing may not detect infections using a single test; therefore, it is necessary to perform multiple examinations to increase the likelihood of detection (6). Serological testing has high sensitivity (19); however, time is required for the results to become available. In addition, sensitivity decreases in patients who are already immunosuppressed, posing a limitation in such cases. Therefore, in cases where patients at risk of S. stercoralis infection become immunosuppressed or are already in an immunosuppressed state, empirical therapy with ivermectin may be acceptable without prior screening (18). Chronic strongyloidiasis is often asymptomatic; therefore, when assessing the risk of Strongyloides infection, decisions should be based on the patient’s country or region of residence rather than symptoms (20). Japanese individuals who spent their childhood in Okinawa Prefecture or the Amami Islands or who served in tropical or subtropical regions during wartime fell into this risk category. In the present case, if the patient’s birthplace and residence history had been assessed before initiating chemotherapy, strongyloidiasis could have been evaluated by stool O&P or serological testing.

In conclusion, we reported a case of disseminated strongyloidiasis that developed after chemoradiotherapy for lung cancer in a patient with HTLV-1 infection who was later found to have originated from an endemic area. Although the number of patients with strongyloidiasis is expected to be decreasing in Japan, physicians who prescribe immunosuppressive agents, in addition to hepatitis B virus and tuberculosis, should not ignore strongyloidiasis as pathogens that can be reactivated by such drugs.

The patient provided his written informed consent for the publication of his case details.

The authors state that they have no Conflict of Interest (COI).

Funding Statement

This study was supported by the Nagoya Co-Creation Research Fund. The funder had no role in the study design; collection, analysis, interpretation of data; writing of the report; or decision to submit the article for publication.