Hyperinfection syndrome in a microscopic polyangiitis patient after treatment with immunosuppressive drugs

A 66-year-old man with a history of microscopic polyangiitis, type 2 diabetes mellitus, bronchiectasis, and emphysema presented to Jiangxi Provincial People's Hospital on September 28, 2021. The patient's major symptoms were fever, diarrhea, cough with sputum for the past month, and gangrene of the lip for the past 6 days. The patient was a farmer residing in Jiangxi Province, who was a nonsmoker with no travel history. In June 2020, his serologies were positive for perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) at 1:1280 and myeloperoxidase (MPO) at 209.9 (0–20) U/mL. His creatinine level was 411 (57–111) μmol/L. Renal ultrasound suggested renal atrophy, and computed tomography (CT) of the lungs revealed interstitial lesions. The diagnosis was microscopic polyangiitis, antineutrophil cytoplasmic antibodies (ANCA)-associated nephritis, and interstitial pneumonia. The administered treatments were glucocorticoids (starting dose of methylprednisolone at 40 mg/day, followed by a gradual reduction to a maintenance dose of prednisone at 10 mg/day), cyclophosphamide (intermittent use from June 2020 to August 2021, totaling 5.0 g), and compound sulfamethoxazole (two tablets every 12 h) for the prevention of Pneumocystis jirovecii (P. jirovecii). The patient developed fever, diarrhea with chills, nausea, vomiting, and a cough with sputum after exertion in August 2021. He consulted another hospital on September 3, 2021, and blood cultures showed a multidrug-resistant Escherichia coli infection. After discontinuing hormone treatment and using cefoperazone/sulbactam sodium and moxifloxacin to fight the infection, the patient's condition did not improve. On September 22, the patient developed oral ulcers, gangrene of the lip, aggravated diarrhea, nausea, vomiting, and a cough. Physical examination revealed an oral mucosal ulcer, gangrene of the lip (Figure 1A), weak breath sounds in both lungs, and wet rales. Laboratory tests (September 28, 2021) included a blood count with the following findings: white blood cells: 8.9 (3.5–9.5) × 109/L, neutrophils: 92.7% (40%–75%), lymphocytes: 5.8% (20%–50%), eosinophils: 0.3% (0.4%–8.0%), hemoglobin: 83 (130–175) g/L, and platelets: 61 (125–350) × 109/L. Biochemical tests revealed: creatinine 178 (57–111) µmol/L. Immunological examinations revealed: C3: 0.51 (0.79–1.52) g/L, C4: 0.15 (0.16–0.38) g/L, and negative results for p-ANCA and classic antineutrophil cytoplasmic antibody (c-ANCA). Infection indicators were as follows: erythrocyte sedimentation rate: 87 (0–15) mm/1 h, CRP: 111 (0–8) mg/L, 1–3-β-d glucan: 203.67 (60–100) pg/mL, and all other pathogen-related tests were negative. Chest CT demonstrated interstitial fibrosis of the lungs (Figure 1B). The patient received meropenem (0.5 g every 12 h). On September 30, bronchoalveolar lavage fluid microscopy revealed a small number of Strongyloides stercoralis(S. stercoralis) and P. jirovecii (Figure 1C). The patient was administered albendazole (400 mg once every 12 h) orally for deworming and compound sulfamethoxazole at an increased dose of two tablets every 6 h for P. jirovecii. One day later, the patient's diarrhea improved, and respiratory symptoms remained the same. The patient was discharged on October 2 at the request of the family. Subsequently, next-generation sequencing of the alveolar lavage fluid identified S. stercoralis (41.43% relative abundance), P. jirovecii (4.18% relative abundance), Aspergillus fumigatus (0.26% relative abundance), human herpesvirus type 5 (3.08% relative abundance), human respiratory syncytial virus type B (relative abundance 11.71%), and Scedosporium apiospermum (relative abundance 0.06%). However, S. stercoralis was not detected in the blood or stools. The final primary diagnosis of the patient was microscopic polyangiitis, S. stercoralis infection, P. jirovecii pneumonia, interstitial pneumonia, bacteremia, and chronic kidney disease stage 5. Oral ulcers are a common manifestation of microscopic polyangiitis. Because the patient presented with diabetes mellitus, gangrene of the lip may have resulted from the lack of appropriate treatment. Despite administering sulfamethoxazole, the patient became infected with P. jirovecii. This indicates that in cases of long-term immunosuppressive drug use, the dose of sulfamethoxazole may need to be increased to prevent infection with P. jirovecii. S. stercoralis is unique among human helminthiases in that it exhibits an autoinfection cycle that enables its long-term, sometimes lifelong, persistence.1 S. stercoralis is distributed worldwide, with the highest prevalence rates in tropical and subtropical areas, but it is also found in temperate climates. In China, the prevalence of S. stercoralis was found to range from 2.7% to 8.1%.2 Jiangxi province has a humid, oceanic climate that may be considered subtropical. Consequently, the prevalence rate of S. stercoralis in this area is likely to be close to the 8.1% upper limit. The current case study presented hyperinfection syndrome (HS), which is defined as an increase in parasite load from a burst in the autoinfection lifecycle, usually caused by impairment of the host's immune status. Debilitating chronic diseases, for example, alcoholism, diabetes mellitus, metastatic carcinomas, and tuberculosis, along with coinfection with human T-lymphotropic virus type 1 (HTLV-1) are recognized risk factors for HS. However, therapies using anticancer drugs, immunosuppressive drugs, or corticosteroids as anti-inflammatory medications, are the most frequent causes of the onset of HS. HS is usually restricted to the gastrointestinal tract and the lungs; however, there is a risk of progression to disseminated strongyloidiasis (DS). Disseminated infection involves the migration of larvae to organs beyond the gastrointestinal tract and lungs. Infective filariform larvae that move “en masse” out of the gut are covered with Gram-negative bacteria from the intestinal lumen, so HS and DS assume the features of a severe bacterial infection, namely septicemia, and in some cases bacterial meningitis or pneumonia. Other organ involvements have been reported. Therefore, HS and particularly DS are severe diseases, in which the fatality rate ranges from 40% to 90%, and are often caused by septic shock. Regarding rheumatology specifically, the risk of HS/DS in this class of patients and prevention of this complication were reported back in 2009.3 Ivermectin, not albendazole, is recommended for the treatment of any form of strongyloidiasis and particularly hyperinfection. However, ivermectin was not available in China, so albendazole was used to treat S. stercoralis infection and in the current case, drug efficacy could not be assessed because the patient was automatically discharged from the hospital. Not treating patients with corticosteroids or immunosuppressive/antimitotic drugs when presenting with blood eosinophilia before strongyloidiasis is ruled out by all appropriate laboratory investigations. Any patient intended for treatment with the above-cited drugs should answer a questionnaire inquiring about their place of birth and travel history, in case strongyloidiasis can be ruled out. For patients living in an endemic area, strongyloidiasis should be systematically ruled out by the attending doctor. If laboratory investigations are negative but strongyloidiasis remains highly suspected, for example, based on epidemiological information, ivermectin should be administered as a safety measure before therapy with corticosteroids or immunosuppressive drugs. The above procedure requires the following timescales: 5 min for the interrogatory questionnaire, 3 h for microscopic examination of stools using the mandatory Baermann method, 3–4 h for specific immunodiagnosis, and, finally, 1 day for molecular diagnosis, if available. The original manuscript was written by Jiao Luo. The data were collected by Haotong Zhou and Jiao Luo. Reviewed and edited by Lihua Duan and Chunhua Shi. All authors read and approved the final manuscript. We would like to thank all the staffs who contributed to this case. This work was supported by Jiangxi Province Medical Leading Discipline Construct Project (Rheumatology), Provincial and Municipal Joint Construction Projects of Medical Disciplines in Jiangxi Province (Rheumatology) and National Natural Science Foundation of China (No. 81960296). The authors declare no conflict of interest. The studies involving human participants were reviewed and approved by the Ethical Committee of Jiangxi Provincial People's Hospital. The patient/participant has signed the informed consent to participate in this study.