HSV-1 infection as a rare trigger of methotrexate toxicity: A diagnostic and therapeutic challenge

Abstract Introduction: We present a novel case of severe pancytopenia in a 63-year-old woman receiving low-dose methotrexate for rheumatoid arthritis (RA), triggered by HSV-1 infection and refractory to leucovorin rescue. Dramatic reversal with corticosteroids highlights a potential therapeutic strategy in methotrexate toxicity unresponsive to standard care, warranting further study. Case Presentation: A 63-year-old female with a history of hypothyroidism, heart failure with preserved ejection fraction (HFpEF), hypertension, type 2 diabetes mellitus, limited systemic sclerosis, and seronegative RA, presented to the hospital with fever, chills, headache, and dysphagia. Four days earlier, she was seen in an outpatient clinic for a cold sore near the corner of her right lip and was prescribed valacyclovir 500 mg twice daily for three days for HSV infection. Her home medications included prednisone 2.5 mg, leucovorin 5 mg and methotrexate 12.5 mg weekly along with adalimumab 40 mg every 14 days. Initial laboratory work-up revealed pancytopenia: white blood cell count (WBC) of 1.34 ×10⁹/L, absolute neutrophil count (ANC) of 0.4 ×10⁹/L, lymphocyte count of 0.95 ×10⁹/L, platelet count of 103 ×10⁹/L, and hemoglobin of 9.8 g/dL (previously 12.3 g/dL nine months earlier). She was started on intravenous (IV) acyclovir for presumed mucocutaneous herpes simplex virus 1 (HSV-1) infection possibly contributing to bone marrow suppression. Methotrexate was withheld, and IV leucovorin 15 mg every 6 hours was initiated. Her methotrexate levels were within normal limits (<0.04 µmol/L). Despite this, her pancytopenia worsened over the next two days, and she developed a fever with a temperature of 102.9 F. Repeat CBC showed WBC 0.90 ×10⁹/L, ANC 0.2 ×10⁹/L, lymphocyte count 0.54 ×10⁹/L, platelet count 14×10⁹/L, and Hb of 8.6 g/dL. The patient was empirically started on cefepime for febrile neutropenia. A peripheral blood smear revealed microcytic anemia, poikilocytosis with occasional schistocytes, and thrombocytopenia. Immunoglobulin G (IgG) was markedly decreased at 420 mg/dL (normal range: 610–1616 mg/dL). An infectious workup, including blood cultures, CMV DNA, HIV RNA, EBV IgM, and parvovirus B19 antibodies, was negative. A bone marrow biopsy was performed, and it showed dysplasia, including dyserythropoiesis and megakaryocyte hyperplasia, with <5% blasts. No cytogenetic or molecular evidence of clonality was found. Additionally, karyotype, FISH, and OncoHeme next-generation sequencing (NGS) were negative for any clonal abnormality. Intravenous hydrocortisone 50 mg twice daily was initiated. Following corticosteroid initiation, the patient's pancytopenia and mucocutaneous lesions improved significantly. After a five-day course of IV steroids and a seven-day course of IV cefepime, she was discharged home on oral acyclovir to complete a 14-day total antiviral course. At outpatient follow-up one month later, CBC showed WBC 15.98 ×10⁹/L, ANC 13.3 X ×10⁹/L, lymphocyte count 1.53 ×10⁹/L, platelet count 412 ×10⁹/L and Hb of 9.8 g/dl. She reported complete resolution of her symptoms. Discussion: Methotrexate is a commonly used disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. Common side effects include nausea, vomiting, fatigue, mild transaminitis, and oral ulcers. Risk factors for MTX toxicity include folate deficiency, renal insufficiency, advanced age, hypoalbuminemia, and infection (Mori, Hidaka, Kawakita, Hidaka, & Tsuda, 2016). This patient was on folic acid supplementation and a stable methotrexate dose, without traditional risk factors. The temporal association between HSV-1 infection and development of severe pancytopenia suggests that HSV-1 may have precipitated low-dose methotrexate toxicity (Ajmani, et al., 2017). The patient did not respond to IV leucovorin, which is the standard of care for low-dose methotrexate toxicity (Bhargava, Kopp, & Naidu, 2023). However, she showed marked improvement after initiation of high-dose corticosteroids. Conclusion: This case suggests that corticosteroids may be a valuable adjunct in patients with suspected methotrexate toxicity who do not respond to leucovorin. Further studies are needed to evaluate the role of corticosteroids in such cases.