In Cureus, Ohta and colleagues presented a case report that highlighted how cytomegalovirus (CMV) infection can thrive on a background of immunosuppression.
An 87-year-old man presented with persistent cough and bloody sputum. His medical history included hypertension, dyslipidemia, and knee osteoarthritis; his medication history included amlodipine and acetaminophen. Upon presentation, the patient was found to have low blood pressure (80/52 mm Hg). Otherwise, he was alert and oriented. A chest examination revealed bilateral late inspiratory crackles. Laboratory investigations revealed significant inflammation, thrombocytopenia, hematuria, and proteinuria.
A chest X-ray demonstrated bilateral infiltration in the upper lungs. Chest computed tomography (CT) showed multiple lesions and ground-glass opacities bilaterally. These findings were suggestive of alveolar hemorrhage. Additional investigations revealed a myeloperoxidase-ANCA level of 88.3 U/mL and glomerulonephritis.
Combined, these findings pointed to a diagnosis of antinuclear cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). The patient was found to have developed thrombocytopenia in the absence of liver function abnormalities. He was started on prednisolone and rituximab, which transiently improved his hemoptysis and thrombocytopenia. However, a recurrence of thrombocytopenia was observed on day 28 of admission, after his third dose of rituximab. A urinalysis was performed, revealing multiple intracytoplasmic inclusion bodies per high-power field.
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The combination of thrombocytopenia and urinary intracytoplasmic inclusion bodies after rituximab administration raised clinical suspicions of CMV infection, which was confirmed via CMV antigenemia testing. He was started on oral valganciclovir on day 31 and was discharged on day 45 with full resolution of the patient’s symptoms.
AAV and CMV Infection
“To effectively treat older patients requiring immunosuppressive treatment, physicians should check for CMV viremia among patients with thrombocytopenia, and detect and treat active infections before treatment,” Ohta et al wrote.
In the case of this patient, a combination of intracytoplasmic inclusion bodies on a background of AAV-associated thrombocytopenia prompted the patient’s physicians to investigate for the presence of CMV infection in view of the patient’s immunocompromised status caused by rituximab administration.
Urinary intracytoplasmic inclusion bodies should raise clinical suspicions of a systemic viral infection, especially when other markers of infection, such as fever, malaise, enlarged lymph nodes, and aches and pains, are present. This patient did not have acute signs of fever or distress, making low platelet count (9.5 × 104/mL) his only sign of CMV infection. Nevertheless, “investigation of CMV in immunosuppressed patients with vague symptoms is mandatory,” according to Ohta and colleagues.
It should be noted that other sources of infection, such as the Epstein-Barr virus, can also arise in patients who are immunocompromised. However, CMV infections are by far the most common among immunosuppressed hosts; they account for up to 80% of cases.
Association With COVID-19
There appears to be a bidirectional relationship between AAV and infection, given prominent case studies detailing patients being diagnosed with AAV after a bout of infection. This is in line with our current understanding of the pathophysiology of AAV; in COVID-19 infection, for example, scientists propose that the high affinity of SARS-CoV-2 for angiotensin-converting enzyme 2 receptors makes it easier for the virus to invade endothelial cells and trigger vasculitis.
In more general terms, infection can drive endothelial cell damage and cause abnormalities in the coagulation/fibrinolytic system. In addition, the host becomes vulnerable to thrombotic microangiopathy. Although the precise cause of AAV is still a matter of lively debate, there are proposals that these vulnerabilities create the right conditions for its development.
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In Internal Medicine, Kawashima and colleagues described the case report of a patient who developed microscopic polyangiitis following COVID-19 infection. A 61-year-old woman underwent polymerase chain reaction testing after being in close contact with a patient and was found to be positive. Her infection self-resolved. However, she developed pyrexia again but was negative for COVID-19.
A suspicious urinalysis resulted in a renal biopsy being performed, demonstrating infiltration of various inflammatory cells. In addition, the renal biopsy revealed the presence of tubulitis, tubular atrophy, and peritubular capillaritis. The small arteries were noted to have vascular wall destruction with fibrinoid necrosis. The patient was diagnosed with highly active nephritis associated with AAV. She was started on pulse steroid therapy, followed by prednisolone and intravenous cyclophosphamide, which achieved disease remission.
This case study is not unique; there are a number of other reports documenting AAV and COVID-19 diagnoses being made in close proximity to each other. The relationship between the two may be driven by evidence derived from animal models suggesting that COVID-19 results in persistent inflammation, raising the production of activated neutrophils and ANCA. In the era of the COVID-19 pandemic, scientists proposed that vaccination be carried out even after infection to prevent reinfection and virus aggravation.
Given the body of evidence detailing the seemingly bidirectional relationship between AAV and infection, it is important for physicians to understand that one might trigger the other, and for appropriate medical surveillance to be carried out. Patients should also be made to understand that the administration of rituximab, an important AAV therapeutic, may result in an immunocompromised state, and that precautions should be taken to avoid opportunistic infections.
References
Ohta R, Naito Y, Nishikura N, Inoue K, Sano C. Thrombocytopenia in anti-neutrophil cytoplasmic antibody-associated vasculitis indicating the presence of cytomegalovirus infection: a case report. Cureus. 2023;15(5):e38850. doi:10.7759/cureus.38850
Kawashima S, Kishimoto M, Hibino T, et al. MPO-ANCA-positive microscopic polyangiitis following COVID-19 infection. Intern Med. 2022;61(4):567-570. doi:10.2169/internalmedicine.8615-21
