Abstract
A 53-year-old otherwise healthy man was referred to our hospital with a fever of unknown origin, headache, and arthralgia. Four days earlier, he had a fever with chills. Treatment with antibiotics and acetaminophen proved ineffective, with the patient subsequently developing headache and joint pain. Blood analysis revealed elevated inflammatory markers, liver impairment, and severe thrombocytopenia (platelet count, 19,000/μL). Subsequent tests revealed elevated levels of anti-cytomegalovirus IgM and IgG. Based on these findings, the patient was diagnosed with severe thrombocytopenia associated with cytomegalovirus infection. Platelet counts increased spontaneously without antiviral therapy. Forty-five days after the initial visit, the symptoms improved, and blood tests revealed resolution of the inflammatory findings, with the platelet count recovering to 155,000/μL. Although the disease may resolve spontaneously, cytomegalovirus infection should be considered as a differential diagnosis in case of severe thrombocytopenia in immunocompetent adults.
Introduction
Cytomegalovirus (CMV) is a globally distributed herpesvirus primarily known for causing infections in immunosuppressed patients. Immunocompetent individuals with CMV infections are often asymptomatic or present with a mononucleosis-like syndrome. 1 However, CMV infection can cause complications such as colitis, meningoencephalitis, blood disorders, thrombosis, uveitis, splenic rupture, and Guillain–Barre syndrome. 2 Although thrombocytopenia is a known complication of viral infections, such as rubella, Epstein–Barr virus infection, mumps, varicella, human immunodeficiency virus infection, and hepatitis, CMV infections rarely cause severe thrombocytopenia in immunocompetent patients. 3 In Japan, when immunocompetent patients present with rapidly progressive thrombocytopenia, it is important to consider diseases such as acute leukemia, thrombocytopenic purpura, hemolytic uremic toxemia syndrome, tsutsugamushi disease, and severe febrile thrombocytopenia syndrome. 4
In numerous cases, thrombocytopenia is caused by an underlying disease; thus, it can be improved by treating the underlying disease. However, in cases of severe bleeding due to thrombocytopenia, immediate platelet transfusion is necessary. In certain situations, such as rickettsial infections, where effective treatment options exist, initiating therapy without a definitive diagnosis may be advisable. 5 Moreover, for severe CMV infection, antiviral agents such as ganciclovir are recommended. 6
Considering CMV infection as one of the differential diagnoses when evaluating a patient with thrombocytopenia can facilitate timely diagnosis and appropriate treatment and thus prevent complications, risky tests, and unnecessary financial expenses due to bleeding. 6 This report aims to describe a case of severe thrombocytopenia due to CMV infection in an immunocompetent adult and emphasize the importance of recognizing such cases in clinical practice.
Case
A 53-year-old otherwise healthy man was referred to our hospital with a fever of unknown origin, headache, and arthralgia. Four days earlier, he had developed a fever of 37.5°C accompanied by chills. The following day, his temperature increased to 39.1°C, and the severity of the chills worsened, which prompted him to visit the local community clinic. The rapid diagnostic tests for influenza and coronavirus antigens were negative; further, chest radiography showed no abnormalities, and the cause of the fever remained unknown. Initial treatment with cefditoren pivoxil, and acetaminophen yielded no improvement. Subsequently, the patient developed bilateral temporal and occipital headaches, arthralgia in both shoulder joints, and back pain, which led to a referral to our hospital. Upon the first hospital visit, the patient’s vital signs were generally normal, except for fever and tachycardia (Glasgow Coma Score 7 , 15; axillary temperature, 39.5°C; blood pressure, 121/76 mmHg; pulse rate, 110 beats/min). Physical examination revealed no abnormal findings, such as heart murmur, enlarged thyroid gland, tonsillar enlargement, enlarged lymph nodes, skin rash, or tick bites. Additionally, there were no neurological abnormalities, including meningeal irritation and gait disturbance. Contrast-enhanced whole-body computed tomography revealed mild lymphadenopathy in the mediastinum and retroperitoneum, as well as fatty liver. Blood tests indicated inflammatory findings, liver damage, and severe thrombocytopenia (19,000/μL; reference range 150,000–350,000/μL) (Table 1). Empiric treatment with minocycline was administered from the first day of the visit to cover tsutsugamushi disease, which could occur in the area where the patient lived until the results of the antibody test were obtained. The next day, a blood test showed an increase in platelet count and improvement in inflammatory findings. Based on the timing and duration of minocycline use, we concluded that the patient was experiencing spontaneous relief rather than an antibacterial effect. Subsequently, we observed a gradual disappearance of symptoms such as fever and headache. Elevated anti-CMV IgM and IgG levels were confirmed after several days (Table 1). Tests for anti-Epstein–Barr virus, anti-tsutsugamushi, and anti-hepatitis virus antibodies showed negative results. The final diagnosis was made clinically as severe thrombocytopenia associated with CMV infection based on anti-CMV IgM results, symptoms consistent with CMV infection, and exclusion of other diseases. Forty-five days after the initial visit, the symptoms improved, and blood tests revealed resolution of the inflammatory findings, with the platelet count recovering to 155,000/μL (Table 1).
Hematological and biochemical test results.
Discussion
This case report highlights two key findings. First, our case highlights the importance of considering CMV infection as a potential cause of severe thrombocytopenia in otherwise healthy adults. The etiology of CMV-induced thrombocytopenia may involve CMV infecting megakaryocytes and their precursors, as observed in vitro, which could contribute toward platelet reduction (direct cytotoxicity of CMV on hematopoietic cells and immune-mediated destruction of infected cells). 8 Additionally, CMV infection may induce nonspecific autoantibodies, ultimately leading to antibody-mediated platelet destruction. 9 It is recognized that CMV is one of the major infectious causes that may induce thrombocytopenia and one of the most common agents that may trigger idiopathic thrombocytopenic purpura (ITP). 10 Furthermore, there may be CMV-induced impairment of bone marrow stromal function. 8 The difficulty in diagnosing CMV infection in immunocompetent individuals could be attributed to the following three factors: (1) the low incidence of severe CMV disease, making clinical suspicion challenging; (2) the broad tissue tropism of CMV infection, resulting in a diverse range of potential clinical manifestations; and (3) the diverse symptoms induced by CMV infection, which may mimic those of other diseases. These conditions may contribute to diagnostic confusion and delays in diagnosis. 6 Considering CMV infection as a differential diagnosis in otherwise healthy patients with thrombocytopenia could prevent unnecessary invasive tests, including bone marrow examination and lymph node biopsy. Instead, noninvasive diagnostic items, such as CMV-PCR, avidity of anti-CMV-IgG, urinary antigen, morphological evaluation of the blood smear, and viral culture, could be employed for diagnosis of CMV infection. One of the limitations of our case report is that the diagnosis is based on antibody testing and clinical presentation, not CMV-DNA.
Second, it is important not to overlook the opportunity for appropriate treatment of CMV-induced thrombocytopenia. The various available therapies for patients with CMV-induced thrombocytopenia include steroids, immunoglobulins, vincristine, splenectomy, and ganciclovir.3,11 Currently, the recommended first-line therapy for severe CMV infection in immunocompromised adults is ganciclovir or valganciclovir; however, the efficacy of these antiviral agents in immunocompetent adults remains unclear. 6 Distinguishing CMV-induced thrombocytopenia from CMV-related secondary ITP can be challenging. For patients with ITP refractory to standard treatments, antiviral therapy may be necessary if CMV infection is present. 11 Although there have been some cases of spontaneous recovery without treatment, 12 including our case, the use of ganciclovir or valganciclovir is appropriate in immunocompetent adults with severe CMV disease.1,6 Ganciclovir carries a risk of myelosuppression and is considered potentially carcinogenic. Therefore, it should be used with caution, especially in immunocompromised young adults, and avoided when possible.3,6 Some physicians suggest avoiding steroid treatment given the risk of exacerbating the primary CMV infection and thus further decreasing the platelet count. 1 Depending on individual patient characteristics and severity, it is important to carefully consider the selection of appropriate drugs and optimal treatment timing.
Conclusion
CMV infection should be considered as a differential diagnosis in cases of severe thrombocytopenia in healthy adults. Although the disease may resolve spontaneously, it is important to seize the opportunity for appropriate treatment.
Footnotes
Acknowledgements
None.
Author contributions
H.M. conceived the idea and wrote the original draft of the manuscript. K.T., T.K., and T.A. developed the theory of this study. All authors discussed the case and commented on the manuscript. H.M., K.T., and T.K. revised and edited the manuscript. All authors gave final approval before submission of the manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics approval
Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent
Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
