Diagnostic Challenges in Pulmonary Embolism in Young Adults: Thrombosis Associated With Cytomegalovirus and Mycoplasma pneumoniae

A 23-year-old man presented with a fever, shaking chills, headaches, nausea, and a dry cough. Investigations showed lymphocytic leukocytosis with atypical lymphocytes in a blood smear. Liver function test results, D-dimer concentrations, and fibrin degradation product concentrations were greatly elevated. Computed tomography of the whole body with contrast showed hepatosplenomegaly with splenic infarction and bilateral pulmonary embolism without deep vein thrombosis. Cytomegalovirus (CMV) immunoglobulin M, and serum CMV pp65 antigenemia were positive, and serum Mycoplasma pneumoniae (M. pneumoniae) antibody was also highly positive. These results suggested the diagnosis of co-infection of CMV and M. pneumoniae complicated by systemic arteriovenous thrombosis, which resulted in pulmonary embolism and splenic infarction. After he started edoxaban tosilate hydrate for the thrombosis, his symptoms resolved in a few days. To the best of our knowledge, this is the first case of co-infection of CMV and M. pneumoniae leading to pulmonary embolism and splenic infarction.


Introduction
Although an acute cytomegalovirus (CMV) infection in immunocompetent patients is generally asymptomatic or self-limiting, CMV associated with vascular thrombosis, including deep vein thrombosis, thrombophlebitis, splenic infarction, and pulmonary embolism has been increasingly recognized. There have been more than 100 case reports, three retrospective studies, two prospective studies, and one cohort trial on this condition. A case-control study showed that 6.4% of 140 patients with acute CMV infection had thrombosis, 3.6% of them had arterial thrombosis, and 2.9% of them had venous thrombosis [1]. Another study showed that 65.9% of 64 patients were immunocompetent [2].
Even though the occurrence of multipathogen infections in children with Epstein-Barr virus (EBV)/CMV primary infection is more than 60% [3], co-infection of EBV/CMV and other agents in adults has not been well reported. Li et al. reported a case of a 19-year-old woman with co-infection of EBV, CMV, and Mycoplasma pneumoniae (M. pneumoniae) associated with splenic infarction [4]. To the best of our knowledge, the present report is the first of pulmonary embolism and splenic infarction associated with the co-infection of CMV and M. pneumoniae.

Case Presentation
A 23-year-old man presented to a general physician with a four-week history of a persistent fever with shaking chills, headaches, nausea, and a dry cough. He had no confusion, stiff neck, seizures, chest or abdominal pain, or skin rash. His medical history included a panic disorder, which was well controlled with anti-depressants and benzodiazepines. He smoked six cigarettes each day. He denied drinking alcohol or using recreational drugs.
On examination, he was tachycardic with a heart rate of 150 beats/minute but normotensive with a blood pressure of 129/90 mm Hg. His temperature was 36.8°C, his respiratory rate was 12/min, and his oxygen saturation was 98% in room air. His Glasgow Coma Scale score was 15. Jolt accentuation of the headache and neck stiffness were negative. Neither tonsils nor lymph nodes were swollen. Cardiac and respiratory examinations were normal, except for tachycardia. He had no abdominal tenderness. There were no abnormal findings of the skin or the joints.
Laboratory findings ( Table 1) showed that the hemoglobin concentration was 13.3 g/dL, platelet count was 358,000 cells/µL, and leukocyte count was 9800 cells/µL (47% of the cells were lymphocytes, 3% were atypical lymphocytes, and 44% were neutrophils). The aspartate aminotransferase concentration was 50 IU/L, alanine transferase concentration was 63 IU/L, alkaline phosphatase concentration was 137 IU/L, γ- glutamyl transferase concentration was 226 IU/L, lactate dehydrogenase concentration was 451 IU/L, serum copper concentration was 226 µg/dL, and ferritin concentration was 691.1 µg/L. The C-reactive protein concentration was 4.25 mg/L, and the erythrocyte sedimentation rate was 38 mm/h. The D-dimer concentration was 14.01 µg/mL and the fibrin degradation product (FDP) concentration was 28.9 µg/mL. Human immunodeficiency virus types 1 and 2 antigens and antibodies were negative. Two sets of blood cultures and a cerebrospinal fluid culture were negative. An electrocardiogram showed sinus tachycardia. A chest radiograph showed no abnormalities in the heart or the lungs.  Chest computed tomography (CT) revealed bilateral pulmonary embolism without consolidation (Figure 1,  2). CT of the abdomen (Figure 3)

FIGURE 1: Initial imaging study of the chest
An enhanced CT image of the chest on initial presentation shows left pulmonary embolisms (framed areas).

FIGURE 2: Initial imaging study of the chest
An enhanced CT image of the chest on initial presentation shows right pulmonary embolisms (framed areas).

FIGURE 3: Initial imaging study of the abdomen
An initial enhanced CT image of the abdomen shows hepatosplenomegaly and a splenic infarction (arrow). After the patient started 30 mg of edoxaban tosylate hydrate for thrombosis, all of his symptoms, including the fever and headaches, resolved in a few days without antiviral medications and antibiotics. A serological test one month later showed that the CMV IgM index was 3.42 (decreased), CMV IgG titer was 137 (increased), and serum CMV pp65 antigenemia was negative. M. pneumoniae antibody was 320 (decreased). A follow-up chest CT one month after the patient's initial presentation revealed resolution of the pulmonary embolism. He completed anticoagulation therapy for four months.

Discussion
CMV infection interferes with coagulation pathways, resulting in thrombosis. CMV activates factor X and systemic endotheliitis, and increased tissue factor expression occurs. The production of factor VIII and von Willebrand factor are also increased. These mechanisms cause platelet and leukocyte aggregation, adhesion, and thrombin formation [5]. CMV is also a causal factor inducing antiphospholipid antibody syndrome with associated vascular thrombosis [6].
M. pneumoniae is associated with secondary thrombosis [7]. Previous case reports showed that pulmonary embolism [8] or splenic infarction [9] with M. pneumoniae infection occurred even without pneumonia.
Although the mechanism of extrapulmonary invasion of M. pneumoniae is poorly understood, direct invasion to a secondary organ, immunological damage, or vascular obstruction is possible. Furthermore, a prospective study of United Kingdom women showed that the use of antidepressant drugs was related to a high risk of venous thromboembolism [10]. Our patient also had a risk of thrombosis because of the longterm use of antidepressants.  [2]. Therefore, screening with lower-extremity Doppler is cost-effective [11]. Chest and abdominal CT scans with contrast are recommended for a more accurate diagnosis of pulmonary embolism, portal vein thrombosis, and splenic infarction. A retrospective study of 43 children with M. pneumoniae associated with thrombosis suggested that 25 (58.1%) patients showed D-dimer concentrations >5.0 mg/L, and the mean Ddimer concentration was 11.1 ± 12.4 mg/L [12].

Conclusions
Physicians should be aware of thrombosis complicated by common infectious diseases, such as CMV and M. pneumoniae, even in immunocompetent young adults. A contrast-enhanced computed tomography scan, echocardiography, and blood vessel ultrasonography are recommended in the case of elevated D-dimer concentrations to detect thrombosis, including pulmonary embolism and splenic infarction.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.