Discussion
CMV is a viral infection that infects up to 60–100% of people in childhood, and it is one of the most common agents to cause infectious complications after transplantation (1, 6). There is a remarkable relationship between kidney transplantation and infection with CMV, with statistics showing that between US kidney transplants, 18% of the transfers are from a seropositive donor to a seronegative recipient (D+/R-) (2, 8-21), 61% are to the seropositive recipient (R+) (2, 11, 22-26 ), and 21% are both donor and recipient seronegative (D-/R-) (2, 27), which made kidney transfer stand out as a risk factor for CMV infections, especially with the use of immunosuppressants after transplantation to reduce allograft rejection(2), other statistics showed that before the effective CMV prevention post-transplantation, the probability of developing an active infection is 69% in (D+/R-) (2, 20, 21), and 67% in (R+) (2), on the other hand, the probability of developing a CMV disease is 56% in (D+/R-) (2, 9-19) and 20% in (R+) (2, 11, 22-26).
In our case, the patient’s serostatus is D+/R+ with a CMV disease, which is the less common type of CMV presentation.
CMV infection in transplant patients can occur in three ways: The most common way of transmission is endogenous reactivation of CMV in the transplant patient. The second most common way is a donor-derived infection transmitted by allograft. The third is a de novo infection acquired from the surrounding population (1). The widespread usage of CMV prevention strategies after kidney transplantation has changed the epidemiology of CMV infection. There are different CMV prevention strategies, including prophylaxis therapy with antiviral medications such as acyclovir (2, 19, 28), ganciclovir (2, 13), and valganciclovir (2, 8-10, 12, 14-17, 20, 23), while some patients didn’t get prophylactic therapy (11, 18, 22, 26, 27, 29). Another prevention method is preemptive treatment once an asymptomatic viral replication is detected in the blood (2).
In our case, the patients didn’t receive any prevention therapy after the transplant. Time of infection development: early-onset CMV infection (appears within the first 6 months after transplantation, five times as common) (5, 9, 10, 12, 13, 15-17, 19-21, 24, 26, 28, 29), late-onset CMV infection (takes more than 1 year to appear, associated with CMV sero-mismatch and impaired allograft function) (5, 8, 14, 17, 18, 22, 25, 31), very late-onset CMV infection (develops 10 years after transplantation) (8, 11, 27, 32).
In our case, our patient had developed a very late onset CMV infection after 15 years of kidney transplant, which is a rare onset of CMV infection. CMV infection in kidney transplant recipients is classified as either asymptomatic CMV infection (2, 20, 21) or active CMV disease. Active CMV disease is divided into CMV syndrome and tissue-invasive CMV disease (2). CMV syndrome is considered to be the presence of detectable viral replication in the blood associated with fever, leukopenia, arthralgia, and thrombocytopenia in the absence of tissue-invasive CMV disease (2, 9, 29, 31). The definition of tissue-invasive CMV disease is the presence of clinical symptoms and indicators of tissue invasion in addition to microbiologic evidence of active CMV infection. It can also be demonstrated in tissue biopsy specimens by histopathology or viral culture (2, 8, 10-20, 22–28, 32). Due to the wide tropism of CMV, tissue-invasive CMV disease has a variety of clinical presentations, such as enteritis (abdominal pain, nausea, vomiting, or diarrhea in the absence of any other cause) (2, 8, 10, 11, 17, 18, 21, 26, 27, 32), hepatitis (an increase in aspartate aminotransferase and alanine aminotransferase in the absence of any other cause) (2, 12), pneumonitis (cough, shortness of breath, or pulmonary infiltrates on radiologic imaging plus CMV in bronchoalveolar lavage fluid) (2, 16), meningoencephalitis (headache, nuchal rigidity, changes in mental state, or paralysis, together with CMV in cerebral spinal fluid) (2), retinitis (ophthalmologist-reported retinal edema or hemorrhage) (2, 12, 22), uveitis (10), sinusitis (23), and a scrotal ulcer (28). The cytopathic effects of CMV infection on kidney transplant cells, which can cause nephropathy (2, 13, 15, 16, 21, 24) and allograft loss (2, 9-11, 16, 21), as well as morbidity and death from severe CMV illness (2, 9, 11, 19), are its direct impacts. In our case, the patient had an invasive-tissue CMV disease confirmed by biopsy that showed eosinophilic intranuclear inclusions and variable granular purple cytoplasmic inclusions. The patient presented with a complaint of watery diarrhea with bloody threads, weakness, asthenia, anorexia, oliguria, and dysphagia and was diagnosed with CMV enteritis. The patient didn’t develop any nephropathy or graft loss and remained alive. Upregulation of human leukocyte antigens (HLAs) and adhesion molecules, which might encourage acute allograft rejection, allograft loss, and death, are indirect effects of CMV infection. While R+ individuals are at moderate risk and D-/R- patients are at low risk, D+/R- patients are at the highest risk of having an active CMV infection or illness through primary infection with the virus. The administration of lymphocyte-depleting therapy or high-dose steroids to treat acute cellular rejection, as well as the use of lymphocyte-depleting agents for induction immunosuppression and mycophenolate for maintenance immunosuppression, are additional risk factors for CMV disease (2). As mentioned earlier, the clinical features of CVM are non-specific and are similar to many diseases, both infectious and non-infectious. The primary method for making the diagnosis is laboratory confirmation. However, CMV infection should be at the top of the differential diagnosis for any kidney transplant patient who presents with signs of CMV syndrome, end-organ damage, and other CMV symptoms previously mentioned. The diagnostic techniques include microbiology, ophthalmology, and histopathology. The most common microbiological methods of diagnosis are viral culture, PCR amplification, and CMV pp65 antigen detection in peripheral blood leukocytes. The results of histopathology can also be used in the diagnosis and supported by in situ hybridization CMV tests or any immunohistochemistry tests. The PCR nucleic acid amplification test, which detects viral DNA or RNA, is currently the golden standard test for diagnosis, and it is the test that was used to establish the diagnosis in our case (2). In our case, the clinical presentation and the medical history of the kidney transplant of our patient led us to consider CMV infection, and after the findings on the upper gastrointestinal endoscopy and PCR test, we managed to confirm the diagnosis. Treatment for CMV infection is always indicated in viral syndrome and CMV disease, and when histological and immunohistochemical changes present tissue and organ damage, the antiviral treatment should be started as soon as the presence of the replicating virus is found by either antigenemia or reverse transcription polymerase chain reaction (RT-PCR) testing (6). The essential treatments for CMV infection in kidney transplant patients are ganciclovir (1, 8-11, 13-17, 19-23, 25-29, 31, 32) and valganciclovir (1, 8-14, 17-19, 21-23, 26, 27, 31,), whereas intravenous ganciclovir is lately considered to be the gold standard treatment for severe CMV infections. On the other hand, there is not enough evidence of the efficiency of oral valganciclovir. As for mild to moderate cases of infection, we can use valganciclovir. The use of valacyclovir and acyclovir is no longer indicated (6). Ganciclovir resistance is an increasingly common problem in kidney transplantation patients. There is not enough information or clinical experience to determine the most appropriate treatment in the case of a resistant CMV infection (21). In cases of resistant CMV infection, the alternative choice is foscarnet, but it has limited use due to its frequent side effects and mainly nephrotoxicity (1, 9-12, 20, 21). Our patient was treated with intravenous ganciclovir; then, the patient remained well with a well-functioning graft and was free of evidence of CMV. CMV infection has a variant of a life-threatening complication such as DVT (which can lead to pulmonary embolism) (7), graft rejection, coronary atherosclerosis, and opportunistic infections (6). CMV viral infection can cause cryoglobulinemia which can induce hyperviscosity syndrome that can be responsible for the DVT(33).
In our case, our patient was admitted for the first time in the hospital for signs of CMV infection, which was treated for and discharged with no signs of DVT. Then, 5 days after the discharge (22 days after the initial CMV infection), he presented to the emergency room with signs of DVT, which were pitting edema, redness, pain, calf rigidity, and increased skin temperature in the lower right limb. He developed superficial vein inflammation, both of which were ipsilateral to the transplanted kidney and as mentioned earlier, in the context of the medical infrastructure in Syria, comprehensive testing, particularly for specialized conditions such as cryoglobulinemia, faces significant challenges. The economic hardships experienced by the patient and his family further compounded the situation, rendering them unable to afford the necessary diagnostic tests, which are not locally available. Additionally, the precarious situation in the country and the unfortunate financial constraints deterred any possibility of seeking these tests in neighboring countries.
Given these circumstances, despite the clinical relevance of a cryoglobulinemia test in confirming the diagnosis of CMV-related DVT, it was practically unfeasible to pursue this diagnostic avenue. Consequently, the clinical diagnosis of CMV-related DVT was established based on the patient’s unilateral symptoms, the timing of DVT onset in correlation with the initial CMV infection, and was treated for both and discharged. Table {3}
In conclusion, cytomegaloviruses can cause deep venous thrombosis through a mechanism that needs to be better studied and analyzed. It is important to note that there is only one case report in the medical literature that is similar to ours (33) to the best of our knowledge, which makes our case considered to be a very rare case. In addition, CMV infection is a predisposing factor for thrombosis that needs to be considered in kidney transplant patients. Therefore, physicians should be aware of this serious complication and consider using prophylactic anticoagulants for high-risk patients.