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.