Sex: F
Vaccine: FLUX
Symptoms: Respiratory viral panel, Thrombocytopenia, Ultrasound abdomen abnormal, Urine analysis normal, White blood cell count decreased
Clinical narrative: Cytomegalovirus viremia; Fever; Chills; Night sweat; Lethargy; Headache; Myalgia; Nausea; Anorexia; left-sided pleuritic chest pain; multiple episodes of watery, non-bloody diarrhea; contracted gallbladder; mild surrounding inflammatory changes (suggestive of colitis).; Leukopenia; Thrombocytopenia; liver function abnormality; This case was reported in a literature article and described the occurrence of cytomegalovirus viremia in a 50-year-old female patient who received Flu Seasonal QIV Dresden (Influenza vaccine Quadrivalent 2017-2018 season) for prophylaxis.   The patient's past medical history included hypertension, polycystic kidney, autosomal dominant, end stage renal disease ((on hemodialysis) underwent a renal transplant (initial transplant) from a living unrelated donor in June 2016), inflammatory reaction ((allograft rejection, infection) included donor-specific antibody mediated rejection), apheresis (for inflammatory disease) and epstein-barr virus infection. Previously administered products included anti-thymocyte globulin, methylprednisolone, IVIG and rituximab. Concurrent medical conditions included polycystic liver disease and polycystic kidney. Concomitant products included sulfamethoxazole + trimethoprim (Sulfamethoxazole-Trimethoprim).   In November 2017, the patient received Influenza vaccine Quadrivalent 2017-2018 season. On an unknown date, 8 days after receiving Influenza vaccine Quadrivalent 2017-2018 season, the patient experienced cytomegalovirus viremia (serious criteria hospitalization and GSK medically significant), fever (serious criteria hospitalization), chills (serious criteria hospitalization), night sweat (serious criteria hospitalization), lethargy (serious criteria hospitalization), headache (serious criteria hospitalization), myalgia (serious criteria hospitalization), nausea (serious criteria hospitalization), anorexia (serious criteria hospitalization), pleuritic pain (serious criteria hospitalization), diarrhea (serious criteria hospitalization), gallbladder disorder (serious criteria hospitalization), colitis (serious criteria hospitalization), leukopenia (serious criteria GSK medically significant), thrombocytopenia (serious criteria GSK medically significant) and hepatic function abnormal. The patient was treated with prednisone, mycophenolate mofetil and tacrolimus. On an unknown date, the outcome of the cytomegalovirus viremia was recovered/resolved and the outcome of the fever, chills, night sweat, lethargy, headache, myalgia, nausea, anorexia, pleuritic pain, diarrhea, gallbladder disorder, colitis, leukopenia, thrombocytopenia and hepatic function abnormal were unknown.   The reporter considered the cytomegalovirus viremia, fever, chills, night sweat, lethargy, headache, myalgia, nausea, anorexia, pleuritic pain, diarrhea, gallbladder disorder, colitis, leukopenia, thrombocytopenia and hepatic function abnormal to be related to Influenza vaccine Quadrivalent 2017-2018 season.  Additional details were reported as follows: This case was reported in a literature article and described the occurrence of cytomegalovirus viremia in a 50-years old female patient, who was vaccinated with unspecified influenza vaccine (manufacturer unknown) for prophylaxis. This case corresponds to first patient reported in this literature article. The patient had past medical history of hypertension, autosomal dominant polycystic kidney disease and end-stage renal disease (on hemodialysis) underwent a renal transplant (initial transplant) from a living unrelated donor in June 2016. The Donor CMV status was CMV seropositive and the recipient CMV status was CMV seronegative. Induction immunosuppressive regimen included anti-thymocyte globulin, methylprednisolone and intravenous immune-globulin (IVIG). Recent inflammatory disease processes (allograft rejection, infection) included donor-specific antibody mediated rejection. The patient had an episode of antibody-mediated rejection. Time period between transplant and inflammatory disease process was 4 months. Treatments for inflammatory disease processes included IVIG, rituximab and apheresis. Duration of inflammatory disease process was 1 month. The patient had no prior episodes of CMV reactivation. Primary/secondary CMV prophylaxis included off CMV prophylaxis at the time of disease presentation. The patient had no recent increase in maintenance immunosuppressive regimen. Time period between transplant and presentation was 17 months. No information on patient's family history was provided. On an unspecified date in November 2017, the patient received unspecified influenza vaccine (administration route and site unspecified, dosage unknown; batch number not provided) at the outpatient transplant nephrology clinic. The age of vaccination was not provided. On an unspecified date, 8 days after the vaccination, the patient presented to next appointment with complaints of fever with chills, night sweats, lethargy, headaches, myalgias, nausea, anorexia, left-sided pleuritic chest pain and multiple episodes of watery, non-bloody diarrhea. The patient was directed to the emergency department for further evaluation. Prophylactic medications at the time of presentation included sulfamethoxazole-trimethoprim (SMX-TMP) single-strength (SS) 1-tablet oral (PO) every twenty-four hours (QD). The patient denied sick contacts, recent travel, medication changes or medication non-compliance. At the time of admission, the patient was on prednisone 5 mg PO (oral) QD, mycophenolate mofetil (MMF) 360 mg PO QID, tacrolimus 0.5 mg PO BID. The patient's vitals on admission were significant for temperature 101.7 F, heart rate 100/minute, blood pressure 118/79 mm Hg, respirations 18/minute and oxygen saturation 98% on room air. Physical exam revealed no acute abnormalities. Admission labs were significant for white blood cell (WBC) 2,070/cubic mm [normal range (N): 3,800-10,500/cubic mm], absolute neutrophil count (ANC) 1,865/cubic mm [N: 1,800-7,400/cubic mm], lymphocyte count 500/cubic mm [N: 1,000-3,300/cubic mm], platelets 108,000/cubic mm [N: 150,000-400,00/cubic mm], aspartate transaminase (AST) 81 U/l [N: 10-40 U/l], alanine transaminase (ALT) 87 U/l [N: 10-45 U/l], alkaline phosphatase (ALP) 137 U/l [N: 40-120 U/l] and normal renal function. Electrocardiogram revealed sinus rhythm with no acute changes. Chest radiography and computed tomography (CT) ruled out the presence of pneumonia. Abdominal ultrasound showed polycystic liver and kidneys, contracted gallbladder with negative sonographic Murphy's sign. Computed tomography (CT) of the abdomen and pelvis confirmed polycystic liver and kidneys, as well as mural thickening of ascending colon with mild surrounding inflammatory changes (suggestive of colitis). Urinalysis was not suggestive of infection. Respiratory viral panel multiplex test was negative. Clostridium difficile toxin test was negative. Stool cultures were negative. Stool microscopy was negative for ova and parasites. Urine cultures revealed Escherichia coli (10,000-49,000 CFU/ml) combined with normal urogenital flora. Blood cultures revealed no growth. Testing for acute hepatitis A, B and C viruses was negative. Epstein-Barr virus serology revealed prior infection. BK virus DNA, Parvovirus B19 DNA and adenovirus DNA were not detected by specific polymerase chain reaction (PCR) tests. Infectious diseases service was consulted. Given the presence of leukopenia, thrombocytopenia, transaminitis and multi-systemic symptoms, there was concern for an ongoing viral process. The patient was started on valganciclovir 900 mg PO BID for presumed CMV disease, with intravenous fluid support. The E. coli in the urine was thought to be a colonization and the patient was successfully monitored off antibiotics. The patient continued to have persistent fevers and diarrhea, with worsening leukopenia (lowest WBC count 1700/cubic mm with lowest ANC 800/cubic mm), thrombocytopenia (nadir 86,000/cubic mm) and liver function abnormalities (AST 139 U/l, ALT 135 U/l, ALP 167 U/l). Given the persistent symptoms and worsening laboratory parameters, MMF was discontinued. Serum CMV PCR testing revealed 154,697 IU/ml (5.19 log10 IU/ml) [lower limit of assay detection 60 IU/ml (1.78 log10 IU/ml)]. Gastroenterology service was consulted for worsening liver function abnormalities and it was attributed the clinical picture to systemic CMV infection. The patient had clinical improvement, with improving CMV PCR tests [504 IU/ml (2.70 log10 IU/ml)] after 12 days of antiviral therapy. The patient was discharged on the twelfth day of hospital stay, with recovery of WBC count to 5,600/cubic mm and platelets 147,000/cubic mm. The patient was followed up by in the outpatient transplant nephrology and infectious diseases clinics. CMV PCR was negative 60 days after initiation of antiviral therapy and the patient was restarted on a lower dose of MMF. After the second negative CMV PCR a week later, MMF dose was increased and valganciclovir was decreased to prophylactic dosing. The patient received valganciclovir for a total of 87 days. The outcome was control of CMV viremia and recovery of cell counts. Graft outcome was stable allograft function. This case has been considered as serious due to hospitalization.  The author commented, "There are multiple risk factors linked to CMV viremia and disease in solid organ transplant recipients (SOTRs) and after hematopoietic stem cell transplant. These include older age, female sex, blood group A, decreased creatinine clearance, allograft impairment, CMV serostatus prior to transplant (donor seropositive-recipient seronegative OR recipient seropositive), transplantation type, use of T-cell depleted stem cell grafts, use of anti-thymocyte globulin before transplant, and occurrence of graft-versus-host disease (GvHD). Vaccination has not been previously reported as a risk factor for CMV viremia. There is a paucity of data on the effects of influenza vaccination leading to viremia in solid organ transplant recipients. Thus, we reviewed the data available in human immunodeficiency virus (HIV)-infected patients, another subset of immunocompromised patients. The research on the effect of influenza virus on HIV replication has produced conflicting results. Some studies have shown that influenza vaccination results in increased HIV replication (and subsequently increased viremia) in patients with uncontrolled or partially controlled viral replication. Other studies have shown that vaccination did not result in increased HIV replication. In some transplant recipients, influenza-like illness has been reported after vaccination. SOTRs are maintained in a state of prolonged immunosuppression after transplant. Thus, there is a possibility that influenza vaccination may lead to transient increase in CMV viral load and subsequent viremia (similar to the transient viremia seen in HIV patients). Both patients had a temporal association of onset of CMV viremia with administration of the influenza vaccine. They were older females at high risk of CMV reactivation (donor CMV seropositive/recipient CMV seronegative). Second Patient was on CMV prophylaxis, while second patient was not receiving valganciclovir (per our institutional protocol of CMV prophylaxis until six months post-transplant). They reported compliance with their home medications, with no recent increases in their maintenance immunosuppression. First Patient had an episode of antibody-mediated rejection, while second patient had an upper respiratory bacterial infection in the preceding months - these resolved completely with appropriate therapy. They had no concurrent inflammatory disease processes at the time of vaccination. Lab testing demonstrated high CMV DNA levels with concomitant leukopenia, neutropenia and lymphopenia. There were no additional factors identified to have contributed to CMV viremia. The CMV viremia was severe enough to warrant therapeutic antiviral therapy and changes in their immunosuppression regimen. We thus believe that CMV viremia resulted from the prior vaccination in our patients. One meta-analysis concluded that the influenza vaccine was associated with statistically significant protection against influenza-like illness in immunocompromised patients, including SOTRs. Through this case report, we wish to highlight the finding of CMV viremia occurring after influenza vaccination, with no other identified triggers. Further research and accumulation of cases is needed to investigate the strength of this association, to determine the mechanisms that resulted in CMV viremia and to recognize the risk factors leading to progression from viremia to clinically relevant CMV disease." The author concluded, "Vaccination may lead to transient viral replication in immunocompromised patients, such as HIV-infected patients (likely due to genetic and immune-mediated mechanisms). Similarly, we believe that influenza vaccination led to transient CMV viremia and CMV disease in our renal transplant recipients on potent immunosuppressive therapies. Further research is needed to assess the strength of this correlation, the mechanisms causing viremia and the risk of progression to clinical disease. Until then, clinicians must continue vaccination of SOTRs per the guidelines, but must also remember to enquire about recent vaccination when evaluating SOTRs with new onset CMV viremia." This article corresponding to this case is not available for regulatory submission due to copyright restriction. This is 1 of the 2 valid cases reported in the same literature article.; Sender's Comments:  US-GLAXOSMITHKLINE-US2020GSK190048:Same reporter