Sex: F
Vaccine: FLUX
Symptoms: Antimicrobial susceptibility test, BK polyomavirus test negative, Blood alkaline phosphatase increased, Blood creatinine increased, Blood urea normal
Clinical narrative: Cytomegalovirus viremia; leukopenia; non-bloody, foul-smelling diarrhea; This case was reported in a literature article and described the occurrence of cytomegalovirus viremia in a 62-year-old female patient who received Flu Seasonal QIV Dresden (Influenza vaccine Quadrivalent 2019-2020 season) for prophylaxis.  The patient's past medical history included endometriosis, chronic kidney disease (received a deceased donor kidney transplant in 1998 that failed in March 2018 and was subsequently on hemodialysis) and upper respiratory tract infection. Previously administered products included anti-inflammatory drug with an associated reaction of chronic kidney disease, anti-thymocyte globulin, methylprednisolone and amoxicillin. Concurrent medical conditions included hypertension. Concomitant products included sulphamethoxazole, trimethoprim (Sulfamethoxazole + Trimethoprim) and valganciclovir.   In September 2019, the patient received Influenza vaccine Quadrivalent 2019-2020 season. On an unknown date, 7 days after receiving Influenza vaccine Quadrivalent 2019-2020 season and an unknown time after starting Sulfamethoxazole + Trimethoprim, the patient experienced cytomegalovirus viremia (serious criteria hospitalization and GSK medically significant), leukopenia (serious criteria hospitalization and GSK medically significant) and diarrhea. The patient was treated with tacrolimus, prednisone, mycophenolate mofetil (Mmf), ganciclovir, letermovir and filgrastim. On an unknown date, the outcome of the cytomegalovirus viremia, leukopenia and diarrhea were unknown.   The reporter considered the cytomegalovirus viremia, leukopenia and diarrhea to be related to Influenza vaccine Quadrivalent 2019-2020 season.  Additional details were reported as follows: This case was reported in a literature article and described the occurrence of cytomegalovirus viremia in a 62-years old female patient, who was vaccinated with unspecified influenza vaccine (manufacturer unknown) for prophylaxis. This case corresponds to patient-2 reported in this literature article. The patient had past medical history of endometriosis, hypertension, chronic kidney disease (likely from anti-inflammatory drug use for management of endometriosis) was being followed in the transplant nephrology clinic. The patient received a deceased donor kidney transplant in 1998 that failed in March 2018 and was subsequently on hemodialysis. The patient received a second renal transplant (re-transplant) from a deceased unrelated donor in June 2019. The Donor CMV status was CMV seropositive and the recipient CMV status was CMV seronegative. Induction immunosuppressive regimen included anti-thymocyte globulin, and methylprednisolone. Recent inflammatory disease processes (allograft rejection, infection) included upper respiratory infection. [The patient had an upper respiratory bacterial infection in the preceding months - these resolved completely with appropriate therapy].  Time period between transplant and inflammatory disease process was 1 month. Treatments for inflammatory disease processes included amoxicillin. Duration of inflammatory disease process was 1 week. The patient had no prior episodes of CMV reactivation. The patient was taking primary CMV prophylaxis. The patient had no recent increase in maintenance immunosuppressive regimen. Time period between transplant and presentation was 3 months. No information on patient's family history was provided. On an unspecified date at the end of September 2019, the patient received unspecified influenza vaccine (administration route and site unspecified, dosage unknown; batch number not provided). The age of vaccination was not provided. On an unspecified date, 7 days (a week) after the vaccination, the patient's routine outpatient labs performed, and the patient was noted to have detectable CMV viral levels [4,983 IU/ml (3.70 log10 IU/ml)] without any symptoms. Prophylactic medications at the time of presentation included sulfamethoxazole-trimethoprim (SMX-TMP) single-strength (SS) 1 tablet oral (PO) every forty-eight hours (QOD) and Valganciclovir 450 mg every twenty-four hours (QD). The levels continued to rise over the course of two months [214,823 IU/ml (5.33 log10 IU/ml)] [lower limit of assay detection 60 IU/ml (1.78 log10 IU/ml)], with no improvement after switching from valganciclovir 450 mg QD to valganciclovir 900 mg QD. The patient was noted to have worsening leukopenia (WBC 1,260/cubic mm), so the patient was admitted for further management. On admission, the patient reported multiple episodes of non-bloody, foul-smelling diarrhea. The patient denied sick contacts, recent travel, medication changes or medication non-compliance. The patient's home medications consisted of tacrolimus ER 8 mg QD, prednisone 5 mg QD, MMF 1000 mg BID, sulfamethoxazole-trimethoprim single-strength tablet QOD, valganciclovir 450 mg QD. The patient was hemodynamically stable on examination. Physical examination revealed no abnormalities. Admission labs revealed WBC count 1,480/cubic mm (ANC 950/cubic mm and lymphocyte count 270/cubic mm [N: 1,000-3,300/cubic mm]), hemoglobin 11.1 g/dl (N: 13-17 g/dL), blood urea nitrogen (BUN) 20 mg/dL [N: 7-23 mg/dL], creatinine 1.53 mg/dl [N: 0.50-1.30 mg/dL], ALP 124 U/l. Chest radiograph revealed clear lungs. BK virus and Parvovirus B19 DNA PCR tests were negative. MMF and valganciclovir was held on admission. Infectious diseases service was consulted and the patient was started on renally-dosed intravenous (IV) ganciclovir (2.5 mg/kg QD) and letermovir 480 mg QD PO. Given the lack of response to outpatient valganciclovir therapy, a sample was sent for CMV resistance testing. With improvement in her creatinine clearance, the ganciclovir dosing was subsequently adjusted. WBC nadir during the hospital stay was 1,450/cubic mm (ANC 780/cubic mm), with subsequent recovery due to intravenous antivirals and one dose of filgrastim. CMV resistance tests revealed the presence of two different populations of virus - wild type and a strain exhibiting resistance at M460V and C603W (two out of seven mutations conferring resistance to ganciclovir). No resistance was noted to cidofovir or foscarnet. The patient was discharged on IV ganciclovir and oral letermovir. The final duration of therapy would be determined by outpatient follow-up with infectious diseases and transplant nephrology. The patient was to continue tacrolimus ER 3 mg QD PO and prednisone 5 mg QD PO at home. 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). Patient 2 was on CMV prophylaxis, while patient 2 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. Patient 1 had an episode of antibody-mediated rejection, while patient 2 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-US2020GSK189937:Same reporter