Sex: F
Vaccine: FLUX
Symptoms: Acute respiratory distress syndrome, Blood culture negative, Chest X-ray abnormal, Computerised tomogram thorax abnormal, Coronavirus infection
Clinical narrative: suspected vaccination failure; influenza A/H1pdm09; coronavirus 229E; shortness of breath; Cough/productive cough; Fever; Death NOS; rhinovirus/enterovirus; rhinovirus/enterovirus; Fatigue; Bacterial pneumonia; Acute respiratory distress syndrome; hypoxic respiratory failure; This case was reported in a literature article and described the occurrence of unknown cause of death in a 61-year-old female patient who received Flu unspecified (Flu vaccine) for prophylaxis.   The subject's past medical history included acute myeloid leukemia (underwent a matched related donor (MRD) stem cell transplant (SCT) in November 2016) and graft versus host disease. Previously administered products included fludarabine, melphalan, alemtuzumab, tacrolimus (prophylaxis), steroids and ruxolitinib. Concurrent medical conditions included neoplasm malignant and immunocompromised.   On an unknown date, the patient received Flu vaccine. In December 2018, less than a year after receiving Flu vaccine, the patient experienced vaccination failure (serious criteria hospitalization and GSK medically significant), influenza a virus infection (serious criteria hospitalization), coronavirus infection (serious criteria hospitalization), pneumonia bacterial (serious criteria GSK medically significant), acute respiratory distress syndrome (serious criteria GSK medically significant), hypoxic respiratory failure (serious criteria GSK medically significant), shortness of breath (serious criteria hospitalization), cough (serious criteria hospitalization), fever (serious criteria hospitalization), enterovirus infection (serious criteria GSK medically significant), rhinovirus infection and fatigue. In January 2020, the patient experienced unknown cause of death (serious criteria death and GSK medically significant). The subject was treated with tacrolimus, oseltamivir, antibiotics nos, steroids nos (Steroids), prednisone, ruxolitinib, oxygen and baloxavir marboxil. In January 2020, the outcome of the unknown cause of death was fatal. On an unknown date, the outcome of the vaccination failure, influenza a virus infection, coronavirus infection, pneumonia bacterial, shortness of breath, cough, fever, enterovirus infection and rhinovirus infection were unknown and the outcome of the acute respiratory distress syndrome, hypoxic respiratory failure and fatigue were recovered/resolved. The subject died in January 2020. The reported cause of death was unknown cause of death.   It was unknown if the reporter considered the unknown cause of death, vaccination failure, influenza a virus infection, coronavirus infection, pneumonia bacterial, acute respiratory distress syndrome, hypoxic respiratory failure, shortness of breath, cough, fever, enterovirus infection, rhinovirus infection and fatigue to be related to Flu vaccine.  Additional details were provided as follows: This case was reported in a literature article and described the suspected vaccination failure in a 61-years-old female patient, who was vaccinated with unspecified influenza vaccine (manufacturer unknown) for prophylaxis. This case corresponds to table 1 reported in this literature article. The patient was a part of the study which described the clinical and virological responses to oseltamivir and baloxavir treatment in five allogeneic SCT recipients, and molecular characteristics of the influenza virus population before and after treatment. [It was used baloxavir to treat five allogeneic SCT recipients that were still symptomatic and shedding influenza virus after completing one or more treatment courses of oseltamivir and characterized the viral isolates before and during treatment. Allogeneic SCT patients with influenza A virus infection who received oseltamivir with no resolution of symptoms and were persistently positive for influenza A virus by the FilmArray Respiratory Pathogen two panel were included in the study]. The patient had a history of acute myeloid leukemia (AML). The patient underwent a matched related donor (MRD) stem cell transplant (SCT) in November 2016 conditioned with fludarabine, melphalan, and alemtuzumab and received tacrolimus as post-transplant graft-versus-host disease (GVHD) prophylaxis. Time duration from SCT was 2.12 years. The patient had active GVHD. The patient (setting) was from inpatient. The patient's post-transplant course was complicated by cytogenetic disease relapse at 1 year. The patient received two donor lymphocyte infusions, which successfully controlled her malignancy but resulted in GVHD necessitating prolonged immunosuppression with systemic steroids, tacrolimus, and ruxolitinib. No information on patient's family history was provided. On an unspecified date, 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 in end of December 2018, an unknown period after the vaccination, the patient was admitted to an outside hospital complaining of shortness of breath, cough, and fever to 39 degree Celsius for 2 days prior to admission. Nasopharyngeal swab in universal viral transport media (BD) was collected as part of routine clinical care. The patient was found to be positive for influenza A. Chest x-ray showed bilateral interstitial opacifications suggesting a possible superimposed bacterial pneumonia. The infection type was pneumonia. The patient required high flow oxygen and was admitted to the intensive care unit. The patient was treated with oseltamivir, broad-spectrum antibiotics, and steroids for possible acute respiratory distress syndrome. Blood cultures were negative. After 4 days, the patient was transferred to the hospital, and on admission, RP2 was positive for influenza A/H1pdm09 (Influenza A virus type: H1N1) and coronavirus 229E. The patient received immunosuppressive therapy at the time of influenza diagnosis included prednisone 20 mg once a day (QD)/Ruxolitinib 5 mg twice a day (BID), Tacrolimus. The patient did not receive Rituximab in prior 6 months. The co-pathogen included rhinovirus/enterovirus. Treatment with oseltamivir for 5 days and broad-spectrum antibiotics for possible bacterial superinfection was continued for 10 days of total course. Despite this treatment, the patient continued to experience profound fatigue, productive cough, and hypoxic respiratory failure requiring oxygen supplementation (2-4L). Chest computerized tomography (CT) performed 3 weeks after admission showed variable change in multilobar pneumonia with improvement within the left upper lobe and progression in the left lower lobe. Weekly RP2 panels during this period were positive for influenza A and coronavirus 229E. Because of the concern for oseltamivir-resistant influenza, the patient received baloxavir (80 mg), once. The patient's respiratory status, cough, and fatigue rapidly improved, and the patient was discharged home four days after baloxavir treatment. A RP2 panel performed at discharge was positive for influenza A/H1pdm09, but it was unable to detect the virus in the same specimen by real-time RT-PCR or next-generation sequencing. The patient missed follow-up appointments because of severe weather conditions and was readmitted for unrelated issues one month after discharge. At that time, the patient was asymptomatic and the RP2 panel was negative for influenza and still positive for coronavirus 229E. The influenza outcome was clearance. Neuraminidase sequence was H275Y and Polymerase sequence was WT (Wild-type). This case has been considered as suspected vaccination failure being the time to onset was unknown.  On an unspecified date in January 2020, the patient succumbed to fatal complications of GVHD. It was unknown whether the patient's autopsy was performed or not. [Nasopharyngeal swabs in universal viral transport media (BD) were collected as part of routine clinical care using standard procedures. Influenza was detected using the RP2 panel. Nucleic acid was isolated both using an automated platform (easyMAG) and using QIAamp kit in accordance with the manufacturers' protocols. Nucleic acids extracted using the easyMAG platform were tested by real-time reverse transcriptase-PCR to confirm the presence of influenza virus. Nucleic acids extracted using QIAamp kits were sequenced with next-generation sequencing methods for whole-genome analysis. A total of five patients who were both symptomatic and persistently positive for influenza A on the RP2 panel after receiving oseltamivir were treated with baloxavir. Oseltamivir was administered at the standard dose of 75 mg twice/day orally. Baloxavir was administered orally as a single or two doses of 40 or 80 mg, based on weight, according to manufacturer's instructions. All patients were profoundly immunocompromised because of allogeneic lymphodepleting SCT. In addition, two had received rituximab (monoclonal antibody directed to the lymphocyte surface protein CD20) within 6 months of influenza diagnosis, two had received prolonged immunosuppressive treatment for graft-versus-host disease (GVHD), and one was obese, a predisposing condition for severe influenza. All patients had coinfection with other pathogens, four of them had pneumonia and were hospitalized].  This case has been considered serious due to suspected vaccination failure, death and hospitalization. The author commented, "It has been repeatedly reported that the treatment of influenza in immunocompromised hosts is problematic, requiring prolonged treatment courses, causing an increased risk of the development of antiviral-resistant influenza variants. Moreover, because uncomplicated influenza in this patient population may present with few initial symptoms and no fever, the diagnosis is often delayed, and treatment with NAI is often initiated after the preferred 48-hour window from onset of symptoms. Baloxavir has been recently approved for the treatment of uncomplicated influenza. It has been shown that treatment with baloxavir is associated with a more rapid viral clearance. Here, we describe the treatment of five allogeneic SCT recipients with baloxavir who were still positive for influenza A after oseltamivir treatment. In 4 of these subjects, including those with demonstrated oseltamivir-resistant variants, treatment with baloxavir was followed by clinical improvement and viral clearance. Three patients did not have any detectable NAI resistance-associated changes in the influenza viruses sequenced at the time they received baloxavir, and we cannot exclude the possibility that more prolonged oseltamivir treatment may have also been effective for symptom resolution and viral clearance. We found that one of the treated subjects developed a PA variant after two doses of baloxavir. Although the patient improved and eventually cleared the infection, the potential for transmission of variant virus raises concern. Despite the small patient number and the lack of a control group, our data suggest that baloxavir may be a useful treatment option for infections with influenza virus with NAI-resistant variants, and/or in SCT patients who fail NAI treatment for other reasons. Combination therapy, including baloxavir and oseltamivir, has shown synergistic activity in vitro. This treatment option might be more effective and may decrease the emergence of resistant influenza variants in the immunocompromised host." The author concluded, "Our data suggest that baloxavir treatment can be effective in treating neuraminidase inhibitor-resistant influenza in profoundly immunocompromised patients. Randomized clinical trials are needed to define the role of baloxavir alone and combined with oseltamivir for the treatment of influenza in SCT recipients and other immunocompromised populations." This is 1 of the 3 valid cases reported in the same literature article.; Sender's Comments:  US-GLAXOSMITHKLINE-US2020GSK205640:Same reporter US-GLAXOSMITHKLINE-US2020GSK205641:Same reporter; Reported Cause(s) of Death: death NOS