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Write-up: Hypotension; Sepsis; Loose stool; suspected vaccination failure; influenza A/H1pdm09/influenza A H1 2009 (Influenza A virus type: H1N1); Chills; Rhinorrhea; recurrent high fevers; Dry cough; left upper lobe pneumonia; Tiredness; Death NOS; Legionella pneumophila; This case was reported in a literature article and described the occurrence of unknown cause of death in a 66-year-old female patient who received Flu unspecified (Flu vaccine) for prophylaxis. Previously administered products included fludarabine, melphalan, alemtuzumab, total body irradiation, tacrolimus (prophylaxis) and rituximab (detectable circulating EBV DNA prior to transplant). Concurrent medical conditions included angioimmunoblastic t-cell lymphoma and chronic myelomonocytic leukemia (received a matched related donor (MRD) stem cell transplant (SCT) (in October 2018)). On an unknown date, the patient received Flu vaccine. In February 2019, less than a year after receiving Flu vaccine, the patient experienced vaccination failure (serious criteria hospitalization and GSK medically significant), h1n1 influenza (serious criteria hospitalization), chills (serious criteria hospitalization), rhinorrhea (serious criteria hospitalization), fever (serious criteria hospitalization), dry cough (serious criteria hospitalization) and legionella pneumophila infection (serious criteria GSK medically significant). In July 2019, the patient experienced unknown cause of death (serious criteria death and GSK medically significant). On an unknown date, the patient experienced lobar pneumonia (serious criteria GSK medically significant), hypotension (serious criteria hospitalization), sepsis (serious criteria hospitalization and GSK medically significant), loose stools (serious criteria hospitalization) and tiredness. The subject was treated with oseltamivir, antibiotics nos, baloxavir marboxil and azithromycin. On an unknown date, the outcome of the unknown cause of death was fatal and the outcome of the vaccination failure, h1n1 influenza, chills, rhinorrhea, fever, legionella pneumophila infection, lobar pneumonia, hypotension, sepsis, loose stools and tiredness were unknown and the outcome of the dry cough was recovered/resolved. The subject died in July 2019. The reported cause of death was unknown cause of death. It was unknown if the reporter considered the unknown cause of death, vaccination failure, h1n1 influenza, lobar pneumonia, hypotension, sepsis, chills, rhinorrhea, fever, dry cough, loose stools, legionella pneumophila infection and tiredness 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 66-years-old female patient, who was vaccinated with unspecified seasonal 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 angioimmunoblastic T-cell lymphoma (AITL) in partial remission and chronic myelomonocytic leukemia (CMML) who received a matched related donor (MRD) stem cell transplant (SCT) (in October 2018). The patient received fludarabine, melphalan, alemtuzumab, and total body irradiation (TBI 400cGy) as conditioning and tacrolimus as post-transplant graft-versus-host disease (GVHD) prophylaxis. Because of detectable circulating EBV DNA prior to transplant, the patient received one dose of rituximab with her transplant conditioning. The patient received Rituximab in prior 6 months. Time duration from SCT was 0.30 years. The patient had not active GVHD. The patient (setting) was from inpatient. No information on patient''s family history was provided. On an unspecified date, the patient received annual unspecified seasonal 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 February 2019, an unknown period after the vaccination, the patient experienced chills, rhinorrhea, cough, and fever to 39 degree Celsius and was diagnosed with influenza A H1 2009 (Influenza A virus type: H1N1) using the RP2 panel. Nasopharyngeal swab in universal viral transport media (BD) was collected as part of routine clinical care. The patient did not receive immunosuppressive therapy at the time of influenza diagnosis. Oseltamivir therapy was initiated (for 5 days), but 5 days later the patient presented to the emergency department with recurrent high fevers to 40 degree Celsius, chills, rhinorrhea, dry cough, and loose stool. CT chest showed left upper lobe pneumonia, and a repeat RP2 panel was still positive for influenza A virus. The infection type was pneumonia. The patient was admitted to the intensive care unit for hypotension/sepsis and received broad-spectrum antibiotics and baloxavir 40 mg for influenza. The next day, a urinary antigen test for Legionella pneumophila serotype 1 was reported to be positive and antibiotic treatment with azithromycin 500 mg daily was started. The co-pathogen included Legionella. Her symptoms rapidly improved but the patient continued to complain of persistent cough and tiredness, and the RP2 panel was still positive for influenza A. A second dose of baloxavir 40 mg was administered 4 days after the initial dose, and the patient was discharged home two days later. When the patient returned to clinic for follow-up 1 and 3 weeks after discharge, her symptoms were much improved, the patient had no cough, but was positive for influenza A/H1pdm09 at both visits. The influenza outcome was persistent shedding. Neuraminidase sequence was WT (Wild-type) and Polymerase sequence was I38T. This case has been considered as suspected vaccination failure being the time to onset was unknown. On an unspecified date in July 2019, the patient died from progressive disease. 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-US2020GSK203425:Same reporter; Reported Cause(s) of Death: death NOS
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