Sex: M
Vaccine: FLUX
Symptoms: Enterovirus test positive, Fatigue, H1N1 influenza, Human rhinovirus test positive, Influenza A virus test positive
Clinical narrative: suspected vaccination failure; bacterial pneumonia; Congestion; Enterovirus infection; influenza A/H1pdm09/influenza A H1 2009 (Influenza A virus type: H1N1); Rhinovirus infection; severe cough/cough; yellow sputum production; worsening fatigue; dyspnea/Shortness of breath; upper respiratory infection; dyspnea on exertion; Activities of daily living impaired; This case was reported in a literature article and described the occurrence of vaccination failure in a 64-year-old male patient who received Flu unspecified (Flu vaccine) for prophylaxis. (The treatment of Influenza in allogeneic hematopoietic stem cell transplant recipients previously treated with oseltamivir. Transplant Infectious Disease 2020.   The subject's past medical history included richter's syndrome, chronic lymphoid leukemia, diffuse large b-cell lymphoma and epstein-barr virus associated lymphoproliferative disorder (with lymph node, liver, and kidney involvement). Previously administered products included fludarabine, melphalan, alemtuzumab, tacrolimus (prophylaxis) and rituximab (received several doses, most recently in October 2018).   In October 2018, the patient received Flu vaccine. On an unknown date, less than 3 months after receiving Flu vaccine, the patient experienced vaccination failure (serious criteria GSK medically significant), pneumonia bacterial (serious criteria GSK medically significant), lung congestion (serious criteria GSK medically significant), enterovirus infection (serious criteria GSK medically significant), h1n1 influenza, rhinovirus infection, cough, sputum discolored, fatigue aggravated, dyspnea, upper respiratory tract infection, exertional dyspnea and activities of daily living impaired. The subject was treated with oseltamivir, azithromycin and baloxavir marboxil. On an unknown date, the outcome of the vaccination failure was unknown and the outcome of the pneumonia bacterial, lung congestion, enterovirus infection, h1n1 influenza, rhinovirus infection, cough, sputum discolored, fatigue aggravated, dyspnea, upper respiratory tract infection, exertional dyspnea and activities of daily living impaired were recovered/resolved.   It was unknown if the reporter considered the vaccination failure, pneumonia bacterial, lung congestion, enterovirus infection, h1n1 influenza, rhinovirus infection, cough, sputum discolored, fatigue aggravated, dyspnea, upper respiratory tract infection, exertional dyspnea and activities of daily living impaired 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 64-years-old male 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 Respiratory Pathogen two panel were included in the study]. The patient had Richter's transformation of chronic lymphoid leukemia to diffuse large B-cell lymphoma, for which the patient received a matched related donor (MRD) allogeneic SCT in January 2017. The patient was conditioned with fludarabine, melphalan, and alemtuzumab and received tacrolimus as post-transplant graft-versus-host disease (GVHD) prophylaxis. The patient's post-transplant course was complicated by Epstein-Barr virus-mediated post-transplant lymphoproliferative disease (PTLD) with lymph node, liver, and kidney involvement, for which the patient received several doses of rituximab (most recently in October 2018). The patient received Rituximab in prior 6 months. Time duration from SCT was 1.97 years. The patient had not active GVHD. The patient (setting) was from outpatient. No information on patient's family history was provided. On an unspecified date in October 2018, the patient received annual 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 at the end of December 2018, an unknown period after the vaccination, the patient presented to the clinic complaining of severe cough with yellow sputum production. Nasopharyngeal swab in universal viral transport media was collected as part of routine clinical care. An RP2 panel was positive for influenza A/H1pdm09 (Influenza A virus type: H1N1) and rhinovirus/enterovirus. The co-pathogen included Rhinovirus/enterovirus. The patient did not receive immunosuppressive therapy at the time of influenza diagnosis. The infection type was upper respiratory infection (URI). The patient received oseltamivir for the treatment of influenza and azithromycin for possible associated bacterial pneumonia, both for 5 days with no improvement. A repeat RP2 panel was still positive for influenza A, and a second course of oseltamivir was administered for an additional five days. [The patient received oseltamivir for 20 days]. The patient was seen in clinic weekly for 3 additional weeks and continued to complain of persistent cough with yellow sputum, worsening fatigue with dyspnea on exertion. Chest x-ray was unremarkable. RP2 tests at each visit remained positive for influenza A. The patient therefore received one dose (80 mg, weight-based) of baloxavir (once). At the follow-up visit 5 days later, his symptoms had improved, and the patient was able to walk without experiencing any shortness of breath. At this time, influenza A was not detected. By the following visit two weeks later, cough, congestion, and shortness of breath had resolved, and the patient had resumed normal activity. 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. [Nasopharyngeal swabs in universal viral transport media 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  and using lavatory kit in accordance with the manufacturers' protocols. Nucleic acids extracted using the platform were tested by real-time reverse transcriptase-PCR to confirm the presence of influenza virus. Nucleic acids extracted using lavatory 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. 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 by the Regulatory Authority  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