Immunosuppressants/oseltamivir

Coronavirus HKU1 infection and development of resistance: case report

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      An event is serious (based on the ICH definition) when the patient outcome is:
    • * death

    • * life-threatening

    • * hospitalisation

    • * disability

    • * congenital anomaly

    • * other medically important event

    “ ”

    A 38-year-old woman developed coronavirus (CoV) HKU1 infection during treatment with cyclophosphamide, fludarabine, methylprednisolone, prednisone and rituximab. Additionally, she also developed resistance during treatment with oseltamivir for influenza A infection [not all dosages stated; routes and durations of treatments to reactions onset not stated].

    The woman had a medical history of diffuse proliferative lupus nephritis, which was resistant to treatment with mycophenolate mofetil, high-dose corticosteroids and cyclophosphamide. For severe systemic lupus erythematosus, she underwent a T-cell depleted autologous haematopoietic stem cell transplant (HSCT). Rituximab, fludarabine and cyclophosphamide were used as conditioning regimen. Eleven weeks following the transplant, she was hospitalised due to dyspnoea and cough. A CT scan did not show any pulmonary disease, and 6 days afterwards, she was discharged following improvement on unspecified bronchodilators. She was readmitted 13 weeks after the transplant with dyspnoea on exertion, dry cough, nasal congestion, postnasal drip and rhinorrhea. Her daughter and son also had cold one after another in the last week, and influenza cases were reported at their school. Physical examination revealed a mildly cushingoid young woman with a constant cough and tachypnoea. Pulmonary examination revealed disseminated wheezing and rhonchi. The arterial blood gas on 35% oxygen revealed hypoxaemia. A CT scan of the lungs, which was performed at the time of this admission, revealed patchy areas of nodular infiltration of the lungs, involving all of the lobes and bilateral pleural effusions. A nasopharyngeal wash was found to be positive for influenza A H3N2 (later shown to be sensitive to oseltamivir). Induced sputum revealed a few neutrophils, gram-negative rods and gram-positive cocci in clusters and pairs. As the differential diagnosis consisted of lupus pneumonitis and influenza infection, she was started on oseltamivir 75mg two times a day and the dose prednisone was escalated to 20 mg/day. A repeat CT scan performed following 8 days of treatment did not show any improvement. Bronchoalveolar lavage (BAL) was found to be positive for influenza A virus. Owing to worsening pulmonary infiltrates, she underwent open lung biopsies on day 15 of the hospitalisation. The right lung revealed diffuse alveolar damage with hyaline membranes. Owing to continued risk about potential lupus pneumonitis, on the basis of the non-specific results of the lung biopsy, the steroids dose was increased to methylprednisolone 60 mg/day. After 21 days (16 weeks following transplant), therapy with oseltamivir was discontinued. Initially, her oxygenation ameliorated, and methylprednisolone dose was reduced; however, her hypoxaemia subsequently aggravated. As repeat BAL fluid and nasopharyngeal washes continued to grow influenza, on hospital day 29 (17 weeks following transplant), therapy with oseltamivir was recommenced at 150mg two times a day. She was administered IV immune globulin, and steroid therapy was continued. An antiviral sensitivity test subsequently revealed high level oseltamivir resistance.

    Therefore, the woman's oseltamivir was withdrawn and zanamivir was initiated. A CD4 count, which was obtained 20 weeks following transplant was found to be decreased. At 21 weeks after transplant, she was discharged on a tapering dose of steroids and zanamivir. When her pulmonary effusions returned and her infiltrates worsened, the steroids were recommenced. Following an improvement in her pulmonary status, the steroids were again tapered. She underwent sequencing of the oseltamivir-resistant H3N2 influenza virus isolate A/Bethesda/956/2006, which revealed an arginine to lysine mutation in the neuraminidase at amino acid 292. This mutation was previously shown to be related to oseltamivir resistance and with diminished viral fitness in animal experiments and instability invitro. Three weeks afterwards (24 weeks after transplant), she was readmitted with worsening pulmonary infiltrates. Zanamivir was maintained as nasopharyngeal washes persisted to grow influenza virus. Ribavirin was added because of her increasing pulmonary infiltrates and persistent shedding of influenza virus from the nasopharynx. This was indicative of decreased sensitivity of the influenza virus to zanamivir. In the final week of life, cyclophosphamide was added due to deterioration of her pulmonary status on tapering doses of corticosteroids and persistent concerns about lupus pneumonitis. Unspecified empiric antifungals and anti-bacterials were added. She died 27 weeks following transplant due to hypotension and cardiac arrest. At autopsy, the lungs revealed diffuse alveolar damage, bronchopneumonia and organising pneumonitis. As the standard tests could not provide an explanation for the progressive clinical course resulting in her death, a degenerate oligonucleotide primer (DOP) polymerase chain reaction (PCR) assay was employed to detect potential viruses in the lungs of this patient. A total of 63 sequence reads were attained from DOP-PCR. The sixty third sequence matched human CoV HKU1 genotype A with 410 of 412 identical nucleotides, overlapping the M and N genes. The results obtained using generic DOP-PCR were confirmed in both autopsy samples and BAL fluid with 3 independent CoV PCRs.

    Reference

    1. Uhlenhaut C, et al. Use of a novel virus detection assay to identify coronavirus HKU1 in the lungs of a hematopoietic stem cell transplant recipient with fatal pneumonia. Transplant Infectious Disease 14: 79-85, No. 1, Feb 2012. Available from: URL: http://doi.org/10.1111/j.1399-3062.2011.00657.x

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    Immunosuppressants/oseltamivir. Reactions Weekly 1808, 148 (2020). https://doi.org/10.1007/s40278-020-79625-x

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