To the Editor: The incidence of influenza A (H1N1) viruses thatcarry the neuraminidase H274Y mutation has increased by 30%this year in the Netherlands.1 Influenza A (H1N1) viruses thatcarry this mutation are resistant to oseltamivir but remainsensitive to zanamivir.2 However, these mutant viruses are consideredto have attenuated pathogenicity.3,4
A 67-year-old man who had received a diagnosis of chronic lymphocyticleukemia 3 years earlier was admitted to the hospital becauseof dyspnea, dry cough, and fever. One week before admission,he had received a course of cyclophosphamide, vincristine, andprednisolone chemotherapy. At admission, his white-cell countwas 137,000 per cubic millimeter, with 99% lymphocytes and noneutrophils. Because of acute respiratory failure, empiricalantibacterial therapy was initiated, and mechanical ventilationwas required by the second hospital day (Figure 1). Computedtomography (CT) revealed patchy infiltrates in both lungs, andinfluenza A (H1N1) virus was detected in respiratory secretions.During the entire hospital course, no other respiratory pathogenswere detected in bronchoalveolar-lavage specimens. The onlyother pathogens identified in blood cultures were Candida albicansand Enterococcus faecium, for which fluconazole and vancomycinwere given.
Figure 1. Leukocyte Counts, Viral Loads, and Treatment during the Hospital Course in a Patient Infected with Influenza A (H1N1) Virus with the H274Y Mutation.
Panel A shows the patient's granulocyte and monocyte counts. The gradual increase in the granulocyte count was consistent with bone marrow recovery. Panel B shows the viral load in the respiratory specimens. The dashed red line indicates the lower limit of detection. Various therapeutic and empirical antiviral therapies, shown in Panel C, and antibacterial and antifungal therapies, shown in Panel D, were given to the patient at different intervals (shaded bars). The red portions of the bars in Panel C indicate detection of resistance mutations for either oseltamivir (neuraminidase H274Y) or amantidine (M2-channel L26F), and the blue boxes indicate detection of the wild-type genotype. The L26F resistance mutation in the M2 protein was detected only on day 20, whereas the H274Y mutation was present before and after oseltamivir was administered.
Oseltamivir was administered for the influenza virus infection,beginning on the sixth hospital day, but it was discontinuedon day 13 because sequence analysis revealed the H274Y mutation,and no decrease in the viral load was observed. In retrospect,the H274Y mutation was present in the specimen obtained beforeoseltamivir therapy was initiated. The patient's hospital recordand his family indicated that he had had no contact with patientswho had received oseltamivir. On day 15, amantadine was addedto the patient's treatment regimen. Four days later, the neutrophilcount increased, indicating bone marrow recovery. Mechanicalventilation was discontinued on day 20, and zanamivir by inhalationwas initiated. However, respiratory failure occurred on day22, mechanical ventilation was reinstituted, and therapy withzanamivir was discontinued. On day 26, the influenza virus wasno longer detectable. Because sequence analyses showed an amantadine-resistancemutation in the viral M2 protein (L26F) and zanamivir therapyhad been limited to three doses, clearance of the virus wasprobably due to recovery of the immune system. A second CT scan,obtained on day 28, revealed progression of the pulmonary infiltrates.Because of the poor prognosis, mechanical ventilation was discontinuedon day 34. The patient died 3 days later.
It has been suggested that the H274Y mutation, which confersresistance to oseltamivir, leaves the influenza A (H1N1) virusseverely compromised.3,4 However, the case we describe suggeststhat this oseltamivir-resistant virus can be pathogenic, atleast in an immunocompromised patient.
Erhard van der Vries, M.Sc. Bart van den Berg, M.D., Ph.D. Martin Schutten, Ph.D. Erasmus University Medical Center 3015CE Rotterdam, the Netherlands
Dr. Schutten reports receiving lecture fees from Roche Diagnostics,the Netherlands. No other potential conflict of interest relevantto this letter was reported.
Ferraris O, Lina B. Mutations of neuraminidase implicated in neuraminidase inhibitors resistance. J Clin Virol 2008;41:13-19. [CrossRef][ISI][Medline]
Ives JAL, Carr JA, Mendel DB, et al. The H274Y mutation in the influenza A/H1N1 neuraminidase acitve site following oseltamivir phospate treatment leave virus severely compromised both in vitro and in vivo. Antivir Res 2002;55:307-17.
Herlocher ML, Truscon R, Elias S, et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis 2004;190:1627-1630. [CrossRef][ISI][Medline]
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