Correspondence

Fatal Oseltamivir-Resistant Influenza Virus Infection

N Engl J Med 2008; 359:1074-1076September 4, 2008

Article

To the Editor:

The incidence of influenza A (H1N1) viruses that carry the neuraminidase H274Y mutation has increased by 30% this year in the Netherlands.1 Influenza A (H1N1) viruses that carry this mutation are resistant to oseltamivir but remain sensitive to zanamivir.2 However, these mutant viruses are considered to have attenuated pathogenicity.3,4

A 67-year-old man who had received a diagnosis of chronic lymphocytic leukemia 3 years earlier was admitted to the hospital because of dyspnea, dry cough, and fever. One week before admission, he had received a course of cyclophosphamide, vincristine, and prednisolone chemotherapy. At admission, his white-cell count was 137,000 per cubic millimeter, with 99% lymphocytes and no neutrophils. Because of acute respiratory failure, empirical antibacterial therapy was initiated, and mechanical ventilation was required by the second hospital day (Figure 1Figure 1Leukocyte Counts, Viral Loads, and Treatment during the Hospital Course in a Patient Infected with Influenza A (H1N1) Virus with the H274Y Mutation.). Computed tomography (CT) revealed patchy infiltrates in both lungs, and influenza A (H1N1) virus was detected in respiratory secretions. During the entire hospital course, no other respiratory pathogens were detected in bronchoalveolar-lavage specimens. The only other pathogens identified in blood cultures were Candida albicans and Enterococcus faecium, for which fluconazole and vancomycin were given.

Oseltamivir was administered for the influenza virus infection, beginning on the sixth hospital day, but it was discontinued on 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 before oseltamivir therapy was initiated. The patient's hospital record and his family indicated that he had had no contact with patients who had received oseltamivir. On day 15, amantadine was added to the patient's treatment regimen. Four days later, the neutrophil count increased, indicating bone marrow recovery. Mechanical ventilation was discontinued on day 20, and zanamivir by inhalation was initiated. However, respiratory failure occurred on day 22, mechanical ventilation was reinstituted, and therapy with zanamivir was discontinued. On day 26, the influenza virus was no longer detectable. Because sequence analyses showed an amantadine-resistance mutation in the viral M2 protein (L26F) and zanamivir therapy had been limited to three doses, clearance of the virus was probably 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 discontinued on day 34. The patient died 3 days later.

It has been suggested that the H274Y mutation, which confers resistance to oseltamivir, leaves the influenza A (H1N1) virus severely compromised.3,4 However, the case we describe suggests that this oseltamivir-resistant virus can be pathogenic, at least 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, 3015 CE Rotterdam, the Netherlands

Dr. Schutten reports receiving lecture fees from Roche Diagnostics, the Netherlands. No other potential conflict of interest relevant to this letter was reported.

4 References

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   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;55:307-317
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