Oseltamivir-Resistant Pandemic (H1N1) 2009 Treated with Nebulized Zanamivir | CDC EID

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Volume 16, Number 11–November 2010
Letter
Oseltamivir-Resistant Pandemic (H1N1) 2009 Treated with Nebulized Zanamivir

Liviana Da Dalt, Comments to Author Arianna Calistri, Chiara Chillemi, Riccardo Cusinato, Elisa Franchin, Cristiano Salata, Dino Sgarabotto, Giuseppe Toscano, Antonio Gambino, and Giorgio Palù
Author affiliations: University of Padova, Padova, Italy (L. Da Dalt, A. Calistri, C. Chillemi, E. Franchin, C. Salata, G. Palù); and Azienda Ospedaliera di Padova, Padova (R. Cusinato, E. Franchin, D. Sgarabotto, G. Toscano, A. Gambino)

Suggested citation for this article

To the Editor: In late November 2009, a 3-year-old immunocompromised boy experienced an upper respiratory tract infection caused by influenza A pandemic (H1N1) 2009 virus, as demonstrated by a positive result for real-time PCR on a nasal swab specimen. His medical history was notable for a congenital intracardiac tumor; an ABO–incompatible heart transplant at 2 months of age; and an Epstein-Barr virus–related humoral rejection 20 months later that was treated with anti-CD20 and plasmapheresis and continuous immunosuppressive therapy with tacrolimus and everolimus. Thus, a 5-day regimen of oseltamivir treatment was undertaken, and the patient's clinical signs improved.

However, 3 days after drug treatment was suspended, the child had a relapse and exhibited fever, cough, and mild respiratory distress. The patient had fine crackles in the left posterior basal lung, normal oxygen saturation, and an infiltrate in the left basal lung, observed on chest radiograph. Infection with pandemic (H1N1) 2009 virus was confirmed. He was then transferred to an isolated ward of the pediatric department, and oseltamivir treatment was again initiated and dosages of immunosuppressive drugs were reduced. However, no clinical or virologic responses were observed during the 3 weeks of drug administration.

Over the next month, the oral dosage of oseltamivir was increased twice, without substantial effects on clinical course and viral clearance of the infection (Figure). Because of persistence of infection, the viral neuraminidase gene was sequenced, which showed the H275Y mutation (1). We immediately requested zanamivir aqueous solution from GlaxoSmithKline (Brentford, UK), and, after the approval of the hospital's ethics committee and parents' consent were obtained, nebulized treatment was carried out for 10 days. Fever and respiratory symptoms and signs resolved after 6 days of treatment and progressive real-time PCR gave negative results. Moreover, at the end of the treatment period, chest radiograph did not show abnormal findings, and results of a hemagglutination-inhibition assay were positive for influenza. No zanamivir-related adverse events were observed, except for a mild bronchospasm that responded to albuterol.

Another notable point is that the clinical course of the disease was not severe, although the child was immunocompromised and the infection persisted for almost 2 months. However, influenza virus persistence, possibly caused by inability of the child's immune system to clear the infection, and prolonged treatment with oseltamivir, led to the appearance of the H275Y mutation. H275Y has been described as the most common mutation that confers oseltamivir resistance in pandemic (H1N1) 2009 infection and has been found in all the resistant isolates reported worldwide (1). Consistent with previous reports (2), in the patient described here, antiviral drug resistance arose early in the treatment course. Retrospective analysis demonstrated the appearance of a mixed population after ≈2 weeks of drug use with a slow progression toward a pure H275Y variant. This latter finding may be explained by other virologic characteristics of this viral isolate, which is currently undergoing deep sequencing of the full genome.

Zanamivir represents the therapeutic option for patients infected with the H275Y mutation of pandemic (H1N1) 2009 virus. Its licensed formulation as a dry powder is suitable only for patients who can actively use inhaled drugs and thus cannot be used in children <7 years of age (3). Intravenous zanamivir solution has been reported to be safe and effective in experimental influenza A virus infection and as compassionate therapy in 2 immunocompromised adult patients who underwent mechanical ventilation for severe pneumonia (4,5). Moreover, successful use of intravenous zanamivir in a critically ill child, who was immunosuppressed after allogenic stem cell transplantation and infected with oseltamivir-resistant pandemic (H1N1) 2009 virus, has been reported (6). In this latter case, the regimen was well tolerated and was associated with a decrease in viral load.

Despite these results showing the efficacy of zanamivir intravenous administration, the inhalatory route for influenza virus–specific drugs should be the first choice, whenever possible, because it delivers therapeutic molecules directly to the site of viral replication, resulting in low systemic exposure. For this reason and because of the mild severity of the patient's disease, we decided to use zanamivir solution nebulized by aerosol. The compliance to this treatment was easily achieved, and the therapy showed good efficacy and was well tolerated by the child. The minor side effect observed has already been reported in the literature (7).

In conclusion, our experience supports the view that in immunocompromised patients with persistent infection, emergence of resistant viral strains should be strictly monitored. In this context, recently developed real-time PCRs for rapid screening of H275Y could be useful (8). Moreover, although a direct cause and effect has not been confirmed, this case suggests that aerosolized zanamivir solution can be considered as a therapeutic option in young children with mild respiratory symptoms who are infected with oseltamivir-resistant influenza viruses. Additional studies should be conducted in young patients with more severe disease.

Financial support was provided to G.P. from Regione Veneto (Centro Regionale Specializzato per la genofenotipizzazione ed epidemiologia molecolare degli agenti da infezione per la diagnostica microbiologica e virale. Dgr n. 448 del 24.02.2009).

References

1. Centers for Disease Control and Prevention. World Health Organization. Pandemic (H1N1) 2009, update 91. 2010 Mar 12 [cited 2010 Mar 23]. http://www.who.int/csr/don/2010_03_12/en/index.html
2. Centers for Disease Control and Prevention. Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients. MMWR Morb Mortal Wkly Rep. 2009;58:893–6.
3. Halasa NB. Update on the 2009 pandemic influenza A H1N1 in children. Curr Opin Pediatr. 2010;22:83–7. PubMed DOI
4. Kidd IM, Down J, Nastouli E, Shulman R, Grant PR, Howell DC, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet. 2009;374:1036. PubMed DOI
5. Gaur AH, Bagga B, Barman S, Hayden R, Lamptey A, Hoffman JM, et al. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med. 2010;362:88–9. PubMed DOI
6. Dulek DE, Williams JV, Creech CB, Schulert AK, Frangoul HA, Domm J, et al. Use of intravenous zanamivir after development of oseltamivir resistance in a critically ill immunosuppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clin Infect Dis. 2010;50:1493–6. PubMed DOI
7. Cheer SM, Wagstaff A. Spotlight on zanamivir in influenza. Am J Respir Med. 2002;1:147–52.
8. Hindiyeh M, Ram D, Mandelboim M, Meningher T, Hirsh S, Robinov J, et al. Rapid detection of influenza A pandemic (H1N1) 2009 virus neuraminidase resistance mutation H275Y by real-time RT-PCR. J Clin Microbiol. 2010;48:1884–7. PubMed DOI

Figure [see the full-text please]

Figure. Schematic showing events surrounding oseltamivir-resistant pandemic (H1N1) 2009 virus infection in 3-year-old immunocrompromised child, Italy...


Suggested Citation for this Article

Da Dalt L, Calistri A, Chillerri C, Cusinato R, Franchin E, Salata C, et al. Oseltamivir-resistant pandemic (H1N1) 2009 treated with nebulized zanamivir [letter]. Emerg Infect Dis [serial on the Internet]. 2010 Nov [date cited]. http://www.cdc.gov/EID/content/16/11/1813.htm

DOI: 10.3201/eid1611.100789

Comments to the Authors

Please use the form below to submit correspondence to the authors or contact them at the following address:

Liviana Da Dalt, Department of Pediatrics, University of Padova, Via N. Giustiniani, 3 – 35121 Padova, Italy; email: liviana.dadalt@unipd.it

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Oseltamivir-Resistant Pandemic (H1N1) 2009 Treated with Nebulized Zanamivir | CDC EID