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Case Report Prolonged Shedding of Amantadine- and Oseltamivir- Resistant Influenza A(H3N2) Virus with Dual Mutations in an Immunocompromised Infant

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Case Report Prolonged Shedding of Amantadine- and Oseltamivir- Resistant Influenza A(H3N2) Virus with Dual Mutations in an Immunocompromised Infant Antiviral Therapy 2010 15:1059–1063 (doi: 10.3851/IMP1657) Case report Prolonged shedding of amantadine- and oseltamivir- resistant influenza A(H3N2) virus with dual mutations in an immunocompromised infant Guillermo Ruiz-Carrascoso1*, Inmaculada Casas1, Francisco Pozo1, Marta González-Vincent2, Pilar Pérez-Breña1 1Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain 2Hospital Infantil Universitario Niño Jesús, Madrid, Spain *Corresponding author e-mail: [email protected] In this study, we report a case of multidrug-resistant contained the substitutions E119V in neuraminidase and influenza A(H3N2) virus isolated from an immunosup- V27A in M2, which produce resistance to oseltamivir and pressed patient with prolonged viral shedding. We also adamantanes, respectively. This is the first report of this describe the genetic characterization of the haemagglu- dual mutation pattern in multidrug-resistant influenza tinin, neuraminidase and M2 influenza genes. The virus A(H3N2) virus. Introduction Influenza, which causes significant morbidity and daily because of neurological toxicity). After receiving mortality in immunocompromised patients, is often fludarabine and melphalan as conditioning therapy, he associated with prolonged viral shedding [1,2] underwent allogenic non-identical peripheral blood regardless of vaccination and antiviral therapy. The transplantation from his mother in May 2005 (day 0). multidrug-resistant influenza viruses, including pan- Total lymphocyte cell (TLC) count prior to transplan- demic A(H1N1) and seasonal A(H1N1) and A(H3N2), tation was 1,340 cells/mm3 (25%). On day 10, fever as reported to date in treated immunocompromised was observed and oxygen therapy was required because patients [1,3–6], have presented the E119V, R292K or of respiratory insufficiency. On day 12, Grade II acute H275Y mutations in the neuraminidase (NA) gene and graft-versus-host disease (GVHD) that affected the skin the S31N mutation in the M2 gene, which confer osel- and liver was observed, and he was treated with corticos- tamivir and adamantane resistance, respectively. In this teroids and tacrolimus. On day 19, respiratory difficulty study, we report the prolonged shedding of influenza persisted and a bronchoalveolar lavage (BAL) sample A(H3N2) virus with an unusual combination of muta- (sample A) was sent to our laboratory (National Influ- tions conferring multidrug resistance to oseltamivir and enza Center, Madrid, Spain) for further testing. Using amantadine in an immunocompromised infant. previously described PCR assays for respiratory viruses A 6-month-old male with a previous history of influ- [7,8], the tested BAL sample was positive for influenza A. enza A infection detected by immunochromatographic On day 26 post-transplant and after 33 days of antiviral antigen detection in March 2005 that developed into therapy, treatment was discontinued and the patient was interstitial chronic pneumonia, also presented a T-cell- discharged from hospital with the influenza A infection negative, natural-killer-cell-negative and B-cell-positive apparently resolved. On day 38, fever, rash and upper severe combined immunodeficiency disease, which was respiratory symptoms reappeared (TLC 1,577 cells/ diagnosed 1 month after initial detection. The chest mm3; 9%). A nasal antigen detection swab showed that X-ray showed interstitial bilateral infiltration and the the influenza A infection remained unresolved. Because antigen detection nasal swab tested positive for influ- of the persistence of the respiratory symptoms and the enza A. The patient (weight 7 kg) received treatment prolonged shedding of influenza A, the patient was again with oseltamivir (12 mg twice daily) and amantadine treated with oseltamivir (12 mg once daily) and aman- (15 mg once daily, which was reduced to 7.5 mg once tadine (7.5 mg once daily) for 15 days. On day 86, a ©2010 International Medical Press 1359-6535 (print) 2040-2058 (online) 1059 AVT-10-OA-1636_Ruiz-Carrascoso 1059 12/10/10 11:25:54 G Ruiz-Carrascoso et al. reactivation of acute cutaneous and intestinal Grade elsewhere [9]. Additional M2 segment amplification III GVHD accompanied by rhinorrhea and crepitation was performed using the outer primers for eight influ- in the right hemithorax with an absence of fever was enza A viral RNA segments [9] and the inner primers observed. The culture and PCR results of a nasal swab designed for the generic amplification of the M2 seg- were positive for influenza A (sample B). The dosage of ment: sense 5′-CCTAYCAGAARCGRATGGG-3′ and corticosteroids was increased and the GVHD resolved. antisense 5′-TTCCTITCGRTAYTCYTCCC-3′. The The respiratory symptoms disappeared with supplemen- sequences of the NA, M2 transmembrane domain tal oxygen. In September 2005 (day 132), another epi- and HA1 domain of HA were directly amplified and sode of fever with upper and lower respiratory symptoms sequenced from the clinical samples. Comparisons occurred (TLC 665 cells/mm3; 10%) and a BAL sample of the sequences were made with reference to A/ tested positive for influenza A virus in culture and PCR Panama/2007/1999 amino acid numbering and the assays (sample C). Antiviral treatment with oseltamivir mutations with reference to the vaccine strains for the (12 mg twice daily) and amantadine (7.5 mg twice daily) 2004–2005 (A/California/7/2004) and 2005–2006 (A/ was reinitiated and continued until November 2005 (day Wisconsin/67/2005) influenza seasons in the Northern 180), when a throat swab sample (sample D) still tested Hemisphere. positive for influenza A on both culture and PCR assays The sequencing of the NA gene revealed an E119V despite the patient being asymptomatic. After progressive substitution (GenBank accession numbers EU652319, immune reconstitution (TLC 1.876 cells/mm3; 39%), the EU652320, EU652321 and EU652322), which was culture and PCR assays results of the nasal swab and associated with resistance to oseltamivir in the four BAL samples (samples E and F, respectively) were finally samples obtained from the reported case (Figure 2A). negative for influenza A in December 2005 (day 222). The segment encoding the M2 transmembrane The courses of antiviral treatment and dates of sample domain showed the V27A mutation (GenBank acces- collection are summarized in Figure 1. sion numbers EU652323, EU652324, EU652325 and All four samples (A, B, C and D) sent to our laboratory EU652326), which was related with the acquisition of (National Influenza Center) and tested between June resistance to adamantanes, in the same samples con- and November 2005 were identified as subtype H3N2 taining the E119V substitution (Figure 2B). The C50F by haemagglutinin (HA) and NA PCR as described substitution was found in M2 in the four samples. This Figure 1. Course of treatment and sample collection in a 6-month-old infant with severe combined immunodeficiency disease with persistent A(H3N2) influenza infection Sample A Sample B Sample C Sample D Samples E and F (T: +19) (T: +86) (T: +139) (T: +180) (T: +222) NA: E119V NA: E119V NA: E119V NA: E119V Influenza-A- ICT: M2: V27A ICT: M2: V27A M2: V27A M2: V27A negative ICT: Influenza- Influenza- Influenza- A-positive A-positive A-positive (T: -7) (T: +38) Mar Apr May June July Aug Sept Oct Nov Dec Admission (T: -9) Peripheral blood transplantation (T: 0) Oseltamivir + Oseltamivir + Oseltamivir + amantadine amantadine amantadine (T: -7 to +26) (T: +38 to +53) (T: +139 to +180) The dotted lines indicate antiviral treatment course. ICT, immunochromatographic antigen detection; M2, M2 gene; NA, neuraminidase gene; T, days before (-) or after (+) transplantation. 1060 ©2010 International Medical Press AVT-10-OA-1636_Ruiz-Carrascoso 1060 12/10/10 11:25:55 Influenza and multiple antiviral drug resistance Figure 2. N2 and M2 amino acid alignment with the A(H3N2) influenza prototype and vaccine strains A A 71 | #A/Panama/2007/1999 TTIEKEICPK LAEYRNWSKP QCKITGFAPF SKDNSIRLSA GGDIWVTREP YVSCDPDKCY QFALGQGTTL NNRHSNDTVH DRTPYRTLLM #A/California/7/2004 .......... .......... ..D....... .......... .......... .......... .......... ..V....... .......... #A/Wisconsin/67/2005 .......... .......... ..N....... .......... .......... .......... .......... ..V....... .......... #Sample A (EU652319) .......... .......... ..D....... .......... ........V. .......... .......... ..V....... .......... #Sample B (EU652320) .......... .......... ..D....... .......... ........V. .......... .......... ..V....... .......... #Sample C (EU652321) .......... .......... ..D....... .......... ........V. .......... .......... ..V....... .......... #Sample D (EU652322) .......... .......... ..D....... .......... ........V. .......... .......... ..V....... .......... #A/Panama/2007/1999 NELGVPFHLG TKQVCIAWSS SSCHDGKAWL HVCVTGHDEN ATASFIYDGR LVDSIGSWSK KILRTQESEC VCINGTCTVV MTDGSASGRA #A/California/7/2004 .......... .......... .......... ......D.K. .......N.. .....V.... E......... .......... ........K. #A/Wisconsin/67/2005 .......... .......... .......... ......D.K. .......N.. .....V.... E......... .......... ........K. #Sample A (EU652319) .......... .......... .......... ......D.K. .......N.. .....V.... E......... .......... ........K. #Sample B (EU652320) .......... .......... .......... ......D.K. .......N.. .....V.... E......... .......A.. ........K. #Sample C (EU652321) .......... .......... .......... ......D.K. .......N.. .....V.... E......... .......A.. ........K. #Sample D (EU652322) .......... .......... .......... ......D.K. .......N.. .....V.... E........
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