Correspondence

Prolonged Shedding of Multidrug-Resistant Influenza A Virus in an Immunocompromised Patient

N Engl J Med 2003; 348:867-868February 27, 2003

Article

To the Editor:

Immunocompromised patients can persistently shed influenza, increasing the potential for resistance to antiviral drugs and for nosocomial transmission.1,2 We report the case of a 23-year-old man with acute lymphocytic leukemia who underwent transplantation of T-cell–depleted hematopoietic stem cells from his HLA-mismatched brother in August 1999 after receiving total body irradiation, thiotepa, fludarabine, and antithymocyte globulin. After transplantation, graft-versus-host disease developed (requiring treatment with prednisone and azathioprine), along with transplant-related nephropathy, avascular necrosis in both ankles, and restrictive lung disease.

In January 2001, rhinorrhea, cough, and fever developed. Computed tomographic scanning showed mucosal thickening in the maxillary, ethmoid, and sphenoid sinuses. Culture of a nasopharyngeal swab was positive for influenza A. The patient received treatment with amantadine for 21 days, then oseltamivir for 7 days. His symptoms persisted, and cultures remained positive for influenza A. In May 2001, the patient underwent endoscopic ethmoidectomy, maxillary antrostomy, and sphenoidotomy for persistent sinus-related symptoms. A culture of purulent sinus exudate grew influenza A. The patient received oseltamivir for five days in July 2001. At that time, his CD4 count was 19 cells per cubic millimeter. In November 2001, he received the 2001–2002 influenza vaccine. More than 40 nasopharyngeal swabs collected between February 2001 and July 2002 tested positive for influenza A. He received rimantadine for 21 days in May 2002 and zanamivir for 10 days in July 2002. Pulmonary rhizopus infection developed, and the patient died in August 2002. Isolation precautions, including the use of gowns, gloves, and masks, were enforced from January 2001 until the patient's death. No secondary cases of influenza were acquired from the patient.

An isolate of influenza A from February 2002 was typed (by the New York Department of Health) as H1N1. Drug-resistance testing was performed on isolates obtained between February 2002 and July 2002.3 The isolates were resistant to rimantadine and oseltamivir and susceptible to zanamivir. Sequencing of the neuraminidase gene revealed an H274Y substitution associated with resistance by H1N1 to oseltamivir but not to zanamivir.3-5

Profound immunodeficiency and abnormal sinonasal mucosa probably contributed to our patient's inability to clear the influenza. Previous reports have described shedding of influenza A for six months and persistence of drug-resistant influenza for two months.1,2 Our patient shed influenza A for 18 months and probably shed drug-resistant virus for more than a year. This case highlights the potential for extremely prolonged shedding of influenza, including drug-resistant strains, and the importance of stringent infection-control measures to prevent possible nosocomial spread.

David M. Weinstock, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
weinstod@mskcc.org

Larisa V. Gubareva, Ph.D.
University of Virginia, Charlottesville, VA 22908

Gianna Zuccotti, M.D., M.P.H.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021

5 References

1. 1

   Boivin G, Goyette N, Bernatchez H. Prolonged excretion of amantadine-resistant influenza A virus quasi species after cessation of antiviral therapy in an immunocompromised patient. Clin Infect Dis 2002;34:E23-E25
   CrossRef | Web of Science | Medline

2. 2

   Klimov AI, Rocha E, Hayden FG, Shult PA, Roumillat LF, Cox NJ. Prolonged shedding of amantadine-resistant influenza A viruses by immunodeficient patients: detection by polymerase chain reaction-restriction analysis. J Infect Dis 1995;172:1352-1355
   CrossRef | Web of Science | Medline

3. 3

   Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother 2001;45:3403-3408
   CrossRef | Web of Science | Medline

4. 4

   Ives JA, Carr JA, Mendel DB, et al. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leaves virus severely compromised both in vitro and in vivo. Antiviral Res 2002;55:307-317
   CrossRef | Web of Science | Medline

5. 5

   Gubareva LV, Kaiser L, Matrosovich MN, Soo-Hoo Y, Hayden FG. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis 2001;183:523-531
   CrossRef | Web of Science | Medline

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1. 1

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2. 2

   N. B. Halasa. (2011) Make New Friends, But Keep the Old: Influenza Vaccines in Children With Cancer. Journal of Infectious Diseases 204:10, 1471-1474
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3. 3

   Christian Renaud, Jane Kuypers, Janet A. Englund. (2011) Emerging oseltamivir resistance in seasonal and pandemic influenza A/H1N1. Journal of Clinical Virology 52:2, 70-78
   CrossRef

4. 4

   Christian Renaud, Angela P. Campbell. (2011) Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients. Current Opinion in Infectious Diseases 24:4, 333-343
   CrossRef

5. 5

   C. Uhlenhaut, J.I. Cohen, S. Pavletic, G. Illei, J.C. Gea-Banacloche, M. Abu-Asab, T. Krogmann, L. Gubareva, S. McClenahan, P.R. Krause. (2011) 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 Diseaseno-no
   CrossRef

6. 6

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   CrossRef

7. 7

   Silvana Carr, Natalia A. Ilyushina, John Franks, Elisabeth E. Adderson, Miguela Caniza, Elena A. Govorkova, Robert G. Webster. (2011) Oseltamivir-resistant Influenza A and B Viruses Pre- and Postantiviral Therapy in Children and Young Adults With Cancer. The Pediatric Infectious Disease Journal 30:4, 284-288
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8. 8

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9. 9

   A. N. Sheth, K. N. Althoff, J. T. Brooks. (2011) Influenza Susceptibility, Severity, and Shedding in HIV-Infected Adults: A Review of the Literature. Clinical Infectious Diseases 52:2, 219-227
   CrossRef

10. 10

    E. Ghedin, J. Laplante, J. DePasse, D. E. Wentworth, R. P. Santos, M. L. Lepow, J. Porter, K. Stellrecht, X. Lin, D. Operario, S. Griesemer, A. Fitch, R. A. Halpin, T. B. Stockwell, D. J. Spiro, E. C. Holmes, K. S. George. (2011) Deep Sequencing Reveals Mixed Infection with 2009 Pandemic Influenza A (H1N1) Virus Strains and the Emergence of Oseltamivir Resistance. Journal of Infectious Diseases 203:2, 168-174
    CrossRef

11. 11

    A. Pizzorno, X. Bouhy, Y. Abed, G. Boivin. (2011) Generation and Characterization of Recombinant Pandemic Influenza A(H1N1) Viruses Resistant to Neuraminidase Inhibitors. Journal of Infectious Diseases 203:1, 25-31
    CrossRef

12. 12

    C. A. Donnelly, L. Finelli, S. Cauchemez, S. J. Olsen, S. Doshi, M. L. Jackson, E. D. Kennedy, L. Kamimoto, T. L. Marchbanks, O. W. Morgan, M. Patel, D. L. Swerdlow, N. M. Ferguson, . (2011) Serial Intervals and the Temporal Distribution of Secondary Infections within Households of 2009 Pandemic Influenza A (H1N1): Implications for Influenza Control Recommendations. Clinical Infectious Diseases 52:Supplement 1, S123-S130
    CrossRef

13. 13

    P. A. Chan, N. T. Connell, A. M. Gabonay, B. Westley, J. M. Larkin, S. P. LaRosa, K. Chapin, L. Mermel. (2010) Oseltamivir-resistant 2009-2010 pandemic influenza A (H1N1) in an immunocompromised patient. Clinical Microbiology and Infection 16:10, 1576-1578
    CrossRef

14. 14

    Hana Hakim, Jerry L Shenep. (2010) Managing fungal and viral infections in pediatric leukemia. Expert Review of Hematology 3:5, 603-624
    CrossRef

15. 15

    Marta Valenciano, Esther Kissling, Bruno Christian Ciancio, Alain Moren. (2010) Study designs for timely estimation of influenza vaccine effectiveness using European sentinel practitioner networks. Vaccine 28:46, 7381-7388
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16. 16

    Michael G Ison. (2010) Influenza, including the novel H1N1, in organ transplant patients. Current Opinion in Infectious Diseases 23:4, 365-373
    CrossRef

17. 17

    Margaret Okomo-Adhiambo, Ha T. Nguyen, Katrina Sleeman, Tiffany G. Sheu, Varough M. Deyde, Rebecca J. Garten, Xiyan Xu, Michael W. Shaw, Alexander I. Klimov, Larisa V. Gubareva. (2010) Host cell selection of influenza neuraminidase variants: Implications for drug resistance monitoring in A(H1N1) viruses. Antiviral Research 85:2, 381-388
    CrossRef

18. 18

    A. Handel, I. M. Longini, R. Antia. (2010) Towards a quantitative understanding of the within-host dynamics of influenza A infections. Journal of The Royal Society Interface 7:42, 35-47
    CrossRef

19. 19

    Aran Lee, Yu Seun Kim, Myoung Soo Kim, Dong Jin Joo, Byung Mo Lee, Hyun Jung Kim, Soon Il Kim. (2010) Swine Influenza A (H1N1) Infection in Renal Transplant Recipients. The Journal of the Korean Society for Transplantation 24:4, 256
    CrossRef

20. 20

    Mohamed A. Kharfan-Dabaja, Ana Velez, Karla Richards, John N. Greene, Teresa Field, Ramon Sandin. (2010) Influenza A/pandemic 2009/H1N1 in the setting of allogeneic hematopoietic cell transplantation: a potentially catastrophic problem in a vulnerable population. International Journal of Hematology 91:1, 124-127
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21. 21

    Rodrigo Zapata, Mario Uribe, Waldo Martínez, Alejandro Andrade, José Luis Leal, Fernando Gomez. (2010) Severe novel H1N1 influenza A infection in the immediate postoperative period of a liver transplant patient. Liver TransplantationNA-NA
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22. 22

    Michael G Ison. (2009) Anti-influenza therapy: the emerging challenge of resistance. Therapy 6:6, 883-891
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23. 23

    S Candon, E. Thervet, P. Lebon, C. Suberbielle, J. Zuber, C. Lima, D. Charron, C. Legendre, L. Chatenoud. (2009) Humoral and Cellular Immune Responses after Influenza Vaccination in Kidney Transplant Recipients. American Journal of Transplantation 9:10, 2346-2354
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24. 24

    Josep Vaqué Rafart, Julita Gil Cuesta, María Brotons Agulló. (2009) Principales características de la pandemia por el nuevo virus influenza A (H1N1). Medicina Clínica 133:13, 513-521
    CrossRef

25. 25

    Gabriele Neumann, Takeshi Noda, Yoshihiro Kawaoka. (2009) Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459:7249, 931-939
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26. 26

    Fred Y. Aoki, Guy Boivin. (2009) Influenza virus shedding—Excretion patterns and effects of antiviral treatment. Journal of Clinical Virology 44:4, 255-261
    CrossRef

27. 27

    Lizheng Guo, Rebecca J. Garten, Angie S. Foust, Wendy M. Sessions, Margaret Okomo-Adhiambo, Larisa V. Gubareva, Alexander I. Klimov, Xiyan Xu. (2009) Rapid identification of oseltamivir-resistant influenza A(H1N1) viruses with H274Y mutation by RT-PCR/restriction fragment length polymorphism assay. Antiviral Research 82:1, 29-33
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28. 28

    Suk See De Ravin, Harry L. Malech. (2009) Partially corrected X-linked severe combined immunodeficiency: long-term problems and treatment options. Immunologic Research 43:1-3, 223-242
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29. 29

    Yacine Abed, Mariana Baz, Guy Boivin. (2009) A Novel Neuraminidase Deletion Mutation Conferring Resistance to Oseltamivir in Clinical Influenza A/H3N2 Virus. The Journal of Infectious Diseases 199:2, 180-183
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30. 30

    Yo Han Lee, Hyo Youl Kim, Hyun Soo Kim, Young Uh, Young Keun Kim, Bo Ra Kim, Ho Yeon Jung, Woo Taek Kim, Hwajung Yi. (2009) A Case of Oseltamivir-Resistant Pandemic Influenza (H1N1 2009) in a Patient with Acute Myeloid Leukemia. Infection and Chemotherapy 42:2, 107
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    Angie Lackenby, Catherine I Thompson, Jane Democratis. (2008) The potential impact of neuraminidase inhibitor resistant influenza. Current Opinion in Infectious Diseases 21:6, 626-638
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32. 32

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33. 33

    John H. Beigel. (2008) Influenza. Critical Care Medicine 36:9, 2660-2666
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34. 34

    Yacine Abed, Benjamin Nehmé, Mariana Baz, Guy Boivin. (2008) Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Research 77:2, 163-166
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35. 35

    J. Scharpé, P. Evenepoel, B. Maes, B. Bammens, K. Claes, A. D. Osterhaus, Y. Vanrenterghem, W. E. Peetermans. (2008) Influenza Vaccination Is Efficacious and Safe in Renal Transplant Recipients. American Journal of Transplantation 8:2, 332-337
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36. 36

    Vanessa Escuret, Emilie Frobert, Maude Bouscambert-Duchamp, Murielle Sabatier, Isidore Grog, Martine Valette, Bruno Lina, Florence Morfin, Olivier Ferraris. (2008) Detection of human influenza A (H1N1) and B strains with reduced sensitivity to neuraminidase inhibitors. Journal of Clinical Virology 41:1, 25-28
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37. 37

    Jane D. Siegel, Emily Rhinehart, Marguerite Jackson, Linda Chiarello. (2007) 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Health Care Settings. American Journal of Infection Control 35:10, S65-S164
    CrossRef

38. 38

    Richard J Whitley. (2007) The role of oseltamivir in the treatment and prevention of influenza in children. Expert Opinion on Drug Metabolism & Toxicology 3:5, 755-767
    CrossRef

39. 39

    L. Kaiser. (2006) Influenza Will Not Miss Opportunities. Clinical Infectious Diseases 43:12, 1562-1564
    CrossRef

40. 40

    M. Baz, Y. Abed, J. McDonald, G. Boivin. (2006) Characterization of Multidrug-Resistant Influenza A/H3N2 Viruses Shed during 1 Year by an Immunocompromised Child. Clinical Infectious Diseases 43:12, 1555-1561
    CrossRef

41. 41

    Aeron C Hurt, Hui-Ting Ho, Ian Barr. (2006) Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors. Expert Review of Anti-infective Therapy 4:5, 795-805
    CrossRef

42. 42

    Vasiliy P. Mishin, Frederick G. Hayden, Kathy L. Signorelli, Larisa V. Gubareva. (2006) Evaluation of methyl inosine monophosphate (MIMP) and peramivir activities in a murine model of lethal influenza A virus infection. Antiviral Research 71:1, 64-68
    CrossRef

43. 43

    Todd D. Barton, Emily A. Blumberg. (2005) Viral Pneumonias Other Than Cytomegalovirus in Transplant Recipients. Clinics in Chest Medicine 26:4, 707-720
    CrossRef

44. 44

    Rodrigo Martino, Rocío Parody Porras, Nuria Rabella, John V. Williams, Elena Rámila, Nuria Margall, Rosa Labeaga, James E. Crowe, Pedro Coll, Jorge Sierra. (2005) Prospective Study of the Incidence, Clinical Features, and Outcome of Symptomatic Upper and Lower Respiratory Tract Infections by Respiratory Viruses in Adult Recipients of Hematopoietic Stem Cell Transplants for Hematologic Malignancies. Biology of Blood and Marrow Transplantation 11:10, 781-796
    CrossRef

45. 45

    PM Colman. (2005) Zanamivir: an influenza virus neuraminidase inhibitor. Expert Review of Anti-infective Therapy 3:2, 191-199
    CrossRef

46. 46

    Jennifer L McKimm-Breschkin. (2005) Management of Influenza Virus Infections with Neuraminidase Inhibitors. Treatments in Respiratory Medicine 4:2, 107-116
    CrossRef

47. 47

    W. Garrett Nichols, Katherine A. Guthrie, Lawrence Corey, Michael Boeckh. (2004) Influenza Infections after Hematopoietic Stem Cell Transplantation: Risk Factors, Mortality, and the Effect of Antiviral Therapy. Clinical Infectious Diseases 39:9, 1300-1306
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