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Successful treatment of avian-origin influenza A (H7N9) infection using convalescent plasma

  • Xiao-Xin Wu
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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  • Hai-Nv Gao
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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  • Hai-Bo Wu
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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  • Xiu-Ming Peng
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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  • Hui-Lin Ou
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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  • Lan-Juan Li
    Correspondence
    Corresponding author. Tel.: +86 13906514210; fax: +86 057187236459.
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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Open AccessPublished:October 16, 2015DOI:https://doi.org/10.1016/j.ijid.2015.10.009

      Highlights

      • The mortality rate for avian-origin influenza A (H7N9) infections remains high (52%).
      • We successfully used convalescent plasma to treat an H7N9 infection in a 45-year-old man.
      • We are the first to use oseltamivir and convalescent plasma to treat H7N9 in China.

      Summary

      In January 2015, there was an outbreak of avian-origin influenza A (H7N9) virus in Zhejiang Province, China. A 45-year-old man was admitted to the First Affiliated Hospital of Zhejiang University with a high fever that had lasted 7 days, chills, and a cough with yellow sputum. Laboratory testing confirmed infection with the H7N9 virus, likely obtained from contact with poultry at a local live poultry market. A large dense shadow was apparent in the patient's left lung at the time of admission. Treatment with oseltamivir (75 mg twice daily) did not improve the patient's condition. The decision was made to try using convalescent plasma to treat the infection. Convalescent plasma was administered 3 days after the patient was admitted to the hospital and led to a marked improvement. To our knowledge, this is the first report of the successful use of convalescent plasma to treat a case of H7N9 infection in China. These results suggest that the combination of convalescent plasma and antiviral drugs may be effective for the treatment of avian-origin H7N9 infection.

      Keywords

      1. Introduction

      Avian-origin influenza A (H7N9) infections have been reported for the past 2 years, but the mortality rate remains unacceptably high (52%). In January 2015, A 45-year-old patient infected with H7N9 have recovered after using convalescent plasma. It is the first report of the successful use of convalescent plasma to treat a case of H7N9 infection in China.

      2. Case report

      A previously healthy 45-year-old man was admitted to the First Affiliated Hospital of Zhejiang University on January 16, 2015. He had a high fever (39 °C) that had lasted for 7 days, chills, and a cough with yellow sputum. The patient had been in contact with live birds at a local live poultry market (January 1, 2015), but had not had contact with influenza patients. On January 9, he had developed a high fever and chills. Four days later he reported being short of breath, and on January 15 he had relatively severe hypoxemia. The patient's oxygen saturation levels fell to less than 80% (mask measurement) and the arterial blood oxygen partial pressure fell to less than 50%. Non-invasive ventilator-assisted breathing was administered upon his admission to the hospital. A chest radiograph performed the day he was admitted showed a large dense shadow in the left lung with a blurred edge; the right lung was clear (Fig. 1A) . Deep sputum was collected through a sputum suction tube and sent to the hospital laboratory for analysis. The influenza A (H7N9) virus was detected by reverse transcriptase PCR (RT-PCR) assay.
      Figure thumbnail gr1
      Figure 1X-ray and computed tomography scans of the chest of a 45-year-old man with pneumonia caused by avian-origin influenza A (H7N9) virus. (A) X-ray image obtained at the time of hospital admission (January 16, 2015). A large dense shadow with blurred edges was observed in the left lung. The right lung was clear. (B) X-ray image obtained on January 17 after treatment with oseltamivir. No improvement was noted from admission. (C) X-ray image obtained on January 19 prior to treatment with convalescent plasma. The large dense shadow noted at admission was still apparent. (D) Computed tomography scan obtained on February 2 at the time of discharge. The dense shadow in the left lung had clearly been absorbed.
      Routine blood tests found a normal number of leukocytes; however, the percentage of neutrophils was elevated (87.9%). The number of lymphocytes was also decreased to 0.4 × 109 cells/l. Routine blood tests were performed every day. Liver function tests indicated elevated alanine aminotransferase (73 U/l) and aspartate aminotransferase (144 U/l) levels. The patient's total cholesterol was normal. Renal function, electrolyte, and blood coagulation tests showed no obvious abnormalities. Arterial blood gas tests detected no obvious abnormalities after intubation. C-reactive protein and procalcitonin were monitored until January 28 (Supplementary Material, Figure S1).
      The patient was admitted to the negative-pressure ward, which is a specialized intensive care unit for treating infectious diseases. He was monitored by electrocardiograph. Nutrition was supplied through a jejunum tube. Treatment with 75 mg of oseltamivir twice daily was started on January 16, 2015 (day of admission). Preventive piperacillin (0.5625 g every 6 h) and tazobactam (0.5625 g every 6 h) were administered from January 16 to January 26. The patient's temperature was recorded daily (Supplementary Material, Figure S2). Cultures were performed on samples from the blood, sputum, feces, and catheter drainage. All of the tests were negative, with the exception of the sputum culture on January 27, 2015, in which a small amount of smoke Aspergillus was detected. The patient was treated with trazodone for 3 days, and the sputum culture was negative after treatment.
      Despite the continuous use of oseltamivir, virus was detected in the sputum specimens by the laboratory. Chest radiographs obtained on January 17 (Fig. 1B) and January 19 (Fig. 1C) showed no improvement from the time of admission. From January 16 until January 19 the patient showed no improvement in his condition, and appeared to be worsening. While he was hospitalized, the patient also received probiotics, human blood albumin, immunoglobulin, methyl prednisolone, acetylcysteine, compound glycyrrhizin, and reduced glutathione. The H7N9 virus in this patient was not obviously resistant to oseltamivir, but there had been a report of oseltamivir resistance in another case.
      • Marjuki H.
      • Mishin V.P.
      • Chesnokov A.P.
      • De La Cruz J.A.
      • Davis C.T.
      • Villanueva J.M.
      • et al.
      Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses.
      We did not attempt to administer oseltamivir 150 mg twice daily or peramivir to this patient, and zanamivir is rarely used in our hospital. The suggestion was made that convalescent plasma could be used to treat the patient and this option was favored by the patient's family members.
      A woman from Zhejiang Province who had recovered from H7N9 infection in April 2014 donated her convalescent plasma. The plasma was collected by apheresis at the Blood Center of Zhejiang Province (200 ml total) and contained a neutralizing antibody titer of 1:80. The convalescent plasma was confirmed free of infectious agents and was stored at −40 °C until it could be used. The 200 ml of convalescent plasma was given to the patient over a period of 3 h beginning at 2 p.m. on January 19 (Supplementary Material, Figure S3). Laboratory results indicated that the H7N9 virus was undetectable on January 23. Oseltamivir was stopped on January 24 after the RT-PCR assay consistently failed to detect the H7N9 virus in the sputum specimens.
      During patient follow-up in the hospital, the patient's liver function improved. Likewise, routine blood tests showed that the number of lymphocytes had normalized on January 23 and the proportion of neutrophils normalized on January 30. The patient's condition improved gradually and the endotracheal tube was removed on January 27. A computed tomography scan obtained on February 1 indicated that the consolidation in the left lung had improved markedly from January 19 (Fig. 1D). The patient recovered and was discharged on February 2, 2015.
      The influenza A (H7N9) virus was isolated successfully from tracheal aspirates obtained from the plasma donor and the patient. The neutralizing antibody titer against the virus was assessed in samples from the patient in a biosafety level 3 laboratory. A hemagglutinin inhibition (HAI) assay was performed simultaneously. The HAI titer exceeded 1:512. Neutralizing antibodies were not detectable on January 19, but increased steadily. At discharge, the patient had a neutralizing antibody titer greater than 1:80. The increase is likely attributable to the treatment with convalescent plasma and the patient's own humoral immune response.

      3. Discussion

      Avian-origin influenza A (H7N9) infections have been reported for the past 2 years. In the absence of an effective treatment, the mortality rate remains unacceptably high (52%). Convalescent plasma has been used successfully to treat Spanish influenza, influenza A (H5N1), and severe pandemic influenza A (H1N1) 2009.
      • Kong L.K.
      • Zhou B.P.
      Successful treatment of avian influenza with convalescent plasma.
      • Zhou B.
      • Zhong N.
      • Guan Y.
      Treatment with convalescent plasma for influenza A (H5N1) infection.
      • Hung I.F.
      • To K.K.
      • Lee C.K.
      • Lee K.L.
      • Chan K.
      • Yan W.W.
      • et al.
      Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection.
      However, to our knowledge this is the first case in which convalescent plasma has been used successfully to treat an avian influenza A (H7N9) infection in China. These results suggest that convalescent plasma combined with antiviral drugs may be a viable option for the treatment of H7N9 infection. These findings remain to be confirmed in a prospective cohort study.

      Acknowledgements

      This work was supported by a grant from the Important National Science and Technology Project-Research of Clinical Treatment for Emerging Severe Acute Respiratory Infectious Disease (2004ZX10004006). We gratefully thank Professor Jun Li (Zhejiang University, China) for his critical review of the manuscript.
      Conflict of interest: The authors declare that they have no conflicts of interest in the research.

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