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Emerg Microbes Infect. Mild infection of a novel H7N9 avian influenza virus in children in Shanghai

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  • Emerg Microbes Infect. Mild infection of a novel H7N9 avian influenza virus in children in Shanghai

    [Source: Emerging Microbes and Infections, full page: (LINK). Extract.]

    Citation: Emerging Microbes & Infections (2013) 2, e41; doi:10.1038/emi.2013.41 - Published online 10 July 2013

    Mild infection of a novel H7N9 avian influenza virus in children in Shanghai


    Xuelian Yu<SUP>1,*</SUP>, Xi Zhang<SUP>1,*</SUP>, Yi He<SUP>1,*</SUP>, Huanyu Wu<SUP>1</SUP>, Xia Gao<SUP>2</SUP>, Qichao Pan<SUP>1</SUP>, Jiaren Shen<SUP>1</SUP>, Jianming Zhu<SUP>2</SUP>, Hongyou Chen<SUP>1</SUP>, Yiyi Zhu<SUP>1</SUP>, Fan Wu<SUP>1</SUP>, Jianwei Wang<SUP>3</SUP> and Zhengan Yuan<SUP>1</SUP>
    <SUP>1</SUP>Shanghai Municipal Center for Disease Control and Prevention, Shanghai 201599, China <SUP>2</SUP>Shanghai Jinshan District Center for Disease Control and Prevention, Shanghai , China <SUP>3</SUP>MOH Key Laboratory of System Pathogen Biology and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Bejing 100730, China

    Correspondence: ZA Yuan, E-mail:; JW Wang, E-mail:

    <SUP>*</SUP>These authors contributed equally to this paper.

    Received 24 April 2013; Revised 20 May 2013; Accepted 6 June 2013

    Dear Editor, Human infection by avian influenza virus (AIV) subtypes H7<SUP>1,2</SUP> and H9N2<SUP>3</SUP> has been reported in various countries over the past few years. Recent research reveals that AIV subtype H7 shares some properties with subtype H5, including causing severe disease in birds<SUP>4</SUP> and outbreaks involving large numbers of infected humans.<SUP>1,5</SUP> Since March 30th, 2013, a reassortment avian-origin influenza A (H7N9) virus characterized by a unique combination of gene segments identified among previous AIV subtype H7N3 (ZJ12), H7N9 (KO14) and H9N2 (BJ16) viruses<SUP>6</SUP> has caused a large number of human infections in China (33 infections, including 14 deaths in Shanghai). The sudden appearance of this disease with high case fatality and severe clinical manifestations has attracted substantial scientific and popular attention and has impacted human health and the economy. Given its wide and rapid spread within China, the newly defined influenza A virus H7N9 may possess pandemic potential. Efficient preparations should be made, but such efforts are complicated by the fact that the clinical traits regarding this new disease remain unclear.



  • #2
    Re: Emerg Microbes Infect. Mild infection of a novel H7N9 avian influenza virus in children in Shanghai

    this letter is Open Access - so to continue from above:

    To address this issue, strengthening case finding, epidemiological investigation and laboratory detection was carried out by the Shanghai Municipal and District Center for Disease Control and Prevention (CDC) through the Surveillance System for Pneumonia of Unexplained Origin and Sentinel Surveillance System for Influenza-like Illness. Once a suspected case of H7N9 infection was identified, the district CDCs conducted the initial field investigations and obtained respiratory specimens, which were shipped to the Influenza Reference Laboratory of the Shanghai municipal CDC for H7N9 laboratory testing. The samples were tested by a real-time reverse transcription polymerase chain reaction (RT-PCR) assay for influenza A (H7N9), according to Guidelines for Prevention and Control of Human Infected Avian Influenza H7N9 Virus Epidemic<sup>7</sup> issued by China National Influenza Center of China CDC. A field investigation team consisting of staff members from the municipal and/or local CDC conducted field investigations of the confirmed cases.

    As of 10th April, 17 adult H7N9-infected cases were reported by Surveillance System for Pneumonia of Unexplained Origin; all suffered severe respiratory infection. Two mild cases (both children) were also identified by Sentinel Surveillance System for Influenza-like Illness. By 31st May, 10 of the 17 severe patients had died, while the other seven severe cases were discharged from the hospital. ILI identified 1799 surveyed cases from which throat swabs were collected, but only two throat swabs, both from children, were positive for H7N9 as measured by the real time RT-PCR assay, suggesting that mild H7N9 infections are not common in Shanghai.

    Studies from AIV H5N1 infections identified several patients that were 5 years or younger.<sup>8</sup> Severe acute respiratory syndrome patients 12 years or younger were associated with milder disease.<sup>9</sup> A similar phenomenon was observed in H7N9 infections. The H7N9 mild cases were males below 4 years of age, while the severe patients were all adults, with a sex ratio of 2.4 (M/F, 12∶5). Compared with the median age of severe patients (67 years old), the patients who died were older (74 years old). People older than 50 seemed to be at an increased risk for infection with the novel H7N9 virus. The same phenomenon was reported in other Chinese provinces, such as Zhejiang, Jiangsu, Anhui and Henan.<sup>10</sup> The age distribution of H7N9-infected patients is also similar to previous seasonal influenzas, but is different from the 2009 pandemic H1N1 influenza [A(H1N1) pdm/09].<sup>11</sup>

    Patients older than 50 appeared to experience more severe illness in H7N9 infection. All 19 patients who fit this criterion suffered from high fever. The median body temperature in mild, severe and fatal H7N9-infected cases were similar, and all were significantly higher than in A(H1N1)pdm/09 infections.<sup>11</sup> Both mild patients developed pharyngalgia and tonsillitis (II&#176, while only one severe and one fatal case displayed pharyngalgia; no severe or fatal cases developed tonsillitis. Cough was the most common symptom in both severe (six) and fatal (eight) infections; three severe and seven fatal cases displayed a productive cough. Compared with the severe H7N9-infected patients, more patients that died experienced chill, dyspena, fatigue, chest stuffiness, somnolence and arthralgia, while less patients who died suffered from diarrhea, muscle ache and runny nose. The details are listed in Table 1. Conjunctivitis, which is common in human infections with other H7<sup>1,2</sup> viruses, was not documented in H7N9-infected patients.

    Table 1 - Demographics, clinical treatments and outcomes of 19 H7N9-infected patients in Shanghai.

    Full table

    A pathological chest radiograph was performed for one mild and all severe and fatal H7N9-infected cases. The X-ray film of the mild patient revealed clear lung texture. All severe patients had abnormal initial radiographic findings similar to severe patients infected with A(H1N1)pdm/09, AIV H5N1<sup>12</sup> or severe acute respiratory syndrome coronavirus. The predominant radiographic finding was patchy consolidation (five severe and eight fatal), most commonly in the lower (five severe and six fatal) and central lung zones (two severe and eight fatal). Two severe and six fatal cases involved ≥3 lung zones. Pleural effusion was observed in two severe and three fatal cases. The computed tomography values of the H7N9 real-time RT-PCR assay in upper respiratory tract exudates from mild, severe and dead patients were similar. Because the computed tomography values correlate with the viral loads in samples, the viral loads in the upper respiratory tract exudates of mild H7N9-infected patients were assumed not to be different from the severe H7N9-infected patients. In Shanghai, both mild patients experiencing upper respiratory tract infections and all severe patients suffering from pneumonia, suggesting that the severe patients may seldom clear viral particles from the upper respiratory tract.

    The median length of time from the onset of illness to the hospital visit for the mild H7N9-infected cases (12 h) was shorter than that for the severe (36 h) or fatal cases (12 h). The median length of time between illness onset to hospital admission for the mild patients (1.5 days) was the shortest among the three categories of patients, and it took a shorter time (4 days) for the severe cases to be admitted into the hospital than for the fatal ones (5.5 days). The median length of disease spectrum in the mild patients (7 days) was significantly shorter than the length for severe patients (26.5 days), while the median length of disease spectrum for the 10 patients who died was 11 days.

    As an inhibitor of influenza virus polymerase, Ribavirin has been reported to have an antiviral effect against the avian influenza H5N1 viruses in mice.<sup>13</sup> Both mild patients in this study were given Ribavirin on the second day post-infection. From our limited data, it appears that Ribavirin may help in mild cases and speed recovery because the inhibitor showed effectiveness during early treatment of H7N9-infected patients to some extent. As a neuraminidase inhibitor, Oseltamivir also has activity against influenza viruses. Because the antiviral resistance to Oseltamivir among circulating influenza viruses is currently low, this drug is prescribed to patients with influenza infections. In this study, in 85.7&#37; (6/7) and 80.0% (8/10) of severe and fatal patient cases, respectively, the patient took Oseltamivir, as well as one patient in a mild patient case. The mild patient took Oseltamivir on day 3 following disease onset, while the six severe patients were given Oseltamivir on the sixth day. The eight fatal cases took Oseltamivir on the seventh day after disease onset. Out of the 10 patients who died, two were never given anti-viral medicine. Compared to the two patients who died that did not take Oseltamivir (5.5 days), the median disease spectrum of the eight fatal cases that received Oseltamivir was significantly longer (12.5 days). Oseltamivir may be effective against H7N9 infection when used during the prodromal period of disease.

    The clinical course and outcome of disease appears to be more favorable in children than adults when infected with highly pathogenic viruses, such as H5N1, novel H7N9 or severe acute respiratory syndrome coronavirus. Several possible reasons may account for this finding: parents take children to visit doctors when the children become sick or anti-viral drugs are more likely to be prescribed to sick children with a high fever. Another important factor for a severe clinical course of H7N9 infection may relate to impaired host immune function. Similar circumstances have been reported for measles infections. Research in measles found that remarkable lymphopenia occurred in measles cases, with a reduction in the number of T cells, B cells, neutrophils and monocytes. The severity of illness in patients parallels the severity and duration of lymphopenia,<sup>14</sup> which is in turn age dependent, with less severe cases in young children but more severe cases in adults. The novel H7N9 virus may act in a similar manner as measles. More fatal cases (40%, 4/10) showed lower leukocyte counts than severe (14.3%, 1/7) or mild cases (0/0), and fatal cases also showed a higher neutrophil percentile (60%, 6/10) than severe (28.6%, 2/7) or mild cases (0/0). In addition, fatal cases (100%, 3/3) showed lower lymphocyte percentiles than severe (28.6%, 2/7) or mild cases (0/0). The lymphocyte subpopulation measurement of one child patient showed downregulated CD16<sup>+</sup>CD56<sup>+</sup> natural killer cells. Attenuated natural killer functions were observed previously in H5N1 infected patients.<sup>15</sup>

    Therefore, we propose that the novel H7N9 virus may induce transient immunosuppression that occasionally results in fatal opportunistic infections, especially in patients with underlying diseases. Our data are limited in the present study, and further research addressing host immune functions relating to H7N9 infection with a larger sample size may provide better answers.
    Top of pageReferences

    1. Belser JA, Davis CT, Balish A et al. Pathogenesis, transmissibility, and ocular tropism of a highly pathogenic avian influenza A (H7N3) virus associated with human conjunctivitis. J Virol 2013; 87: 5746–5754. | Article | PubMed | CAS |
    2. Fouchier RA, Schneeberger PM, Rozendaal FW et al. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci USA 2004; 101: 1356–1361. | Article | PubMed | CAS |
    3. Butt KM, Smith GJ, Chen H et al. Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003. J Clin Microbiol 2005; 43: 5760–5767. | Article | PubMed | ISI | CAS |
    4. Bertran K, Perez-Ramirez E, Busquets N et al. Pathogenesis and transmissibility of highly (H7N1) and low (H7N9) pathogenic avian influenza virus infection in red-legged partridge (Alectoris rufa). Vet Res 2011; 42: 24. | Article | PubMed |
    5. Koopmans M, Wilbrink B, Conyn M et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 2004; 363: 587–593. | Article | PubMed | ISI |
    6. Gao R, Cao B, Hu Y et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 2013; 368: 1888–1897. | Article | PubMed | CAS |
    7. China Center for Disease Prevention and Control. Guideline for prevent and control human infected avian influenza H7N9 virus epidemic. Beijing: Chinese Center for Disease Control and Prevention, 2013. Chinese.
    8. Yuen KY, Chan PK, Peiris M et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998; 351: 467–471. | Article | PubMed | ISI | CAS |
    9. Bitnun A, Allen U, Heurter H et al. Children hospitalized with severe acute respiratory syndrome-related illness in Toronto. Pediatrics 2003; 112: e261. | Article | PubMed |
    10. Li Q, Zhou L, Zhou M et al. Preliminary report: epidemiology of the avian influenza A (H7N9) outbreak in China. N Engl J Med 2013 Apr 24. DOI: 10.1056/NEJMoa1304617 | Article |
    11. Yu X, Zhang X, Zhao B et al. Intensive cytokine induction in pandemic H1N1 influenza virus infection accompanied by robust production of IL-10 and IL-6. PLoS ONE 2011; 6: e28680. | Article | PubMed |
    12. de Jong MD, Hien TT. Avian influenza A (H5N1). J Clin Virol 2006; 35: 2–13. | Article | PubMed |
    13. Ilyushina NA, Hay A, Yilmaz N, Boon AC, Webster RG, Govorkova EA. Oseltamivir ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice. Antimicrob Agents Chemother 2008; 52: 3889–3897. | Article | PubMed |
    14. Okada H, Kobune F, Sato TA et al. Extensive lymphopenia due to apoptosis of uninfected lymphocytes in acute measles patients. Arch Virol 2000; 145: 905–920. | Article | PubMed | ISI | CAS |
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    This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit


    • #3
      Re: Emerg Microbes Infect. Mild infection of a novel H7N9 avian influenza virus in children in Shanghai

      I think it is important to remember that flu viruses evolve over time and that a "mild" virus today could be a virulent virus tomorrow.


      • #4
        Re: Emerg Microbes Infect. Mild infection of a novel H7N9 avian influenza virus in children in Shanghai

        It is also important to note the positive correlation between the influenza polymerase inhibitor ribavirin and the rapid clinical symptoms resolutions in the described cases. The PA inhibitory property is also cited in other paper cit.


        • #5
          Re: Emerg Microbes Infect. Mild infection of a novel H7N9 avian influenza virus in children in Shanghai

          Originally posted by Giuseppe Michieli View Post
          It is also important to note the positive correlation between the influenza polymerase inhibitor ribavirin and the rapid clinical symptoms resolutions in the described cases. The PA inhibitory property is also cited in other paper cit.
          Remarks on
          Toxic Anti-Virals

          Ribavirin is demonstrated to be profoundly toxic.

          For 43 years.

          Toxicity is a primary evaluation point around which the extensive body of ribavirin research revolves. Human studies, even of short duration, frequently result in subjects leaving the investigation prior to completion due to toxicity or other physiologically-limiting outcomes.

          CardioVascular Contra-Indication

          Furthermore, the known contra-indications of ribavirin are also common correlators to the subject groups and factors surrounding pandemic influenza or host-transition viral outbreaks. An obvious and prominent concern is that host-transition virus reservoirs dismay us with fatal clinical outcomes correlated with antecedent cardiac muscle failure, vascular musculature failure, disseminated intravascular coagulation (DIC) and organ failure (liver). The contra-indication profile of ribavirin provides direct risk factors in these areas. The thousands of amputations employed on children infected by pH1N1 after DIC allows a rational researcher to steer clear of ribavirin for future pandemic influenza.

          Child-Bearing Age Contra-Indication

          Citizens of Child-Bearing age (male and female) risk their future child's life and / or deleterious genetic mutation of their child when ribavirin is engaged. We are all familiar with the fact that host-transition viral reservoirs are dangerous to males and females of child-bearing age and that pregnancy creates exceptional risk of high morbidity and fatality with host-transition viral reservoirs. Ribavirin as a standard in an influenza pandemic risks damaging the current and the future generation.

          Eye Concerns

          Additionally, retinopathy is associated with the more modern combinational therapies employing this toxic pharmaceutical. As we have recently seen, H7 influenza serotypes tend toward ocular involvement. Human H7N7 outbreaks showed conjunctivitis as a common presenting symptom. Emergent H7N9 infection through the eye is demonstrated in the lab to result in mammal respiratory infection [US CDC: FT#503653]. Maintaining eye integrity may feature as a public health recommendation during an H7 pandemic.


          Ribavirin and other inhibitors in the IMPDH group are recognised for immuno-suppressive activity and are often employed for that particular mechanism of action. Like many influenza reservoirs (pH1N1) and individual clades, emergent H7N9 is proposed, even by the authors of this paper, to be microbiologically and clinically immuno-suppressive.

          Unintended amplification of immuno-suppression is a risk that may lead to super-infection when treating an emerging pandemic virus with ribavirin. Super-infection, we are told, is a substantial contributor to fatality in pandemic influenza. Considering the extended durations in hospital observed with the first wave of emergent H7N9 human cases, clinicians will be wise to consider the potential gravity of amplified immuno-suppression leading to super-infection and then fatality.
          Emerging Microbes & Infections (2013) 2, e41; doi:10.1038/emi.2013.41 - Published online 10 July 2013

          Therefore, we propose that the novel H7N9 virus may induce transient immunosuppression that occasionally results in fatal opportunistic infections, especially in patients with underlying diseases.

          Revenue Enhancement

          Re-Marketing has become a revenue enhancement strategy promoted and economically idealised by medical consultants over the last decade. The failure of corporations to bring us working solutions provides those very same teams the suffering subjects they need to re-market their previous bad ideas (because nothing new is available). This economically beneficial re-cycling of inappropriate and out-dated techniques has recently resulted in medical tragedies.

          While we may hold some sympathy for the frustrated clinicians who are influenced by these advising vultures to "throw everything you have at that infection", we also hold those clinicians to the responsibility of providing some semblence of input toward THEIR patient's treatment. Due to the vacuum found where new ideas should be arising, off-label usage is too regularly adopted by leading professors and clinicians for untested, even bizarre, treatment modalities.

          Ribavirin as a standard for influenza care surpasses bizarre, however, and moves into the patently absurd. As if the blind being allowed to lead the blind is no longer enough, we are now being asked to allow the blind to create the blind?

          Originally posted by Vibrant62 View Post
          Originally published:
          Researcher devises drug cocktail for coronavirus [FT Thread #493730]

          A primary issue here is that ribivarin - whilst an effective anti-viral agent - is highly toxic. For this reason it was largely discounted as potential treatment for H5N1 human infections.

          The primary clinical toxicity of Ribavirin is hemolytic anemia. The anemia associated with Ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with Ribavirin [see Warnings and Precautions (5.2), Adverse Reactions (6.1), and Dosage and Administration (2.3)].

          Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to Ribavirin. In addition, Ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Therefore, Ribavirin, including Ribavirin tablets, is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking Ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6 month post treatment follow-up period

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          Last edited by NS1; July 11, 2013, 02:30 AM. Reason: formatting; additional content