Participating centers were identified by the National Influenza A pH1N1 2009 Clinical Investigation Group of China. This is a national network for the diagnosis and treatment of pH1N1, and includes the Chinese Disease Control and Prevention (CDC) and community hospitals and teaching hospitals around China that are under the guidance by the Chinese Ministry of Health (MOH). Hospitalized patients were included in this study if they met the diagnostic criteria of having new radiographic abnormality indicating pneumoniawith laboratory-confirmed case of pH1N1 virus between September 1 and December 31, 2009. Pneumonia was defined as an acute lower respiratory tract illness with two or more of the following symptoms or signs: cough, productive sputum, fever, chills, dyspnea, pleuritic chest pain, crackles, and bronchial breathing plus an opacity or infiltrate seen on a chest radiography that was interpreted as pneumoniaby the treating physicians. Both adult and child inpatients were included. According to the pH1N1 2009 Clinical guideline (Third Edition, 2009) released by China MOH, a severe or critical case was defined as those who met at leaset one of the following criteria on admission: (1) respiratory failure; (2) septic shock; (3) multiple organs insufficiency; (4) other critical clinical conditions requiring intensive care. Hospitalized patients were excluded if they did not have pneumonia. Patients were also excluded if they had been treated as outpatients or in emergency rooms, had a duration of hospitalization ,24 hours, or if there was an incomplete record of clinical outcome . All patients who were treated with corticosteroids were also excluded in order to reduce any bias from corticosteroids treatment as far as possible.
normal infectious particles except in that they contain at least one genomic segment that has undergone a massive deletion. Any one of the 8 genomic segments can give rise to a DI RNA, although DI RNAs arise most frequently from segments 1, 2 or 3. The situation is made more complex as the position of the central deletion in any one segment can vary considerably, so giving rise to many different DI RNA sequences. Natural populations of DI influenzavirus can contain greater than 50 different defective RNA sequences [21,22], and initially it was impossible to produce a defined DI virus preparation that could be quality controlled. We solved this problem by using cloning techniques to isolate single, naturally occurring DI RNAs of known sequence . One of these DI RNAs, originating from segment 1 (called 244), was incorporated by reverse genetics into A/PR/8/34 influenzavirus to form the DI virus 244/PR8. This DI virus is highly effective in protecting against clinical disease causedby a lethal influenza challenge in a mouse model . In mice a single intranasal dose administered before or at the same time as the infectious virus completely suppresses clinical disease symptoms causedby H1N1, H2N2, H3N2 or H3N8 viruses also given intranasally. Post-infection therapy is also effective. 244/PR8 is not toxic and generates no adverse clinical effects, and the administered preparation is not infectious. Different strains of mice and elderly mice are well protected [24–26]. Infection of mice with severe-combined immunodeficiency (SCID) shows that the adaptive immune response is not required for protection but is needed to clear infection . Interferon is made locally in the respiratory tract in response to DI virus but is not required for protection from influenza A viruses. However, interferon affords protection from heterologous respiratory viruses such as influenza B and a paramyxovirus, pneumoniavirusof mice [26,27]. On this basis DI virus offers a potentially attractive new addition to the armoury of anti-influenza treatments.
We used glucocorticoid therapy for most H7N9-infected patients in our observational study. Some controversies exist in the use of glucocorticoid therapy for IAV infection. Han et al. reported that early use of parenteral glucocorticoid therapy for fever reduction andpneumonia prevention in patientswithpandemicinfluenza A (H1N1) infection increased the risk of critical disease and death . Likewise, He et al. advised that glucocorticoids should not be used in critically ill patientswith H1N1 influenza infection . However, Carter argued that while steroids should not be used as monotherapy in the treatment of avian influenza, they might provide therapeutic benefits as an adjunct therapy to antiviral agents if prescribed at appropriate dosages . We found no clear association between glucocorti- coid therapyand clinical outcomes in H7N9-infected patients in our study. Future studies with larger patient populations are required to evaluate the benefits and risks asscocaited with glucocorticoid therapy in treatment of H7N9 infections.
The first influenzapandemicof the 21st century was causedby a novel swine-origin H1N1 influenzavirus that emerged in early 2009. This virus is substantially less virulent than the 1918 influenzavirus, but it has the potential to acquire amino acid changes in its viral proteins that would increase its pathogenicity. To prepare for such events and future pandemics, we need to understand the molecular basis of the high-virulence phenotype of the 1918 pandemicvirus to help identify virulence factors in other emerging pandemic viruses. Additionally, the fact that more than 97% of the people infected with the 1918 virus survived raises the intriguing possibility of some contribution of host genetics to the consequences ofinfluenza (i.e., survival or death). Thus, it is also important to explore host factors that are involved in resistance or susceptibility to influenzavirus infection. Such information could accelerate the development of new antiviral drugs for prophylaxis and treatment, which are urgently needed given the obstacles to rapid development of an effective vaccine against pandemicinfluenza.
Influenza A virus (IAV) infections are endemic in pork producing countries around the world. The emergence of the pandemic 2009 human H1N1 influenza A virus (pH1N1) raised questions about the occurrence of this virus in Brazilian swine population. During a 2009-2010 swine influenzavirus research project at Embrapa Swine and Poultry (CNPSA), an outbreak of a highly transmissible H1N1 influenza A virus disease was detected in a pig herd in Santa Catarina State, Brazil. The viruscaused a mild disease in growing pigs and sows without mortality. Three clini- cally affected piglets were euthanized. Gross lesions included mild to moderate consolidation of cranioventral areas of the lung. Microscopically, the lesions were characterized by necrotizing obliterative bronchiolitis and bronchointerstitial pneumonia. Immunohistochemistry using a monoclonal antibody against type A influenzavirus nucleoprotein revealed positive staining in the nuclei of the bronchiolar epithelial cells. Lung tissue from three piglets and nasal swabs from five sows and four piglets were positive for influenza A by RT-PCR. Influenzavirus was isolated from one lung, later confirmed by the hemagglutination test (HA titer 1:128) and RT-PCR. Sequence analyses of Hemmaglutinin (HA) and Matrix (M) genes revealed that the virus was consistent with the pandemic (A/H1N1) 2009 influenzavirus strain that circulated in humans. This is the first report of an outbreak ofpandemic A/H1N1 influenzavirus in pigs in Brazil.
Although systemic corticosteroid treatment for severe pneumonia due to influenza A(H1N1)pdm09 has been controversial [1,2,3], systemic corticosteroid treatment in pneumoniapatients especially presenting with acute wheezing induced byinfluenza A(H1N1)pdm09 was frequently administered at the early stage of their illness in hospitals in Japan during pandemic period. Wheezing is the end result of a narrowing of the intrathoracic airways and a limitation of expiratory air flow and is causedby many illnesses. Asthma and bronchiolitis were the main illnesses which caused wheezing in influenza A(H1N1)pdm09 virus infection [4,5,6,7,8]. Acute exacerbation of asthma is usually diagnosed in patientswith wheezing and a history of asthma. It is treated with anti-asthma agents as well as systematic corticosteroids depending on the disease severity following the asthma treatment guidelines [9,10,11]. On the other hand, a previous study in preschool
Only one hospitalized patient died. Hospitalized patients were a group of high morbidity and clinical severity, since they had more underlying chronic disease (73%), low vac- cine coverage of A influenza (28%), developed pneumonia as a complication (47%), and required more often oxygen (61%) and antibiotic therapy (73%). The main clinical complications ofpatientswith A/H1N1 influenza were otitis, pneumonias, meningitis, myositis and myocarditis. These findings are quite similar to those reported by other authors who analyzed pedi- atric populations with A/H1N1 influenza, especially in the 2009 pandemic. 1,2,4,7,9,13–15,17,24,32–37
The threat from avian influenza H1N5 prompted many countries to establish a stockpile ofantiviral drugs, [1,2,3,4], such as oseltamivir and zananivir. The size of the antiviral stockpile and its proposed use, therapy or prophylaxis, were keenly debated during the preparation ofpandemic management plans. The emergence ofpandemic H1N1 in 2009 prompted a variety of strategies for the use ofantiviral drugs and motivates this look at the use ofantiviral drugs for prophylaxis and implications for decisions on the size of an antiviral stockpile for a future pandemic. The possibility of using antiviral drugs for prophylaxis, to mitigate transmission ofpandemicinfluenza, arises because their use to protect against currently circulating strains ofinfluenza indicates a reduced chance of being infected [5,6,7,8,9]. Also observed are reduced levels ofvirus shedding [5,6,10,11,12,13,14], which suggests a reduction in infectivity in the event of a breakthrough infection. Use of these observations in modeling studies suggests that stockpiles ofantiviral drugs held by some nations are sufficiently large to defer the peak of the epidemic until a newly developed vaccine is available to control transmission [15,16,17,18]. These results could be expected to apply to pandemic H1N1 since, with a reproduction number estimated to be of the order 1.2-1.5 in some localities [19,20], its transmissibility is relatively modest.
To further investigate the effect of raising treatment level, we simulated the model when treatment is initially administered at 25% and 50% (below the optimal level). The results show a significant reduction in the total number of clinical infections compared with that achieved at the optimal constant level (Figure 5c,d). However, the effectiveness of this strategy depends critically on the initial scale of drug-use and the time at which the level of treatment is raised. As is evident from Figure 5d, for lower treatment levels, an earlier increase in antiviral use is required for achieving the minimum final size. This is due to the fact that the wild-type virus spreads more rapidly (and therefore depletes the pool of susceptible individuals more quickly) during the initial low treatment phase. The findings suggest that the impact of this strategy is much more pronounced in mitigating a pandemic than a constant treatment plan, even if treatment can be maintained at the optimal level throughout the entire course of an outbreak. Figures 6c and 6d indicate that a timely increase in the level of drug-use can also prevent large outbreaks causedby the emergence of highly transmissible resistant viruses.
Our current case is also an example of the use of ECMO therapy as a bridge to LTPL. Soon after the introduction of extracorporeal life support for respiratory failure, ECMO was not recommended as a therapy for ARDS because of its high associated mortality. However, recent advances in ECMO technology have enabled the possibility of achiev- ing a survival beneit with this intervention in patientswith severe ARDS.[2,17] Despite the many controversies sur- rounding it, the recent CESAR trial did indicate that ECMO might improve the outcomesofpatientswith severe refractory hypoxemia if they did not respond to other con- ventional rescue therapies and could be transferred to a cen- ter that could provide this treatment. Recently, ECMO therapy has been attempted as a bridge to LTPL at many centers. Because the use of ECMO itself cannot guaran- tee recovery from the underlying lung disease, it should not be applied in any patient with a condition that is expected to be irreversible. LTPL is an effective life-saving treatment for patientswith irreversible end-stage lung disease, so the use of ECMO as a bridge to LTPL could be considered ac- ceptable in such cases. In our present case, the irst ECMO therapy two weeks after intensive care unit admission was administered on the expectation that he could improve with- in a certain period of time. However, when we elected for a second application of ECMO because of the subsequent rap- id deterioration that followed weaning from his irst ECMO therapy, our decision was made under the premise that he might need LTPL as the ultimate treatment. Indeed, he had a relative contraindication for ECMO therapy i.e. prolonged mechanical ventilation for more than 7 days. However, in accordance with current international guidelines, he had no organ dysfunction other than respiratory failure and no absolute contraindication, such as a precluding anticoagula- tion therapy. Thus, we elected for him to receive a second round of ECMO therapy.
This study describes the duration of pH1N1 virus RNA detection, the correlation between rRT-PCR-positive results andvirus isolation, and clinical symptoms associated with pH1N1 virus detection in patients living in a densely populated community with low socioeconomic status in sub-Saharan Africa. Pandemic H1N1 RNA was detected from respiratory specimens by rRT-PCR for a median duration of 8 days but up to 17 days after symptoms onset. This duration ofvirus RNA detection is similar to the median of 6 and 8 days reported in studies from China and Hong Kong, respectively [7,10]. In our study, we did not find any differences in the duration of pH1N1 RNA detection among various age groups or between males and females. These results were similar to those reported by a study in Hong Kong, which reported no correlation between influenza viral load and age , and one from Canada which showed no differences in shedding between children and adults . In contrast, studies in Hong Kong and China found that younger age and male gender were risk factors for prolonged pH1N1 virus detection [7,10]. Our study population, was mostly children (79% of the patients were ,14 years old), thus associations between age and duration of pH1N1 RNA virus detection were difficult to assess. In addition, our study population included outpatients only, the China and Hong Kong studies mentioned above included hospitalized patients [7,10].
complication risks [16–18, 22–25]. Moreover, some studies indicated that depression and psychological stress may induce an immune function imbalance and stimulate the production of proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) [13–15]. Additionally, levels of those proinflammatory cytokines were associated with disease degeneration [26, 27]. One meta-analysis revealed that an elevated level of inflammatory markers might reduce the lung function ofpatientswith COPD . Another study also showed that a higher circulating concentration of IL-6 indicated exacerbation of a hemodynamic condition and increasing heart failure symptoms in patientswith congestive heart failure . In addition, Yende et al. found a relationship between higher levels of baseline TNF and IL-6 in the systemic circulation of elderly individuals and an increased risk of subsequently developing community- acquired pneumonia (CAP) requiring hospitalization . They reported that the highest tertiles of TNF and IL-6 were independent predictors of CAP
noted that “avian inluenza subtypes have the propensity to invade the brain along cranial nerves to target brainstem and diencephalic nu- clei” and we should be aware of this during the pre sent out- break H7N9 inluenza. Observation for neurological problems in patientsand further study on this topic are the challenges facing neurologists.
grades 5–8 at a school that was closed due to an outbreak of H1N1pdm. We asked about the students’ behavior during the closure, their infection status, and their family details. Ethics approval for this study was sought and obtained from the Harvard School of Public Health Office of Human Research Administra- tion. Prior to taking the anonymous survey, parents and students were given a description of the survey and its purpose and were told that the survey was optional. Consent was implied for those who filled in the survey. We did not obtain written consent because that would increase the risk of linking a student with her (or her parents’) response.
10. Buchbinder S., Vittinghoff E., Colfax G., Holmberg S. Declines in AIDS incidence associated with highly active antiretroviral therapy (HAART) are not reflected in KS and lymphoma incidence. Abstract S7. Presented at the Second National AIDS Malignancy Conference, Bethesda, Md, April 6-8, 1998.
(F3/F4), HIV coinfection and treatment failure with pegylat- ed interferon plus ribavirin were not negatively related with SVR12 in our population. However, we observed a larger proportion of genotype 3 and 4, HCV RNA viral load > 800 000 IU/mL, HCV/HIV coinfection, advanced fibrosis (F3/ F4) and previous exposure to treatment in patients who re- lapsed when compared withpatients who achieved SVR12. The cause or causes for this finding are not known and re- quires further analysis. In the relapsers, it was not possible to identify the reinfections. Today, the use of sofosbuvir plus ribavirin for genotype 3 treatment is considered suboptimal, so the introduction of new drugs in this setting justifies fur- ther research.
Patientswith hepatitis C virus-related decompensated cirrhosis can benefit from interferon- based antiviraltherapy, but the common complication of cytopenia is a contraindication for this treatment. Splenectomy prior to interferon therapy may alleviate this problem. To investigate whether splenectomy improves the efficacy ofantiviraltherapy, 13 interferon- naïve hepatitis C virus decompensated cirrhotic patients underwent splenectomy between January 2008 and January 2011, followed 1–3 months later by an interferon-based ther- apeutic regimen (pegylated/standard interferon-␣ combined with ribavirin for 48 weeks). Ten (76.9%) of the patients developed postoperative complications, which included minor portal vein thrombosis (2/13, 15.4%) and transient ascites (8/13, 61.5%). At one-month post- splenectomy, the patients showed significantly increased platelet (pre-surgery: 48.2 ± 15.9 vs. 186.0 ± 70.6 × 10 3 L −1 , p < 0.001) and leukocyte (2.1 ± 0.5 vs. 5.7 ± 1.4 × 10 3 L −1 , p < 0.001)
To determine whether the antiviral effects of LAAs could be observed with avian strains and a swine strain isolate of the 2009 pandemicinfluenza, plaque inhibition assays were carried out with the highest non-toxic concentration of the various compounds. For the swine strain (A/Swine/OTH-33-2/2009 (H1N1)), chloroquine, amodiaquine and quinacrine were most effective in inhibiting replication (more than 60% inhibition) compared to primaquine (less than 20% inhibition) (Figure 5). At equivalent concentrations of LAAs, the swine OTH-33-2 isolate and the human pH1N1/2009 (Figure 5 and Table 1) seemed to have comparable sensitivities although the swine isolate was slightly less sensitive. This might be attributable to possible genetic variations between isolates. Interestingly, amo- diaquine was the most potent compound at inhibiting the replication of the highly pathogenic avian influenza H5N1 (HPAI; A/Domestic Goose/Germany/R1400/2007 (H5N1)) rather than the low pathogenic avian influenza strain (LPAI; A/Teal/Germany/WV632/2005 (H5N1)) (Figure 5A). In con- trast, chloroquine, primaquine and quinacrine seem more effective at inhibiting the low pathogenic avian influenza stain rather than the highly pathogenic (Figure 5B–D). All LAAs were only capable of inhibiting Emu-Tx avian strain (A/Emu/ Texas/39924/1993 (H5N2)) replication by less than 40% (Figure 5). Overall, we demonstrated that the swine isolate (H1 subtype) appears to be generally more sensitive to inhibition of endosomal acidification induced by LAAs than the avian strains (H5 subtype), except for the primaquine. Again, in accordance with the study by Di Trani et al. that used only chloroquine, LAAs were less effective against human than avian strains suggesting that endosomal pH dependence is more Table 2. Cytotoxicity of LAAs and CMs in MDCK cells.
Introduction: During the first pandemic wave of the influenza A H1N1 2009 virus, morbidity was particularly high in Brazil. Hospitalizations resulting from severe respiratory disease due to suspected influenza-like illness created an opportunity to identify other respiratory viruses causing lower respiratory infections. Objective: The purpose of this study was to assess viral etiologies among samples collected during the first pandemic wave of H1N1 2009 from hos- pitalized patientswith suspected cases in a Brazilian Sentinel Hospital. Patientsand methods: Viral etiologies were investigated in samples from 98 children and 61 adults with fever, cough and dyspnea who were admitted to São Paulo Sentinel Hospital with suspected H1N1 infection. Results: From August to November 2009, in 19.5% (31/159) of the samples 2009 H1N1 virus was detected with 23% (14/61) in adults (median age 25 years, range: 14-55 years) and 18.4% (17/92) in children (median age 5 years, range: 4 months - 11 years). Among the negative sam- ples, a wide range of causative etiologic agents was identified. Human rhinovirus was the most frequent virus (23.91%) in children and human metapneumovirus (11.48%) was the second most frequent in adults, following 2009 H1N1 virus (22.95%). Conclusions: These data high- light the need to diagnose other viral infections that can co-circulate withinfluenzaand may have been neglected by physicians as causes of severe respiratory diseases.