Influenza Epidemic And Its Control In Shanghai

Ⅰ. BackgroundInfluenza as acute respiratory infectious disease is serious threatening human health. It had caused huge population and economic losses for many times in the history of human society. Recently, avian influenza A virus H5N1, H7N9 frequently broke through the species barrier and infected humans raised the fear that next influenza pandemic may approach. At high-risk of influenza are children under the age of 5 and elderly population over the age of 60. Influenza is more likely to to result in serious complications such as pneumonia for those groups, and cause high economic disease burden.To vaccinate the susceptible population is the most effective means of prevention, which reduces the risk of infection, disease and complications. Free vaccination for the elderly population aged over 60 is one of the basic strategies of influenza prevention in many countries but currently influenza vaccination is only recommended in China and Shanghai, and is not free or covered by the national medical insurance.There are many impact factors of influenza activities, including biological factors such as population immunity levels, virus variation, natural environmental factors such as weather and air pollution, social factors such as economic development, behavior habits and living conditions. Currently, there are no effective methods to prevent and control a flu pandemic, and also there is lack of a reliable warning or forecasting technology. Only through continuous influenza surveillance, can we grasp the trends and characteristics of the flu timely. The earlier detection of influenza virus antigen variation and evaluate the risk, the more time we buy for the pandemic response.Ⅱ. Study goal1. To determine the epidemiological characteristics, impact factors and virus antigen variation of influenza in Shanghai area. Further, to clarify the epidemic regularity and to develop an early prediction and warning system.2. To collect and analyze data for costs of confirmed flu cases aged over 60 in Shanghai area, which will help to develop vaccination strategy for high risk groups.3. To determine the epidemic characteristics and transmission mode of the influenza A (H1N1) 09pmd pandemic in different time periods of Shanghai area, and the disease spectrum. Provide scientific evidence for the development of influenza control strategy and response plans.4. To analyze the etiological characteristics, clinical manifestation and epidemiological features of human infection of avian influenza A (H7N9) virus, and to evaluate the potential risk of pandemic.5. To conduct a summary analysis for the strategies and measures taken in the control of influenza A (H1N1) 09pmd and human infection of avian influenza A (H7N9) virus in Shanghai area.Ⅲ. Study contents and methodologies1. We analyzed the surveillance date from 2006 to 2010 which were collected from 27 flu sentinels and laboratory network of Shanghai area, calculated the percentage of the ILI visitors to the sentinels and determined the prevalent strains. The analysis of the influenza A viruses included seasonal influenza A(H1N1),season influenza A(H3N2) and the influenza A (H1N1) 09pmd, which were isolated from the laboratory of flu network in Shanghai area by gene sequencing and phylogenetic tree analysis to find the antigen variation. By collecting the meteorological data as well as the ILI from the year 2006-2010, we established several nonlinear regression candidate models based on the GAM. These models consider the nonlinear dependence on the meteorological data, i.e. weekly average temperature and weekly average (maximum) temperature difference and the ILI.2. A prospective, observational study was conducted over the 2008-2009 influenza season. People aged 60 years and above with acute onset of influenza-like illness (ILI) were enrolled and tested by PCR for influenza virus infection. Influenza-positive patients were visited 2 weeks later to determine healthcare costs and resources used.3. Data of confirmed influenza A (H1N1) 09pmd cases were collected from May 2009 to Apr 2010, and then analyzed and described for the distribution in Shanghai. From January-September 2010, we conducted 3 serologic cross-sectional surveys on influenza A (H1N1) 09pmd, each time we used a multistage-stratified random sampling method to select 4,500 subjects who met eligibility criteria and collected serum samples and administered a standardized questionnaire. Antibody response to H1N1 pmd09 was measured by using haemagglutination inhibition (HI) assay. Multivariable logistic regression analyses were conducted to examine risk factors for the seropositivity. We carried out an evaluation on the administration and efficiency of influenza A (H1N1) 09pmd vaccine in Shanghai from Oct through Dec 2009. We collected the information of incidence, characteristics and outcomes of adverse reactions to evaluate the safety of the vaccines. A stratified sampling method was applied to select 111 public security staff,146 elementary and high school students and 320 health care professionals. Serum samples were were collected serum samples from the participants and were tested for influenza A (H1N1) 09pmd antibodies before and in 5-6 weeks after the vaccination to evaluate the immunological effect. The vaccinated and non-vaccinated students in six districts of Shanghai were selected as the overall sampling population of epidemiological evaluation. The daily report of fever and cases of influenza-like illness were collected by the district CDCs. The epidemiological effects of influenza vaccine were evaluated by using the protection rate and the protection index. During the pandemic of influenza A (H1N1) 09pmd from 2009 to 2010, using face to face questionnaire survey, chart review and epidemiological survey, we collected the direct and indirect economic cost of randomly selected influenza outpatients, all severe hospitalized and death patients in Shanghai area. We estimated the total economic disease burden for the patients of influenza A (H1N1) 09pmd infection of the city by using FluAid Special Edition software.4. We obtained and analysed clinical, epidemiologic. and virologic data from three patients infected with a novel avian-origin influenza A (H7N9) virus. Respiratory specimens were tested for influenza and other respiratory viruses by means of real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, viral culturing, and sequence analyses. Field investigations were conducted for each confirmed case of H7N9 virus infection in Shanghai. A patient was considered to be a confirmed case if the presence of the H7N9 virus was verified by means of real-time RT-PCR, viral isolation, or serologic testing. Information on demographic characteristics, exposure history, and illness timelines was obtained from confirmed cases. Close contacts were monitored for 7 days for symptoms of illness. Throat swabs were obtained from contacts whose symptoms developed and were tested for the presence of the H7N9 virus testing by means of real-time RT-PCR.5. For a summary we first looked through relevant reports and literatures to evaluate the risk of the next influenza pandemic. Secondly, based on the WHO preparedness and response plans and guidelines on influenza pandemic, we combined and integrated the WHO Suggestions for prevention and control of an influenza pandemic. Further, through the analysis of the successful experience in controlling the influenza A (H1N1) 09pmd pandemic in 2009 and the detecttion and management of human infection of avian influenza A (H7N9) virus in 2013, we summarized the local strategies of influenza pandemic response. Finally, by comparing with the public health prevention and control system of the developed countries in the world, we identified the shortages in Shanghai area and put forward policy suggestions.Ⅳ.Main study results1. The activity of Influenza in Shanghai had an obvious seasonal characteristic, two peaks in winter and summer. The baseline influenza-like illness visit percentage of shanghai was 2.56%. The prevalent strains of influenza appeared a regular alternative, generally occured once every six months. Influenza pandemic and the mass vaccination in the crowd had large influence on the alternative.The sequence analysis results showed that in 2009-2011 the Seasonal influenza A (H1N1) virus s may not be evolved from the prevalence virus in 2006-2008. It seems that the virus was come from abroad or other region. The seasonal influenza A (H1N1) virus existed in the crowd in an extremely sporadic status since 2009. The Seasonal influenza A (H3N2) virus only had some tiny antigenic drift since 2005 and there was no significant change of antigens. Meanwhile, the influenza A (H1N1) 09pmd evolved obviously, phylogenetic tree analysis showed the gap between the virus and the vaccine strain become more and more wide, the mutation rate was increasing slowly. There were no significant differences between the virus isolated from the pigs in the country and the humans which mean the virus circulated in hunman and animals hadn’t significant variation.The AIC suggests two simplified models which are implemented for further analysis and prediction. Finally numerical examples show that the proposed models shed light on the connection between the meteorological data and the ILI.If the average week temperature below 25 degrees Celsius, week’s maximum daily temperature difference was small and the humidity between 50% and 70%, there would be less influenza-like illness; Once in extreme meteorological conditions namely the average temperature over 35 degrees Celsius, and week’s maximum daily temperature difference became bigger, there would be a peak of ILIs.2. From January 2009 to December 2009,1,946 subjects were recruited from 12 hospitals and community health centers. Among the 1,804 patients with ILI symptoms who met the inclusion criteria.422 (23.4%) tested positive for influenza virus infection.352 (83.4%) of patients with laboratory confirmed influenza (LCI) received ambulatory care only while 70 (16.6%) were hospitalized. Almost all LCI patients had been prescribed at least one medication (93%), had seen at least one time a physician (95.7%) and had had at least one laboratory test (92.2%). Influenza infection managed as an outpatient cost a mean of 381 RMB per case. When influenza led to hospitalization, the average length of stay was 16.2 days and the mean total inpatient cost reached 8737 RMB. The public health insurance paid 64% and 79% of the mean outpatient and inpatient costs per patient respectively.3. From the first case of influenza A (H1N1) 09pmd reported in May 25th 2009 to Aug 2009, imported cases were decreasing while local cases began to account for high proportion. Influenza A (H1N1) 09pmd cases increased rapidly, reaching peak in late Nov and Dec 2009. By Apr 30th in 2010. there were reported 3.678 confirmed cases, including 331 hospitalized cases and 10 death cases. According to disease severity, there were 3,551 mild cases,98 severe cases, and 29 critical severe cases. Population distribution showed that patients under 30 years old accounted for 76.6% and most of them were students. Most of the severe cases were children under 10 years old as well as people aged above50, and the ratio of male to female was 2.4:1.The three cross sectional seroprevalence of influenza A (H1N1) 09pmd among the population of Shanghai area were 29.3%(unvaccinated 19.1%),31.4%(unvaccinated 19.6%),42.8%(unvaccinated 32.2%). Higher in rural areas compared to urban. By excluded the baseline seroprevalence giving an attack, rate of influenza A (H1N1) 09pmd in the first pandemic wave of 17.9% in the period May 2009 to January 2010, that was higher than the evaluated 11%of Flu Aid Special Edition software.From Oct 15 to Dec 31,2009, there were almost 1.4 million doses of influenza A (H1N1) 09pmd vaccine have been up taken in Shanghai. The total reported adverse events following immunization (AEFI) were 620 cases, reported incidence was 45.1 per 100000. The positive rate of influenza A (H1N1) influenza antibody increased from 38.6% to 98.3%. Compared with the control group after inoculation, the vaccine’s protection rate of influenza-like illness in vaccinated group was 72%, and the protection index was 3.6.Mathematical model showed that in the Shanghai area, a total of more than 2 million people were infected with influenza A (H1N1) 09pmd, the attack rate is about 11%, caused nearly 90,000 mild outpatients,11,000 hospitalized cases and almost 900 deaths. The work loss caused by influenza A (H1N1) 09pmd was about 3.8 million labor day which means 623 million RMB. Evaluation results show that the influenza A (H1N1) 09pmd vaccine had a good economic and social efficiency, the vaccination benefit-cost ratio (BCR) 1.6:1.4. Some patients with severe respiratory infection were detected in Shanghai. They all onset with influenza like illness, and progressed to double pneumonia rapidly. Chest radiography revealed diffuse opacities and consolidation. Complications included acute respiratory distress syndrome and multiorgan failure. A novel reassortant avian-origin influenza A (H7N9) virus was isolated from respiratory specimens obtained from 2 patients from shanghai and 1 patients from Anhui and was identified as H7N9 by the CNIC. Sequencing analyses revealed that all the genes from these three viruses were of avian origin, with six internal genes from avian influenza A (H9N2) viruses. Substitution Q226L (H3 numbering) at the 210-loop in the hemagglutinin (HA) gene was found in the A/Anhui/1/2013 and A/Shanghai/2/2013 virus but not in the A/Shanghai/1/2013 virus. A T160A mutation was identified at the 150-loop in the HA gene of all three viruses. A deletion of five amino acids in the neuraminidase (NA) stalk region was found in all three viruses.Among 33 persons with confirmed H7N9 virus infection, the median age was 67 years (range,2 to 89),88%(29/33) were male. Confirmed cases occurred in 12 District areas of Shanghai. Of all 33 confirmed cases,91% had a history of exposure to live animals, among them 52%(17/33) had multi-exposure,91%(29/33) had underlying disease condition. Finally,18(54.5%) cases didn’t make through, only 15 cases recovered. The median time from onset to death was 14.5 days, while 23 days from onset to recovery. In two family clusters, human-to-human transmission of H7N9 virus could not be ruled out, especial in a couple whom had no blood relationship. A total of 455 close contacts of the patients completed the medical observation, respiratory symptoms developed in 3 of them (0.7%),1 was tested positive for the H7N9 virus.5. In 2009, the Shanghai municipal government formulated a preparedness and response plan ahead of the pandemic. For different stages of the pandemic, targeted strategies and measures were taken, in the early period the implementation of rapid containment, in the medium time prevented community spread and crowd vaccination in the later. It prevented and controlled the spread of influenza A (H1N1) 09pmd effectively in Shanghai area, no outbreaks and epidemic were found during the pandemic; In 2013, Shanghai was the first place to detect the novel H7N9 avian flu virus in the world, by reporting the findings timely, analysis the risk factors and close live poultry market, the epidemic was terminated in time which was given a high praise by the WHO. In addition, in the disposal of flu pandemic or novel avian infection, the domination of response by the government at all levels, early establishment of a joint defense mechanism, fully social mobilization, adequate reserves of drugs and vaccines, timely and transparent information disclosure had been proved to be functional strategies.V.Conclusion1. In recent years, the activity of Influenza in Shanghai was smooth and had an obvious seasonal characteristic. The prevalent strains of influenza appeared a regular alternative. The extremely sporadic seasonal influenza A (H1N1) virus may cause local outbreaks and epidemic. The influenza A (H1N1) 09pmd evolved obviously, needed to be on high alert. GAM can be used to fit the frequencies of ILI and meteorological factors in Shanghai, the proposed models can accurately analyze the onset of ILI which implies that GAM may be suitable for the prediction and analysis of those meteorological correlative diseases.2. This study allowed describing the management of a confirmed influenza case in people aged more than 60 years in Shanghai and estimating the economic burden of influenza per patient in particular from the public healthcare system perspective, with expensive consequences among hospitalized patients. In a second step, these costs per patient could potentially be used in an economic model to estimate the overall burden of influenza in the population aged over 60 years in Shanghai, and the medical and economic benefits of different vaccination strategies.3. The influenza A (H1N1) 09pmd pandemic in Shanghai had experienced two stages from imported to the local spread, it had obviously seasonal characteristics. By scientific prevention and control measures, the pandemic was finally under control. The population of Shanghai area had experienced a relatively high attack rate in 2009 of this virus. The influenza A (H1N1) 09pmd vaccines proved to be safe and demonstrated good immunological and epidemiological effectiveness. During the pandemic, the total cost of disease burden and economic work loss were very high. Routine control measures such as vaccination especially for the high risk population to reduce transmission and spread of seasonal and pandemic influenza viruses was recommended.4. The novel reassortant H7N9 viruses were associated with severe and fatal respiratory disease which has a serious potential risk of pandemic. Most of the 33 patients with confirmed H7N9 virus infection in shanghai were critically ill and epidemiologically unrelated. Laboratory-confirmed human-to-human H7N9 virus transmission was not documented among close contacts, but such transmission could not be ruled out in two family clusters.5. Shanghai has successful experience in preventing and controlling influenza A (H1N1) 09pmd pandemic in 2009, and first detected and disposed the novel H7N9 avian influenza infection’effectively, rapidly and professionally’ in 2013. Avian influenza H5N1, H7N9 had triggered a potential pandemic threat to human being, in facing next pandemic, the experience and lessons in the Shanghai area could be a good reference. On the other hand, the public health system of the Shanghai area still has room for further improvement.