| BackgroundPneumonia is a significant cause of morbidity and mortality worldwide and a major public health threat to children in China.WHO estimated 30000 and 19000 children under 5 years of age died due to Streptococcus pneumoniae(Sp)and Haemophilus influenzae type b(Hib)respectively in China in 2000,and the numbers of deaths caused by Sp and Hib in China were the 6th and 5th greatest in the world respectively.However,there are a few studies on the disease burden of pneumonia in children in China due to no special surveillance for pneumonia.There is lack of local disease burden data for the pneumococcal vaccine,influenza vaccine and Hib vaccine into the Chinese Expanded Program on Immunization(EPI).By 2015,there were 129 and 191]WHO member countries which introduced Pneumococcal Conjugate Vaccine(PPCV)and Hib vaccine respectively into their immunization programs.In 2017,the State Council asked the health and financial departments to introduce the safe,effective and affordable category ? vaccines gradually into the Chinese EPI.The considerations for adding a vaccine to a national EPI included disease burden,vaccine safety,effectiveness,economic evaluation,budget analysis,vaccine production,supply capacity,ect.It is difficult for China to assess the disease burden of Sp and Hib due to lack of pneumonia,meningitis,otitis media and other special disease surveillance,the weakness of bacteriological testing and antibiotic abuse.There has been no economic evaluation of Hib vaccine into Chinese EPI published by now.There were some problems in the existing economic evaluation of pneumococcal vaccine,such as the morbidity,mortality and sequelae of pneumonia and meningitis mostly from neighboring countries and regions;lack of local survey data,ignoring the EPI cost and Adverse Events Following Immunization(AEFI)cost.It is difficult of the economic evaluation to reflect the real burden of disease and the vaccine cost effectiveness.In this study,the prospective surveillance and retrospective survey of children with pneumonia under 5-year-old were conducted to understand the morbidity and economic burden.The economic evaluation of pneumococcal vaccine and Hib vaccine into the Chinese EPI was made to understand the econom)y and provide the economic decision-making data for the health administrative departments.ObjectiveTo set out the population-based retrospective investigation of children with pneumonia and carry out the hospital-based prospective surveillance of children with pneumonia in order to understand the disease distribution and economic burden of children under 5-year-old with pneumonia in Baiyin city.To set up the standard methods of economic evaluations for adding a vaccine to the Chinese EPI.To establish decision tree-Markov models of the pneumococcal vaccine and Hib vaccine and to carry out health economic assessments in order to provide theoretical basis and data evidence for the decision makers.Method1.The study on disease burden of children under 5-year-old with pneumonia in Baiyin city is described mainly through the incidence density,direct economic burden,indirect economic burden,place distribution,time distribution,person distribution,drug resistance,ect.To conduct a population-based retrospective survey of children with pneumonia,make case definitions and target population,calculate the sample size,use multi-stage sampling,investigate parents of children and search hospital medical records.All the data of onset information,direct and indirect economic burden of children with pneumonia under 5-year-old from Sep 1.2015 to Aug 31.2016 were investigated in questionnaire in the vaccination units.To set up a hospital-based prospective surveys of children with pneumonia,make case definitions,select hospitals,conduct prospective surveillance for 3 years,collect and test specimens.The data of epidemiological characteristics,clinical manifestations,laboratory tests and direct medical costs of children with pneumonia under 5 years of age were investigated.The Epi data 3.1 was used to build databases.The Epi info 7.2 was used to analysis the mean and 95%Con.fidence Interval(CI)of incidence density of each age group by the complex sample frequencies method.The mean and 95%CI of capita cost per children under 5-year-old with pneumonia,and the cost differences between age and area were analyzed by SAS 9.4.2.The study on the economic evaluations for adding pneumococcal vaccine and Hib vaccine to the Chinese EPI was to set up the standard methods and frameworks of cost effectiveness analysis,establish the decision tree-Markov models of the pneumococcal vaccine and Hib vaccine and carry out health economic assessments.The target audiences in this study included the Chinese Advisory Committee on Immunization Practices and health administrative departments.The study questions were as folloxw:whether it is economy to add pneumococcal vaccine and Hib vaccine to the Chinese EPI in the existing category II vaccines prices?If the pneumococcal vaccine and Hib vaccine will be introduced into the Chinese EPI,which prices are economy in the available and baseline disease burden?The target population in this study is the birth cohort of 100000 children who are vaccinated with 4 doses of PPCV13 or 4 doses of Hib vaccine from the 2nd(or 3rd)month or vaccinated with 1 dose of PPSV23 in the 25th month.All the observation end points are 5-year-old.The decision tree-Markov models were made by Tree Age Pro 2017.The morbidity,mortality,pathogen detected,economic burden of pneumonia was got from the retrospective study.The morbidity,mortality,pathogen detected,economic burden of meningitis,otitis media,epiglottitis,neurological sequelae and hearing loss were got from literature and systematic reviews.The vaccine serotype coverage,immunogenicity and other variables were got from WHO position papers.The cost,benefit,utility,incremental cost,incremental benefit,incremental utility,and Incremental Cost Effectiveness Ratio(ICER)of the vaccine into the immunization program were analyzed by the TreeAge Pro 2017.Probabilistic Sensitivity Analysis was used to assess the effect of uncertainty on all the variables.The threshold of willingness to pay for the incremental effect was estimated.Based on the available baseline data,the economic price range of the pneumococcal vaccine and the Hib vaccine into the EPI were estimated.The literature and data xwere searched on the websites of PubMed,Wanf-ang Data.CNKI,US CDC,WHO and DOH in Taiwan.Microsoft Excel 2013 was used to build the databases.R(V3.3.2.Vienna,Austria)statistical software and "meta" package was used to estimate the average rate and 95%CI The percentage of variation across studies due to heterogeneity was estimated by the I2 index.A fixed effects model was used if significant homogeneity(12<50%,p>0.1)was observed between studies;otherwise,a random effects model was adopted.Result1.The disease burden of children under 5-year-old in Baiyin city.The incidence density of pneumonia cases under 5-year-old in Baiyin city was 0.074 per person-year in 2015-2016,with 0.084 per person-year in urban areas and 0.069 per person-year in rural areas,and the lowest(0.044 per person-year)in the zero-year-old group and the highest(0.088 per person-year)in the 1-year-old group.The total cost per case was 6215.9 yuan RMB,including 4462.8 yuan of direct cost and 1753.1 RMB of indirect cost.The highest cost(73]4.7 yuan)in the zero-year-old group and the lowest cost(5279.3 yuan)in the 3-year-old group.The cost difference between urban and rural areas was not statistically significant.The major costs of children with pneumonia were the hospitalization fee(2876.7 yuan,45.06%),labor loss fee of caring(1691.0 yuan,26.49%),extra accommodation fee(407.1 yuan,6.38%),extra accommodation fee of caring(400.0 yuan,6.27%)and own-paid drug fee(276.6 yuan,4.33%)In a total of 97 303 children under 5-year-old in Baiyin in 2016,the total number of pneumonia and estimated costs were estimated as 7197 and 44.24 million yuan respectively.The per capita expenditure was 454.6 yuan.There were 3031 cases of children with pneumonia under 5-year-old from Apr I.2012 to Dec 31.2014.The positive rate detected of Sp from children with pneumonia under 5-year-old was 10.56%.the lowest(7.97%)in the 2-year-old group and the highest(14.23%)in the 1-year-old group.The positive rate detected of Hi from children with pneumonia under 5-year-old was 1.85%,the lowest(1.54%)in the 4-year-old group and the highest(2.35%)in the 3-year-old group.The positive rates detected of Sp from children with pneumonia under 5-year-old in urban areas and in rural areas were 8.89%and 10.96%respectively.The positive rates detected of Hi from children with pneumonia under 5-year-old in urban areas and in rural areas were].80%and 1.47%respectively.More than 90%of children with pneumonia caused by Sp and Hi were diagnosed as the alveobronchiolitis.The antibiotics with higher resistance rates for Sp were the trimethoprim,cefuroxime,nitrofurantoin,oxacillin,tetracycline,erythromycin,clindamycin,ceftazidime,ect.The higher rates of antibiotics resistance for Hi were the oxacillin,gentamicin,ect.2.The economic evaluations for adding pneumococcal vaccine and Hib vaccine to the Chinese EPI.According to the vaccine specifications,100 000 children are vaccinated with 4 doses of PPCV13 or 4 doses of Hib from the age of 2nd(or 3rd)month,or 1 dose of PPSV23 in the 25th month.All the vaccines coverages are 90%and all the observation end points are 5-year-old.The prices of PPCV 13.PPSV23 and Hib vaccine are 698 yuan,180 yuan and 68)yuan per dose respectively.The cost of disease surveillance,cold chain,propaganda,health education,etc,was 7.82 yuan per dose.The subsidy was no less than 5 yuan per dose under the requirements of the Ministry of health.The vaccination cost was set as 12.82 yuan per dose in this study.Cost-benefit analysis The costs of PPCV13 vaccination,EPI and AEFI are 256 million yuan.The total costs avoided of diseases caused by Sp are 11.20 million yuan in the 5 years,including 32.25 million yuan for the pneumonia,28.28 million yuan for the meningitis,2.00 million yuan for the otitis media.The costs of PPSV23 vaccination,EPI and AEFI are 17.36 million yuan.The total costs avoided of diseases caused by Sp are 21.12 million yuan in the 3 years,including 18.97 million yuan for the pneumonia,515.99 thousand yuan for the meningitis,1310.42 thousand yuan for the otitis media.The costs of Hib vaccination,EPI and AEFI are 29.10 million yuan.The total costs avoided of diseases caused by Hib are 23.43 million yuan in the 5 years,including 18.77 million yuan for the pneumonia,3.24 million yuan for the meningitis,821.59 thousand yuan for the neurological sequelae.The costs of pneumonia and meningitis caused by Sp or Hib were more than 90%of the total costs.The net benefits of PPCV13.PPSV23 and Hib vaccines vaccination are-223.67 million,3.76 million and-5.67 million yuan respectively.Cost effectiveness analysis The 2709 cases of pneumonia,27 cases of meningitis,17972 cases of otitis media,65 cases of hospitalization bacteremia,97 cases of outpatient bacteremia,29 deaths,11 cases of neurological sequelae and 5 cases of hearing loss caused by Sp are prevented by PPCV13.The 1714 cases of pneumonia,12 cases of meningitis,111 222 cases of otitis media,34 cases of hospitalization bacteremia,54 cases of outpatient bacteremia,10 deaths,3 cases of neurological sequelae and 1 cases of hearing loss caused by Sp are prevented by PPSV23.The 1781 cases of pneumonia,53 cases of meningitis,15 cases of epiglottitis,25 deaths.20 cases of neurological sequelae and 9 cases of hearing loss caused by Hib are prevented by Hib vaccine.Cost utility analysis The 121 Quality Adjusted Life Years(QALYs)are saved by PPCV13.The ICER of PPCV13 is 1.86 million yuan per QALY which is more than 37 times of per capita national GDP.It is not economical for PPCV13 into the Chinese EPI.The 70 QALYs are saved by PPSV23.The ICER of PPSV23 is 53.74 thousand yuan per QALY which is lower than per capita national GDP.The 40 QALYs are saved by Hib vaccine.The ICER of Hib vaccine is 143.27 thousand yuan per QALY which is less than 3 times of per capita national GDP.It is economical for the Hib vaccine into the Chinese EPI.Sensitivity analysis In the PPCV13 decision tree-Markov model,the major impact factors of ICER are the incidence of pneumonia,the QALY value of Acute Otitis Media(AOM),the PPCV13 price,the incidence of AOM and the detection rate of Sp from pneumonia.In the PPSV23 decision tree-Markov model,the major impact factors of ICER are the QALY value of AOM,the PPSV23 price,the detection rate of Sp from pneumonia,the cost of pneumonia and the preventive efficacy of AOM by PPSV23.In the Hib decision tree-Markov model.the major impact factors of ICER are the pneumonia incidence,the detection rate of Hi from pneumonia,the Hib vaccine price.the meningitis incidence caused by Hib and the cost of meningitis.In a word,the higher of the morbidity,mortality,detection rate,vaccine serotype coverage,immune effectiveness,the lower of ICER;The lower of the vaccine price,health utility value.the lower of ICER.Vaccines prices analysis If the vaccines will be introduced into the Chinese EPI and the ICERs are fully worthwhile,the prices of PPCV13 and Hib should be less than 90 and 55 yuan per dose respectively.If the ICERs are acceptable,the price of PPCV13 should be less than 120 yuan per dose.ConclusionThe incidence density and 95%CI of children with pneumonia can be estimated from the multi-stage sampling and the population-based retrospective survey,which provides robust parameters for sensitivity analysis of economic evaluation.The method and framework of adding new vaccine to the Chinese EPI were made and verified by pneumococcal vaccine and Hib vaccine in this study.It is helpful for the economics evaluation of new vaccines to follow the guidelines,and to improve the quality of evaluation,interpretation and extrapolation of results.The incidence density of pneumonia cases under 5-year-old in Baiyin city was 0.074 per person-year,lower than the average of the Region for the Western Pacific,and like the average of the Region for the Americas,which may be related to the general health improvement in China.The incidence density of pneumonia cases was higher in the 1-year-old group which suggested that the routine immunization of PPCV,Hib vaccine should be completed before 1-year-old to provide effective protection for children.Pneumococcal and Hib pneumonia occure throughout the Baiyin city and the year.There are a few of typical clinical features of pneumococcal and Hib pneumonia,and the main diagnostic name is the alveobronchiolitis.The alveobronchiolitis should be included in the pneumococcal and Hib pneumonia surveillance.The treatment of specific antimicrobial agents is more complex due to the more antibiotic resistance of Sp and Hi.The average of direct medical cost(hospitalization fee)of children with pneumonia under 5-year-old is 2876.7 yuan,which is between the national average hospitalization fee of children with alveobronchiolitis in the municipal hospitals and in the county-level hospitals.In this study,the total of indirect medical cost and indirect economic burden were higher than the direct medical costs.If only the direct medical costs were used in the disease burden and economic evaluation,the disease burden and the cost-effectiveness of vaccines will be underestimated.The EPI cost was 12.824 yuan per dose which means that the EPI cost was an important part of the economic evaluation.The baseline parameters can only be used to judge whether the vaccine is economic.The distribution of the parameters by the probability sensitive analysis can provide the probability of adding the vaccine into the Chinese EPI economically.The Probability Sensitive Analysis provides more robust basis for decision-maker than the baseline parameters.The costs of pneumonia and meningitis caused by Sp or Hib were more than 90%of total costs,which means that the pneumonia and meningitis are the most important disease burden and the core disease states in the economic evaluation.In this study,the pneumonia incidence and economic burden were investigated and the results of bacterial meningitis surveillance and special survey from China CDC were cited.The core disease status and cost parameters in the economic evaluation of pneumococcal vaccine and Hib vaccine were more scientific and accurate.In the existing prices of category ? vaccines,it is economical for PPSV23 and Hib vaccines introduced into the Chinese EPI,and not economical for PPCV13.In the sensitivity analysis,the vaccine price is the only factor that can be intervened.The reduction of PPCV13,PPSV23 and Hib vaccine prices help them to be introduced into the Chinese EPI and are also feasibe. |
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