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t r v n d s n n n3 nd dd s r s r ry syndr m r n v r s sys m r v w nd m n ys s d w n w n y s n s v s n n y n d r n y r s nd n n v rs y r n r n n d s r Over the past two decades a number of severe acute respiratory infection outbreaks such as the influenza N and the iddle ast respiratory syndrome coronavirus RS oV have emerged and presented a considerable global public health threat pidemiologic evidence suggests that diabetic subjects are more sus ceptible to these conditions owever the prevalence of diabetes in N and RS oV has not been systematically described The aim of this study is to conduct a systematic review and meta analysis of published reports documenting the prevalence of diabetes in N and RS oV and compare its frequency in the two viral conditions eta analysis for the proportions of subjects with diabetes was carried out in studies for N n and for RS oV n verage age of N patients years was significantly younger than that of subjects with RS oV years ompared to RS oV patients subjects with N exhib ited fold lower frequency of cardiovascular diseases and and fold higher prevalence of obesity and immunosuppression respectively The overall prevalence of diabetes in N was a fold lower than in RS oV The prevalence of diabetes among N cases from sia and North merica was two fold higher than those from South merica and urope The prevalence of diabetes in RS oV cases is higher than in N Regional comparisons suggest that an etiologic role of diabetes in RS oV may exist distinctive from that in N n r d n For the past two decades pandemics of severe acute respiratory infections S R have been serious threats to global health causing significant morbidity and mortality Reassorted novel strains of influenza viruses and coronaviruses continue to arise rendering vac cinations if developed less useful and posing increased risks to humans Two prominent viruses influenza N and the iddle ast respiratory syndrome coronavirus RS oV have markedly affected humans N since the pandemic has caused about deaths both directly via respiratory infections and indirectly from the cardiovascular diseases secondary to bacterial infections n addition RS oV since its first emergence in has infected individuals causing deaths and was reported in countries although the vast majority of reported cases originated from the rabian eninsula N and RS oV both target the respiratory tract and share many similar clinical symptoms The most common symptoms are fever cough shortness of breath and sore throat followed always by gastrointestinal symptoms such as nausea vomiting and diarrhea oth diseases often lead to complications such as pneumonia acute respiratory distress syndrome organ failure and even death omplications mostly lie within the respiratory system with organ fail ure commonly noted in the respiratory system followed by renal and cardiovascular systems ndividuals infected with N usually belong to those aged between and years and have a mean age in the early s RS oV on the other hand mostly infects older adults with a median age of years This difference was hypothe sized to be related to the development of cross reactive antibodies against influenza viruses from previous exposures to seasonal influen za in elder people nother difference between N and RS oV relates to the length of the incubation period N has a short incu bation period between and days whereas RS oV has a much longer period of days any infected individuals exhibit comorbidities diabetes hypertension asthma and obesity rendering them more susceptible to complications iabetes is one of the known documented con tributing host related risk factor in both N and RS oV severe cases and is frequent in individuals developing fatal disease compli cations This observation may suggest an etiological relationship between diabetes and acute viral respiratory infections iabetes and its related conditions downregulate the innate and humoral immune systems by reducing the function of T cells and neutrophils yperglycemia impairs critical components of innate immunity n such as chemotaxis phagocytosis and the bactericidal activity of neutrophils and macrophages and lead to secondary infections The direct influence of diabetes however on acute respiratory infections Outbreaks of the influenza N and the iddle ast respira tory syndrome coronavirus RS oV have presented a considerable global public health threat over the past few years vidence suggest that infected subjects who are also diabetic are more likely to be suscep tible to severe outcome of N and RS oV Systematic analysis of N cases and RS oV cases indicated an overall prevalence of and for diabetes in N and RS oV cases respectively This may suggest a possible etiological relationship between diabetes and each of the two infectious conditions ntroduction of effective public health vaccination intervention strate gies against severe acute respiratory infections should be developed to target subjects with chronic disorders such as diabetes obesity and car diovascular conditions r Non commercial use onlystill needs more research to estimate the frequency of diabetes in severe viral conditions and to elucidate the etiologic role on diabetes in disease severity The present study was undertaken to conduct a sys tematic review and meta analysis of published literature to describe the prevalence of diabetes in two of the emerging severe acute respira tory infections such as N and RS oV and to explore its possible contribution to the severity and complication of the two viral condi tions r s nd ds search was conducted in ub ed Ovid N mbase and mbase lassic databases to the last week of uly using the search terms eS N or RS oV iddle ast respiratory syn drome coronavirus and iabetes The search resulted in articles selected for title and abstract review as they satisfied our selection cri teria see below We limited the studies into those in humans and excluded reports published as review articles letters case studies edi torials conference abstracts vaccination trials or family based studies fter eliminating duplicate listings and only considering articles in full text a total of peer reviewed original studies were selected for full text review Full article review resulted in the further exclusion of reports that were not documenting the prevalence of diabetes in N or RS oV no association studies examining only a small number of travellers as a case report n subjects reporting season al influenza alone reviewing already reported cases RS oV or simply documenting national surveys bibliography search of the remaining articles identified two additional studies total of peer reviewed articles studies for N and for RS oV were identified for this article Figure The abstracts of the identified studies were independently reviewed by two readers and S ifferences were resolved through discus sions for a consensus to be reached ercentage agreement and ohen s Kappa statistic were calculated and interpreted in accor dance with andis and Koch s benchmarks for assessing the agree ment between reviewers as poor slight fair moderate substantial and excellent The agreement on the inclusion between the two reviewers was with The methodological quality of each study was evaluated as previously described with some modification uality of the study was based on four criteria the number of study subjects n at least the median of for N and for RS oV comprehensive reporting of patients demographic information describing a minimum of dis ease associated symptoms and reporting at least comorbidities in addition to diabetes For each criterion each study was given a score or with fulfilling the criteria The total score was calcu lated for each study score range uality scores of and were considered poor fair good and very good respectively ata extracted from the selected studies included the first author s name publication date country dates of recruitment ethnicity total sample size divided to males and females age prevalence of symp toms including fever shortness of breath sore throat cough and cute hysiology and hronic ealth valuation and percentage of comorbidities at the time of presentation including obesity immunosuppression or V and heart conditions such as hypertension cardiovascular diseases and or coronary arterial diseases Tables and t i r yst ti it r t r r 0i w ro ss ow di r d s ri s t syst ti r 0i w o it r t r on t ontri tion o di t s to s 0 r nd o tot o ni st di s w r id nti i d st di s or nd or o ro n initi x in d tit s Non commercial use only t Weighted average was used to calculate the average age and the overall prevalence of clinical symptoms and comorbidities ublication bias was assessed both by the visual inspection of funnel plot Figure and by gger s test gger s test is widely used to assess the tendency for the effects estimated in small sample size studies to differ from those estimated in larger studies The results of gger s test are presented in terms of bias coefficient To measure the prevalence of diabetes in the two viral conditions we extracted the proportion of the disease in the reported cases of severe respiratory infections subgroup analysis was carried out by region only for the N studies Table Region sub group analysis for RS oV was not doable since all the identified studies were conducted on Saudi populations with one study of pooled analysis where region country designation was not possible The pri mary outcome measure was to evaluate the prevalence of diabetes in N and RS oV cases The meta analysis of proportions and s was calculated for the identified studies Figure and in a sub group analysis within each region Table eta analysis tests were conducted using the Open eta nalyst version a free cross plat form open source program We used binary random effects model since we assumed that the relationship between diabetes and severe respiratory infection is varied across populations T test was used to compare between average age in N and RS oV since this factor was normally distributed in the two sets of studies ann Whitney U test was employed to compare the prevalence of clinical symptoms and comorbidities between the two diseases as these conditions were not normally distributed To assess whether there is true heterogeneity among the selected studies and that all the studies are evaluating the same effect we used the test test only informs about the presence versus the absence of heterogeneity and does not report on the extent of such heterogeneity Therefore we calculated the index to comple ment the test and quantify the degree of heterogeneity among stud ies iven the poor power of test to detect true heterogeneity among a small number of studies we also quantified the true heterogeneity by estimating the between study variance in the random effects model as previously described was considered to be statistically significant Forest plots were used to illustrate the prevalence of dia betes in N and RS oV severity from the selected studies and to inspect the heterogeneity of the individual findings r t risti s o t id nti i d st di s Stu 7 ountr7 t s g S7mptoms omor t s u t7 mm 77 7r Scor v r Shortn ss Sor ough s t7 mm of r th hro t l oub a a llam dia ag haw a ada alaga e akuma dia hawla dia ime ez a cia pai u z ie z ge i a u yap a ad Vallejo ge i a ziz aumga e ge i a howell exico elgada od iguez pai o e a cia pai a ija ojicic ille Wa e wa da huda ama dia ilca a ada Wa d u alia oko a azil Va e khove ooled lla d a ada a cio e u alia aja do olci exico oegele be g f ica Ve ka a Xi hi a wa e o al Weigh ed ve age cu e hy iology a d h o ic eal h valua io V hype e io co o a y a e y di ea e ca diova cula di ea e mm immu odeficie cy bo igi al o ia a d e zegovi a Non commercial use only s s The present systematic review examines the relationship between diabetes and the N and RS oV total of studies that report the prevalence of diabetes in N n cases from studies Table and RS oV n cases from studies Table were selected The funnel plot Figure demonstrated a non symmetrical distribution of the effect size of each study on either side of the pooled estimate This seemingly non symmetrical appearance of the plot sug gested evidence of publication bias gger s test also supported this notion particularly in RS oV studies where the bias coefficient was not statistically significant given the assumption for evidence of small study effects is based on for the N studies and for the RS oV studies These findings are supported by the significant heterogeneity among the selected studies see below ccording to our quality scoring criteria see above the majority of the studies were between fair score reports and good score reports quality with studies that fulfilled all quality scor ing criteria score very good Within the selected studies sex ratio male female in the majority of the N reports was whereas it was in the RS oV cases The average age of N cases years range years was significantly younger than RS oV cases years range years t test The prevalence of fever shortness of breath sore throat and cough was not statistically different between N and RS oV cases from the two sets of studies ann Whitney U test at We observed a non statistically significant fold higher frequency of obesity kg m in the RS oV patients compared to their N counterparts t r t risti s o t o id nti i d st di s Stu 7 t s g S7mptoms omor t s u t7 mm 77 7r Scor v r Shortn ss Sor ough s t7 mm of r th hro t halhoub l awfi l awfi abi emi h i i i i emi h W o al Weigh ed ve age ll udie we e f om excep W exami ed ample pooled f om a ce e ma y aly o da a a u i ia o abb evia io ee able t n ys s or t r 0 n o di t s in s 0 r s s y r ion g on um r rc nt pr v nc of t s t rog n t7 n 7s s of su j cts n ochr n s St t st c u ope ia f ica No h me ica ou h me ica i r nn ot or syst ti r 0i w on t r 0 n o di t s in nd o st di s o it 0 nt r t or r 0 n orizont xis is r s nt d inst t st nd rd rror o t o o o it 0 nt r t 0 rti xis or nd o st di s in0 rs y orr s onds to t st dy siz sy try o t ot n indi t i tion i s n ir s indi t t indi0id st di s Non commercial use only The combined frequencies of cardiovascular diseases hypertension and cardio artillery diseases were fold higher in RS oV cases than in N eta analyses for the proportion of diabetes in N and RS oV are shown in Figures and respectively The overall proportion of diabetes in N is fold lower than its pro portion in RS oV The two sets of studies displayed a significant heterogeneity among the selected studies test for N for RS oV dditionally the degree of heterogeneity among studies was statistically significant and comparable between the two sets of studies index for N for RS oV The between study variance in the random effects model was markedly lower among the N studies than the RS oV reports Subgroup analysis by region for N studies Table showed that the frequency of diabetes in N from sia and North merica is fold higher than its prevalence in the cases recruit ed from urope and South merica ases from frica showed a non significant slightly lower diabetes preva lence compared to those from sia and North merica t should be noted however that the frequency estimate from frica was developed only from two studies compared to and studies from sia and North merica respectively and studies from each of urope and South merica The heterogeneity tests for the studies included in all regional sub analyses exhibited significant overall heterogeneity test degree of heterogeneity among studies index and between study variance in the random effects model test s ss n The present systematic review evaluates the frequency of diabetes in S R conditions such as N and RS oV We observed a large dif ference between the volume of literature and total number of subjects evaluated for each condition and identified studies for N with subjects and for RS oV with patients bout of the selected studies out of had a quality score between good and very good Tables and This indicates that a large set of the studies had a sufficient enough number subjects to substantiate the outcome and have provided a comprehensive reporting of patients demographic information Furthermore the majority of the selected studies reported a set of disease associated symptoms and comorbidi ties that permitted developing a comprehensive profile of the infec tious disease and its complication This difference reflects the discrep ancy between the two diseases in their global N versus regional RS oV spread and the period during which they emerged mmediately following its outbreak in the N triple reassortant swine influenza viruses contained genes from avian swine and human influenza viruses and sustained a rapid between human transmission to spread globally On the other hand in the emer gence of RS oV was to a great extent contained within the rabian eninsula and dromedary camels were identified as the intermediate host with a closely related virus sequences found in bats part from a number of nosocomial outbreaks involving healthcare workers caring for RS oV patients little evidence has been initially reported for sustained person to person transmission owever during the RS oV outbreak in the Republic of Korea it was demonstrated that among cases of the transmission events were linked to only super spreaders all of whom had pneumonia at presentation and contacted hundreds of people adding evidence to the person to person transmission in RS oV The characteristic pattern of transmission and spread of N and RS oV may have resulted in a distinctive sex ratio for each condi tion RS oV cases exhibited a sex ratio male female of twice that noted for N cases Tables and The male predominance of RS oV reflects the higher likelihood of exposure to the infectious agent in males than in females in iddle astern cultures n addition i r t n ysis or t ro ortion o di t s in s s i ts r t d ro in ry r ndo ts od n ysis s r r s nt ro ortion o di ti s s in t ti nts nd t ro n ity n ysis w s rri d o t sin t st t on st di s 0 ri tion ind x nd in tw n st dy 0 ri n in t r ndo ts od i r t n ysis or t ro ortion o di t s in o s s i ts r t d ro in ry r ndo ts od n ysis s r r s nt ro ortion o di ti s s in t o ti nts nd t ro n ity n ysis w s rri d o t sin t st t on st di s 0 ri tion ind x nd in tw n st dy 0 ri n in t r ndo ts od t Non commercial use onlymost males who tested positive for the virus and died also had under lying medical conditions which could explain the severity of cases in older males n agreement RS oV cases were significantly older years than their N years counterparts The average age of N patients is similar to that in N cases where percent of the subjects were years or younger s noted with N cases it can be estimated that of elder people may have resid ual immunity against this N flu strain following their life time exposures to multiple influenza outbreaks This immunogenicity does not apply to coronaviruses and may explain the younger average age of N cases compared to RS oV cases ndeed it was pro posed over years ago that repeated exposures to antigenic variants of influenza viruses may result in antibodies recognizing a large num ber of common flu antigens and develop a reinforced immunity that lower the risk of infection with newly emerging variants The clinical presentations of S R generally include respiratory symptoms such as fever new onset or exacerbation of cough breath ing difficulty and sore throat Severe illnesses may vary from pneumo nia acute respiratory distress syndrome encephalitis myocarditis or other severe and life threatening complications The frequency of fever shortness of breath sore throat and cough was similar between N and RS oV cases n contrast underlying medical conditions and comorbidities varied significantly between the two viral conditions atients with RS oV had fold higher rates of obesity and fold higher combined frequencies of cardiovascular diseases hypertension and cardio artillery diseases Tabl