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Emerging Infectious Diseases www cdc gov eid Vol 22 No 1 January 2016 49 Risk factors for primary Middle East respiratory syndrome coronavirus MERS CoV illness in humans are incomplete ly understood We identified all primary MERS CoV cases reported in Saudi Arabia during March November 2014 by excluding those with history of exposure to other cases of MERS CoV or acute respiratory illness of unknown cause or exposure to healthcare settings within 14 days before illness onset Using a case control design we assessed differences in underlying medical conditions and environ mental exposures among primary case patients and 2 4 controls matched by age sex and neighborhood Using multivariable analysis we found that direct exposure to dromedary camels during the 2 weeks before illness onset as well as diabetes mellitus heart disease and smoking were each independently associated with MERS CoV ill ness Further investigation is needed to better understand animal to human transmission of MERS CoV M iddle East respiratory syndrome coronavirus MERS CoV is a newly recognized respiratory pathogen first identified in a patient from Saudi Arabia in June 2012 1 MERS CoV causes acute respiratory disease that has a high case fatality rate 2 All cases have been linked to countries in or near the Arabian Peninsula 85 of cases have been reported from Saudi Arabia 2 Outbreaks of MERS CoV have been associated primarily with trans mission in healthcare settings 3 5 Transmission among household contacts of case patients has been documented 6 but sustained human to human transmission has not 7 Low level infections with MERS CoV have been re ported but seroprevalence of MERS CoV antibodies in the general population in Saudi Arabia is low 8 Strategies to prevent and control infection are recommended to limit secondary transmission in healthcare settings and among household contacts 9 10 MERS CoV cases continue to be reported in Saudi Arabia in healthcare settings and in the community 2 Animals have been suspected as a source of primary infection since early in the emergence of MERS CoV par ticularly given the similarities to severe acute respiratory syndrome coronavirus a zoonosis known to cause human respiratory disease often severe with sustained human to human transmission and amplification in healthcare settings 11 Persons with early cases of MERS CoV infection were observed to have had exposure to dromedary camels henceforth dromedaries and subsequent serologic studies from the Arabian Peninsula confirmed high seroprevalence of MERS CoV neutralizing antibodies in dromedaries 12 14 Other studies have detected partial genome sequences of MERS CoV from dromedary specimens 15 17 and more recently infectious MERS CoV has been isolated from dromedaries 16 18 21 Additionally a recent report provided virologic and serologic evidence of transmission of MERS CoV from a sick dromedary to a human in Saudi Arabia 19 Despite these reports risk factors for primary illness with MERS CoV i e cases in persons without apparent exposure to other infected persons are not well understood Risk Factors for Primary Middle East Respiratory Syndrome Coronavirus Illness in Humans Saudi Arabia 2014 Basem M Alraddadi John T Watson Abdulatif Almarashi Glen R Abedi Amal Turkistani Musallam Sadran Abeer Housa Mohammad A Almazroa Naif Alraihan Ayman Banjar Eman Albalawi Hanan Alhindi Abdul Jamil Choudhry Jonathan G Meiman Magdalena Paczkowski Aaron Curns Anthony Mounts Daniel R Feikin Nina Marano David L Swerdlow Susan I Gerber Rana Hajjeh Tariq A Madani Author affiliations King Faisal Specialist Hospital and Research Centre Jeddah Saudi Arabia B M Alraddadi Centers for Disease Control and Prevention Atlanta Georgia USA J T Watson G R Abedi J G Meiman M Paczkowski A Curns A Mounts D R Feikin N Marano D L Swerdlow S I Gerber R Hajjeh Ministry of Health Jeddah A Almarashi A Turkistani A Housa A Banjar T A Madani Ministry of Health Najran Saudi Arabia M Sadran Ministry of Health Riyadh Saudi Arabia M A Almazroa N Alraihan A J Choudhry Ministry of Health Alwajh Saudi Arabia E Albalawi Ministry of Health Hail Saudi Arabia H Alhindi King Abdulaziz University Jeddah T A Madani DOI http dx doi org 10 3201 eid2201 151340RESEARCH 50 Emerging Infectious Diseases www cdc gov eid Vol 22 No 1 January 2016 No risk factors for primary transmission of MERS CoV to humans have been confirmed by epidemiologic studies in cluding a link with exposure to dromedaries or any other animal species We conducted a case control study to as sess exposures in primary cases and to identify risk factors associated with primary MERS CoV illness in humans Methods Study Design In Saudi Arabia all laboratory confirmed MERS CoV cases are reported to the Ministry of Health MoH and routinely investigated to assess preillness exposures All cases reported during March 16 November 13 2014 were screened for inclusion For cases reported before May 13 2014 a confirmed case was defined as illness in any person hospitalized with bilateral pneumonia and laboratory con firmation of MERS CoV infection on the basis of a positive real time reverse transcription PCR targeting 2 genes the upstream of E gene and the open reading frame 1a gene 22 The case definition was revised on May 13 after which a confirmed case was defined as laboratory confirmation and any 1 of the following 4 clinical definitions 1 fever and community acquired pneumonia or acute respiratory dis tress syndrome based on clinical or radiologic evidence 2 healthcare associated pneumonia based on clinical and ra diologic evidence in a hospitalized person 3a acute febrile 38 C illness b body aches headache diarrhea or nau sea vomiting with or without respiratory symptoms and c unexplained leucopenia leukocytes 3 5 10 9 cells L and thrombocytopenia platelets 150 10 9 L 4 protected or unprotected exposure of a person including a healthcare worker to a confirmed or probable MERS CoV infection and upper or lower respiratory illness within 2 weeks after exposure 23 25 For this study case patients were select ed from among symptomatic patients whose illness met the case definition in place at the time of report and who met the study inclusion criteria described below Case and Control Selection Primary MERS CoV cases were defined as cases in persons without known exposure to other MERS CoV cases or re cent within 14 days exposure to healthcare settings 3 5 MERS CoV case patients meeting this definition were presumed to have acquired infection through nonhuman contact A trained MoH interviewer contacted the case patient or proxy by phone or in person to conduct an initial screening Case patients were excluded if within 14 days before onset of their MERS CoV illness they had been ad mitted to or visited any healthcare facility had worked in a healthcare facility in any capacity had a recognized epi demiologic link with another person either with confirmed MERS CoV infection or with an acute respiratory illness as perceived by the participant of unknown cause were 18 years of age or did not provide consent for interview either personally or by proxy i e a family member or close friend familiar with the preillness activities and usual habits of the case patient for case patients who had died or were too ill to give consent personally For each case patient we randomly selected up to 4 neighborhood controls matched by age and sex For case patients 18 to 25 years old controls were matched within 10 years of age First starting at the case patient s household a random direction was selected by flipping a coin Second the distance in number of houses from the case patient s residence was randomly deter mined from 1 to 10 by choosing from a random number list For multifamily structures the starting floor and apartment were randomly chosen Once a household was identified 1 control was selected on the basis of the matching criteria the exclusion criteria used for case patients were also ap plied for all controls If 1 person in the household met matching criteria 1 was randomly chosen If no matching control was found in the selected household the next house in the same direction was visited and so on until an eli gible control was enrolled Interview Process A case control protocol developed by the World Health Organization was adapted to create a standardized ques tionnaire for assessing risk factors associated with MERS CoV illness This questionnaire was used by MoH staff to conduct in person interviews with case patients or their proxies and controls 26 The 14 day period before illness onset was defined as the exposure period both for case pa tients and their corresponding controls Data Collection The questionnaire addressed demographic information medical history travel history and information about hu man food and animal exposures Human exposure ques tions addressed preillness exposures to healthcare settings or persons with acute respiratory illness Food exposure questions assessed consumption of fruit vegetables un pasteurized milk meats urine or chewing of siwak a twig from the Salvadora persica tree traditionally used for teeth cleaning Animal exposure questions addressed multiple species dromedaries goats sheep horses cattle and whether any direct or indirect exposure to animals oc curred Direct animal exposure in the 14 days before ill ness onset was defined as physical contact with animals or animal products carcasses body fluids secretions urine excrement or raw meat in any setting farm livestock market slaughterhouse racetrack stable or other ani mal related venue or engaging in certain animal related Emerging Infectious Diseases www cdc gov eid Vol 22 No 1 January 2016 51 Risk Factors for Primary MERS CoV Illness activities feeding animals cleaning housing slaughtering assisting with birth milking kissing or hugging or oth er related tasks Indirect animal exposure in the 14 days before illness onset was defined as having visited settings where animals were kept but without having direct con tact or exposure to household members who themselves had direct animal exposure When assessing animal expo sure during the previous 6 months participants self defined direct physical contact Interviews with case patients and controls were conducted in Arabic or English Because this investigation was part of a public health response MoH and the US Centers for Disease Control and Prevention CDC Atlanta GA USA determined it to be nonresearch and therefore not subject to institutional re view board review We obtained written informed consent from all participants or their proxies Statistical Analysis We used Epi Info 7 CDC Atlanta GA USA for data entry and SAS version 9 3 SAS Institute Inc Cary NC USA for data analysis Characteristics that were not part of the matching process for case patients and con trols were compared using 2 tests Fisher exact tests or t tests We used exact conditional logistic regression to estimate odds ratios ORs 95 mid p CIs and exact p values for potential risk factors for MERS CoV illness Factors found to be significant p 0 05 in the univariate analysis were further evaluated in multivariable analyses We created a final multivariable model through stepwise elimination of nonsignificant variables until all remain ing variables in the multivariate model were significant at p 0 05 Interactions between risk factors were also evalu ated in the multivariable analyses Results During March 16 November 13 2014 a total of 535 pa tients with laboratory confirmed MERS CoV infection were reported to the MoH After screening based on the ex clusion criteria 34 patients were identified as possible pri mary case patients Two persons refused to participate and 2 did not meet the age criteria for inclusion The remaining 30 case patients representing 8 of 13 regions in Saudi Ara bia were enrolled in the study Figure Symptom onset dates for enrolled case patients ranged from February 25 through November 2 2014 We identified and included 116 controls 4 age sex and neighborhood matched controls for each of 28 case patients and 2 controls for each of the 2 remaining case patients Of the 116 controls ages for 6 exceeded the age matching criteria by 1 5 years One case patient did not have a formal residence after his interview 4 controls were selected from the vicinity of the area where he spent his nights Case patients and controls were interviewed during June 8 November 29 2014 Interviews with case patients and controls were conducted on the same day a median of Figure City or governorate of residence of persons with primary Middle East respiratory syndrome coronavirus included in the study Saudi Arabia March 16 November 13 2014 RESEARCH 52 Emerging Infectious Diseases www cdc gov eid Vol 22 No 1 January 2016 27 days range 0 192 days interquartile range 12 70 days after case patients illness onsets Median age of case patients was 49 years 97 were male Table 1 Rate of ownership of a barn or farm with animals was similar between case patients and controls but income was higher for case patients than for controls 53 vs 34 respectively had a monthly income of 6 000 SAR US 1 600 2013 gross national income per capita is 2 188 month in Saudi Arabia 27 Other demographic features between the groups were similar At the time of interview 7 23 case patients were deceased and 10 33 were too ill to be interviewed For these 17 57 case patients and for 1 1 control a family member served as proxy Case patients interviewed by proxy were more likely than those interviewed directly to have under lying medical conditions but were similar in age other de mographic characteristics and animal related exposures Several exposures were associated with MERS CoV by univariate analysis Table 2 During the 14 days be fore illness onset case patients were more likely than con trols to have had direct dromedary exposure 33 vs 15 OR 3 73 95 CI 1 24 11 80 to keep dromedaries in or around the home 30 vs 15 OR 3 34 95 CI 1 04 10 98 or to have visited a farm where dromedaries were present 90 vs 53 OR 11 57 95 CI 2 67 Among those who visited a farm where livestock were kept during the exposure period case patients were more likely than controls to have milked dromedaries 50 vs 23 OR 10 36 95 CI 2 47 Case patients also were more like ly than controls to live in the same household as someone who had visited a farm with dromedaries during the previ ous 14 days 30 vs 12 OR 3 95 95 CI 1 23 13 72 and to have had direct contact with a dromedary while there 40 vs 15 OR 5 03 95 CI 1 66 16 88 Case patients also were more likely than controls to have had direct physical contact with dromedaries in the previous 6 months 37 vs 13 OR 7 67 95 CI 2 10 36 08 Case patients were no more likely than controls to report exposure to bats goats horses sheep or the products of these animals however direct cattle exposure was signifi cantly associated with illness 13 vs 3 OR 6 00 95 CI 1 02 48 44 No differences were noted in consump tion of fruits vegetables or animal products including uncooked meat unpasteurized animal milk or dromedary urine online Technical Appendix Table 1 http wwwnc cdc gov EID article 22 01 15 1340 Techapp1 pdf We observed no significant differences in dromedary expo sures between case patients interviewed directly and those interviewed by proxy Case patients were more likely than controls to have 1 underlying medical condition 70 vs 42 OR 5 11 95 CI 1 70 18 67 Diabetes mellitus 55 vs 28 OR 3 72 95 CI 1 45 10 25 heart disease 37 vs 12 OR 5 11 95 CI 1 81 15 46 and chronic lung disease 13 vs 1 OR 17 68 95 CI 4 22 were each reported sig nificantly more frequently among case patients than among controls No significant differences were identified in other reported health conditions asthma kidney failure chronic liver disease cancer blood disorders or conditions requir ing corticosteroid use Case patients also were more likely than controls to currently smoke tobacco 37 vs 19 OR 3 14 95 CI 1 10 9 24 Using siwak during the ex posure period was associated with a lower risk for MERS CoV illness 25 vs 49 OR 0 24 95 CI 0 06 0 77 Table 1 Demographic characteristics of Middle East respiratory syndrome coronavirus case patients compared with age and sex matched neighborhood controls Saudi Arabia March 16 November 13 2014 Variable Total no n 146 Case patients no n 30 Controls no n 116 p value Sex 1 000 F 5 3 1 3 4 3 M 141 97 29 97 112 97 Interview respondent 6 000 SAR 55 38 16 53 39 34 Marital status 0 475 Never married 8 5 3 10 5 4 Married 133 91 26 87 107 92 Widowed 5 3 1 3 4 3 Median ages ranges in years are as follows case patients 49 20 72 controls 50 19 74 all 50 19 74 p 0 846 pooled t test Fisher exact test Statistically significant p 0 05 2 test Emerging Infectious Diseases www cdc gov eid Vol 22 No 1 January 2016 53 Risk Factors for Primary MERS CoV Illness Multivariable analysis yielded a final model in which direct dromedary exposure in the 2 weeks before illness onset was associated with MERS CoV illness adjusted OR 7 45 95 CI 1 57 35 28 along with having diabe tes adjusted OR 6 99 95 CI 1 89 25 86 or heart dis ease adjusted OR 6 87 95 CI 1 81 25 99 or currently smoking tobacco adjusted OR 6 84 95 CI 1 68 27 94 online Technical Appendix Table 2 When substituting direct physical contact with dromedaries in the previ ous 6 months for direct dromedary exposure in the past 2 weeks we found this exposure to be significantly associ ated with MERS CoV illness adjusted OR 14 59 95 CI 2 38 89 55 along with previously identified risk factors having diabetes adjusted OR 6 95 95 CI 1 85 26 12 or heart disease adjusted OR 6 09 95 CI 1 61 22 94 or currently smoking tobacco adjusted OR 7 36 95 CI 1 75 30 94 We identified no significant interactions for direct dromedary exposure having diabetes having heart disease or currently smoking tobacco and other exposures underlying conditions or behaviors Discussion By carefully identifying persons with primary MERS CoV infections and systematically comparing their characteris tics to age and sex matched neighborhood controls our study supports a link between exposure to dromedaries and Table 2 Animal related exposures underlying health conditions current tobacco use and siwak use for Middle East respiratory syndrome coronavirus case patients compared with matched controls Saudi Arabia March 16 November 13 2014 Variable No with exposure Odds ratio 95 CI p value Case patients n 30 Controls n 116 Animal related exposures Household members frequently visit farms with dromedaries 12 30 40 14 115 12 7 06 2 23 26 46 0 001 Household members visited a farm with dromedaries during exposure period 9 30 30 14 115 12 3 95 1 23 13 72 0 018 Household members had direct contact with dromedaries during exposure period 12 30 40 17 114 15 5 03 1 66 16 88 0 004 Spouse 4 30 13 4 116 3 4 26 0 86 23 41 0 065 Other relatives 7 30 23 7 116 6 4 59 1 36 16 27 0 012 Domestic help 5 30 17 3 116 3 15 04 1 96 369 59 0 006 Dromedaries kept in around home during exposure period 9 30 30 17 115 15 3 34 1 04 10 98 0 047 Goats kept in around home during exposure period 1 30 3 22 115 19 0 08 0 003 0 58 0 011 Horses kept in around home during exposure period 1 29 3 0 115 0 4 00 0 44 0 200 Bats in around house during exposure period 3 28 11 11 112 10 1 60 0 24 9 23 0 646 Sheep kept in around home during exposure period 10 30 33 22 115 19 3 34 0 97 12 19 0 057 Sheep present at a slaughterhouse visited during exposure period 1 30 3 18 116 16 0 15 0 001 0 56 0 040 Visited farm where livestock were kept during exposure period 10 29 34 32 116 28 1 67 0 52 5 42 0 393 Dromedary present on farm 9 10 90 17 32 53 11 57 2 67 0 013 Milked dromedaries while on farm 5 10 50 7 31 23 10 36 2 47 0 013 Visited other livestock venue i e not farm market slaughterhouse racetrack or stable during exposure period 7 29 24 12 111 11 3 33 1 001 11 05 0 040 Direct physical contact with dromedary during last 6 mo 11 30 37 15 116 13 7 67 2 10 36 08 0 001 Any direct