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Risk factors for human to huma n transmission of Middle East respiratory syndrome coronavirus MERS CoV are largely unknown After MERS CoV infections occurred in an extended family in Saudi Arabia in 2014 relatives were test ed by using real time reverse transcription PCR rR T PCR and serologic methods Among 79 relatives 19 24 were MERS CoV positive 1 1 were hospitalized and 2 died Elev en 58 tested positive by rR T PCR 8 42 tested nega tive by rR T PCR but positive by serology Compared with MERS CoV negative adult relatives MERS CoV positive adult relatives were older and more likely to be male and to have chronic medical conditions Risk factors for household transmission included sleeping in an index patient s room and touching respiratory secretions from an index patient Casual contact and simple proximity were not associated with transmission Serology was more sensitive than stan dard rR T PCR for identifying infected relatives highlighting the value of including serology in future investigations M iddle East respiratory syndrome coronavirus MERS CoV was first reported in September 2012 in a patient in Saudi Arabia 1 2 MERS CoV is known to cause a severe acute febrile respiratory illness in humans after an incubation period of 2 14 days 3 As of May 1 2016 a total of 1 728 laboratory confirmed cases includ ing 624 deaths had been reported globally 4 all patients have been linked to the Arabian Peninsula 5 6 Studies suggest dromedary camels as a possible natural host 7 although most patients report no exposure to camels 8 Sustained human to human transmission in community set tings has not been observed 6 but transmission has been documented in healthcare settings 9 10 and in households 11 14 Specific risk factors for secondary transmission remain unknown In Saudi Arabia real time reverse transcription PCR rRT PCR of nasopharyngeal or oropharyngeal swabs is used for routine MERS CoV diagnosis and contact tracing rRT PCR identifies and amplifies viral RNA indicating ac tive infection More recently developed serologic assays identify antibodies to MERS CoV indicating previous in fection MERS CoV antibodies are rare in the general pop ulation a nationwide serosurvey in Saudi Arabia in 2013 found antibodies in 15 0 15 of 10 009 persons 15 MERS CoV cases in Saudi Arabia increased substan tially during March April 2014 16 in association with transmission in healthcare settings 9 10 In May 2014 as the number of urban cases decreased 10 17 a new cluster was identified 400 km south of Jeddah in an area that had not previously reported cases All identified patients were members of 1 extended family from the town of Al Qouz near Al Qunfudah The first MERS CoV diagnosis was re ported on May 20 2014 in a hospitalized patient after 14 days of worsening respiratory symptoms and impending re spiratory failure by May 29 this man s wife brother and nephew and the nephew s paternal uncle had been hospital ized with confirmed MERS CoV These 5 relatives lived in 4 different households within Al Qouz On June 4 5 2014 representatives from the Saudi Arabia Ministry of Health Jeddah US Centers for Dis ease Control and Prevention CDC Atlanta GA USA and King Abdulaziz University Jeddah joined the Al Qunfudah Regional Health Department to investigate the family cluster The objectives were to characterize the clus ter by identifying additional cases through both rRT PCR for viral RNA and serologic testing for MERS CoV anti bodies to determine transmission risk factors for MERS CoV within the affected households and to assess possible Middle East Respiratory Syndrome Coronavirus Transmission in Extended Family Saudi Arabia 2014 M Allison Arwady Basem Alraddadi Colin Basler Esam I Azhar Eltayb Abuelzein Abdulfattah I Sindy Bakr M Bin Sadiq Abdulhakeem O Althaqafi Omaima Shabouni Ayman Banjar Lia M Haynes Susan I Gerber Daniel R Feikin Tariq A Madani Emerging Infectious Diseases www cdc gov eid V ol 22 No 8 August 2016 1395 Author affiliations Centers for Disease Control and Prevention Atlanta Georgia USA M A Arwady C Basler L M Haynes S I Gerber D R Feikin King Faisal Specialist Hospital and Research Center Jeddah B Alraddadi Ministry of Health Jeddah Saudi Arabia B Alraddadi E I Azhar E Abuelzein A I Sindy B M Bin Sadiq A O Althaqafi O Shabouni A Banjar T A Madani King Abdulaziz University Jeddah E I Azhar T A Madani Ministry of National Guard Jeddah A O Althaqafi DOI http dx doi org 10 3201 eid2208 152015RESEARCH MERS CoV infections in the larger community sampling both local healthcare settings and local animal workers Methods Cluster Investigation To find cases we interviewed clinicians reviewed regional records and searched a national laboratory database We interviewed all persons who had received a MERS CoV diagnosis in the region and reviewed hospitalized patients medical charts proxy interviews were conducted for pa tients who were in the intensive care unit or who had died We then conducted a retrospective cohort study to assess in fection risk factors among household members We aimed to interview and test all members of the 4 households of the 5 known MERS CoV infected patients as well as relatives who regularly visited these households and were present on the day of the on site investigation On June 5 trained nurses collected 1 oropharyngeal and 1 nasopharyngeal swab for rRT PCR and 1 blood sample for serologic testing from all available household members and visiting relatives Hospitalized persons per sons who previously had tested positive by rRT PCR and children 14 years of age with questionnaire data for all MERS CoV negative relatives 14 years of age We excluded children from analysis because they had not had antibody testing of serum A household secondary transmission analysis comprised relatives 14 years of age residing only in the 4 affect ed households Results for MERS CoV positive house hold members who had illness onset or tested MERS CoV positive at least 2 days after the household s index patient s illness onset were compared with results for MERS CoV negative household members Because this investigation was part of a public health response it was not considered by CDC and the Saudi Ara bia Ministry of Health to be research that was subject to review by an institutional review board Participants gave verbal consent Results Nineteen extended family members had evidence of MERS CoV by rRT PCR or presence of MERS CoV anti bodies Figure 1 Seventy nine relatives were interviewed and tested for MERS CoV by both rRT PCR and unless already positive by rRT PCR or 14 years of age serol ogy These persons comprised 50 96 of the 52 relatives living in the 4 original households including 13 children 14 years of age 26 relatives visiting those households including 6 children 14 years of age and 3 ill adults 1396 Emerging Infectious Diseases www cdc gov eid V ol 22 No 8 August 2016MERS CoV T ransmission in Extended Family identified in a separate branch of the family tree J K and O Figure 1 after the household investigation All 26 visit ing relatives were MERS CoV negative by both rRT PCR and for adults serology Standard Diagnosis and Disease Presentation MERS CoV was diagnosed in 11 58 of the 19 patients by rRT PCR the standard method in Saudi Arabia Table 1 http wwwnc cdc gov EID article 22 8 15 2015 T1 htm For 7 of these including the 5 original patients illness was diagnosed during May 20 June 9 while they were hospi talized Figure 2 For the other 4 patients L M N and O MERS CoV infection was diagnosed during May 22 June 11 through routine contact tracing and rRT PCR by regional health officers One of these contacts denied symp toms 2 reported mild symptoms i e cough subjective fe ver but had not sought medical care and 1 N the only child given a MERS CoV diagnosis had visited an emer gency department with fever In the 4 households all non hospitalized family members were rRT PCR negative when tested on June 5 indicating little risk for ongoing household transmission Serologic Diagnosis and Disease Presentation For 8 42 of the 19 positive family members MERS CoV infection was diagnosed only retrospectively by using serology All 8 previously had tested negative by rRT PCR during April 21 May 29 while hospitalized or during routine contact tracing and all again tested nega tive on June 5 Two of these rRT PCR negative patients A and B had extended hospitalizations 2 patients G and H had brief hospitalizations 2 patients R and S had sought medical care but not required hospitalization and 2 P and Q denied symptoms Some of these patients had Emerging Infectious Diseases www cdc gov eid V ol 22 No 8 August 2016 1397 Figure 1 Family relationships and household distribution of persons infected with MERS CoV Al Qouz Saudi Arabia 2014 Black lines denote standard family tree relationships Patients are lettered in order of symptom onset or if asymptomatic by test date Green boxes indicate households all persons living in households 1 4 were tested except for 2 adults living in household 4 not shown Index patient person with earliest symptom onset diagnosed by rR T PCR in each household is underlined Uninfected indicates person in household with negative rR T PCR results and if 14 years of age negative serologic testing for MERS CoV V isiting relatives indicates extended family members who regularly visited the 4 households and were present in the households on the day of the field investigation MERS CoV Middle East respiratory syndrome coronavirus rR T PCR real time reverse transcription PCR RESEARCH multiple negative tests during an April 2014 hospitaliza tion in Jeddah patient A the first patient in this family to become ill had 3 negative rRT PCR results of nasopha ryngeal swabs Among the 19 relatives in whom MERS CoV infec tion was diagnosed 11 58 were hospitalized 3 16 were treated in an emergency department for symptoms but not hospitalized 2 11 reported mild symptoms but had not sought medical care and 3 16 were asymptom atic Five 26 were intubated 2 of whom 11 died while hospitalized Fever was the most commonly reported symptom 74 followed by cough 63 shortness of breath 44 and diarrhea 44 The 11 hospitalized pa tients were ill at home for a median of 3 days before hospi tal admission range 0 9 days Figure 2 Infection Risk Factors among Adults Fifteen 83 of 18 MERS CoV positive adults were male compared with 15 37 of 41 MERS CoV nega tive adults p 0 0009 Table 2 MERS CoV positive adults were more likely to have smoked sheesha the tra ditional water pipe for flavored tobacco than were MERS CoV negative adults 2 18 11 vs 0 41 p 0 003 and were more likely to have traveled to Jeddah 10 56 vs 9 22 p 0 011 and visited a hospital there 7 39 vs 5 12 p 0 019 during the month before becom ing ill MERS CoV positive adults were older median age 37 years vs 25 years p 0 0011 and more likely to re port chronic medical problems 8 44 vs 5 12 p 0 006 including diabetes mellitus and heart disease All MERS CoV positive relatives denied animal contact dur ing the 14 days before testing Household Transmission In household 1 eight of the 12 adults a husband and wife 5 of their adult sons and 1 son s wife and 1 of the 7 children received a MERS CoV diagnosis household at tack rate 44 household adult attack rate 64 Figure 1 In household 2 five of the 12 adults a husband and wife and 3 of their adult sons received a MERS CoV di agnosis household attack rate 29 household adult attack rate 42 In households 3 and 4 only the index patients both adult men tested positive no secondary patients were identified All family members in whom MERS CoV symptoms developed or who had positive rRT PCR results reported contact with at least 1 ill relative in the preceding 14 days Figure 3 When we compared results for the 9 secondary adult patients adults who tested MERS CoV positive with ill ness onset after the presumed index patient in these 4 households with the results for 21 adults in the households who tested negative we identified several major risk factors for MERS CoV transmission in univariate analysis Table 3 These risk factors included sleeping in the same room as an index patient RR 4 1 95 CI 1 5 11 2 touching his respiratory secretions RR 4 0 95 CI 1 6 9 8 and removing his biological waste RR 3 2 95 CI 1 2 8 4 Notable variables not associated with being a secondary patient included hugging or social kissing sharing plates cups meals sheesha or a toilet and cleaning or feeding the index patient Community Transmission Except for members of this extended family the regional hospital admitted no other MERS CoV patients Of 131 1398 Emerging Infectious Diseases www cdc gov eid V ol 22 No 8 August 2016 Figure 2 T imeline of illness onset and testing for MERS CoV positive family members Al Qouz Saudi Arabia 2014 Patients M and N had mild symptoms during 2 weeks before their rR T PCR positive results but did not identify a specific onset date their illness dates are estimated Patients R and S reported symptoms during the month preceding their positive serology tests but also without a specific onset date their illness dates are not displayed Patients L P and Q denied symptoms at any time HH household MERS CoV Middle East respiratory syndrome coronavirus Pt patient rR T PCR real time reverse transcription PCR S positive serology date for rR T PCR negative persons MERS CoV T ransmission in Extended Family hospital workers who cared for patient C 1 0 8 a nurse who remained asymptomatic tested positive by rRT PCR on May 23 All 44 persons tested at the outpatient clinic 21 patients with respiratory complaints and 23 staff were MERS CoV negative by both rRT PCR and serology All 11 slaughterhouse workers and 10 livestock market par ticipants tested negative by rRT PCR One 5 asymp tomatic slaughterhouse worker demonstrated antibodies to MERS CoV by serology He had no known contact with any family members in the cluster Discussion This investigation defined the epidemiology of a large fam ily cluster of MERS CoV infection in Saudi Arabia identi fied multiple possible household transmission risk factors and highlighted the useful role of serology in describing the extent of family clusters and spectrum of illness For approximately half 42 of the 19 MERS CoV infected family members rRT PCR results were negative while they were ill or after recognized exposure and infection was diagnosed only retrospectively by serology this in cluded patients tested during extended hospitalizations and demonstrates real world limitations in rRT PCR or timing of specimen collection transport and testing This finding highlights the need for clinicians to consider MERS CoV diagnoses in appropriate clinical settings even in patients with negative rRT PCR results Clinicians should consider obtaining lower respiratory tract specimens to improve the sensitivity of rRT PCR particularly if nasopharyngeal and oropharyngeal test results are negative and clinical suspi cion is high and they should consider follow up serologic testing Most importantly clinicians should apply appro priate infection control practices for patients with clinically suspected illness regardless of initial rRT PCR results Only 3 of the 19 MERS CoV infected family mem bers were women all wives of patients Infection predomi nance in males has characterized MERS CoV since its identification 64 of patients globally have been male 5 and might reflect biologic or behavior differences such as men and women socializing separately 21 22 Underlying illness has previously been linked to more severe MERS CoV symptoms and signs 23 but whether underlying ill ness also makes persons more susceptible to initial MERS CoV infection is less clear This study in which 96 of household members were tested found an increased infec tion risk among persons with underlying chronic illnesses Our data indicate close contact e g sleeping in the same room as an index patient and direct patient care Emerging Infectious Diseases www cdc gov eid V ol 22 No 8 August 2016 1399 Table 2 D e m ographi c risk f a c t or and sym p t om c harac t eri st i c s of adul t s w i t h ME R S CoV p o s i t i ve and M E RS CoV n egat i ve test r es ul t s i n an e x t ended fam i l y A l Q ouz S audi A rabi a 2014 Charac t eri s t i c T e st r e su l ts n o R i s k r a ti o 9 5 C I P os i t i ve n 18 Negat i ve n 41 M a le s ex 15 83 15 37 4 8 1 6 15 0 Report ed c hroni c m edi c al probl e m 8 44 5 12 2 8 1 4 5 7 D iab e t e s melli t u s 5 28 1 2 3 4 1 9 6 1 H y pert ens i o n 4 22 3 7 2 1 1 0 4 6 A s t hm a 1 6 1 2 1 7 0 4 7 1 H eart di s ea s e 4 22 0 3 1 1 6 5 8 S m o k ed c i g a ret t e s 2 11 1 2 2 3 0 9 5 7 S m o k ed s hees ha 2 11 0 3 6 2 4 5 4 Report ed ac t i v i t i e s V i s i t ed ani m a l m a r k e t duri n g pre c edi n g 14 d 0 2 5 0 undef ine d T o u c hed l i v e ani m a l duri n g prec ed i n g 14 d 0 1 2 0 undef ine d T o u c hed c a m el duri n g prec edi n g 14 d 0 0 0 undef ine d T rav el e d t o J eddah duri n g prec edi ng m ont h 10 56 9 22 2 6 1 2 5 6 V i s i t ed J eddah ho s pi t al duri n g pre c edi n g m on t h 7 39 5 12 2 5 1 2 5 0 I l l nes s at any t i m e duri n g prec edi n g m ont h S ought m e di c al c are 13 72 4 10 6 4 2 7 15 2 A d m i t t ed t o ho s pi t al 11 61 0 0 6 9 3 5 13 6 Fev e r 13 72 3 7 7 0 3 0 16 5 C ough 12 67 5 23 4 9 2 2 11 0 Shortness of breath 8 44 1 2 4 4 2 4 8 1 Diarrhea 8 47 3 8 3 7 1 9 7 4 V o m i t ing 2 12 1 3 2 4 1 0 6 0 C h il ls 5 29 1 3 3 5 1 9 6 5 B ody ac he s 9 53 1 3 5 3 2 7 10 3 B o ld in d icat e s s ta tisti ca l si g n ifi ca n ce A n a l y sis i n clu d e s a ll r e l a tive s 1 4 y of age t es t ed f or M E R S CoV n 5 9 r e g a r d les s o f h o u s e h o ld o r vi sito r st a tu s P o sitive i n d ic a t e s p o sitiv e r RT P CR o r se r o l o g ic a n tib o d y te sti n g fo r M E RS Co V n e g a tiv e i n d ic a te s n e g a tive r RT P C R a n d se r o l o g ic a n tib o d y te sti n g Childr e n one 2 y ear o ld r RT P CR po s i t i v e c hi l d and 1 9 r RT PC R n e g a tiv e ch il d r e n wer e e xclu d e d b e ca u se th e y d i d n o t h a ve s e r o lo g ic a n tib o d y te stin g L ist e d c h r o n ic m e d ic a l p r o b l e m s w e r e s el f re por t e d n o o ne r e po rt e d c hro ni c l ung or k i d ne y di s eas e a nd ot he r s el f r ep ort ed pr obl em s h y p e r th y r o idi sm a ll e r g i e s a n d so li ta r y k idn e y wer e e x clu d e d ME R S C o V M idd le E a st r e s p ir a to r y s y n d r o m e co r o n a vir u s r RT P CR r eal time r e ve r se transcriptio n P CR A ges w e re as f ol l o w s ME R S CoV p o sitive m e di a n 37 y range 16 73 y ME R S CoV ne gat i v e m e di a n 25 y range 14 60y Of the 17 persons for whom this information was reported O f t he 4 0 p ers ons f o r w h om thi s i nf or m at i on w a s re por t e d RESEARCH activities e g touching a patient s respiratory secretions and removing his body waste rather than casual contact or simple proximity increases risk for transmission Al though smoking sheesha was a statistically significant risk factor for infection the 2 infected family members who smoked sheesha denied smoking together making it an unlikely mechanism of transmission Guidance on preventing household transmission of MERS CoV should emphasize minimizing close contact with patients Out side of this extended family and 1 asymptomatic exposed nurse and 1 asymptomatic camel slaughterhouse worker we did not find evidence for wider community transmis sion of MERS CoV Two 11 of the infected family members died As of May 1 2016 Saudi Arabia had reported 588 deaths among 1 380 confirmed MERS CoV patients for an overall 43 case fatality rate 17 The substantially lower fatality rate in this family most likely reflects aggressive contact trac ing and use of serology to identify mildly symptomatic and asymptomatic patients Patients in this family also were younger median age 37 years than MERS CoV patients globally median 48 years 5 The case f