【病毒外文文獻(xiàn)】2013 A family cluster of Middle East Respiratory Syndrome Coronavirus infections related to a likely unrecognized asympt

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International Journal of Infectious Diseases 17 2013 e668 e672 Contents lists available at SciVerse ScienceDirect International Journal of Infectious jou r nal h o mep ag e w ww elsevier co e Deputy Minister of Health for Public Health Ministry of Health Director WHO Collaborating Center for Mass Gathering Medicine Professor College of Medicine Alfaisal University Riyadh 11176 Kingdom of Saudi Arabia 1 Introduction A novel coronavirus causing severe respiratory infection was first described in September 2012 1 The virus which later became known as Middle East Respiratory Syndrome Coronavirus MERS CoV belongs to lineage C of the genus Betacoronavirus and is closely related to bat coronaviruses HKU4 and HKU5 2 3 Though an animal reservoir is considered likely none has been identified yet 4 The exact mechanism through which MERS CoV infection is acquired remains uncertain Up to 24 July 2013 a total of 90 confirmed cases of MERS CoV infection have been reported to the World Health Organization WHO including 45 deaths The majority of infections are sporadic Human to human transmission has been documented in at least 3 hospital settings 6 8 and 4 community clusters 9 12 We report the clinical and epidemiologi cal details of a second family cluster of two confirmed and one probable MERS CoV infections in Riyadh Saudi Arabia occurred in February and March 2013 We hypothesize that the index case in the cluster is likely to have acquired the infection whilst in hospital from a contact with unrecognized MERS CoV infection 2 Case histories Patient 1 was a 51 year old male with history of obesity and uncomplicated type II diabetes mellitus He was admitted on 30 January 2013 thru the Emergency Department in Hospital A in Riyadh Saudi Arabia with a 2 month history of progressive back pain lower limb weakness and urinary incontinence There was no history of travel or recent contact with sick animals Magnetic A R T I C L E I N F O Keywords Middle East Respiratory Syndrome Coronavirus MERS CoV Viral pneumonia Cluster Saudi Arabia A B S T R A C T Background Ninety confirmed cases of Middle East Respiratory Syndrome Coronavirus MERS CoV have been reported to the World Health Organization We report the details of a second family cluster of MERS CoV infections from Riyadh Saudi Arabia Methods We present the clinical laboratory and epidemiological details of 3 patients from a family cluster of MERS CoV infections Results The first patient developed respiratory symptoms and fever 14 days after admission to hospital for an unrelated reason He died 11 days later with multi organ failure Two of his brothers presented later to another hospital with respiratory symptoms and fever MERS CoV infection in the latter 2 patients was confirmed by reverse transcriptase polymerase chain reaction testing All 3 patients had fever cough shortness of breath bilateral infiltrates on chest x ray thrombocytopenia lymphopenia and rises in serum creatinine kinase and alanine transaminase No hospital or other social contacts are known to have acquired the infection It appears that the index patient in this cluster acquired MERS CoV infection whilst in hospital from an unrecognized mild or asymptomatic case Conclusion MERS CoV acquisition from unrecognized mild or asymptomatic cases may be a more important contributor to ongoing transmission than previously appreciated C223 2013 International Society for Infectious Diseases Published by Elsevier Ltd All rights reserved Corresponding author Tel 9661 2124052 fax 9661 2125052 Mobile 966 5 05483515 E mail addresses asomrani A S Omrani mmatin64 M A Matin qaishaddad Q Haddad dralfardjh D Al Nakhli zmemish Z A Memish draalbarrak A M Albarrak 1201 9712 36 00 see front matter C223 2013 International Society for Infectious Diseases Published by Elsevier Ltd All rights reserved http dx doi org 10 1016 j ijid 2013 07 001 A family cluster of Middle East Respiratory infections related to a likely unrecognized Ali S Omrani a Mohammad Abdul Matin b Qais Haddad Ziad A Memish e Ali M Albarrak a a Consultant Infectious Diseases Physician Division of Infectious Diseases Department of Medicine b Consultant Physician Division of Internal Medicine Department of Medicine Prince Sultan c Consultant Infectious Diseases Physician Department of Infection Control Security Forces d Director of Infection Prevention and Control Department of Infection Prevention and Control Syndrome Coronavirus asymptomatic or mild case c Daifullah Al Nakhli d Prince Sultan Military Medical City Riyadh Saudi Arabia Military Medical City Riyadh Saudi Arabia Hospital Riyadh Saudi Arabia Prince Sultan Military Medical City Riyadh Saudi Arabia Diseases m loc ate ijid resonance imaging showed evidence of a paraspinal mass at the 4 th lumbar vertebral level Further investigations confirmed a diagnosis of multiple myeloma He was transferred to a medical ward on 8 February 2013 for further management On 13 February 2013 14 days after hospital admission he developed high fever cough shortness of breath and hypoxia requiring high flow oxygen via face mask He commenced meropenem vancomycin vorico nazole and oseltamivir By the morning of 15 February 2013 his condition deteriorated with respiratory failure and progressive pulmonary infiltrates on chest x ray He was transferred to the intensive care unit ICU where he was intubated and put on mechanical ventilation Renal failure ensued and continuous renal replacement therapy was started on 18 February 2013 Colistin and tigecycline were added on 20 February 2013 The patient s condition remained poor and he passed away on 24 February 2013 11 days after the onset of his respiratory symptoms Bacterial cultures of blood urine and sputum were all negative Patient 2 a 39 year old brother of Patient 1 and Patient 2 became unwell on 24 February 2013 with fever generalized fatigue cough productive of bloody sputum and progressive shortness of breath He had had no significant past medical history prior to this acute illness He visited a private clinic on 27 February 2013 and was prescribed a course of oral cefuroxime without any improvement He was admitted on 28 February to Hospital B in Riyadh Saudi Arabia with hypoxia and extensive bilateral pulmonary infiltrates Figure 1 He received vancomycin piper acillin tazobactam azithromycin and oseltamivir in addition to taken on 2 March 2013 Sputum smear microscopy for acid fast bacilli and mycobacterial cultures were negative Patient 3 a 40 year old brother to patient 1 and 2 became ill on 2 March 2013 He was overweight but had no pre existing chronic medical illness He was admitted to Hospital B on 4 March 2013 with fever and cough productive of clear sputum His initial chest x ray was unremarkable He received ceftriaxone azithromycin and oseltamivir A chest x ray taken 3 days later showed focal areas of consolidation in the right middle and upper lobes A computerized axial tomographic scan of the chest showed bilateral peripheral air space consolidation with some degree of ground glass changes Figure 2 His clinical course remained largely uncomplicated He did not receive any corticosteroids immune modulatory therapy or antivirals other than oseltamivir Patient 3 was discharged from hospital alive and well on 11 March 2013 Cultures of respiratory tract samples blood and urine were all negative Sputum smear microscopy for acid fast bacilli and mycobacterial cultures were also negative Key clinical findings for the 3 patients are summarized in Table 1 Figure 3 illustrates the clinical course and timelines for the A S Omrani et al International Journal of Infectious Diseases 17 2013 e668 e672 e669 intravenous hydrocortisone and high flow oxygen by a face mask Twenty four hours later he required endotracheal intubation and mechanical ventilation The next day vancomycin and piperacil lin tazobactam were substituted with linezolid and imipenem and his ventilation was switched to high frequency oscillatory mode On 2 March 2013 continuing respiratory failure prompted a shift to extra corporal membrane oxygenation The patient s clinical condition failed to improve and he passed away 2 hours later 7 days after the onset of symptoms Cultures of blood urine and sputum taken at the time of admission to hospital were all negative Candida albicans was isolated from culture of sputum Figure 1 Chest radiograph from patient 2 with severe MERS CoV pneumonia showing bilateral pulmonary infiltrates 3 patients 3 Laboratory testing Patient 1 had no samples tested for respiratory viruses or MERS CoV Nasopharyngeal swabs from Patient 2 and Patient 3 and a tracheal aspirate from Patient 2 were all negative by reverse transcriptase polymerase chain reaction RT PCR for Influenza A virus RNA Influenza B virus RNA H1N1 Influenza virus RNA Respiratory syncytial virus RNA Adenovirus DNA Rhinovirus RNA and seasonal Coronavirus RNA HCoV 229 OC43 NL63 RT PCR testing for MERS CoV upE ORF 1b and N genes was positive on upper and lower respiratory tract samples from Patient 2 Two upper respiratory tract samples from Patient 3 were negative while a lower respiratory tract sample collected a day earlier was positive for MERS CoV All RT PCR tests for MERS CoV were performed at the Saudi Ministry of Health regional laboratory in Jeddah and confirmed at the Public Health England United Kingdom Laboratories 13 14 4 Contact investigation All 3 patients lived in one large house in Urban Riyadh There were 10 adults in the household the mother who had history of Figure 2 Computerized tomography scan from patient 3 with mild to moderate MERS CoV infection showing bilateral peripheral air space consolidation multiple medical problems including diabetes mellitus hyperten sion bronchial asthma and hypothyroidism Patient 1 and his wife 4 others sons including Patient 2 and Patient 3 2 daughters and a female housemaid Moreover 4 married daughters and their spouses and children visited the family home frequently and often slept over too The married couple shared one bedroom Each of the other members of the household had his or her own bedroom The men and women usually had their meals separately Patients 2 and in the house garden from time to time to pollinate the dates None of the other family members frequented Patient 1 s farm Patient 1 was initially admitted to a curtained off bed in the Emergency Department where he stayed for 9 days He was then transferred to a 2 bedded room in a medical ward where he stayed for 2 nights A comatose patient who had no visitors occupied the second bed in the room Patient 1 was moved once more to another 2 bedded room in the same ward His roommate was discharged Table 1 Clinical and investigational features of a family cluster of 3 patients with Middle East Respiratory Syndrome Coronavirus MERS CoV infections from Riyadh Saudi Arabia and from previously reported cases a Patient 1 Patient 2 Patient 3 Data from previous MERS CoV reports b Fever Yes Yes Yes 30 33 90 9 Cough Yes Yes Yes 30 33 90 9 Dyspnea Yes Yes Yes 20 33 60 6 Gastrointestinal symptoms No No No 12 33 36 4 Chest x ray infiltrates Yes Yes Yes 25 33 75 8 Lymphopenia Yes Yes Yes 9 9 100 Thrombocytopenia Yes Yes Yes 11 32 34 4 Creatinine kinase rise Yes Yes Yes 2 2 100 Alanine transaminase rise Yes Yes Yes 3 7 42 9 Lactate dehydrogenase rise Not available Yes Yes 3 6 50 Acute renal failure Yes Yes No 7 10 70 ICU c admission Yes Yes No 26 33 78 8 Mechanical ventilation Yes Yes No 26 33 78 8 a Data collated from reports in which clinical details of patients with MERS CoV infection were made available 1 7 8 10 19 24 27 b Numerator indicates number of patients in whom a particular characteristic was present denominator indicates the total number in which the presence or absence of the particular characteristic was reported c ICU denotes intensive care unit A S Omrani et al International Journal of Infectious Diseases 17 2013 e668 e672e670 3 are described as very close spending most of their free time together There were no domestic animals or birds in the family home but bats had been noted in a small neglected park behind the house Patient 1 had a farm outside Riyadh in which he kept sheep chicken ducks and pigeons He visited the farm once or twice a week His last visit was 2 days prior to his admission to hospital Patient 2 visited the farm occasionally He also climbed palm trees Figure 3 Clinical timelines for three patients with definite or probable Middle home 2 days later and the bed remained unoccupied for the remainder of the time that Patient 1 was in the room Patient 2 and Patient 3 visited Patient 1 in the ward and in the ICU several time but usually did not stay for too long Numerous friends relatives and work colleagues visited Patient 1 while he was in the ward before developing fever and respiratory symptoms Patient 1 s wife and 2 of his unaffected brothers spent especially long periods of East Respiratory Syndrome Coronavirus MERS CoV infection A S Omrani et al International Journal of Infectious Diseases 17 2013 e668 e672 e671 time at his bedside throughout his hospital admission All nursing and medical care for Patient 1 followed standard infection control precautions Influenza was suspected upon Patient 2 s admission to Hospital B He was transferred to a single room within 2 hours of his arrival and healthcare staff implemented contact and droplet infection control precautions throughout the patient s hospital stay 15 The patient s visitors were directed to do the same On clinical deterioration Patient 2 was transferred to the Resuscitation Bay in the main Emergency Department where he was intubated in the presence of 5 healthcare workers HCWs all of whom wore surgical masks gloves and full length isolation gowns Patient 2 was later transferred to a single room in the ICU where droplet and contact precautions continued MERS CoV infection was suspected upon Patient 3 s presenta tion He was thus admitted directly into a single room where all care was provided under strict contact and droplet infection control precautions 15 Nasopharyngeal swabs obtained from all household contacts of the patients were negative by RT PCR for MERS CoV infection Moreover all household contacts were followed daily for 14 days for presence of respiratory symptoms and none developed any Serum samples were also obtained and stored pending the availability of validated serological assays In the ensuing weeks no HCWs in either hospital developed any symptoms to fulfill the surveillance requirement for MER CoV testing 16 Patient 2 was overtly symptomatic during Patient 1 s funeral None of the dozens of mourners who attended the funeral is known to have developed a respiratory illness consistent with MERS CoV infection 5 Discussion Patient 1 s clinical course and subsequent microbiological confirmation of MERS CoV infection in his brothers provide adequate basis for labeling his illness as probable MERS CoV infection 17 The onset of his symptoms was 14 days after admission to hospital He had spent 9 days in the Emergency Department before he was transferred to 2 different 2 bedded rooms The upper end of MERS CoV incubation period is thought to be around 14 days with most patients having symptoms within the first week of contact 8 18 It is therefore likely that Patient 1 acquired MERS CoV infection during his hospitalization This could have been from an asymptomatic HCW one of the patients who were placed in close proximity to Patient 1 during his stay in the Emergency Department or from one of the numerous visitors he received whilst in the medical ward In a previously described family cluster of MER CoV infections the index patient had a protracted clinical course including urinary tract infection and cardiac failure before respiratory infection became apparent 10 The authors suggest that in hospital acquisition might be one explanation Furthermore in the largest human to human cluster of MERS CoV infections described so far one of the index cases was identified as a probable case based on his son s subsequent positive test 8 Unrecognized MERS CoV infection in the community and in healthcare settings may be a more significant problem than previously appreciated The two family contacts of Patient 1 who went on to develop MERS CoV infection had substantially less direct contact with him than other family members It was suggested that higher viral shedding during the earlier phase of the clinical illness may result in higher infectiousness 19 In our report however Patient 1 s wife and two of his unaffected brothers were in regular close contact with him throughout his illness without ever taking any specific infection prevention precautions They as well as numerous other social and healthcare contacts remained well It continues to be unclear why some close contacts of individuals with MERS CoV infection develop a clinical illness while others do not A large number of HCWs were in close contact with Patient 1 and Patient 2 some of which did not adhere strictly to appropriate infection control precautions None of them was apparently infected This is not dissimilar to the observations from four previous extensive public health investigations into cases of MERS CoV infections Out of over 400 HCWs who had been in contact with 31 patients in 4 different countries only 2 had documented MERV CoV infection 8 9 20 21 Whether HCWs play a role in transmitting MERS CoV through hand and surface contamination is an interesting but yet unproven hypothesis Fourteen confirmed cases of asymptomatic MERS CoV infection have so far been reported to the WHO including 4 HCWs 22 Such asymptomatic carriage may explain some of the transmission that has taken place in hospital and in community settings Furthermore phylogenetic analyses of the available MERS CoV genomes suggested a common ancestor halfway through the year 2011 8 19 It appears that the virus circulated in the community for at least one year before the first clinical case was recognized The relatively low attack rate amongst social and HCW contacts in our report and in previous reports is reassuring but should not detract from continuing aggressive efforts to understand the pathogenesis of MERS CoV Two recent documented outbreaks illustrate the possible risks Human to human transmission in 3 hospitals in eastern Saudi Arabia was responsible for 21 out of 23 MERS CoV infections of which at least 15 were fatal 8 Another outbreak in Jordan in April 2012 affected a total of 13 individuals including 10 HCW 6 23 The recommended contact and droplet precautions were implemented to a reasonable extent during the hospital care for all patients in our report 15 Reassuringly this appears to have been effective in preventing nosocomial transmission of MERS CoV Previous studies showed that from the onset of illness MERS CoV was detectable by RT PCR up to 14 days in lower airway samples 13 days in urine and 16 days in stool 7 19 24 The importance of stringent infection control practice to interrupt any potential sustained MERS CoV transmission can not be over stated MERS CoV infection was fatal in 2 of the 3 patients described in our report The high mortality rate associated with MERS CoV infection increasingly appears to be due to the under diagnosis of mild and asymptomatic cases as a result of the restrictive case definition put forward by WHO 16 All 3 patients in our report had fever cough shortness of breath pulmonary infiltrates on chest x rays lymphopenia thrombocytopenia and rises in serum creati nine kinase and alanine transaminase All these are relatively common clinical features amongst patients with MERS CoV infection Table 1 Many of these were also seen in patients affected by Severe Acute Respiratory Syndrome Coronavirus SARS CoV outbreak in 2003 however the 2 diseases have distinctly different infectivity patterns 25 Although not necessarily diagnostic the presence of these findings without an alternative explanation should pro