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Chapter 14 Middle East Respiratory Syndrome Coronavirus MERS CoV Infection Jaffar A Al Tawfiq 1 and Ziad A Memish 2 1 Saudi Aramco Medical Services Organisation Saudi ARAMCO Dhahran KSA 2 Ministry of Health Al Faisal University Riyadh KSA CASE PRESENTATION A 45 year old male had a history of heavy smoking type 2 diabetes mellitus a history of atrophied right kidney and ischemic heart disease He presented with a 3 day complaint of fever of 38 C14 C and a cough that had become pro ductive A chest film was unremarkable and he was discharged home The following day he visited the hospital s emergency room with the same complaints The oxygen saturation on room air and chest film was normal and he was discharged home on oral cefuroxime Two days later he returned to the emergency room with worsening dyspnea and required continuous positive airway pressure CPAP to maintain oxygenation Chest film revealed patchy infiltrates in his right lower lobe Treatment with parenteral ceftriaxone azithromycin and oral oseltamivir were commenced after specimens were collected for diagnostic testing He became progressively more hypoxic over the next 24 hours Chest film revealed patchy infiltrates in his right lower lobe Routine bacteriology acid fast bacillus smears and screening influenza exams were negative He further deteriorated and required intubation and mechanical ventilation Antibiotics were changed to piperacillin tazobactam plus linezolid treatment with corticosteroids was initiated Immunofluorescent staining of respiratory epithelial cells for influenza A B respiratory syncytial virus RSV parainfluenza 1 3 and adenovirus were negative and he was con firmed to be seronegative for human immunodeficiency virus HIV Mycoplasma pneumoniae Q fever and Brucella Upper tract swabs in viral transport media were forwarded to the Saudi Ministry of Health regional 185 Emerging Infectious Diseases DOI http dx doi org 10 1016 B978 0 12 416975 3 00014 5 2014 Elsevier Inc All rights reserved laboratory for Middle East respiratory syndrome coronavirus MERS CoV upE reverse transcriptase polymerase chain reaction RT PCR A second set of specimens including tracheal aspirate was collected Respiratory speci mens were positive for MERS CoV In the intensive care unit renal function deteriorated and he was started on continuous renal replacement for 2 days then three hemodialysis sessions Subsequently oxygen requirements were moderated and he gradually defer vesced although chest radiographs continued to show infiltrates He was then weaned off mechanical ventilation and was extubated He was subse quently discharged home This is a published case report Saudi Medical Journal 2012 33 1265C09 1 1 WHAT IS THE CAUSATIVE AGENT Middle East respiratory syndrome coronavirus MERS CoV is a new human disease that was first reported from Saudi Arabia in September 2012 after identification of a novel coronavirus CoV from a male Saudi Arabian patient who died from severe pneumonia 2 3 MERS CoV had caused a signi ficant mortality of about 50 since that time 4 The MERS CoV is a novel coronavirus that was initially designated HCoV EMC 3 The virus was later designated after global consensus as MERS CoV 5 Coronaviruses are common viruses that usually cause mild to moderate upper respiratory tract illnesses in humans The viruses have crown like spikes on their surfaces and hence the name coronavirus Human coronaviruses enveloped RNA viruses are not new and were first identified in the mid 1960s There are four virus clusters within the Coronavirinae sub family These are alphacoronavirus betacoronavirus and gammacoronavirus The fourth cluster is a provisionally assigned new group called delta corona viruses All known human coronaviruses belong to the genera Alphacoronavirus HCoV 229E and HCoV NL63 and Betacoronavirus HCoV OC43 HCoV HKU1 and SARSCoV 3 MERS CoV formerly HCoV EMC is the first human coronavirus in lineage C of the Betacoronavirus genus 3 2 WHAT IS THE FREQUENCY OF THE DISEASE PREVALENCE INCIDENCE BURDEN AND IMPACT OF THE DISEASE Between April 2012 and February 7 2014 there were 182 documented cases of MERS CoV infection worldwide 5a The majority of these occurred in the Kingdom of Saudi Arabia where 148 cases were reported MERS CoV appears to have a predilection for individuals with underlying medical comorbidities 1 4 6C08 186 Emerging Infectious Diseases 3 WHAT ARE THE TRANSMISSION ROUTES The main modes of transmission are contact transmission droplet transmiss ion and person to person transmission as supported by epidemiologic and phylogenetic analyses 4 Currently the MERS CoV seems to have three epidemiological patterns of the disease There are sporadic cases occurring in the communities of different Middle East countries mainly the Kingdom of Saudi Arabia Qatar United Arab Emirates and Jordan The second pattern is nosocomial transmission within healthcare facilities to healthcare workers and other patients 4 Intrafamilial transmission of MERS CoV was also described 1 4 7 9C011 4 WHICH FACTORS ARE INVOLVED IN DISEASE PATHOGENESIS WHAT ARE THE PATHOGENIC MECHANISMS The pathogenesis of the disease has been elucidated in recent studies MERS CoV has spike glycoprotein S that targets the cellular receptor dipeptidyl peptidase 4 DPP4 12 13 This viral spike has a putative receptor binding domain RBD 13 MERS CoV RBD has a core and a receptor binding subdomain which interacts with DPP4 propeller MERS CoV RBD 13 The MERS CoV spike protein interacts with CD26 also known as DPP4 and causes viral attachment to host cells and virus cell fusion 14 This is thought to be the first step in viral infection The MERS CoV infection results in profound apoptosis of infected respiratory cells within 24 hr 15 5 WHAT ARE THE CLINICAL MANIFESTATIONS MERS CoV causes respiratory tract infection that ranges in severity from mild to fulminant respiratory infection Mild respiratory illness was described in patients from Tunisia 16 and from the United Kingdom 11 The clinical presentation of MERS CoV is similar to SARS3 The initial phase is non specific fever and mild non productive cough lasting several days followed by progressive pneumonia 4 6 In MERS CoV infections most patients present with serious respiratory disease resulting in a high mortality rate of 60 6 The mean age of affected patients was 56 years with a range of 14C094 years 6 A recent case of a 2 year old patient was described 17 The most common symptoms are fever 87 cough 87 and shortness of breath 48 4 6 About 35 of patients had accompanying gastrointestinal symptoms including diarrhea 22 and vomiting 17 Of the total cases 50 had two medical co morbidities diabetes and chronic renal disease 6 Important laboratory abnormalities in patients with MERS CoV include leucopenia 14 lymphopenia 34 thrombocytopenia 36 increased lactate dehydrogenase LDH 49 increased alanine aminotransferase 187Chapter 14 MERS CoV Infection ALT 11 and increased aspartate aminotransferase AST 15 6 Chest radiographic abnormalities include increased bronchovascular markings 17 unilateral infiltrate 43 bilateral infiltrates 22 and diffuse reticulonodular pattern 4 4 6 HOW DO YOU DIAGNOSE Laboratory testing for MERS CoV is a challenge Currently there are no validated serologic assays The main testing method relies on identification of MERS CoV using real time reverse transcriptase polymerase chain reaction RT PCR from respiratory tract secretions It is not clear at this point of time whether sputum or nasopharyngeal samples are superior to throat swabs 4 7 HOW DO YOU DIFFERENTIATE THIS DISEASE FROM SIMILAR ENTITIES To date there are no specific laboratory abnormalities or clinical data that differentiate pneumonia due to MERS CoV from pneumonia caused by other viruses or other bacterial pathogens The primary diagnosis of MERS CoV infection relies on the identification of the virus in respiratory secretions using real time RT PCR 8 WHAT IS THE THERAPEUTIC APPROACH The main therapeutic options for MERS CoV infection are not known There is no specific therapy for MERS CoV infection Recently in vitro studies showed that MERS CoV is 50C0100 times more sensitive to alpha interferon IFN treatmentthanSARS CoV 18 In a recent decision sup port document convalescent plasma was given an order of recommendation of 1 followed by interferon protease inhibitors order of recommendations of 2 and intravenous globulin order of recommendations of 3 19 Further randomized controlled trials of these agents are needed to establish the effi cacy and side effects 9 WHAT ARE THE PREVENTIVE AND INFECTION CONTROL MEASURES The main infection control measures to prevent the transmission of MERS CoV include contact isolation standard precautions droplet isolation and airborne infection isolation precautions especially when healthcare workers perform aerosol generating procedures 20 Droplet precautions include wearing a medical mask when in close contact within 1 meter and upon entering the room or cubicle of the patient The Centers for Disease Control 188 Emerging Infectious Diseases and Prevention CDC recommends placing patients with suspected or confirmed MERS CoV infection in an airborne infection isolation room AIIR 21 If an AIIR is not available the patient should be transferred as soon as is feasible to a facility where an AIIR is available Pending transfer place a facemask on the patient and isolate him her in a single patient room with the door closed 21 Performing hand hygiene in accordance with the World Health Organization s WHO 5 moments of hand hygiene is of paramount importance and could not be stressed more Additional measures include wearing a particulate respirator when performing aerosol generating procedures in addition to other precautions In a recent MERS CoV outbreak in a healthcare setting there was evidence of person to person transmission and the outbreak was aborted by the implementation of infection control measures 4 REFERENCES 1 AlBarrak AM Stephens GM Hewson R Memish ZA Recovery from severe novel coronavirus infection Saudi Med J 2012 33 1265C09 2 Centers for Disease Control and Prevention CDC Severe respiratory illness associated with a novel coronavirus Saudi Arabia and Qatar 2012 MMWR Morb Mortal Wkly Rep 2012 61 820 3 Zaki AM van Boheemen S Bestebroer TM Osterhaus AD Fouchier RA Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia N Engl J Med 2012 367 1814C020 4 Assiri A McGeer A Perl TM et al Hospital outbreak of Middle East respiratory syndrome coronavirus N Engl J Med 2013 369 407C016 5 de Groot RJ Baker SC Baric RS et al Middle East respiratory syndrome coronavirus MERS CoV announcement of the Coronavirus Study Group J Virol 2013 87 7790C02 5a Middle East respiratory syndrome coronavirus MERS CoV C0 update Available at http www who int csr don 2014 02 07mers en 6 Assiri A Al Tawfiq JA Al Rabeeah AA Al Rabiah FA Al Hajjar S Al Barrak A et al Epidemiological demographic and 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Agency HPA UK Novel Coronavirus Investigation Team Evidence of person to person transmission within a family cluster of novel coronavirus infections United Kingdom February 2013 Euro Surveill 2013 18 20427 189Chapter 14 MERS CoV Infection 12 Mou H Raj VS van Kuppeveld FJ Rottier PJ Haagmans BL Bosch BJ The receptor binding domain of the new MERS coronavirus maps to a 231 residue region in the spike protein that efficiently elicits neutralizing antibodies J Virol 2013 87 9379C083 13 Wang N Shi X Jiang L Zhang S Wang D Tong P et al Structure of MERS CoV spike receptor binding domain complexed with human receptor DPP4 Cell Res 2013 23 986C093 14 Lu G Hu Y Wang Q Qi J Gao F Li Y et al Molecular basis of binding between novel human coronavirus MERS CoV and its receptor CD26 Nature 2013 500 227C031 15 Tao X Hill TE Morimoto C Peters CJ Ksiazek TG Tseng CT Bilateral entry and release of middle east respiratory syndrome coronavirus induces profound apoptosis of human bronchial epithelial cells 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Infection Prevention and Control Recommendations for Hospitalized Patients with Middle East Respiratory Syndrome Coronavirus MERS CoV Available at http www cdc gov coronavirus mers infection prevention control html last accessed 26 07 2013 190 Emerging Infectious Diseases