1. Middle East Respiratory Syndrome (MERS) NEJM 2013, 2014, WHO, CDC 김선혜

2. CONTENTS 1)Introduction 2)Virology 3)Epidemiology 4)Clinical manifestations 5)Diagnosis 6)Treatment 7)Prevention 8)Prognosis

3. INTRODUCTION Middle East Respiratory Syndrome (MERS) an illness caused by a virus called Middle East Respiratory Syndrome Coronavirus (MERS-CoV), RNA beta-coronavirus. MERS affects the respiratory system (lungs and breathing tubes). Most MERS patients developed severe acute respiratory illness (SARI) with symptoms of fever, cough and shortness of breath.

4. VIROLOGY Middle East respiratory syndrome coronavirus (MERS-CoV) A lineage C beta-coronavirus Different from the other human beta- coronaviruses (severe acute respiratory syndrome (SARS) coronavirus, OC43, & HKU1) Closely related to several bat coronaviruses Dipeptidyl peptidase 4 (DPP4; CD26) is present on the surfaces of human nonciliated bronchial epithelial cells, is a functional receptor for MERS-CoV. N Engl J Med 2012;367:1814-1820.

5. VIROLOGY MERS-CoV infected several human cell lines, including lower (but not upper) respiratory, kidney, intestinal, and liver cells, as well as histiocytes. Because of a large increase in cases in Saudi Arabia in the spring of 2014, there was concern that MERS-CoV might have mutated to become more transmissible or virulent. However, cell culture experiments of viruses isolated during these outbreaks showed no evidence of changes in viral replication rate, immune escape, interferon sensitivity, or serum neutralization kinetics compared with a contemporaneous. J Infect Dis. 2013;207(11):1743 Clin Infect Dis. 2015;60(3):369.

6. EPIDEMIOLOGY As of 5 June 2015, 1211 laboratory-confirmed cases of human infection with MERS-CoV have been reported to WHO since 2012, including at least 492 deaths. Overall, 66% of cases reporting gender (n=1165) are male The median age is 49 years (range 9 months–99 years; n=1172).

7. EPIDEMIOLOGY 25 countries have reported cases – in the Middle East : Egypt, Iran, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia (KSA), United Arab Emirates (UAE) and Yemen; – in Africa: Algeria, and Tunisia; – in Europe: Austria, France, Germany, Greece, Italy, the Netherlands, Turkey and the United Kingdom – in Asia: China, Republic of Korea, Malaysia and Philippines; and – in North America: the United States of America (USA). The majority of cases (>85%) have been reported from Saudi Arabia. Since May 2015 two new countries have been affected (China and Republic of Korea).

8. www.mers.go.kr 질병관리본부 2015.6.7. Case 122 Death 10

9. Epidemiology

11. EPIDEMIOLOGY 1.4 million deaths

12. EPIDEMIOLOGY- Modes of transmission Current epidemiologic data suggest multiple zoonotic transmissions from an animal reservoir leading to human infection, sometimes with secondary transmission events in humans. – Bats: Although bats might be a reservoir of MERS-CoV, it is unlikely that they are the immediate source for most human cases because human contact with bats is uncommon. – Camels: The strongest evidence of camel-to-human transmission of MERS-CoV comes from a study in Saudi Arabia in which MERS-CoV was isolated from a man with fatal infection and from one of his camels. Limited secondary transmission from human to human has also been confirmed in both health care and household settings. – More than 50% of all laboratory-confirmed secondary cases have been associated with healthcare settings World Health Organization, 2015. N Engl J Med 2014;370:2499-2505.

13. Epidemiology

14. EPIDEMIOLOGY A key epidemiological parameter early in an emerging epidemic is the basic reproductive number (R0), which describes the average number of new cases of infection generated by one primary case in a susceptible population. – R0 affects the growth rate of an outbreak and the total number of people infected by the end of the outbreak. – If R0 < 1, a sustained epidemic will not occur. – Using epidemiological and genetic data, the authors estimated that R0 was small, but might be slightly greater than 1. – However, R0 estimates based on disease cluster sizes were lower than 1, suggesting that cluster identification leads to application of successful control measures. Lancet Infect Dis. 2014 ;14.

15. CLINICAL MANIFESTATIONS (1) Incubation period – In an outbreak of MERS-CoV infection in Saudi Arabia that resulted in laboratory-confirmed MERS-CoV in 23 individuals, the median incubation period for secondary cases a/w limited human-to-human transmission was 5.2 days (95% CI 1.9-14.7 days). – In one secondary case that occurred in a patient in France who shared a room with an infected patient, the incubation period was estimated at 9 to 12 days. – Infectivity during the incubation period : no cases reported N Engl J Med. 2013;369(5):407.

16. CLINICAL MANIFESTATIONS (2) Lancet Infect Dis. 2013;13(9):752. Symptoms and SignsNumber of patients (%) Fever (>38°C)46 patients (98 %) Fever with chills or rigors41 patients (87 %) Cough39 patients (83 %) Shortness of breath34 patients (72 %) Hemoptysis8 patients (17 %) Sore throat10 patients (21 %) Myalgias15 patients (32 %) Diarrhea12 patients (26 %) Vomiting10 patients (21 %) Abdominal pain8 patients (17 %) Abnormal chest radiograph47 patients (100 %) Clinical features

17. CLINICAL MANIFESTATIONS (3) Clinical features – Most patients with MERS-CoV infection have been severely ill with pneumonia and ARDS, and some have had acute kidney injury (AKI) and septic shock. – Many patients have required mechanical ventilation, and some have required extracorporeal membrane oxygenation (ECMO). – The median time from illness onset to hospitalization is approximately 4days. – In critically ill patients The median time from onset to ICU admission : approximately 5 days The median time from onset to death: approximately 12 days The median duration of mechanical ventilation:16 days The median ICU length of stay: 30 days 58% mortality at 90 days Ann Intern Med. 2014;160:389-397.

18. CLINICAL MANIFESTATIONS (4) Risk factor : unclear – In a study of 47 patients with MERS-CoV infection in Saudi Arabia, 45 (96 %) had underlying comorbidities, including diabetes mellitus (68 %), hypertension (HTN) (34 %), chronic cardiac disease (28 %), and chronic kidney disease (CKD) (49 %). – The median number of comorbid conditions was 3 (range 1 to 6). – The high rate of comorbidities reported must be interpreted with caution, because approximately half of the 47 patients described in the 1st study were part of an outbreak in a hemodialysis unit, where rates of CKD and HTN would be expected to be high. Lancet Infect Dis. 2013;13(9):752. Ann Intern Med. 2014;160(6):389. Lancet Infect Dis. 2013;13(9):752.

19. CLINICAL MANIFESTATIONS (6) Laboratory abnormalities – Leukopenia (14 %), lymphopenia (34 %), lymphocytosis (11 %), thrombocytopenia (36%), elevated AST (15%), elevated ALT (11 %), and elevated LDH(49 %). – Some patients have shown progressive renal failure (elevated BUN and Cr) – DIC and hemolysis have also been reported. Imaging findings – Chest x-ray: abnormalities on chest x-ray were noted in all 47 cases (100%). increased broncho-vascular markings, airspace opacities, patchy infiltrates patchy to confluent airspace consolidations nodular opacities, reticular opacities, reticulo-nodular shadowing pleural effusions, and total opacification of lung segments & lobes – Chest CT : M/C findings - bilateral predominantly peripheral & basilar airspace changes with more extensive GGO than consolidation. N Engl J Med. 2013;369(5):407. Ann Intern Med. 2014;160(6):389-397.

20. DIAGNOSIS (1) Confirmed case – A person with laboratory confirmation of infection with MERS-CoV irrespective of clinical signs and symptoms Probable case – A probable case is defined by the following criteria:  A febrile acute respiratory illness with clinical, radiographic, or histopathologic evidence of pulmonary parenchymal disease (eg, pneumonia or ARDS) and  A direct epidemiologic link with a confirmed MERS-CoV case and  Testing for MERS-CoV is unavailable, negative or a single inadequate specimen, or inconclusive OR  A febrile acute respiratory illness with clinical, radiographic, or histopathologic evidence of pulmonary parenchymal disease (eg, pneumonia or ARDS) and  The person resides in or traveled to the Middle East or countries where MERS-CoV is known to be circulating in dromedary camels or where human infections have recently occurred and  Testing for MERS-CoV is inconclusive OR  An acute febrile respiratory illness of any severity and  Direct epidemiologic link with a confirmed MERS-CoV case and  Testing for MERS-CoV is inconclusive World Health Organization, 2015 Surveillance : the person develops an unusual or unexpected clinical course, especially sudden deterioration despite appropriate treatment, without regard to place of residence or history of travel, even if another etiology has been identified that fully explains the clinical presentation.

21. DIAGNOSIS (1) 대한감염학회 (2015.6.8)

22. DIAGNOSIS (3) 1> Polymerase chain reaction (PCR) and sequencing – Lower respiratory tract specimens (sputum, tracheal aspirates, BAL fluid) more sensitive for detection of MERS-CoV by rRT-PCR testing than those from the upper respiratory tract – Upper respiratory tract specimens (combined nasopharyngeal & throat swab, nasopharyngeal aspirates) still useful for diagnosing MERS-CoV. – Other specimens: stool, urine and blood. also detectable – In some cases, sequencing should be performed for confirmation. World Health Organization, 2015

24. DIAGNOSIS (5) 2> Serology – Immunofluorescence assays (IFA) and protein microarray assay developed for the detection of MERS-CoV antibodies – CDC : two-stage approach enzyme-linked immunosorbent assay (ELISA) for screening indirect immunofluorescence test or micro-neutralization test for confirmation any positive test by a single serologic assay should be confirmed with a neutralization assay. – WHO : serologic test (+) even if PCR testing (-) or sequencing (-) considered probable cases if they meet the other elements comprising the case

25. DIAGNOSIS (6)

26. TREATMENT (1) As with other coronaviruses, no antiviral agents are recommended for the treatment of MERS-CoV infection. Systematic review to summarize the available options for treatment for novel coronavirus infection based on previous reports of therapy of SARS, a related coronavirus. The most commonly used agent was the broad spectrum antiviral ribavirin and interferon alfa – The timing of the start of antiviral agents is important ; – started within 48 hours of hospitalization or after diagnosis – started after 10-14 days of symptoms; might have led to the poorer outcomes Lancet Infect Dis. 2014 Nov;14(11):1090-5./J infect Dis. 2013 oct;17(10):e792-8. The combination therapy, started a median of 3days after diagnosis (20 patients), significantly improved survival at 14 days compared with 24 patients who received only supportive care (70 VS 29 % survival), but not at 28 days (30 versus 17 percent survival, a non-significant difference)

27. TREATMENT (2) The addition of lopinavir/ritonavir to ribavirin regimen was associated with improved clinical outcome and reduces the death rate comparing to ribavirin regimen alone in observational studies. Few studies addressed the effect of convalescent plasma. Glucocorticoids have been administered sporadically to MERS-CoV infected patients with no clear criteria for use and no clear conclusions regarding their effect. Other in vitro studies have failed to yield potent therapeutic agents despite a search including DPP4 inhibitors Hong Kong Med J 2003;9:399–406.,Thorax 2004;59:252–6. :(Nature 2013,495:251–254.3 Eur J Clin Microbiol Infect Dis 2005;24:44–6. N Engl J Med 2003;349:507-8. / J Clin Virol 2004;31:304-9.

28. TREATMENT (3) 대한 감염 학회 항바이러스제 치료지침 (2015.06.08)

29. TREATMENT (4) : 495, Pages:251–254 Date J infect Dis. 2013 oct;17(10):e792-8.

30. TREATMENT (5) – Adverse effect

32. PREVENTION – WHO, CDC The WHO recommends – Standard and droplet precautions be used when caring for patients with acute respiratory tract infections – Contact precautions and eye protection should be added when caring for probable or confirmed cases of MERS-CoV infection. – Airborne precautions should be used when performing aerosol-generating procedures. The CDC recommends – The use of standard, contact, and airborne precautions for the management of hospitalized patients with known or suspected MERS-CoV infection. – Patients placement : Airborne Infection Isolation Room (AIIR) The Korea CDC recommends – Same as the WHO recommends Centers for Disease Control and Prevention (CDC), 2015 World Health Organization, 2014

33. PREVENTION World Health Organization, 2014

35. PROGNOSIS As of May 31, 2015, 442 of 1179 patients (37 %) with laboratory- confirmed MERS-CoV infection reported to the World Health Organization (WHO) have died. – The reported case-fatality rate might therefore be an overestimate. – Because limited clinical data for MERS-CoV patients are available; most published clinical information to date is from critically ill patients. Case-fatality rates rose with increasing age – from 39 % in those younger than 50 years of age, to 48 % in those younger than 60 years of age, to 75 % in those aged 60 years or older. World Health Organization, 2015 Lancet Infect Dis. 2013;13(9):752./ Lancet Infect Dis. 2014;14:50