key: cord-0875253-iikfcc4y
authors: Saad, Mustafa; Omrani, Ali S.; Baig, Kamran; Bahloul, Abdelkarim; Elzein, Fatehi; Matin, Mohammad Abdul; Selim, Mohei A.A.; Mutairi, Mohammed Al; Nakhli, Daifullah Al; Aidaroos, Amal Y. Al; Sherbeeni, Nisreen Al; Al-Khashan, Hesham I.; Memish, Ziad A.; Albarrak, Ali M.
title: Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia
date: 2014-10-07
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2014.09.003
sha: 1fa4e53e298871ed4d6c9ec3f471cc5d49d20acf
doc_id: 875253
cord_uid: iikfcc4y

OBJECTIVES: To report the experience with Middle East respiratory syndrome coronavirus (MERS-CoV) infection at a single center in Saudi Arabia. METHODS: Cases of laboratory-confirmed MERS-CoV occurring from October 1, 2012 to May 31, 2014 were reviewed retrospectively. Information sources included medical files, infection control outbreak investigations, and the preventive medicine database of MERS-CoV-infected patients. Data were collected on clinical and epidemiological aspects and outcomes. RESULTS: Seventy consecutive patients were included. Patients were mostly of older age (median 62 years), male (46, 65.7%), and had healthcare acquisition of infection (39, 55.7%). Fever (43, 61.4%), dyspnea (42, 60%), and cough (38, 54.3%) were the most common symptoms. The majority developed pneumonia (63, 90%) and required intensive care (49, 70%). Infection commonly occurred in clusters. Independent risk factors for severe infection requiring intensive care included concomitant infections (odds ratio (OR) 14.13, 95% confidence interval (CI) 1.58–126.09; p = 0.018) and low albumin (OR 6.31, 95% CI 1.24–31.90; p = 0.026). Mortality was high (42, 60%), and age ≥65 years was associated with increased mortality (OR 4.39, 95% CI 2.13–9.05; p < 0.001). CONCLUSIONS: MERS-CoV can cause severe infection requiring intensive care and has a high mortality. Concomitant infections and low albumin were found to be predictors of severe infection, while age ≥65 years was the only predictor of increased mortality.

Arabia alone during the period April 11 to June 9, 2014. 2 This in turn has raised concerns about the pandemic potential of MERS-CoV infection.

MERS-CoV is capable of causing a spectrum of illness ranging from asymptomatic infection to severe pneumonia requiring intensive care unit (ICU) admission. 4 While the infection is still associated with high mortality, specific antiviral therapy is lacking and management remains mainly supportive. 2, 5 The available literature describing the clinical and epidemiological features and outcomes of MERS-CoV infection is limited to case reports and descriptions of relatively small cohorts. 3, [6] [7] [8] [9] [10] [11] [12] [13] [14] We describe herein our clinical experience with 70 laboratoryconfirmed MERS-CoV infection patients diagnosed at Prince Sultan Military Medical City (PSMMC) over a period of 20 months. PSMMC is a 1200-bed, tertiary medical center in Riyadh, Saudi Arabia, with around 40 000 annual admissions and 118 000 emergency room visits per year.

This was a retrospective study of all patients who were diagnosed with a laboratory-confirmed MERS-CoV infection at our center over the period October 1, 2012 to May 31, 2014. Patients were identified from the microbiology and infection control records. In addition to the medical file review, data were collected from infection control outbreak investigations and the preventive medicine database of MERS-CoV-infected patients. Demographic and clinical details, epidemiological exposures, laboratory investigations, and outcomes were collated. A consultant radiologist reviewed and summarized all radiological investigations. Patients were followed until discharge from the hospital or death. MERS-CoV infection was diagnosed by reverse transcriptase PCR (RT-PCR) testing of respiratory tract samples for the MERS-CoV upE, ORF 1b, and N genes. 15 All RT-PCR tests for MERS-CoV were performed at the Saudi Ministry of Health National Laboratories in Jeddah and Riyadh, Saudi Arabia. The study was approved by the institutional research ethics committee.

Infection was classified as healthcare-associated if the onset of MERS-CoV illness was more than 48 h after the current admission, or if the onset of illness was within 14 days of discharge from a clinical area where cases of MERS-CoV infection had been documented. A cluster was defined as two or more persons with onset of symptoms within the same 14-day period, and who were associated with a specific setting (healthcare or household). 4 Concomitant infections included all bacterial, fungal, and viral infections that occurred within 14 days of the diagnosis of MERS-CoV infection. Severe infection requiring care in an ICU and death were considered poor outcomes.

The Chi-square test or Fisher's exact test was used to compare categorical data, while the Student's t-test was used to compare continuous variables. All p-values were two-tailed and considered statistically significant at a cut-off of <0.05. Risk factors for a poor outcome were initially assessed in a univariate analysis. Those factors that were found to be significant were then entered into competing logistic regression (ICU care) or Cox regression (death) in order to determine the independent risk factors for a poor outcome. Graphical and statistical tests indicated that the proportional hazard assumption was not violated. A forward stepwise method was used to identify the determinants of a poor outcome, with the probability of entry set at 0.05. Statistical analyses were performed using Microsoft Excel 2007 (Microsoft Corp., Redmond, USA) and IBM SPSS Statistics software, version 21.0 (IBM Corp., Armonk, NY, USA).

A total of 70 consecutive patients were included in the study. The majority of patients were males (46, 65.7%), of older age (median 62 years), residents of Riyadh (57, 81.4%), and of Saudi nationality (57, 81.4%). Comorbid conditions were documented in 57 (81.4%) patients, with a median age-adjusted Charlson comorbidity index (CCI) score of 5 (interquartile range (IQR) 0.25-6.0). Over half of MERS-CoV infections (39, 55.7%) were healthcare-associated. Only seven (10.0%) patients were obese and nine (12.9%) were smokers. A history of exposure to animals, including camels, within the 2 weeks preceding the onset of MERS-CoV infection was very uncommon ( Table 1 ).

The majority of patients (67, 95.7%) with confirmed MERS-CoV infection were symptomatic. The most common symptoms were fever (43, 61.4%), shortness of breath (42, 60.0%), and cough (38, 54.3%). Non-respiratory symptoms were also relatively common, including generalized fatigue (29, 41.4%), vomiting or diarrhea (21, 30 .0%), abdominal pain (17, 24.3%), confusion (18, 25 .7%), and myalgia or arthralgia (14, 20%) . Most patients had pneumonia (63, 90%). The most common radiological abnormality on chest X-rays was bilateral pulmonary infiltrates, which were reported in 53 (75.7%) patients. For patients with community-acquired MERS-CoV infection, the median time from onset of symptoms to hospital admission was 5.0 (IQR 3.0-8.5) days (Table 2) . Overall, the median time from illness onset to diagnosis was 7 (IQR 3.0-13.8) days. Acute lung injury (28, 40%), acute kidney injury (30, 40.9%), and hepatic dysfunction (22, 31 .4%) were the most common complications. Cardiac arrhythmias, including variable tachyarrhythmias and severe bradycardia requiring temporary pacemaker insertion, occurred in 11 (15.7%) cases (Table 2) .

Of the patients with MERS-CoV infection, 10 were healthcare workers; one was an ICU nurse, six were non-ICU nurses, two were physicians, and one was a radiology technician. Interestingly, three (30%) had only mild upper respiratory symptoms and three (30%) were asymptomatic. Only one healthcare worker had a community-acquired MERS-CoV infection.

There Laboratory abnormalities that were commonly present at the time of diagnosis included low hemoglobin (median 10.7 g/dl; IQR 9.1-13.4), lymphopenia (median 0.85 Â 10 9 /l; IQR 0.6-1.2), low albumin (median 27 g/l; IQR 24.5-33.5), and elevated aspartate aminotransferase (median 59 IU/l; IQR 29-87). Several abnormal laboratory parameters were commonly observed during the hospital course of the MERS-CoV infection (Table 3) .

The distribution of new cases was variable during the study period, with peaks of increased activity in September 2013 and April 2014. The increased disease activity in the community was associated with an increase in healthcare transmission of infection and overall testing of suspected cases ( Figure 1 ).

Cases of laboratory-confirmed MERS-CoV infection occurred sporadically and in clusters. There were three documented family clusters, each involving two to four individuals. Infected family members within those clusters received treatment in more than one hospital, including four cases in our hospital. Furthermore, a total of eight clusters of healthcare-associated MERS-CoV infection were documented; these ranged in size from two to 15 and involved patients in more than one clinical area. The largest cluster, which involved 15 individuals, occurred in the emergency department and included 10 cases who had apparently acquired the infection from a single patient ( Figure 2 ). In addition, Figure 2 documents multiple occurrences of secondary transmission of infection in the healthcare-associated clusters. However, tertiary transmission of infection was only observed once -in the healthcare-associated cluster in March 2014.

Severe infection requiring ICU care occurred in the majority (49, 70.0%) of patients; 46 (65.7%) of these patients required invasive mechanical ventilation and three (4.3%) required non-invasive ventilation. In the univariate analysis, factors associated with severe infection requiring ICU care were age !65 years (odds ratio (OR) 9.47, 95% confidence interval (CI) 2.45-36.56; p = 0.001), male gender (OR 3.05, 95% CI 1.05-8.84; p = 0.04), higher age-adjusted CCI score (OR 1.35, 95% CI 1.11-1.65; p = 0.003), the presence of bilateral pulmonary infiltrates on chest X-ray (OR 4.89, 95% CI (Table 5) .

Overall, 42 (60%) patients with MERS-CoV infection died. The median time from illness onset to death was 20.5 (IQR 11.8-28.0) days. All patients who died, except one, had severe MERS-CoV infections requiring ICU care and were placed on mechanical ventilation. Among those who died, 33 (78.6%) had a progressive disease course until death, while nine (21.4%) patients had an initial clinical improvement before they eventually died. Univariate analysis showed that mortality was increased in patients aged !65 years (OR 4.39, 95% CI 2.13-9.05; p < 0.001), those with a higher age-adjusted CCI score (OR 1.27, 95% CI 1.12-1.44; p < 0.001), and those with concomitant infections (OR 3.15, 95% CI 1.60-6.18; p = 0.001) (Table 4 ). However, multivariate analysis showed age !65 years to be the only independent risk factor for associated with increased mortality (OR 4.39, 95% CI 2.13-9.05; p < 0.001) ( Table 5) .

Among the healthcare workers with MERS-CoV infection, two developed severe infections and required ICU care; one died due to a progressive MERS-CoV infection. Interestingly, in the univariate analyses of risk factors for both severe infection requiring ICU care and death, healthcare profession was associated with a lower risk of a poor outcome (Table 4 ).

We report herein our experience with 70 consecutive cases of laboratory-confirmed MERS-CoV infection at a single tertiary medical center. There are several important findings of this study that need to be highlighted.

In this study, MERS-CoV was shown to have a tendency to infect males and older patients. We could not find any obvious epidemiological risk to explain this finding. Healthcare exposure to infection was the most important risk factor for the development of MERS-CoV infection. However, in the ICU setting, where more strict infection control measures were applied (single rooms, dedicated 1:1 nurses, and more compliance with hand hygiene and isolation precautions), only one healthcare worker acquired the infection, while no patient-to-patient transmission occurred. These findings highlight the importance of applying infection control measures in healthcare facilities where patients with suspected MERS-CoV infection are admitted.

Healthcare transmission of infection is well-documented herein, with peaks of increased disease activity correlating with increased healthcare transmission. Nevertheless, healthcare transmission was preceded by an increased influx of patients with MERS-CoV infection from the community, as observed in the spikes of September 2013 and April 2014. Therefore, there appears to be a true variation in the distribution of cases over the year that should not be attributed merely to increased healthcare transmission. Indeed, other factors, such as seasonal variation, should be evaluated carefully to explain this observation.

Another interesting observation in our study is the occurrence of multiple healthcare-associated clusters of MERS-CoV infection. Moreover, a single patient transmitted the infection to 10 others. Isolated incidents of high-level MERS-CoV transmission have been reported previously. 8, 16 However, the scale of transmission remains small compared with the super-spreader events that were described in association with the outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. 17 Furthermore, nosocomial transmission was promptly interrupted with the application of effective infection control measures. This is consistent with previous reports that have suggested the potential for self-sustained MERS-CoV transmission to be low, especially once appropriate infection control is implemented. 18, 19 Several studies have focused on the possible role of camels in the transmission of MERS-CoV infection to humans. [20] [21] [22] In this study, animal exposure was rare and only one patient had had recent exposure to camels. In our opinion, this observation does not rule out the possible role of camels; instead, there may be a missing link in the transmission of MERS-CoV infection from camels to humans.

Most patients with MERS-CoV infection in our cohort were symptomatic; nonetheless, a significant proportion of patients had atypical presentations. This, coupled with the lack of known exposures in most of the community-acquired cases, led to the diagnosis being elusive, and several cases went undiagnosed until a cluster of infection became apparent. Assiri et al. Albumin, in our analysis, was observed to be an independent risk factor for the development of severe MERS-CoV infection. Although there is no clear explanation for this observation, albumin may reflect the nutritional status and the general wellbeing of the patient.

Finally, the overall case fatality rate was high in our cohort of patients, but similar to that reported by Assiri et al. 3 Similarly, high mortality rates were reported by Arabi et al. (58%) and Assiri et al. (65%). 7, 8 In contrast, the overall case fatality rate reported by the World Health Organization (WHO) was 30%. 2 The main difference between the patients in our cohort and the overall cases reported by the WHO is age; the median age of our cohort was 62 years compared to 47 years in the WHO report. 2 Furthermore, we found age !65 years to be the only independent risk factor for mortality. This underscores the importance of age, not only as a risk factor for acquiring MERS-CoV infection, but also as an important predictor of MERS-CoV-related mortality. Our finding is similar to that reported by Breban et al., 18 but different from the report of Assiri et al., 3 who found no association between older age and the risk of mortality. Our study has several limitations inherent to its design. First, this was a retrospective study with the potential of incomplete and possible variation of data recording according to the primary care providers. We minimized this limitation by collecting the data from the patients' medical files in addition to the infection control and preventive medicine records. Second, the virus was not isolated for further genotyping and viral kinetic studies were not done for most of the patients. Therefore viral shedding was not assessed, and clusters of infection were only investigated epidemiologically.

In conclusion, in our cohort of patients, MERS-CoV infection caused a spectrum of disease ranging from asymptomatic to severe infection requiring ICU care. Severe infection developed in the majority of patients. Concomitant infections and low albumin were predictors of severe infection. Age !65 years was the only predictor of mortality.

Conflict of interest: No conflict of interest to declare.

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