Setting
Three patients from King Abdulaziz Medical City in Riyadh presented from the community in February and March 2014. They were admitted to different wards and were managed separately prior to admission to the ICU. There was no hospital transmission of MERS-CoV among healthcare workers during their hospitalization. Approval to collect data for these patients and report them was obtained from the Institutional Review Board of the Ministry of National Guard-Health Affairs. The consent was waived because of the observational nature of the study as per the institutional policy.
Patients
The clinical course as well as the laboratory and radiological findings of three patients with community-acquired MERS-CoV and progressive neurological findings were assessed by reviewing medical records and interviewing the managing team. Testing for MERS-CoV was performed by real-time reverse transcription polymerase chain reaction (RT-PCR) as described in the online supplement.
Patient 1
A 74-year-old Saudi male patient with diabetes, hypertension, and dyslipidemia presented with a 3 days of ataxia, vomiting, confusion, and fever of 39.5 °C (Fig. 1). Examination revealed dysmetria and decreased motor power on the left side. Chest radiograph showed infiltrate in the mid right lung zone. Computerized tomography (CT scan) of the brain showed multiple chronic lacunar strokes but no acute changes. He was admitted to the ward with a working diagnosis of community-acquired pneumonia and possible stroke and was started on broad-spectrum antibiotics, and required no intensive care at that time. Because of his neurologic symptoms, brain magnetic resonance imaging (MRI) on hospital day (HD) 5 was obtained and showed moderate chronic small vessel ischemic changes (Fig. 2).
On HD 7, he was referred to the critical care response team because of increasing dyspnea and hypoxia, persistent fever, and progression in air space disease on chest radiographs (Online Figure 1) and was started on oseltamivir, bronchodilators, and methylprednisolone. MERS-CoV RT-PCR was sent from tracheal aspirate according to guidelines for management of critically ill patients with lower repertory illness and returned positive. Further history revealed exposure to camels. On HD 9, he was transferred to the ICU, where he was awake but severely hypoxic with oxygen saturation of 68–75 % on 100 % oxygen via non-rebreather mask. During his ICU stay, patient was managed as a case of severe acute respiratory distress syndrome (ARDS), which required intubation and mechanical ventilation by lung protective strategy, intravenous sedation, neuromuscular blockers, prone positioning, and inhaled nitric oxide. He required vasopressors and continuous renal replacement therapy. On HD 11, he was given peginterferon alpha-2b and ribavirin [5]. Subsequent MERS-CoV tests were positive until HD 28 (Fig. 1).
On HD 24, his respiratory status improved and tracheostomy was performed. However, he remained comatose with Glasgow Coma Scale of 3–4; and a repeat CT scan of the brain showed an interval development of numerous patchy hypodensities in the periventricular deep white matter and subcortical region, bilateral basal ganglia, thalami, pons, cerebellum, and cerebellar pedicles in addition to a large hypodensity in the splenium and posterior body of the corpus callosum. MRI identified multiple bilateral patchy areas of signal abnormality that appeared high on T2/FLAIR images seen in the periventricular, deep white matter, subcortical area, corpus callosum, bilateral brachium pontis, midbrain as well as in the left cerebellum and upper cervical cord. The lesions were non-enhancing and showed diffusion restriction (Fig. 2).
Cerebrospinal fluid (CSF) analysis showed a white cell count of 1 cell and protein of 0.56 g/L (reference 0.15–0.40 g/L) and negative MERS-CoV RT-PCR. The patient had lymphopenia throughout his illness (Online Figure 2). Lymphocyte subset analysis revealed critically low absolute CD4 and CD8 count with a normal ratio (Table 1). Other tests are available online. Due to deep coma, poor overall condition and worsening cardiovascular and respiratory status, he expired on HD 34.
Table 1 Lymphocyte subset analysis in patients 1 and 3
Patient 2
A 57-year-old diabetic, hypertensive, Saudi male with peripheral vascular disease presented with 3 days of flu-like illness, fever (39.0 °C), and a gangrenous toe. His working diagnosis was diabetic foot and was empirically started on broad-spectrum antibiotics. On HD 2 he developed acute myocardial ischemia with pulmonary edema (Online Figure 1) for which he was intubated. An emergency coronary angiography revealed chronic severe 3-vessel disease with no acute vessel closure (Fig. 1). Troponin level peaked to 13.5 ng/mL at 12 h and his electrocardiogram returned to normal within 48 h consistent with non-ST elevation myocardial infarction (NSTEMI). He was extubated on HD 4 but 2 h later he became unresponsive, hypotensive with left-sided facial paralysis, and required reintubation. Brain CT scan showed two subtle hypodensities seen at the right semiovale and left basal ganglia likely representing small lacunar infarctions. CT angiography showed near total occlusion at the origin of both internal carotid arteries with intracranial narrowing of the left middle cerebral artery at M1 segment and intact anterior communicating artery, and bilateral anterior cerebral arteries (ACA) with no radiographic features of vasculitis. (Online Figure 3). On HD 6, he had recurrence of fever with leukopenia (WBC 3.2 × 109) and a respiratory sample for MERS-CoV tested positive. On HD 8, repeat brain CT scan showed interval multiple patchy hypodensities bilaterally in the periventricular, deep white matter and bilateral basal ganglia, and a large area of hypodensity in the proximal half of the corpus callosum up to the mid part of his body. MRI showed signal abnormality bilaterally in the deep watershed and in the parasagittal region as well as scattered foci in the cortical and subcortical regions of the temporal, parietal, and occipital lobes with restriction on the diffusion weighted images (DWI) consistent with acute infarction (Fig. 2). On HD 9, his condition progressed to severe shock and acute kidney injury, had multiple cardiac arrests and expired. No CSF samples were taken on this patient.
Patient 3
A 45-year-old diabetic, hypertensive Saudi male with chronic kidney disease and ischemic heart disease presented with a 10-day history of productive cough, dyspnea, rigors, fever, and diarrhea with no significant travel or animal exposure. He was conscious and had no focal neurological findings. Chest radiograph showed an infiltrate in the lower and mid right zones. He was admitted with a working diagnosis of community-acquired pneumonia and acute kidney injury. He was started on broad-spectrum antibiotics, oseltamivir, and renal replacement therapy. On HD 2, he required intubation and ICU admission for severe ARDS, which was managed by a lung protective strategy, intravenous sedation, neuromuscular blockers, and nitric oxide. He required vasopressors and continuous renal replacement therapy. His tracheal aspirate tested positive for MERS-CoV and no other pathogens were detected. On HD 9, he was given peginterferon alpha-2b and ribavirin [5]. Subsequent MERS-CoV tests from respiratory samples were positive (Fig. 1). He recovered from septic shock and respiratory failure, and had tracheostomy placed on HD 24. Because of low Glasgow Coma Scale and fever, brain CT scan was performed and showed no acute abnormality. MRI showed confluent T2WI/FLAIR hyperintensity within the white matter of both cerebral hemispheres and along the corticospinal tract. There was no diffusion restriction or abnormal enhancement after administration of contrast. These findings were considered to be consistent with encephalitis. CSF analysis showed a white cell count of 2 cells, and protein of 0.85 g/L with negative MERS-CoV RT-PCR. Other tests are listed in the online supplement. Lymphocyte counts were low (Online Figure 2) and lymphocyte subsets were markedly reduced (Table 1). This patient was discharged home on HD 107.