Characteristics of patients
During the study period, 350 patients with MERS SARI were admitted to the participating ICUs. Patients with diabetes constituted 48.9% of the cohort. Table 1 describes the characteristics and presenting symptoms of patients with diabetes and no diabetes. Compared to patients with no diabetes, those with diabetes were older (median age 61.0 years (Q1, Q3: 53.0, 72.0) versus median age 54.0 years (Q1, Q3: 35.0, 67.0), p<0.0001) and more likely to have other comorbid conditions such as chronic renal disease (71 (41.5%) versus 39 (21.8%), p<0.0001) and cardiac disease (95 (55.6%) versus 60 (40.5%), p<0.0001). They were more likely to present with dyspnea and sputum production. The time from symptom onset to ICU admission was similar.
Table 1. Baseline characteristics of patients with diabetes and Middle East Respiratory Syndrome (MERS) compared to patients with no diabetes and MERS.
Variables
|
Diabetes N=171
|
No Diabetes N=179
|
P-value
|
Age (year), median (Q1, Q3)
|
61.0 (53.0, 72.0)
|
54.0 (35.0, 67.0)
|
<0.0001
|
BMI (Kg/m2), median (Q1, Q3)
|
29.3 (24.6, 33.3)
|
28.3 (24.1, 33.0)
|
0.31
|
Male sex – no. (%)
|
114 (66.7)
|
127 (70.9)
|
0.39
|
|
|
|
|
Healthcare worker – no. (%)
|
4 (2.3)
|
28 (15.6)
|
<0.0001
|
Community-acquired – no. (%)
|
102 (59.6)
|
83 (46.4)
|
Healthcare-associated (Non-healthcare worker) – no. (%)
|
65 (38.0)
|
68 (38.0)
|
|
|
|
|
Days from the onset of symptoms to the emergency room, median (Q1, Q3)
|
5.0 (3.0, 8.0)
|
4.0 (2.0, 7.0)
|
0.30
|
Days from symptom onset to ICU admission, median (Q1, Q3)
|
7.0 (4.0, 10.5)
|
7.0 (4.0, 11.0)
|
0.66
|
Days from symptom onset to intubation, median (Q1, Q3)
|
8.0 (5.0, 12.0)
|
8.0 (5.0, 13.0)
|
0.37
|
Presenting symptoms – no. (%)
|
Lower respiratory
|
Dyspnea
|
136 (79.5)
|
123 (68.7)
|
0.02
|
Cough
|
122 (71.3)
|
117 (65.4)
|
0.23
|
With sputum
|
75 (43.9)
|
58 (32.4)
|
0.03
|
With bloody sputum
|
11(6.4)
|
18 (10.1)
|
0.22
|
Chest pain
|
36 (21.1)
|
32 (17.9)
|
0.45
|
Wheezing
|
10 (5.8)
|
9 (5.0)
|
0.74
|
Upper respiratory
|
Earache
|
2 (1.2)
|
1 (0.6)
|
0.62^
|
Rhinorrhea
|
6 (3.5)
|
11 (6.1)
|
0.25
|
Sore throat
|
23 (13.5)
|
24 (13.4)
|
0.99
|
Systemic symptoms
|
Fever (temperature > 38°C)
|
130 (76.0)
|
131 (73.2)
|
0.54
|
Myalgia or arthralgia
|
32 (18.7)
|
34 (19.0)
|
0.95
|
Headache
|
14 (8.2)
|
21 (11.7)
|
0.27
|
Fatigue
|
66 (38.6)
|
55 (30.7)
|
0.12
|
Abdominal pain
|
22 (12.9)
|
25 (14.0)
|
0.76
|
Lymphadenopathy
|
1 (0.6)
|
2 (1.1)
|
>0.99^
|
Diarrhea
|
20 (11.7)
|
18 (10.1)
|
0.62
|
Vomiting/nausea
|
28 (16.4)
|
30 (16.8)
|
0.92
|
Altered consciousness/ confusion
|
44 (25.7)
|
30 (16.8)
|
0.04
|
Seizures
|
2 (1.2)
|
2 (1.1)
|
>0.99^
|
Other comorbidities – no. (%)
|
Chronic pulmonary disease (including asthma)
|
22 (12.9)
|
24 (13.4)
|
0.88
|
Liver disease
|
12 (7.0)
|
10 (5.6)
|
0.58
|
Chronic renal disease
|
71 (41.5)
|
39 (21.8)
|
<0.0001
|
Chronic cardiac disease
|
95 (55.6)
|
43 (24.0)
|
<0.0001
|
Chronic neurological disease
|
22 (12.9)
|
16 (8.9)
|
0.24
|
BMI > 30 (Kg/m2)
|
55 (45.5)
|
60 (40.5)
|
0.42
|
Rheumatologic disease
|
2 (1.2)
|
5 (2.8)
|
0.45^
|
Any malignancy including leukemia, lymphoma, or solid tumors
|
14 (8.2)
|
20 (11.2)
|
0.35
|
Immunosuppressant use before admission
|
6 (3.5)
|
15 (8.4)
|
0.06
|
|
|
|
|
SOFA score on ICU day 1, median (Q1, Q3)
|
9.0 (6.0, 12.0)
|
8.0 (5.0, 11.0)
|
0.02
|
BMI: Body mass index; ICU: intensive care unit; Q1: first quartile, Q3: third quartile; SOFA: Sequential Organ Failure Assessment
The denominator of the percentage is the total number of subjects in the treatment group.
For continuous variables, Mann-Whitney U test was used to calculate the P-value. For categorical variables, Chi-square test was used to calculate the P-value unless otherwise noted. ^Fisher’s exact test was used to calculate P-value.
The laboratory findings are presented in Table 2. There were no differences in white blood cell and platelet counts between the two groups. Patients with diabetes had higher blood glucose (median 12.1 mmol/L (Q1,Q3: 9.9, 16.1) versus median 8.5 mmol/L (Q1,Q3: 6.5, 11.6), p<0.0001), blood urea nitrogen (median 12.0 mmol/L (Q1,Q3: 7.3, 20.8) versus median 9.1 mmol/L (Q1,Q3: 4.1, 16.9), p=0.0002) and creatinine (median 141.4 mmol/L (Q1,Q3: 91.0, 327.0) versus median 114.9 mmol/L (Q1,Q3: 67.0, 217.0), p=0.0004).
Table 2. Physiological parameters on day 1 of admission to ICU in patients with diabetes and Middle East Respiratory Syndrome (MERS) compared to patients with no diabetes and MERS.
Variables
|
Diabetes
N=179
|
No Diabetes
N=171
|
P-value
|
Respiratory parameters on ICU day 1, median (Q1, Q3)
|
PaO2 (mmHg)
|
65.1 (56.0, 79.0)
|
71.0 (60.2, 86.4)
|
0.01
|
SaO2 (%)
|
92.0 (87.0, 95.0)
|
93.5 (90.0, 95.0)
|
0.004
|
FiO2,
|
0.7 (0.45, 1.0)
|
0.6 (0.45, 1.00)
|
0.24
|
PaO2/FiO2 ratio
|
98.0 (64.0, 160.0)
|
122.6 (73.4, 187.5)
|
0.02
|
Extrapulmonary parameters on ICU day 1, median (Q1, Q3)
|
Mean arterial pressure (mmHg)
|
70.0 (61.0, 83.0)
|
70.0 (60.0, 80.0)
|
0.72
|
Leukocyte (× 109/L)
|
7.90 (4.50, 11.60)
|
6.80 (4.20, 11.20)
|
0.31
|
Hemoglobin (g/dL)
|
10.4 (9.0, 12.50)
|
11.0 (8.5, 13.0)
|
0.48
|
Hematocrit
|
33.0 (28.55, 38.50)
|
35.0 (28.0, 40.0)
|
0.24
|
Platelets (x109/L)
|
188.0 (117.0, 253.0)
|
168.5 (113.0, 253.0)
|
0.32
|
Glucose (mmol/L)
|
12.1 (9.9, 16.1)
|
8.5 (6.5, 11.6)
|
<0.0001
|
Blood urea nitrogen (mmol/L)
|
12.0 (7.3, 20.8)
|
9.1 (4.1, 16.9)
|
0.0002
|
Creatinine (μmol/L)
|
141.4 (91.0, 327.0)
|
114.9 (67.0, 217.0)
|
0.0004
|
Bilirubin (μmol/L)
|
12.3 (7.8, 23.7)
|
12.0 (7.8, 22.9)
|
0.86
|
PaO2: partial pressure of oxygen; SaO2: Oxygen saturation; FiO2: Fraction of inspired oxygen; PaO2: FiO2 ratio: the ratio of the partial pressure of oxygen to the fraction of inspired oxygen; ALT: alanine aminotransferase, AST: aspartate transaminase; Q1: first quartile, Q3: third quartile.
Data on variables were not available for some patients; the number of patients with missing data in the Diabetes group and the No diabetes group, respectively, were as follows: PaO2: 5 patients and 3 patients, SaO2: 3 patients and 3 patients, FiO2: 8 patients and 17 patients, PaO2: FiO2 ratio: 9 patients and 19 patients, MAP: 5 patients and 5 patients, Leukocyte: 5 patients and 9 patients, Hemoglobin: 5 patients and 10 patients, Hematocrit:7 patients, and 9 patients, Platelets: 6 patients and 5 patients, Glucose: 23 patients and 26 patients, Blood urea: 8 patients and 9 patients, Creatinine:4 patients and 2 patients, Bilirubin level: 22 patients and 23 patients.
Management in the ICU
Table 3 shows the management interventions performed during the ICU stay. More patients with diabetes were treated with non-invasive ventilation and with invasive mechanical ventilation (89.5% versus 81.6%, p=0.04) than non-diabetics. The time from symptom onset to intubation was similar. In comparison to patients with no diabetes, there was more use of nitric oxide in patients with diabetes (28 (16.4%) versus 16 (8.9), p=0.04, but less use of ECMO (6 (3.5%) versus 16 (8.9%), p=0.04).
Table 3. Main interventions and outcomes in patients with diabetes and Middle East Respiratory Syndrome (MERS) compared to patients with no diabetes and MERS.
Variables
|
Diabetes N=171
|
No Diabetes N=179
|
P-value
|
Interventions
|
Non-invasive positive pressure ventilation – no. (%)
|
64 (37.4)
|
43 (24.0)
|
0.007
|
Invasive ventilation – no. (%)
|
153 (89.5)
|
146 (81.6)
|
0.04
|
Duration, median (Q1, Q3)
|
9.5 (4.0,17.0)
|
9.0 (4.0, 16.0)
|
0.68
|
Neuromuscular blockade – no. (%)
|
55 (32.2)
|
78 (43.6)
|
0.03
|
High-frequency oscillation ventilation – no. (%)
|
16 (9.4)
|
10 (5.6)
|
0.18
|
ECMO – no. (%)
|
6 (3.5)
|
16 (8.9)
|
0.04
|
Nitric oxide – no. (%)
|
28 (16.4)
|
16 (8.9)
|
0.04
|
Prone positioning – no. (%)
|
14 (8.2)
|
19 (10.6)
|
0.44
|
Duration, median (Q1, Q3)
|
3.0 (2.0,3.0)
|
3.0 (2.0, 3.0)
|
0.97
|
Any oxygen rescue therapy – no. (%)
|
73 (42.7)
|
84 (46.9)
|
0.43
|
Vasopressors – no. (%)
|
147 (86.0)
|
129 (72.1)
|
0.002
|
Duration, median (Q1, Q3)
|
6.5 (4.0,13.0)
|
6.0 (3.0, 14.0)
|
0.83
|
Blood transfusion – no. (%)
|
59 (34.5)
|
58 (32.4)
|
0.68
|
|
|
|
|
Antivirals – no. (%)
|
|
|
|
Both interferon and ribavirin – no. (%)
|
70 (40.9)
|
47 (26.3)
|
0.02^
|
Interferon only – no. (%)
|
4 (2.3)
|
5 (2.8)
|
Ribavirin only – no. (%)
|
10 (5.8)
|
8 (4.5)
|
Oseltamivir – no. (%)
|
89 (52.0)
|
107 (59.8)
|
0.15
|
Corticosteroids – no. (%)
|
100 (58.5)
|
75 (41.9)
|
0.002
|
Renal replacement therapy – no. (%)
|
103 (60.2)
|
71 (39.7)
|
0.0001
|
Duration, median (Q1, Q3)
|
8.0 (4.0,14.0)
|
8.0 (3.0, 14.0)
|
0.92
|
Intravenous immunoglobins – no. (%)
|
9 (5.3)
|
15 (8.4)
|
0.25
|
Tracheostomy – no (%)
|
5 (2.9)
|
9 (5.0)
|
0.32
|
Outcomes
|
|
|
|
ICU mortality – no. (%)
|
133 (77.8)
|
95 (53.1)
|
<0.0001
|
Hospital mortality – no. (%)
|
136 (79.5)
|
102 (57.0)
|
<0.0001
|
90-day mortality – no. (%)
|
135 (78.9)
|
98 (54.7)
|
<0.0001
|
28-day mortality – no. (%)
|
127 (74.3)
|
90 (50.3)
|
<0.0001
|
14-day mortality – no. (%)
|
89 (52.0)
|
76 (42.5)
|
0.07
|
ICU length of stay (days), median (Q1, Q3)
|
11.0 (6.0,19.0)
|
8.0 (5.0, 17.0)
|
0.05
|
Hospital length of stay (days), median (Q1, Q3)
|
18.0 (10.0,33.0)
|
20.0 (10.0, 37.0)
|
0.63
|
ECMO: extracorporeal membrane oxygenation. ICU: Intensive care unit. The denominator of the percentage is the total number of subjects in the group.
Outcomes of patients
The mortality at 90 days was higher in patients with diabetes (78.9% versus 54.7%, p<0.0001) (Table 3). On multivariable logistic regression analysis, in both the models (I and II) diabetes was associated with increased mortality (OR, 2.09; 95% CI, 1.18-3.72). Other predictors of mortality were age (OR per 1-year increment, 1.04; 95% CI, 1.02-1.06), female gender (OR 1.68; 95% CI, 1.06-2.67), SOFA (OR per 1-point increment 1.20; 95% CI, 1.14-1.26).(Table 4).
Table 4. Multivariable model to examine whether diabetes is an independent predictor of mortality in patients with Middle East Respiratory Syndrome (MERS). We adjusted for age, sex, asthma or chronic pulmonary disease, chronic neurological disease, immunosuppressant use before admission, body mass index (BMI), and SOFA score. Model I: Complete case analysis with no imputation (participants with any missing data are excluded). Model II: Multiple imputation (participants with missing data identified and replaced).
Variables
|
Model I (N=266)
|
Model II (N=350)
|
OR (95% CI)
|
P-value
|
OR (95% CI)
|
P-value
|
Diabetes
|
2.09 (1.18, 3.72)
|
0.005
|
2.13 (1.15, 3.95)
|
0.02
|
SOFA (per one-unit increase)
|
1.20 (1.14, 1.26)
|
<0.0001
|
1.17 (1.12, 1.23)
|
<0.0001
|
Female sex
|
1.68 (1.06, 2.67)
|
0.02
|
1.74 (1.09, 2.79)
|
0.02
|
Age (per one-year increase)
|
1.04 (1.02, 1.06)
|
0.0002
|
1.04 (1.02, 1.06)
|
<0.0001
|
Chronic neurological disease
|
3.07 (0.80, 11.81)
|
0.07
|
3.40 (1.04, 11.14)
|
0.04
|
BMI (kg/m2) (per one-unit increase)
|
0.97 (0.90, 1.03)
|
0.23
|
0.96 (0.91, 1.02)
|
0.21
|
Immunosuppressant use before admission
|
1.24 (0.29, 5.26)
|
0.74
|
1.13 (0.35, 3.64)
|
0.84
|
Asthma or chronic pulmonary disease
|
1.20 (0.66, 2.20)
|
0.51
|
1.04 (0.57, 1.91)
|
0.90
|
OR: Odds Ratio; CI: Confidence Interval; BMI: body mass index; SOFA: Sequential Organ Failure Assessment.
ICU LOS was longer for patients with diabetes (Table 3). The time to clearance of MERS-CoV RNA was similar in both groups (23 days (Q1, Q3: 17, 36) in patients with diabetes and 21.0 days (Q1, Q3: 10, 33) in patients with no diabetes). Figure 1 demonstrates the Kaplan Meir curves for time-to-clearance of MERS-CoV rRT-PCR and shows no difference between patients with diabetes and no diabetes.