This is an online COVID-19 pre-publication manuscript which has been submitted to WPSAR. Pre-publication manuscripts are preliminary reports and have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.
Title: Comorbidities and clinical features related to Invasive Ventilatory Support among COVID-19 cases in Malaysia
Author: Wan Shakira Rodzlan Hasani, Shubash Shander Ganapathy, Chong Zhuo Lin, Halizah Mat Rifin, Mohammad Nazaruddin Bahari, Muhammad Haikal Ghazali, Noor Aliza Lodz, Muhammad Hafizuddin Taufik Ramli, Nur Liana Ab Majid, Jane Ling Miaw Yn, Muhammad Fadhli Mohd Yusoff, Noor Ani Ahmad, Anita Suleiman, Ahmad Faudzi Yusoff, Venugopalan Balan, Sha’ari Ngadiman
ABSTRACT
Background: Pre-existing comorbidities are predictive of severe COVID-19 infection requiring intubation and mechanical ventilation. This study determined comorbidity and additional predictive factors for invasive ventilatory support among Malaysian COVID-19 patients.
Method: Field data collected during COVID-19 outbreak in Selangor, Malaysia up to 13th April 2020 were used. It contained sociodemographic characteristics, comorbidities, and presenting symptoms of COVID-19 cases. Their medical records were traced for information on intensive care unit admission requiring intubation and mechanical ventilation.
Results: A total of 1,287 COVID-19 positive cases were included in the analysis.
The most common comorbidities among COVID-19 patients were hypertension (15.5%) and diabetes (11.0%). More than one third of symptomatic patients presented with fever (43.8) and cough (37.1%). Among all 25 intubated cases, 68.0% had hypertension, 88.0% had fever, 40.0% had dyspnoea and 44.0% was lethargic. Multivariable regression model showed that the odds of being intubated among COVID-19 patients were significantly higher among older person (aged ≥60 years) [adjusted odd ratio (aOR=3.9)], those who had hypertension (aOR =5.7), presented with fever (aOR=9.8), dyspnoea (aOR=9.6), and lethargy (aOR = 7.9).
Conclusion: Old age, hypertension, and several presenting symptoms were strong risk factors for invasive ventilatory support among COVID-19 patients. They must be diagnosed early and monitored closely to improve clinical outcome.
INTRODUCTION
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This infection was first detected in Wuhan, China and has since spread to every part of mainland China (1) and all over the world. COVID-19 is the third coronavirus infection that spread extensively after Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)(2). On March 11, 2020, the World Health Organization declared COVID-19 a pandemic (3). As of April 14, 2020 the rapid spread of COVID-19 has led to 1,848,439 diagnosed cases and 117,217 deaths worldwide (4). Malaysia has also not been spared from the pandemic with a total of 4,987 infected people and 82 deaths up to April 14, 2020 (5).
With the increasing number of confirmed cases and escalating number of fatalities owing to COVID-19, the underlying comorbidities such as cardiovascular diseases and immunocompromised status of patients have generated considerable concern, especially among elderly patients. A number of studies have shown that underlying comorbidities are predictors of severe disease outcome and greatly affect the prognosis of the COVID-19 patients (6-8). COVID-19 causes severe acute respiratory syndrome and is often associated with intensive care unit (ICU) admission and subsequent mortality. In China, about 15% of the patients developed severe pneumonia, and about 6% needed non-invasive or invasive ventilatory support (9).
Identifying the risk factors that predicts severity and outcome of COVID-19 patients early in the presentation would be extremely helpful for clinicians in managing the patients. Previous findings from other countries such as China and Italy suggested that risk factors for severe COVID-19 include underlying health
conditions (10, 11). However, to our best knowledge, to date, there is no study describing the risk of underlying health conditions among Malaysian COVID-19 patients. This study aimed to describe the proportion of non-communicable disease (NCD) comorbidities and clinical presentations, and to determine their risk with the need for invasive mechanical ventilator support (intubation) among COVID-19 positive cases in Selangor, Malaysia.
Material and methods
This is a retrospective study using data collected during COVID-19 outbreak in Selangor, Malaysia. Selangor is a state on the West Coast of Peninsular Malaysia, which recorded the highest number of COVID-19 cases in Malaysia. COVID-19 confirmed cases in Selangor that were notified up to 13th April 2020 were included into this study. A positive case of COVID-19 is confirmed based on positive Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) testing (12).
Measures
The outcome variable was ICU admission that required intubation with mechanical ventilatory support. Predictor variables included history of having hypertension, diabetes, heart disease, chronic respiratory disease (inclusive of asthma, chronic obstructive pulmonary disease [COPD], and emphysema), cancer, and kidney disease and main symptoms of COVID-19 such as fever, cough, dyspnoea, lethargy, arthralgia, myalgia, headache, and diarrhoea. These variables and socio-demographic characteristics were based on the case investigation reports obtained from district health offices in-charge of each patient. All the admitted
COVID-19 cases were then followed up and verified via hospital medical report for information on ICU admission requiring intubation.
Data Analysis
Descriptive analysis was used to determine the socio-demographic characteristics, the proportion of the COVID-19 cases with NCD comorbidities and clinical presentation, and also the proportion of ICU admission with mechanical ventilatory support (intubated). Multiple logistic regression analysis was performed to identify the factors associated with intubation among COVID-19 cases. Considering the variables with p-values <0.25 from univariable analysis, important variables based on biological plausibility and also considering to avoid overfitting the model, twelve variables namely sex, age, hypertension, diabetes, heart disease, CKD, current smoker, fever, cough, dyspnoea, lethargy and diarrhoea were included in the multivariable model. Multicollinearity problems and all possible two way interaction terms were checked one by one together with main effect. Model fitness using Goodness of fit statistics was used to assess the fit of the regression model against the actual outcomes. We excluded variables from the univariable analysis if their between group difference were not significant or not meaningful, if the cell size was too small to calculate the odd ratios and if they had collinearity with others independent variable. Two-sided p-values less than 0.05 were considered to be statistically significant. Statistical Program Social Sciences (SPSS) statistical software version 24 was used for analysis.
RESULTS
In total, 1,287 laboratory confirmed positive cases of COVID-19 in Selangor were included in this analysis. Of those, 750 patients (58.3%) were male and majority were of Malay ethnicity (74.0%). Median age was 36 years with the highest percentage of COVID-19 infection among those between 18 to 29 years of age. The most commonly reported underlying NCD comorbidities among COVID-19 patients were hypertension (15.5%) and diabetes (11.0%). More than one third of symptomatic patients presented with fever (43.8%) or cough (37.1%). Only 5.5%
experienced dyspnoea while 6.1% were lethargic (Table 1).
Among the hospitalized patients, 25 (1.9%) were admitted to the ICU and required intubation with mechanical ventilatory support. Out of the 25 intubated cases, 56% aged ≥60 years, 68.0% had hypertension, 40% had diabetes, 88.0%
presented with fever, 56.0% with cough, 40.0% with dyspnoea and 44.0% with lethargy (Table 2). Due to the fact that all intubated patients were symptomatic, we carried out the regression model to investigate presenting symptoms in addition to comorbid factors in predicting the need for intubation.
The logistic regression analysis to identify factors associated with invasive ventilator support (intubation) among COVID-19 patients is presented in Table 3 with crude and adjusted odd ratio. Our final regression model demonstrated that the odds of being intubated among older COVID-19 patients (≥ 60 years) was 3.9 times (aOR:
3.90, 95% CI: 1.41, 10.80) higher than those aged below 60 years after controlling for sex, comorbidities and presenting symptoms. Those who had underlying hypertension had 5.7 times more odds of being intubated compared to those with no underlying hypertension (aOR: 5.71, 95% CI: 1.99, 16.45). Presenting symptoms such as fever (aOR: 9.8, 95% CI: 2.48, 38.95), dyspnoea (aOR:9.61, 95% CI: 3.31,
27.96) and lethargy (aOR:7.92, 95% CI: 2.84, 22.09) had significantly higher risk for intubation. We also performed the same regression model using age as continuous variable (not presented in the table) which found that with every increase in one year of age, the odds of being intubated increased by 8% (aOR: 1.08, 95% CI: 1.03, 1.12).
DISCUSSION
This is to our best knowledge the first paper that describes the association between NCD comorbidities and clinical picture with the risk for intubation among COVID-19 patients in Malaysia. Our study demonstrated that underlying hypertension and diabetes were the most common comorbidities among COVID-19 cases, consistent with the finding on the clinical features of COVID-19 in Wuhan (13) and meta-analysis on the prevalence of comorbidities in COVID-19 patients (14).
Bornstein et al., (2020) also reported that hypertension and types II diabetes were the most common comorbidities in patients with coronavirus infection and this is due to the metabolic inflammation caused by this infection that compromises the immune system (15). In addition, diabetes and hypertension have also been reported as the most common comorbidities for other coronavirus infections such as SARS and MERS-CoV (16).
Older age with underlying comorbidities has been predictors of poor outcome in viral infections (17, 18). This study found that the percentage of COVID-19 patient requiring ICU admission and intubation increased with age. Regression model showed that the odds of being intubated was 3.9 times higher among older adults aged 60 years and above after controlling for comorbidities and presenting symptoms. Similar to the reports from other countries, the risk for poor prognosis is
higher in older age groups. Data from China demonstrated that older adults with underlying severe health conditions are at higher risk for severe COVID-19 associated illness and death (19). Reports from Italy also suggested the risk factors for severe disease include older age and the presence of at least one of several underlying health conditions among COVID-19 cases (11).
Preliminary findings from the United States (US) suggested that people with underlying health conditions appear to be at higher risk for severe disease from COVID-19 (20). A study from China showed that almost 70% of COVID-19 patients who were admitted to ICU had concurrent comorbidities (21). Our finding shows that COVID-19 patients with underlying hypertension contributed for high percentage of ICU admission with invasive mechanical ventilator support. Patients with underlying hypertension also had 3.9 times the odds of being intubated with mechanical ventilatory support after adjusting for age, other comorbidities and clinical presentations. Hypertension was the most common NCD that predicted poor prognosis in patients with COVID-19. Systematic review and meta-analysis done by Jing Yang et al. (2020) showed that the pool odds of hypertension in severe patients compared to non-severe patients was 2.36 (95% CI: 1.46-3.83) (22). Most patients with hypertension were frequently treated with angiotensin‐converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) therapy. Previous study suggested the hypothesis that these drugs might play a role in the severe course of Covid‐19 cases and act as potential risk factor for COVID-19 fatalities (23). In addition, Fang et al., (2020) suggested that patients with hypertension who were treated with ACE-2 increasing drug were at higher risk for severe COVID-19 infection (24).
Other than age and underlying hypertension, the presenting symptoms related to COVID-19 infection also play an important role in predicting poor prognosis.
Consistent with other studies, the most common presenting symptoms in this study were fever followed by cough, dyspnoea and lethargy (10, 13, 25-27). Our finding indicates that symptomatic COVID-19 patients with fever, dyspnoea and lethargy had strong significant associations with the risk for intubation. A study done by Li et al., (2020) demonstrated significant differences in clinical symptoms and CT scan manifestation between patients with or without severe/critical COVID-19 after controling for age and comorbidities (28). This finding is very important for clinicians in risk-stratifying their patients based on presenting symptoms. In addition to dyspnoea that is already a known risk factor for intubation and ventilation, patients presenting with fever or lethargy should also be monitored closely too.
This study also found that there was no significant association between being a current smoker and risk for intubation among COVID-19 cases. This was consistent with meta-analysis findings based on five studies from China which concluded that being an active smoker was not significantly associated with enhanced risk of progression towards severe disease in COVID-19 (29). However, study on specific COVID-19 association with pneumonia by Liu et al (2020) indicated that the history of smoking was a risk factor of disease progression after controlling for age, maximum body temperature at admission, respiratory failure, albumin, C- reactive protein (30). Thus, the potential impact of smoking on the disease outcomes of patients with COVID-19 requires further observation and research.
Limitation
The data in this analysis was based on the report from a single state in Malaysia and may not necessarily represent the whole population of Malaysia. Data on outcomes, including ICU admission with intubation and comorbidities were missing for a small number of patients (less than 20% overall).
CONCLUSION
COVID-19 patients >=60 years old, who had hypertension, or who presented with fever, dyspnoea, or lethargy, were more likely to be intubated and ventilated.
These patients need to be screened for COVID-19 when presented to any healthcare facility and monitored closely by clinicians upon diagnosis and admission.
In addition, public health interventions should aim to provide additional protection to older population or people with comorbidity such as hypertension found to be more vulnerable to severe disease progression if infected with COVID-19.
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Table 1: Socio-demographic, Comorbidities and clinical presentation characteristics of COVID-19 Positive Cases in Selangor (N=1287)
Characteristics COVID-19
Positive Cases Sex, n (%)
Male 750 (58.3)
Female 537(41.7)
Age (years)
Median (IQR) 36.0 (30.0)
Mean (SD) 38.8 (18.2)
Age groups, n (%)
<18 years 116 (9.0)
18-29 years 366 (28.4)
30-39 years 239 (18.6)
40-49 years 151 (11.7)
50-59 years 214 (16.6)
60 years and above 201 (15.6)
Ethnicity, n (%)
Malay 952 (74.0)
Chinese 118 (9.2)
Indian 43 (3.3)
Others 174 (13.5)
Nationality, n (%)
Malaysian 1122 (87.2)
Non Malaysian 165 (12.8)
Comorbidities, n (%)
Hypertension 200 (15.5)
Diabetes 141 (11.0)
Heart disease /problem 50 (3.9)
Chronic respiratory disease 40 (3.1)
Chronic kidney disease 18 (1.4)
Cancer 7 (0.5)
Current smoker 57 (4.4)
Symptoms, n (%)
Fever 564 (43.8)
Cough 477 (37.1)
Lethargy 78 (6.1)
Dyspnoea 71 (5.5)
Headache 71 (5.5)
Myalgia 53 (4.1)
Diarrhoea 41 (3.3)
Arthralgia 31 (2.4)
Status Hospital Admission, n (%)
Intubated (Invasive ventilator support) 25 (1.9)
Non Intubated 1262 (98.1)
Table 2: Proportion of Intubated cases of COVID-19 by socio demographic, NCD comorbidities and clinical presentation
Variables
Intubated (Invasive Mechanical Ventilation)
(n=25)
Not Intubated (n=1262) Sex, n (%)
Male 18 (72.9) 732 (58.0)
Female 7 (28.0) 530 (42.0)
Age groups, n (%)
<60 years 11 (44.0) 1075 (85.2)
60 years and above 14 (56.0) 187 (14.8)
Comorbidities, n (%)
Hypertension 17 (68.0) 183 (14.5)
Diabetes 10 (40.0) 131 (10.4)
Heart disease 4 (16.0) 46 (3.6)
Chronic respiratory disease
0 (0.0) 40 (3.2)
Chronic kidney disease 3 (12.0) 15 (1.2)
Cancer 0 (0.0) 7 (0.6)
Current smoker 1 (4.0) 56 (4.4)
Symptoms, n (%)
Fever 22 (88.0) 542 (42.9)
Cough 14 (56.0) 463 (36.7)
Lethargy 11 (44.0) 67 (5.3)
Dyspnoea 10 (40.0) 61 (4.8)
Diarrhoea 3 (12.0) 38 (3.0)
Arthralgia 1 (4.0) 30 (2.4)
Myalgia 1 (4.0) 52 (4.1)
Headache 0 (0.0) 71 (5.6)
Table 3: Factors associated with intubation among positive case COVID-19 cases using binary logistic regression model (n=1287)
Risk factors
Simple Logistic Regression (SLR) Multiple Logistic regression (MLR)
b Crude OR
(95 % CI) p-Value b Adjusted OR*
(95 % CI) p-Value Sex
Male 1 1
Female -0.62 0.54 (0.22, 1.30) 0.166 -0.21 0.82 (0.30, 2.22) 0.689
Age group
< 60 years 1 1
≥ 60 years 1.99 7.32 (3.27, 16. 36) <0.001 1.36 3.90 (1.41, 10.80) 0.009 Hypertension
No 1 1
Yes 2.53 12.53 (5.33, 29.46) <0.001 1.74 5.72 (1.99, 16.45) 0.001
Diabetes
No 1 1
Yes 1.75 5.76 (2.53, 13.07) <0.001 0.06 1.06 (0.35, 3.23) 0.914
Heart Disease
No 1 1
Yes 1.62 5.04 (1.66, 15.26) 0.004 -0.18 0.84 (0.22, 3.23) 0.796
Chronic Kidney Disease
No 1 1
Yes 2.43 11.34 (3.06, 41.99) <0.001 1.19 3.30 (0.62, 17.50) 0.161
Current smoker
No 1 1
Yes -0.11 0.90 (0.12, 6.75) 0.916 -1.32 0.27 (0.02, 3.34) 0.307
Fever at presentation
No 1 1
Yes 2.28 9.74 (2.90, 32.72) <0.001 2.29 9.83 (2.48, 38.95) 0.001
Cough at presentation
No 1 1 -
Yes 0.787 2.20 (0.99, 4.88) 0.053 -0.21 0.81 (0.31, 2.13) 0.672
Dyspnoea at presentation
No 1 1
Yes 2.58 13.13 (5.66, 30.42) <0.001 2.26 9.61 (3.31, 27.96) <0.001
Lethargy at presentation
No 1 1
Yes 2.64 14.01 (6.13, 32.05) <0.001 2.07 7.92 (2.84, 22.09) <0.001
Diarrhoea at presentation
No 1 1
Yes 1.48 4.39 (1.26, 15.31) 0.020 0.15 1.16 (0.24, 5.51) 0.853
*Backward LR Multiple Logistic regression was applied.Multicollinearity and interactions were checked and not found.Hosmer Lameshow test P value = 0.951, Classification Table (overall correctly classified percentage = 98.2%) and ROC curve (area under ROC curve=94.6 %) were accepted to check model fitness.
** Univariable analysis was also done for cancer, chronic respiratory disease, and symptoms at presentation such as arthralgia, myalgia, and headache, but not presented in the table due to small cell size that led to not meaningful OR and CI
