Higher coronavirus disease-19 mortality linked to comorbidities: A comparison between low-middle income and high-income countries.

BACKGROUND: Global burden of disease (GBD) provides the estimates of mortality and morbidity, while case fatality rate (CFR) helps in understanding the severity of the disease. People infected with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) with underlying medical conditions have shown higher levels of unfavorable outcomes including mortality. We assessed the association of SARS-CoV-2 CFR with disability-adjusted life years (DALY) of various comorbidities in the low-middle income countries (LMIC) and high-income countries (HIC) to study the relationship of coronavirus disease-19 (COVID-19) mortality with GBDs and to understand the linkage between COVID-19 mortality and comorbidities.
MATERIALS AND METHODS: This was an ecological study with secondary data analysis comparing the DALY of various morbidities from GBD with CFR of COVID-19. Gross domestic product was the basis of stratifying 177 countries into low-middle income (LMIC) and high-income groups (HIC). The mortality was analyzed using Pearson correlation and linear regression.
RESULTS: The median global CFR of SARS-CoV-2 was 2.15. The median CFR among LMIC (n = 60) and HIC (n = 117) was 2.01 (0.00-28.20) and 2.29 (0.00-17.26), respectively. The regression analysis found that, in both LMIC and HIC, maternal disorders were associated with higher SARS-CoV-2 CFR, while tuberculosis, mental health disorders, and were associated with lower CFR. Further, in LMIC, musculoskeletal disorders and nutritional deficiencies were associated with higher CFR, while respiratory disorders were associated with lower CFR.
CONCLUSIONS: SARS-CoV-2 infection appears to be a systemic disease. Individuals with comorbidities, such as maternal disorders, neurological diseases, musculoskeletal disorders, and nutritional deficiencies, have poorer outcomes with COVID-19, leading to higher mortality. Copyright:

Introduction

Novel coronavirus infection has now emerged as an unprecedented threat to mankind with more than 17 million confirmed cases and 0.68 million deaths.[1] Coronavirus disease-19 (COVID-19) is caused by a novel strain of coronavirus, named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially, presumed to be a disease of the respiratory system, it is now speculated that it has a systemic impact involving all the major organ systems. To start with, the disease was limited to a few countries, but within months, COVID-19 has spread all over the world at a tremendous pace. The disease has overtly spread to both developed and developing nations. Although high-income countries (HICs) have successfully vanquished many infectious diseases, the novel coronavirus has proved challenging to quell.

Novel coronavirus mortality has been linked to the patients’ comorbidities majorly noncommunicable diseases (NCDs).[2] The world has transitioned gradually from a predominant communicable disease pattern to a largely NCD-dominated disease burden, with the changing disease landscape in the developing countries too. Globally, it has been found that NCDs contribute to 48% of premature deaths and nearly 40 million NCD mortality in 2015.[3] The COVID-19 mortality among patients has shown an increasing trend among those with age more than 60 years, and people with preexisting conditions (such as heart diseases, diabetes, kidney diseases, and respiratory conditions).[2456789] It has also been found that severity of COVID-19 was higher among patients with preexisting NCDs such as hypertension (23.75%), diabetes mellitus (16.2%), coronary artery disease (5.8%), chronic obstructive pulmonary disease (3.5%), and cerebrovascular disease (2.3%).[8] Studies also suggest the evidence of severe disease in patients of COVID-19 admitted with preexisting neurological disease and may have a significantly higher in-hospital mortality, incident delirium, higher disability than patients without COVID-19.[101112] Some studies have reported poor prognosis in maternal conditions such as pregnancy and can lead to complications and death.[1314]

Surprisingly, there has been some connection between COVID-19 mortality and other communicable diseases such as tuberculosis (TB), malaria, and maternal disorders. However, rigorous infection control practices and personal protection are fundamental to prevent the risk of in-hospital transmission, especially when dealing with a highly vulnerable population.[1516]

However, with the rapidly evolving dynamics of the pandemic across the world, the comorbidities continue to influence the mortality due to COVID-19. The dynamics of the disease may be affected by the disease patterns already existing in the countries. Moreover, there are limited data in a comprehensive form to assess the linkage between the preexisting diseases. Therefore, we assessed the link between the burden of major diseases (both communicable and noncommunicable) NCDs and CDs with COVID-19 case fatality rate (CFR). Our study explored the relation of NCDs and CDs with COVID-19 outcomes among different countries to get a better perspective of the disease. This would provide evidence to the health system to deal efficiently affected patients with coexistent morbidities, which in turn can reduce the severity and burden of COVID in the community.

Materials and Methods

Study design and setting

This ecological study is a secondary data analysis of data from 177 countries selected based on the availability of the data on novel coronavirus mortality and the global burden of disease (GBD).

Study participants and sampling

All 177 countries were stratified into four groups based on gross domestic product as – low income, ($1,025 or less), low middle ($1,026 to $3,995), high ($3,996 to $12,375) and very high-income groups ($12,376 or more). The data were collected for a period of December 01, 2019–July 31, 2020.[17]

Data collection tool and techniques

The COVID-19 variables were collected in terms of the total number of cases and the total number of deaths for the countries.[1] CFR for every country was calculated separately.

CFR of COVID-19 = Number of deaths from COVID-19/number of total cases of COVID-19 × 100.

CFR depicts the severity of the disease. The CFR was used to assess the link between COVID-19 severity and the burden of NCDs and communicable diseases.

The burden of the NCD and CD was measured in terms of disability-adjusted life years (DALY). DALY was defined as the years of healthy life lost to premature death and disability. It is a measure of the overall disease burden.

DALY = year lived with disability + years of life lost.

For our study, the DALY for NCD and CD was obtained from the GBD.[1819]

The cardiovascular diseases included were rheumatic heart disease, hypertension, ischemic heart disease, cardiomyopathy, and other circulatory system disorders. Respiratory diseases included chronic obstructive disease, asthma, and other respiratory disease. Digestive diseases included peptic ulcer disease, cirrhosis, inflammatory bowel disease, and other digestive disorders including genitourinary disease. Musculoskeletal disease included rheumatoid arthritis, osteoarthritis, gout, and neck and back problems. Neurological diseases included Alzheimer's disease, parkinsonism epilepsy, migraine, headaches, and other neurological diseases. Diabetes and other endocrine disorders included diabetes and chronic kidney disorders. Cancer included tumors of all major organs. Other NCDs included accidents, and injuries. In CD, maternal and neonatal disorders included common disorders such as congenital anomalies, birth asphyxia, preterm babies, and respiratory system included upper and lower respiratory infections. Diarrheal disease included the intestinal nematodes infection. Malaria and neglected tropical diseases included diseases caused by parasites such as lymphatic filaria, malaria, dengue, and chikungunya. Human immunodeficiency virus (HIV) and TB were considered a separate entity.[20]

Data were extracted and tested for normality. Data analysis was done using the Statistical Package for the Social Sciences (SPSS) version 20.0 (Armonk, NY: IBM Corp). DALY and CFR being nonnormally distributed were expressed in median. Kruskal–Wallis test was used to assess the significance of the CFRs. However, for analysis, the data were converted for normal distribution using a logarithmic scale. Pearson correlation was used to analyze the relationship between the COVID-19 CFR and the GBD (DALY) of various countries. The factors were further analyzed with linear regression with the backward elimination method, and the beta coefficient was interpreted.

Ethical consideration

As the study involved secondary data analysis from publicly available free datasets, ethical permission was not required.

Results

The median global CFR of SARS-CoV-2 was 2.15 as per the data available in our study period. The CFR of 177 countries ranged of COVID-19 ranged from 0.00 to 28.20. The median CFR in low-income countries (n = 29) and low-middle income countries (LMIC) (n = 36) was 1.98 (0.72–4.21) and 2.09 (1.35–3.14), respectively. The SARS-CoV-2-2 CFR among the HIC (n = 52) and the very HIC (n = 60) was comparatively higher 1.72 (0.89–3.40) and 3.74 (2.83–5.04), respectively [Figure 1]. For further analysis, the low and LMIC were emerged as “LMIC” and high and very HIC were merged to form “HIC.”

Figure 1

Severe acute respiratory syndrome coronavirus 2 case fatality rate with country categories according to gross domestic product

LMICs contribute to the majority of the global burden of maternal disorders (86.7), neonatal disorders (79.2), nutritional deficiencies (83.2), malaria and neglected tropical diseases (82.8), HIV/AIDS (70.3), and TB (85.3). NCDs are nearly equally contributed by low middle-income countries (47.2) and high and very HICs (52.8). Further, LMICs contribute to high burden of cardiovascular diseases (43.9), cancer (32.2), respiratory disorders (53.1), diabetes and endocrine disorders (49.5), liver disorders (56.5), mental and substance abuse (44.5), neurological disorders (41.9), musculoskeletal disorders (38.9), digestive disorders (53.0), and other NCDs (58.5) [Figure 2].

Figure 2

Contribution of country categories according to the global burden of disease

A positive correlation was found with the NCD in high-income group neurological disorders, musculoskeletal disorder, digestive disorders, cardiovascular disorders, cancer, respiratory disorders, and liver disorders [Table 1].

Table 1

Correlation between noncommunicable disease (disability adjusted life years) and case fatality rate (correlation coefficient)

Noncommunicable disease (DALY)	Low middle-income countries - CFR (n=65)	High income countries - CFR (n=112)
Cardiovascular disorders
Rho	0.076	0.256
P	0.563	0.01*
Cancer
Rho	0.011	0.316
P	0.934	0.01*
Respiratory disorders (DALY)
Rho	0.024	0.245
P	0.858	0.01*
Diabetes and endocrine disorders (DALY)
Rho	0.065	0.220
P	0.620	0.01
Liver disorders (DALY)
Rho	−0.015	0.265
P	0.908	0.01*
Mental and substance abuse (DALY)
Rho	0.041	0.257
P	0.756	0.04
Neurological disorders (DALY)
Rho	0.044	0.26
P	0.738	0.01*
Musculoskeletal disorders (DALY)
Rho	0.074	0.243
P	0.573	0.01*
Digestive disorders (DALY)
Rho	0.013	0.257
P	0.964	0.016*
Other NCD (DALY)
Rho	0.047	0.203
P	0.724	0.04*

*P<0.05 considered as statistically significant. DALY=Disability adjusted life years, CFR=Case fatality rate, NCD=Noncommunicable disease, Rho=Correlation coefficient

The regression analysis found that, in both LMICs and HICs, burden of maternal disorders was associated with higher SARS-CoV-2 CFR, while TB, mental health disorders, and were associated with lower SARSsu-CoV-2 CFR [Table 2]. In LMICs, musculoskeletal disorders and nutritional deficiencies; while in HICs, burden of cancer, neurological disorders, and other NCDs were associated with higher CFR. In low-income countries, respiratory disorders were associated with lower CFR while malaria and neglected tropical diseases and neonatal disorders were associated with lower CFR [Table 3].

Table 2

Correlation between communicable disease (disability adjusted life years) and case fatality rate (correlation coefficient)

Communicable disease (DALY)	Low middle-income countries - CFR (n=65)	High income countries - CFR (n=112)
Maternal disorders
Rho	0.006	0.07
P	0.601	0.435
Neonatal disorders
Rho	0.010	0.112
P	0.939	0.254
Nutritional deficiencies
Rho	0.014	0.108
P	0.916	0.274
Malaria and neglected tropical diseases
Rho	0.066	−0.020
P	0.617	0.836
Diarrheal and infectious diseases
Rho	−0.060	0.155
P	0.646	0115
HIV/AIDS
Rho	−0.179	0.833
P	0.171	0.399
Tuberculosis
Rho	−0.207	0.048
P	0.113	0.630

DALY=Disability adjusted life years, CFR=Case fatality rate, Rho=Correlation coefficient, HIV=Human immunodeficiency virus

Table 3

Regression analysis between burden of the disease (disability adjusted life years) and case fatality rate

Burden of disease (DALY)	Standardized β coefficient	t	P	95%CI (lower limit-upper limit)	Model equation for linear regression
Low -middle income countries
Musculoskeletal disorders	3.94	3.109	0.03*	−0.817-3.789	R2=0.36
Maternal disorders	0.748	2.173	0.01*	0.031-0.781
Nutritional deficiencies	0.874	2.054	0.04*	0.012-1.012
Mental and substance abuse	−3.27	−2.724	0.01*	−3.509-−0.533
Respiratory disorders	−1.131	−2.018	0.04*	−1.313-−0.04
Tuberculosis	−1.039	−4.118	0.01*	−0.765-−0.264
Very high-income countries
Cancers	0.962	1.726	0.08	−0.069-0.994	R2=0.426
Mental and substance use disorders	−4.831	−4.864	0.01*	−3.328-−1.399
Neurological disorders	2.946	2.206	0.03*	0.143-2.710
Maternal disorders	1.347	3.810	0.00*	0.280-0.890
Neonatal disorders	−1.516	−2.340	0.02*	−1.325-−0.109
Malaria and neglected tropical diseases	−0.387	−2.125	0.03*	−0.253-−0.009
Tuberculosis	−0.489	−2.078	0.04*	−0.376-−0.009
Other NCDs	2.167	1.942	0.05	−0.024-2.153

*P<0.05 statistically significant. DALY=Disability adjusted life years, NCD=Noncommunicable disease, CI=Confidence interval

Discussion

COVID-19 initially originated as pneumonia-like disease, but recent evidence shows that it affects almost every system of the body. Similar to SARS-CoV, SARS-CoV-2 enters through angiotensin-converting enzyme 2 receptors that have been found in many different organs of the body. Our study found a positive correlation between COVID-19 mortality with majority of the NCDs in the bivariate correlation analysis. Many other studies have also reported higher severity of the disease with NCDs.[810111213142122]

Studies have shown diabetes as a worsening factor for SARS-CoV-2 infection, as it can augment the risk of acute complications through direct negative effects on β-cell function. This effect may lead to diabetic ketoacidosis, hyperglycemia, and an increase in hospital admission.[2324] Our study found an association of COVID-19 and diabetes in bivariate analysis in HICs with higher severity of the disease. Furthermore, we found an association with severity of SARS-CoV-2 with nutritional deficiencies, there have been studies that reported the role of Vitamin D in the prevention of progress and severity of the SARS-CoV-2.[25]

Our study also found an association of neurological disorders with an increased CFR of SARS-CoV-2. Previously, Kim et al. reported similar findings that patients requiring treatment in the intensive care unit were more likely to be older, male sex, and have an underlying comorbidity.[26] In another study conducted by Du et al., the univariate analysis showed that preexisting cerebrovascular diseases were predictive of mortality (odds ratio [OR] = 11.09, 95% confidence interval = 4–30).[27] In addition, there have been studies that found the coexistence of Parkinson's disease in COVID-19 with a poor prognosis.[2829]

Severe disease in preexisting neurological disease, such as dementia may be due to limited access to accurate information about preventive measures during the pandemic period of social distancing and home isolation.[30] Neurological disease leads to neuromuscular weakness or musculoskeletal weakness or invasion of the medullary cardiorespiratory center that may lead to respiratory insufficiency in COVID-19 patients, leading to adverse outcomes.[31] The SARS-CoV-2 receptor is expressed in the nervous system. Commonly reported symptoms included hyposmia, headaches, weakness, and altered consciousness. Encephalitis, demyelination, neuropathy, and stroke have been associated with COVID-19. Therefore, it can be speculated that SARS-CoV-2 has a detrimental effect on the nervous system, leading to poor outcomes is in people with preexisting neurological diseases. Further studies are needed to clarify the prevalence of the neurological complications of SARS-CoV-2 infection, investigate their biological backgrounds, and test treatment options. In COVID-19, increased D-dimer levels caution the risk of microthrombosis.[31] Physicians should be cautious not to overlook other neurological diagnoses that can mimic COVID-19 during the pandemic.[3233]

In COVID-19 cases, some studies suggest that viral shedding may be prolonged in patients treated with corticosteroids, and their routine use is currently avoided.[34] In addition, immunoglobulins are used to treat neuroinflammatory diseases that increase the risk of thromomembolism.[35] However, in our study, association of preexisting musculoskeletal disorders with higher case fatality, similar reasoning can be sought. Further, our study demonstrated lower mortality with malaria and neglected tropical disease which may be because of the usage of chloroquine and its derivatives that have some antiviral properties for reducing the severity of the disease.[363738394041]

Our study shows an increase in the severity of COVID-19 with preexisting maternal disorders. It may be due to the hypercoagulable state during pregnancy. Previous studies indicate that pregnant women were more likely to be hospitalized and have adverse events than normal women but mortality remained the same. Our study corroborates with recommendations that pregnant women and their families take preventive measures to reduce their risk of contracting COVID-19.[42]

Our study found lower severity of SARS-CoV-2 with preexisting neonatal disorders. There are very few studies that report fatality in newborns and few cases have been observed in children and adolescents who seem to have a more favorable clinical course than other age groups, and even fewer in newborn babies. Studies found that most newborns who have tested positive for COVID-19 had mild or no symptoms and have recovered fully. Only a small number of other complications, such as preterm (early) birth, have been reported in babies born to mothers who tested positive for COVID-19. Although vertical transmission from the mother to her fetus or neonate has yet to be proven, case reports of sick neonates exist. Early identification and isolation, adequate management, prevention, and vaccine development are the keys to controlling disease spread. Further studies on the different faces of COVID-19 are required to fight this viral pandemic.[4344]

In LMICs, TB and respiratory diseases are the major public health problems and in our study, they were found to be associated with lower mortality. However, it has been found that the majority of the people suffering from such diseases are young with fewer comorbidities, although studies show higher mortality is likely to occur in elderly patients with comorbidities and TB. However, mortality benefit in TB may be due to better respiratory hygiene and social distancing among the patients and general public. Studies have also reported that COVID-19 cases on active TB are clinically manageable with adequate care. With infection control practices and social distancing, the risk of in-hospital transmission can be prevented.[45]

Mental health and substance abuse were associated with lower severity of the diseases. There are very limited data published in how preexisting mental health has been associated with mortality in COVID-19 infections. The behavioral disorders that improve personal hygiene and personal protective measure in mental ailments may help patients to protect themselves from SARS-CoV-2. Studies have reported a social change toward improved personal hygiene and personal protective measure.[46] However, other NCDs such as intentional harm and suicides may be associated with higher case fatality due to paranoid behaviors. COVID-19 appears to be a systemic disease that affects on all the major health systems of the body. Hence, health practitioners in COVID-19 crisis need reliable information and evidence. Majority of this is derived from new experiences, such as lessons learned from the initial spread in China and continuation of use, improve personal hygiene and personal protective measure.[47]

Limitation and recommendation

Our study has demonstrated a series of associations with preexisting diseases in LMIC and HIC. Our study is novel to depict a mortality pattern of COVID-19 according to pre-existing disease patterns prevalent in LMICs and HIC. Although we have tried to discuss every factor irrespective of their country group, the CFR does depend on the response and surge capacity of the health care system. Furthermore, this being an ecological study, the results need to be interpreted with caution, with potential for systematic differences between areas in recording disease frequency and measurement of exposure. This study was an attempt to discuss every factor irrespective of their country group, the CFR depends on many factors such as health-seeking behavior, health system, and surveillance that have not been considered in the present study. A better reporting system provides us with accurate parameters and a better understanding of the novel coronavirus in HIC.[47] However, the common factors influencing the CFR in low-income countries also add upon the epidemiological knowledge of the COVID 19 pandemic. Our study warrants further research into the comorbidities aspects of COVID-19 mortality to be better prepared and save lives of the individuals with preexisting diseases within the limited surge capacity of the health system.

Conclusions

COVID-19 has spread all over the world with varying mortality in different countries. There are links of SARS-CoV-2 mortality and severity with preexisting NCDs and CDs. SARS-CoV-2 appears to be a systemic disease than just a respiratory illness. Preexisting maternal disorders, neurological diseases, musculoskeletal disorders, and nutritional deficiencies may have poorer outcomes with COVID-19. Our study warrants further studies into the comorbidity's aspects of COVID-19 mortality to be better prepared and save lives of the individuals with preexisting diseases with adequate and timely interventions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.