Key words
SARS-CoV-2 - COVID-19 - obesity - diabetes mellitus - hypertension, cardiovascular
incidences - cardiovascular disease
ARDS Acute respiratory distress syndrome
SARS-CoV-2 Acute respiratory syndrome coronavirus 2
ACC American College of Cardiology
ADA American Diabetes Association
AHA American Heart Association
ARB Angiotensin II receptor blocker
ACE2 Angiotensin-converting-enzyme 2
ACEI Angiotensin-converting-enzyme inhibitor
BMI Body mass index
CVD Cardiovascular diseases
CSC Chinese Society of Cardiology
COPD Chronic obstructive pulmonary disease
CI Confidence interval
COVID-19 Coronavirus disease 2019
DDG Deutsche Diabetes Gesellschaft
DGK Deutsche Gesellschaft für Kardiologie
D&CVD Diabetes and Cardiovascular
Study Group Disease Study Group
DPP-4 Dipeptidyl peptidase-4
EASD European Association for the Study of Diabetes
EASO European Association for the Study of Obesity
ESC European Society of Cardiology
ESH European Society of Hypertension
GLP-1 Glucagon-like peptide-1
HR Hazard ratio
HFSA Heart Failure Society of America
ICU Intensive care unit
IL-6 Interleukin-6
IVM Invasive mechanical ventilation
MERS-CoV Middle East respiratory syndrome coronavirus
OR Odds ratio
SARS-CoV Severe acute respiratory syndrome coronavirus
SGLT-2 Sodium-glucose cotransporter-2
T1DM Type 1 diabetes mellitus
T2DM Type 2 diabetes mellitus
Introduction
The year 2020 has thus far mainly been dominated by the emergence of a new coronavirus
- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - which has become
a global pandemic within a couple of month. By the end of August 2020 the associated
respiratory disease – coronavirus disease 2019 (COVID-19) – has been diagnosed in
more than 23 000 000 individuals, resulting in more than 800 000 deaths [1]. In Italy, one of the countries strongly impacted by SARS-CoV-2, total mortality
for March 1 to April 4, 2020 was increased by 104.5% compared with the average number
of deaths for the prior 5 years [2]. The impact on mortality rates for Italy is considerably greater than indicated
by official COVID-19 deaths [3] and similar observations have been made for other European countries [4]. This might be driven by restriction in chronic and acute care opportunities implemented
in the respective countries. Even with the high mortality rates it needs to be considered
that in more than 80 % of individuals with SARS-CoV-2 infection no or only mild symptoms
can be observed [5].
Infection with SARS-CoV-2 and progression of COVID-19 is characterised by an initial
infection phase, followed by a respiratory distress phase and a severe hyperinflammation
state [5]
[6]. Virus infiltration is mediated via the angiotensin-converting-enzyme 2 (ACE2) receptor,
which is widely expressed in several organs. Its expression by endothelial cells might
enable SARS-CoV-2 to infect blood vessels and thus contribute to a wide distribution
of the virus [7]. Following virus infection, host inflammatory response is amplified, which will
culminate in systemic inflammation and a so called cytokine storm [6]
[8]. As a result, SARS-CoV-2 infection does not only lead to pneumonia but may also
cause damage to other organs including the heart, liver and kidneys [9]
[10]. Many studies have indicated a higher incidence of COVID-19 in males compared to
females. Sama and colleagues speculated that higher plasma concentrations of ACE2
in men, as observed by cohort studies might explain this discrepancy [11].
A scaled analysis of data collected by the OpenSAFELY analytic platform of more than
17 000 000 individuals in the UK identified factors associated with COVID-19 death
[12]. A higher risk for fatal COVID-19 course was seen with increasing obesity, diabetes,
severe asthma, respiratory disease, chronic heart disease, liver disease, stroke/dementia,
other neurological diseases, reduced kidney function, autoimmune disease and other
immunosuppressive conditions [12]. An analysis of the first described collective with COVID-19 in Germany revealed
a higher rate of obesity and a history of respiratory disease in individuals with
acute respiratory distress syndrome (ARDS) compared to individuals with less severe
disease progression [13]. Another observational study from Germany revealed an in hospital-mortality of 22%,
predominantly affecting patients receiving mechanical ventilation, patients >80 years
and those requiring dialysis [14]. The most common underlying comorbidities of COVID-19 were chronic diseases, such
as obesity, diabetes, hypertension and cardiovascular diseases (CVD) [15]. We would like to highlight the impact the abovementioned chronic diseases might
have on SARS-CoV-2 infection and COVID-19 (see [Fig. 1]), which views international scientific organisations represent, and which key learnings
might be of importance for the future.
Fig. 1 Risk factors for severe disease course and mortality in patients with Covid19.
COVID-19, Obesity & Diabetes
COVID-19, Obesity & Diabetes
Obesity
Obesity is considered one of the prominent risk factors for an increased severity
of COVID-19. A number of retrospective studies and analyses suggest a high prevalence
of obesity in COVID-19 patients [16]
[17]
[18]
[19]
[20]. A French study could show that the prevalence of obesity, defined by body mass
index (BMI) of at least 30 kg/m2 was 1.35 times (95 % CI 1.08 – 1.66) higher in patients with severe COVID-19 than
in the general French population [16]. The prevalence of obesity in critically ill COVID-19 patients, determined by admission
to intensive care units, was also higher than in the general French population [16]. Simonnet and colleagues observed high numbers of obese and overweight individuals
admitted to intensive care, indicating a more severe disease progression. The median
BMI of the participants who required invasive mechanical ventilation (IVM) was 31.1 kg/m2, as compared to 27.0 kg/m2 for those who did not require IVM [20]. In another study, COVID-19 patients with higher BMI were more likely to develop
ARDS and to experience disease exacerbation [21]. A study from New York found that individuals with obesity were more likely to require
acute medical care and admission to intensive care units, especially those younger
than 60 years [22]. Notably, individuals with obesity had a longer hospital stay compared to non-obese
COVID-19 patients [23]. Obesity does not only appear to be associated with a worse prognosis of COVID-19
but was also found to be a significant predictor for mortality [24].
Obesity has previously been determined as a risk factor for a number of virus infections,
due to its underlying chronic inflammatory phenotype [25]
[26]
[27]. It negatively affects immunity; high levels of cytokines are prominent in obese
individuals. This low-grade inflammation can result in an increased insulin resistance,
further activating the pro-inflammatory cascade. Obesity is also associated with the
development of dyslipidaemia, atherosclerosis, type 2 diabetes mellitus (T2DM) and
hypertension, all risk factors for a more severe COVID-19 progression [28]
[29]
[30]
[31]. Thus, a SARS-CoV-2 induced cytokine storm exacerbates the pre-existing, obesity-associated
subclinical inflammatory situation, predisposing obese individuals to an increased
risk of severe COVID-19 outbreak [25]. In addition to the negative impact on inflammation, factors associated with obesity
influencing mechanical ventilation may increase the severity of lower respiratory
tract infection and contribute to secondary infection [26]. Furthermore, obesity causes significant changes in the mechanics of the lungs and
chest wall. These make mechanical ventilation difficult and can lead to asthma-like
symptoms such as dyspnoea, wheezing and hypersensitivity of the airways [32]. These symptoms can aggravate pulmonary disease due to COVID-19.
Managing COVID-19 patients with obesity on the intensive care unit can present management
challenges, specifically with regard to ventilation support, vascular access and decubital
skin breakdown [33]
[34]. In view of the severity of the situation, addressing obesity by improving immune
modulation e. g. by a balanced diet, mild caloric restriction and physical exercise
should be recommended as preventive measures for individuals at risk [35].
Recommendations
The European Association for the Study of Obesity (EASO) published a position statement
on the global COVID-19 pandemic [36] to advocate their commitment in supporting individuals with obesity by creating
resources for health care professionals, patients and policymakers. There is currently
a lack of data describing health effects and impacts of COVID-19 on obesity during
lockdown, quarantine, and self-isolation, thus the EASO petitions for novel and high-impact
research and support tools related to COVID-19 and obesity [36].
Diabetes
Early during the pandemic, there were indications for an increased risk of SARS-CoV-2
infection specifically for people with diabetes [37]. Reports and observational studies from China and Italy identified a high number
of individuals with diabetes among hospitalised COVID-19 patients, as well as among
individuals with fatal outcomes [9]
[10]
[19]
[29]
[30]
[31]
[38]
[39]. Further investigations then determined an increased severity of COVID-19 and mortality
outcomes associated with diabetes, rather than an increased incidence [15]
[37]
[40]
[41]
[42]
[43]
[44]
[45]
[46]. It should be stated, that most observational studies did not assess prevalence
of COVID-19 or its severity in people with diabetes in relation to the overall respective
populations, especially not adjusted for age.
An observational study of 193 patients with severe COVID-19 showed an increased mortality
rate of patients with diabetes compared to patients without diabetes (81.3% vs. 47.6%,
with an overall mortality rate of 56.0%) [40]. Individuals with diabetes already had higher laboratory parameters at hospital
admission and had more comorbidities, which might have additionally influenced severity
of COVID-19 as well as mortality [40].
A retrospective longitudinal, multicentre study assessed a potential association of
glycaemic control and clinical outcomes in people with T2DM and COVID-19 [47]. The study included 7337 COVID-19 patients of whom 13% had T2DM, which is in alignment
with the prevalence of T2DM in China with about 10.9% [48]. The median duration from first symptoms to hospital admission was 10 days (interquartile
range [IQR], 6−19); major symptoms for both groups were similar to the general population
of patients. People with T2DM had an increased need to receive medical interventions
during COVID-19, and had a higher in-hospital death rate compared to control individuals.
The higher occurrence of adverse outcomes in people with T2DM was associated with
the level of blood glucose control. Individuals with an HbA1c of 8.1% had worse laboratory
characteristics and required more intense therapeutic management than individuals
with an HbA1c of 7.3%, who were comparable to the control group with regard to most
analysed parameters [47].
A retrospective observational study from the US suggested that uncontrolled hyperglycaemia
might have a stronger influence on hospital length of stay and mortality than a high
HbA1c. In the study, mortality rates of patients with diabetes (HbA1c 9.1%) were lower
than in COVID-19 patients with uncontrolled hyperglycaemia (HbA1c 5.9%): 14.8% vs.
41.7%, respectively [49]. These data raise the question, whether high glucose variability rather than chronic
hyperglycaemia are predominantly driving COVID-19 severity and mortality and whether
improving glucose variability should be the focus of glycaemic management.
Another observation made by a retrospective study with Chinese individuals hospitalised
with COVID-19 indicates an excessive disease severity in people with newly diagnosed
diabetes compared to those with known diabetes, hyperglycaemia and normal glucose
[50]. This might be in accordance with the above statements, that not only hyperglycaemia
but also glycaemic variability are associated with COVID-19 outcomes. Several studies
support the view that at-admission hyperglycaemia emerges as an independent factor
for poor prognosis and outcome in patients with COVID-19 not only in individuals with
diabetes. In hospitalised patients without pre-existing diabetes at-admission hyperglycaemia
accounts for a 30 % higher mortality rate. The Pisa Study suggested a bidirectional
relationship between COVID-19 and hyperglycaemia mediated by an increase of ACE2 activity
[51]
[52]
[53]. In a retrospective analysis of COVID-19 patients with T2DM 56.6% of participants
had abnormal blood glucose levels, including both pre- and postprandial excursions
[54]. This highlights the importance of stringent glucose management in individuals with
T2DM not infected with SARS-CoV-2, especially in view of the increased disease severity
and mortality in individuals with uncontrolled glycaemia.
There is not only a potential interaction between diabetes and glycaemic control with
COVID-19 severity and related mortality; SARS-CoV-2 infection and associated treatment
options can also negatively influences blood glucose level in people with diabetes.
Already in previous pandemic/epidemic incidences triggered by viruses, such as severe
acute respiratory syndrome coronavirus (SARS-CoV), H1N1 influenza virus infection
and Middle East respiratory syndrome coronavirus (MERS-CoV), diabetes increased the
risk of complications [55]
[56]
[57]
[58]. It is well known that diabetes and especially hyperglycaemia concur with immune
dysfunctions, such as cytokine dysregulation and inflammation [59]
[60]
[61]. As for obesity, it was discussed that the pro-inflammatory state, characterised
by an inappropriate cytokine response could be causative for the increased severity
of COVID-19 in individuals with diabetes. The additional cytokine storm induced by
SARS-CoV-2 leads to ARDS, shock and rapid deterioration of COVID-19 [15]. Additionally the underlying pro-thrombotic state in people with diabetes further
heightens the over-activation of the coagulation cascade in COVID-19 [62]. A direct effect of SARS-CoV-2 on the pancreatic β-cells can lead to worsening of
insulin resistance and insulin sensitivity. It has been shown that coronavirus infection
– specifically SARS-CoV – can damage islet cells of the pancreas and cause acute insulin
dependent diabetes [63]. 51% of patients of a study investigating the pathogenesis of glucose intolerance,
surviving SARS-CoV infection developed diabetes during hospitalisation. At 3 years
of follow-up, only 5% of these patients still had diabetes, indicating that the damage
of islets by SARS-CoV was transient [63]. It was discussed, that SARS-CoV-2 infection might also infect the pancreas, leading
to hyperglycaemia and thereby instigating upregulation of glycosylated ACE2 in the
lung and thus further virus binding and inflammation [64]
[65].
The treatment of COVID-19 might negatively influence glycaemic control in people with
diabetes. Corticosteroids, azithromycin and other therapeutics can, for example, lead
to glycaemic excursions and increase the risk for dysglycaemia [66]. On the other hand, hydroxychloroquine, which has frequently been used in the treatment
of COVID-19 has a positive impact on glycaemic control and is an approved glucose-lowering
medication for T2DM in India [67]. Thus, dose adjustments for oral antidiabetic drugs and/or insulin might be necessary
to ensure stable glycaemic profile in individuals with COVID-19 and diabetes.
The discussion on the increased severity of COVID-19 in individuals with diabetes
is closely associated with aspects of therapeutic measures, e. g. the continuation
or discontinuation of glucose-lowering medication. It was suggested to discontinue
sodium-glucose cotransporter-2 (SGLT-2) inhibitors due to the risk of dehydration
and diabetic ketoacidosis. Similarly, physicians should consider discontinuation of
metformin therapy [68]
[69]. Current evidence on pioglitazone and liraglutide does not support any changes in
the ongoing medications [70]. As dipeptidyl peptidase-4 (DPP-4) is the primary receptor for MERS-CoV [71], it has been speculated whether treatment with DPP-4 inhibitors might be beneficial
in context of COVID-19. An association of DPP-4 and SARS-CoV-2 has not been observed
and there are currently no studies arguing for or against a positive influence of
DPP-4 inhibitors in patients with COVID-19, nor any information indicating the necessity
for discontinuation of treatment. Most hospitalised patient with COVID-19, especially
those with respiratory distress, would require initiation of insulin therapy [68]. However, an early retrospective study suggested that long-term insulin utilisation
was associated with progression to severe or critical illness or in-hospital death
(adjusted odds ratio (OR)=3.58; 95% confidence interval (CI) 1.37–9.35) [72]. It is however unclear, whether this association is a direct consequence of insulin
utilisation or diabetes progression. Changing therapy strategies to e. g. initiating
insulin therapy should consider severity of COVID-19, nutritional status, actual glycaemic
control, risk of hypoglycaemia, renal function, and drug interactions [73]. Overall, enhanced self-management, supportive healthcare services and public health
measures should be implemented to minimise the risk for people with diabetes for SARS-CoV-2
infection [74].
Recommendations
In recent months, many scientific associations and societies have published opinions,
statements and recommendations on how to approach the current situation – on large
and small scales. The Infectious Diseases Society of America published a guideline
on the treatment and management of patients with COVID-19, which is regularly updated
[75]. Focusing on diabetes, the American, European and German associations (ADA, EASD
and DDG), amongst others, provided platforms for health care professionals to educate
themselves on a variety of topics in relation to SARS-CoV-2 and COVID-19. The ADA
additionally issued a special “Diabetes and COVID-19” section in the peer-reviewed
journal “Diabetes Care”. No official guidelines or recommendations are available as
of yet by ADA and EASD. In Germany, the DDG has published practical recommendations
for adult individuals with diabetes and COVID-19 [76]. The authors recommend a discontinuation of SGLT-2 inhibitors, as well as of metformin,
sulfonylureas and pioglitazone in patients with fever >38.5°C; for glucagon-like peptide-1
(GLP-1) receptor agonists and DDP-4 inhibitors no safety concerns are apparent, nevertheless
therapy adaptations in favour of insulin should be considered in severe COVID-19 cases.
Management of risk factors such as hypertension and lipids should be continued, although
a close monitoring of parameters is required [76]. The DDG statement additionally provides specific recommendations and targets on
glucose management in intensive care units using intravenous insulin therapy [76].
There are a number of independent recommendations and position statements available,
addressing diabetes management in COVID-19 patients [77]
[78]
[79]. These are clearly stated as “recommendations and reflections based on expert opinions,
awaiting the outcome of randomised clinical trials” [77]. People with diabetes not infected with SARS-CoV-2 should continue their diabetes
management and follow means of primary prevention of COVID-19. Recommendations for
individuals with diabetes and COVID-19 are in accordance with those provided by the
DDG: consideration of discontinuation of potential metabolically interfering medications
such as SGLT-2 inhibitors and metformin [77]
[78]
[79]. Decisions on therapy adaptations should only be made in concert with the respective
health care professional. Recommendations are summarised in [Table 1].
Table 1 Current key recommendations/position statements by scientific associations.
|
Chronic disease
|
Scientific association
|
Recommendation/position statement
|
Reference
|
|
Diabetes mellitus
|
DDG
|
-
Management of hypertension and lipids should be monitored, therapies should be continued
-
Discontinuation of metformin, sulfonylureas pioglitazone, and SGLT-2 inhibitors in
patients COVID-19 and fever >38.5°C
-
No safety concerns for GLP-1 receptor agonists and DPP-4 inhibitors
Therapy adaptation in favour of insulin should be considered in severe COVID-19
|
[96]
|
|
EASD
|
No official guidelines or recommendations have been published
|
|
|
ADA
|
No official guidelines or recommendations have been published
|
|
|
D&CVD Study Group/Bornstein et al., 2020/Hartmann-Boyce et al., 2020
|
|
[77]
[78]
[79]
|
|
Hypertension
|
ESC
|
▪ Continue treatment with antihypertensive medication according to ESC-ESH guideline
2018
|
[102]
[122]
|
|
ESH
|
|
[99]
|
|
Joint Statement of AHA, HFSA, ACC
|
|
[101]
|
|
Obesity
|
|
|
|
|
Cardiovascular disease
|
DGK
|
|
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
|
|
ESC
|
Recommendations on
-
▪ Strategies for diagnosing SARS-CoV-2
-
Protective measures for health care personnel and patients in cardiology
-
Triage systems (reorganisation and redistribution)
-
Diagnosis of cardiovascular conditions in COVID-19 patients
-
Categorisation of emergency/urgency of invasive procedures
-
Management/treatment pathways
-
Treatment of SARS-CoV-2 infection
Patient information
|
[122]
|
|
ACC
|
No official guidelines or recommendations have been published
|
|
|
AHA
|
No official guidelines or recommendations have been published
|
|
|
CSC
|
General recommendations on
-
Risk assessment
-
Protection of patients and medical staff
-
Adapting measures tailored to specific local epidemic situations
-
Consider conservative medical treatment as a top priority
Recommendations on medical therapyRecommendations on strategies of cardiovascular
intervention
-
Conditions warranting invasive intervention
-
In-hospital transport of patients undergoing interventional procedures
-
Protection in cardiac catheterization labs
-
Perioperative management
Other recommendations
-
Optimising laboratory testing
-
Referral between hospital
-
Telemedicine
Psychological intervention
|
[123]
|
Acute respiratory syndrome coronavirus 2 (SARS-CoV-2); American College of Cardiology
(ACC); American Diabetes Association (ADA); American Heart Association (AHA); Angiotensin
II receptor blocker (ARB); Angiotensin-converting-enzyme inhibitor (ACEI);Chinese
Society of Cardiology (CSC); Coronavirus disease 2019 (COVID-19); Deutsche Diabetes
Gesellschaft (DDG); Deutsche Gesellschaft für Kardiologie (DGK); Diabetes and Cardiovascular
Disease Study Group (D&CVD Study Group); Dipeptidyl peptidase-4 (DPP-4); European
Association for the Study of Diabetes (EASD); European Society of Cardiology (ESC);
European Society of Hypertension (ESH); Glucagon-like peptide-1 (GLP-1); Heart Failure
Society of America (HFSA); Sodium-glucose cotransporter-2 (SGLT-2).
COVID-19, Hypertension & Cardiovascular Disease
COVID-19, Hypertension & Cardiovascular Disease
Hypertension
Similar to the abovementioned conditions, hypertension is commonly reported as one
of the most common underlying comorbidity of COVID-19 [15]
[80]. This might in part be due to the strong association of hypertension with older
age as well as other comorbidities. Adjusting for these confounders however indicates
a direct association of hypertension with the increased severity of COVID-19 and an
increased COVID-19-related mortality. Also similar to the abovementioned conditions,
prevalence of hypertension in the overall number of SARS-CoV-2 infected individuals
was comparable to the respective country-specific prevalence (e. g. China 26.6%, Italy
25.9% [81]
[82]).
A number of retrospective studies as well as propensity score matched and meta-analyses
showed that hypertension could significantly increase severity and fatality of COVID-19
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]. In a retrospective observational study, COVID-19 patients with hypertension had
a higher mortality rate (24.8% vs. 15.2%), a higher proportion of severe patients
(63.7% vs. 42.1%), a higher proportion of patients receiving non-invasive mechanical
ventilation (16.8% vs. 7.6%), and a higher proportion of patients transferred to the
intensive care unit (ICU) (23.9% vs. 12.2%). Adjusting for confounding effects of
other complications, the increased risk for COVID-19 severity and ICU admission was
still observed, whereas for mortality and length of hospital stay no significant difference
remained between individuals with or without hypertension [84]. A recent meta-analysis, published as a Letter to the Editor, summarised that the
prevalence of hypertension in patients with severe COVID-19 progression as significantly
higher than in non-severe patients [85]. In another meta-analysis, hypertension was associated with increased risk for poor
outcomes in patients with COVID-19. Adjusting for confounders, such age, gender, presence
of CVD, diabetes or chronic obstructive pulmonary disease (COPD) did not affect the
association [86]. A propensity-score matched analysis including COVID-19 patients from Wuhan showed
that patients with hypertension had significantly higher risk of death (hazard ratio
(HR) 2.679;95% CI [1.237–5.805]; P=0.012;) [87].
It was discussed, that hypertension is a risk factor for severe COVID-19 either due
to a strong relation to age or due to potential end-organ damage in hypertensive individuals
[91]. As mentioned above, many studies and meta-analysis were however able to adjust
for confounding effects such as age and CVD, questioning the abovementioned theory
[84]
[86]
[92]. On the other hand, there has been a focus on a potential association of inflammation
and immunity with hypertension (and CVD) [93]
[94] which, similarly to obesity and diabetes, might contribute to the increased risk
for severe COVID-19. For example, immune-inflammation responses in hypertension are
mainly regulated by interleukin-6 (IL-6), which is strongly linked to clinical outcomes
of COVID-19 [95]
[96].
ACEI/ARBs
As for diabetes and CVD, it was discussed for hypertension that the higher risk for
COVID-19 severity is associated with ACE2 and a dysregulation of the renin-angiotensin
system (RAS) cascade [97]. Thus it was questioned whether treatment with ACE inhibitors (ACEI)/ angiotensin
II receptor blockers (ARBs) might be harmful in hypertensive patients with COVID-19.
A retrospective study from China compared all-cause mortality of individuals treated
with or without ACEI/ARBs. Individuals with COVID-19 and coexisting hypertension had
lower risk of all-cause mortality when treated with ACEI/ARB [98].
Recommendations
All major scientific societies have published position statements, specifically addressing
the use of ACEI/ARBs [99]
[100]
[101]
[102]
[103]
[104]. The European Society of Hypertension has generated a review on the relation of
hypertension, RAS and the risk for lower respiratory tract infections and lung injury
[100]. They strongly highlight that currently available data do not support a differential
use of ACEI/ARBs in patients with COVID-19. Decisions on discontinuation in patients
with severe symptoms, sepsis or haemodynamic instability should be made on a case-to-case
basis [99]. The American Heart Association , the Heart Failure Society of America and the American
College of Cardiology issued a joint statement, strongly recommending continuation
of ACEI/ARBs in hypertensive individuals with COVID-19 [101]. The European Society of Cardiology stated in March 2020 that speculations on the
safety of ACEI/ARB treatment in relation to COVID-19 are not based on scientific evidence,
and should thus not be discontinued as a consequence of a SARS-CoV-2 infection [102].
Cardiovascular Disease
In line with the abovementioned risk factors, CVD such as coronary heart disease,
myocardial infarction and heart failure are associated with in increased COVID-19
severity [37]
[105]
[106]. Similar to obesity, diabetes and hypertension, many studies and reports show increased
rates of mortality in patients with COVID-19 and a pre-existing CVD [106]. In one retrospective cohort study, fatal cases had a higher rate of e. g. coronary
heart disease compared to survivors: 24 vs. 1%, respectively [107]. In another small retrospective study, CVD was more prevalent in fatal COVID-19
cases than in survivors: 13 of 68 vs. 0 of 82, respectively [108]. A meta-analysis suggested a fivefold higher risk of mortality in individuals with
CVD compared to COVID-19 patients without CVD (unadjusted OR 4.85, p<0.001; 95% CI
3.06–7.70; [109]). Another study could show that the risk of severe disease progression was higher
in individuals with CVD compared to those without (27.8 vs. 8.8%). Mortality rates
showed a similar range (22.2 vs. 9.8%) [110].
In addition to being a highly associated comorbidity for COVID-19 severity, cardiac
injury is a common condition in individuals infected with SARS-CoV-2 [111]
[112]
[113]
[114]. Heart tissue is frequently affected by viral infections, resulting in e. g. myocarditis,
acute coronary syndromes or heart failure [107]
[115]. Studies from China report an increased morbidity and mortality in individuals with
COVID-19 and myocarditis [105]
[111]
[113]. For example, more individuals with cardiac injury required non-invasive or invasive
mechanical ventilation than those without cardiac injury. Also mortality rates are
higher in patients with COVID-19 and a cardiac injury than in those without (42 of
82 [51.2%] vs. 15 of 334 [4.5%]; P<0.001) [113]. Autopsy reports could show that more than half of the investigated individuals
with fatal COVID-19 had a viral presence in the myocardium, which could explain the
cardiac injuries frequently observed in COVID-19 patients [116]. Prior experience with virus induced myocarditis suggests a direct cellular response
to viral entry and the innate immune response resulting in myocardial necrosis [117]. Aside from a viral presence in cardiomyocytes, it can be speculated that myocardial
injuries are a result of the inflammatory response to SARS-CoV-2 infection and/or
microvascular damage caused by intravascular coagulation and thrombosis [114]
[118].
The long-term effects of COVID-19 on individuals cannot be estimated yet. It is likely
to assume that cardiac injury might persist, thus increasing the risk for future CVD
[119]
[120]. Long-term follow-up studies with SARS-CoV survivors for example indicated a high
rate of morbidities 12 years after recovery, with e. g. 44% having abnormalities in
the cardiovascular system [121].
Recommendations
The European Society of Cardiology has provided guidance on the diagnosis and management
of CVD during the COVID-19 pandemic, strongly highlighting the preliminary nature
of the document and the lack of evidence-based treatment of SARS-CoV-2 infections.
The guidance reviews the association between CVD and COVID-19 and provides detailed
recommendations on the management and diagnosis of CVD in current circumstances [122]. Similarly, the Chinese Society of Cardiology published an expert consensus on principles
of clinical management of individuals with CVD during the COVID-19 pandemic [123]. They provide insights on general principles such as risk assessment and protection
of patients and medical staff, as well as on medical therapies, cardiovascular interventions
and the introduction of telemedicine to support guidance of individuals with CVD [123]. The American Heart Association provides a number of resources on their website,
where physicians and people with CVD can inform themselves about e. g. managing blood
pressure [124], while the American College of Cardiology is currently working on a Clinical Guidance
for Global Cardiovascular Clinicians [125]. A consensus statement by physicians from Australia and New Zealand emphasises the
“importance of maintaining contact with patients by primary care physicians” to avoid
delayed intervention and adequately manage individuals with CVD e. g. with regard
to medication [126]. Statements from national scientific associations such as the Deutsche Gesellschaft
für Kardiologie (DGK) highlight the necessity to concentrate on guideline-recommended
care of individuals with cardiovascular disease [127]. This includes a continuation of therapies such as ACEI / ARB [103]
Practical Aspects
The current situation provides a major challenge for routine care for chronic diseases.
Regular consultations were limited, disease management was mostly reduced to a minimum.
A study from the US showed a decrease in HbA1c testing volume during March and April
2020 [128]. Although some conversion was observed in the following weeks, this might have resulted
in an increase in HbA1c [129]
[130]. In contrast to the abovementioned study, evaluations of glycaemia in individuals
with type 1 diabetes mellitus (T1DM) as well as T2DM during lockdown in Italy showed
a stable or even improved glycaemic control [131]
[132]
[133]. Although major cutbacks in care provided to people with chronic diseases were necessary,
possibilities to exercise were limited and severe psychological stress imposed by
the overall situation, people with diabetes apparently were able to focus on diabetes
management [131]
[132]. Additionally it was suggested, that the knowledge that diabetes can worsen the
outcomes of COVID-19 might have contributed to a more compliant diabetes management
[131]
[132].
Delay in medical care and practical implications
An analysis by the Department of Veteran Affairs in the US evaluated the changes in
hospital admissions, treatment of emergency conditions and cancelled elective procedures
during the first 16 weeks of 2019 and 2020 [134]. The number of patients admitted to hospital decreased by more than 40% from Jan-March
2020 compared to March-April 2020. A similar decrease was not observed for hospital
admissions during the same time in 2019 [134]. For Italy even stronger decreases have been observed for paediatric emergency department
visits– ranging from 73% to 88% compared to the same period in 2018 and 2019 [135]. In Germany hospital admissions were reduced by 13% in the first 22 weeks of 2020
compared to 2019, with a reduction of 38% in week 14, when COVID-19 rates were highest
[136]. Several examples of delayed hospital admission provided by the study authors emphasize
the risk these delays pose for the patients, e. g. intensive care admission after
delayed diagnosis of T1DM, death in consequence of acute-onset leukaemia and others
[135]. Similarly, German diabetes centre reported an increase in diabetic ketoacidosis
in children at the time of diabetes diagnosis March to May 2020 compared to previous
years. This observation might be explained by the decreased availability of medical
services during lockdown, as well as fear for approaching health care institutions
[137].
In addition to the consistent decrease in medical care the COVID-19 pandemic also
has indirect consequences on individuals with chronic and/or acute CVD. One study
from the US for example reported a 40% reduction in ST-segment elevation myocardial
infarction activations [138], in another weekly rates of hospitalization for acute myocardial infarction were
reduced by 48% [139]. Similar findings were observed in a study from northern Italy [140]. In France, a population-based, observational study revealed a significant increase
in out-of-hospital cardiac arrest between March and April 2020 compared to previous
years from 13·42 (95% CI 12·77–14·07) to 26·64 (25·72–27·53) per million inhabitants
(p<0·0001) [141]. It was discussed that lockdown and movement restrictions imposed in France as well
as a reluctance of patients to call emergency services and visit hospitals are causative
for this prominent increase [141].
Long-term consequences and opportunities
A high number of individuals recently recovered from SARS-CoV-2 infection appears
to have had cardiac involvement (78%) and ongoing myocardial inflammation (60%), irrespective
of pre-existing comorbidities and course of COVID-19 [142]. The insights provided by this study are of great importance with regard to a potentially
considerable burden of inflammatory disease in the overall population. Although the
results need to be verified for a larger cohort the implications for upcoming challenges
remain.
Not only the physical health aspects of SARS-CoV-2 infection, but also the mental
strain the COVID-19 pandemic has put on the population will require continued follow-up.
According to a survey among the UK Household Longitudinal Study cohort the population
prevalence of clinically significant levels of mental distress increased from 18.9%
in 2018/2019 to 27.3% in April 2020. This increase was especially prominent in individuals
between the age of 18 and 34 years, and in people living with young children [143]. The survey might be indicative of the early emotional response of individuals towards
the COVID-19 pandemic and associated lockdown, it is unclear whether people have adjust
to the current situation, stabilizing their psychological well-being [143]. The mental strain of this challenging situation should however be acknowledge and
be met with appropriately resourced services.
The COVID-19 pandemic is a challenge not only for every individual that has to take
regular precautions such as social distancing, but more so for people with chronic
diseases and every health care system. Individuals with chronic diseases are advised
to continue their medication unless explicitly informed by their physician to do otherwise.
Scientific societies have published recommendations in their respective fields to
advice physicians and patients in their day-to-day disease management [144]. The abovementioned decline in individuals presenting to emergency units indicates
a requirement for an adaptation of health care services, focusing on telemedical support.
Thus, the current situation might presents itself as an opportunity to considerably
expand the use of telemedicine in the management of chronic diseases. An online survey
targeted at health care professionals (202 participants from 47 countries) suggests.
They reported a change from in-person routine care to virtual communication, with
diabetes, COPD, and hypertension being the most impacted conditions [145].
Gaps in Knowledge
The impact SARS-CoV-2 and COVID-19 already have had on the individual as well as on
health care systems is hardly measureable. Scientific, medical and economic policy
makers have been working nonstop to handle the situation as best and straightforward
as possible. Trying to understand both virus and resulting disease have been the main
focus of scientists all around the world. As of August 2020 the number of publications
listed on PubMed NCBI just on COVID-19 is higher than 43 000. Focusing on observational
studies and case reports in peer-reviewed publications provides first insights in
mechanisms of action, risk factors for disease progression and therapeutical approaches.
Nevertheless many open questions remain and can only be answered in the long run e. g.:
how does SARS-CoV-2 infection influence the immune system of individuals? What are
the long term consequences of COVID-19? How did the pandemic affect medical care of
chronic diseases? Which measures to contain the virus were most effective and how
did they affect medical care or mental health? What have we learned with regard to
telemedicine and remote care? With increasing numbers of infections these questions
remain of great importance and need to be considered when discussing how to proceed
in managing this unique situation. The “Lean European Open Survey on SARS-CoV-2 infected
patients” (LEOSS database and research platform, trying to uniformly record confirmed
cases, might be a first step in establishing an evidence base for best practice in
clinical management [146].
Conclusion
The numbers of SARS-CoV-2 infections are still increasing globally. This pandemic
is far from over, thus adapting daily management of chronic diseases to this “new
normal” is of the utmost importance. The association of e. g. cardiovascular comorbidities,
such as obesity, diabetes mellitus, hypertension and cardiovascular disease with a
higher risk for morbidities and mortality when infected with SARS-CoV-2 highlights
the responsibilities of health care professionals and health care systems in providing
adequate care for individuals with chronic diseases.
