Effect modification of the association between comorbidities and severe course of COVID-19 disease by age of study participants: a systematic review and meta-analysis

Various factors determine the risk of a severe course of COVID-19 disease and COVID-related deaths. Some of them are demographic in nature, such as age and sex, and others have to do with diagnosed conditions such as diabetes and hypertension [1‐5]. Furthermore, behavioural and occupational risk factors have also been discussed [6‐9]. Accordingly, some non-pharmacological interventions are aimed towards protecting affected population groups like the elderly [10].

The definition of exact target groups for health measures other than the elderly [11, 12] has often been vague. A part of the reason for this is that research evidence for such predisposing factors is based on incomparable data sources, indicators and calculations, and denominators. Estimates are further challenged not only by the interrelation between co-morbidities and disease severity, but also their interaction with age [13‐15]. In most studies, effect estimates for factors experienced by patients are missing, as they focus on data description in the form of clinical case series [16‐18].

In order to prioritise current vaccination strategies against COVID-19 infection, national and international policies require information on major risk groups. An evidence synthesis to quantify the risk of individual predisposing factors and their interactions with regard to disease severity is needed. The existing systematic reviews on that subject have been published as pre-print or as peer-reviewed publications to date [6‐8, 19‐23]. Some of these focus on one association to a particular endpoint, e.g., cardiovascular morbidity and severity of the course of the disease but do not quantify the actual risk of patients with these comorbidities in relation to important health outcomes [24‐26]. Some assess several comorbidities [4, 23] but do not cover many studies, as they have been conducted at a very early stage of the pandemic. Importantly, although age is studied as a risk factor, the interaction of age with comorbidities has rarely been studied (this information is available in the Supplement, Table 1). To our knowledge, no existing review provides comparative relative risk (RR) measures of the major predisposing conditions, using both crude data and reported RR measures, while taking the age structure—not just as a potential confounder but also as a potential effect modifier—of the respective study population into account.

We conducted a meta-analysis on risk for COVID-related hospitalisation, intensive care unit (ICU) admission, and death and its association with demographics, comorbidities, and behavioural factors. We extracted and included crude study data to understand the magnitude of the effect of comorbidities and other factors on COVID-19 health outcomes. By focussing on these outcomes, our objective was to generate evidence for prioritising health measures for vulnerable population groups. Our results were made publicly made available (https://​www.​medrxiv.​org/​content/​10.​1101/​2020.​07.​30.​20165050v1). With this communication, we aim to focus not only on the relation between individual co-morbidities and disease severity (e.g., as measured by ICU admission) but also further identify potential interactions with age.

We identified a total of 7429 records. We retrieved 190 of them for full-text screening and 75 studies met the inclusion criteria (Fig. 1). All of them were used for our qualitative analysis, and 74 for the quantitative analysis. One study was excluded as the number of confirmed COVID-19 cases was reported [33].

The majority of reports (n=66) were from China, followed by the USA (n=5). Studies were based on medical or clinical records (n=69) or official reported data (n=4) and were conducted between late December 2019 and April 2020 with follow-up of 5–30 days. Endpoints were hospitalisation (n= 43), admission to ICU (n=17), and death (n=26; mostly within 30 days or in-hospital deaths). Three studies had composite endpoints, three others reported multiple endpoints.

The sample sizes were between 19 and 44,672 confirmed COVID-19 cases and individuals were aged between 33 and 82 years; in seven studies children were also included (Supplement, Table 2). To our knowledge and after multiple reviews, most studies were published in peer-reviewed journals, except one that appears still as a preprint (Liu et al. (2020) Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019) [34].

We believe that our meta-analyses add to existing evidence [17, 19‐22] by assessing the magnitude of risk associated with comorbidities and other factors on the one hand and hospitalisation, ICU admission, and death on the other hand. Importantly, we take into account potential interactions with one main modifier, which is age. Our results have public health implications in four main fields:

First, we confirm that the risk of dying from COVID-19 is associated with the most prevalent existing comorbidities, such as cerebrovascular and cardiovascular diseases, hypertension, COPD, and renal disease, with RRs between two and three. Given the limited human and financial resources, knowing the exact magnitude of risk is important for effective protection and identification of the most vulnerable population groups. Explanations for the RR increase are in some instances related to the pathophysiology of the disease itself. For cardiovascular disease and hypertension, for example, a dysregulated innate immune response was found to influence severe COVID-19 infections [43]. In addition to that, it has been documented that the angiotensin-converting enzyme 2 (ACE2) has a vital role in the cardiovascular and immune systems, and it is involved in the heart function and the development of hypertension and diabetes mellitus [44]. Moreover, Zheng et al. considered that disease severity in patients with cardiovascular disease can be associated with increased secretion of ACE2 [45]. There is evidence that hypertensive patients may experience a decreased expression of ACE2, and consequently, an elevation of the angiotensin II levels that generates a severe manifestation of the disease [46]. The same protein and its poor regulation may also explain the link between COPD and smoking in terms of COVID-19 severity and mortality [22, 47]. Additionally, exacerbations in COPD cases are triggered by viral infections and environmental conditions [48]. For diabetes, the increased RR is explainable by reduced pulmonary function and a thickening of the pulmonary basal lamina [1, 49]. Factors like sex determine the COVID-19 risk and women might be protected by hormonal factors [8].

Second, we showed results of previous meta-regressions on the potential effects of age on COVID-19 outcomes and comorbidities [22]. For several comorbidities (cardiovascular disease, hypertension, and diabetes), we showed weaker associations with deaths among studies with a higher median age of patients. We want to highlight the effect modification of associations between comorbid conditions and severity of COVID-19 course as it is important for the NPIs just as for vaccination strategies. We considered that (i) adjusting for age will in most studies decrease associations and (ii) including adjusted estimates for our pooled estimates would, in most cases, leave age as the main predictor of severe course of the disease. However, this would disguise the considerable difference between those with predisposing conditions at young age and those healthy in young age.

Third, our analysis shows that the association of these comorbidities with hospitalisation and ICU admission is generally less strong for these same comorbidities and other risk factors and death. This corresponds to public data from Europe, where the proportion of infected people of older age or of other risk groups is relevantly higher in those who died compared to those who were hospitalised. In Spain, among infected aged 70 years and older, the risk of dying was higher than the risk of hospitalisation. In terms of comorbidities, while COVID-19 mortality risk among those with cardiovascular conditions is relevantly raised, the risk to be hospitalised or admitted to ICU is only moderately increased. Other studies have also found that for patients with cerebrovascular disease and with diabetes the risk increase of ICU admission was lower than the risk of dying compared to other population groups [19, 50]. This finding is important, as it implies that public health measures to protect healthcare surge capacities should not be equalled with measures to protect the vulnerable population from death in the fight against COVID-19. Even if—hypothetically—protecting all people at high risk of death, the effect on healthcare surge capacities, measured by hospital beds, critical care beds, healthcare workers, and healthcare expenditure [51], will not be equally effective. Interestingly, our meta-analyses showed less risk of severe outcomes of COVID-19 for healthcare professionals. This might be explained by a lower likelihood for underreporting in this population group but also by the healthy worker effect [52]. Therefore, comparative studies on this occupational group are needed.

The limitations of our work derived from the restricted and rapid search in one main database of medical literature. As we did not include articles in the Chinese language in our search due to lack of interpreters, that could have affected our findings. The nature of the included data was often based on hospital recording implying bias in a sense that more severely symptomatic patients are more likely included. Although our assessment revealed high to moderate study quality, studies based on hospital records are highly selective regarding the population included.

The limitation of the results from publicly available data derived from the limited and varying data sources, which restrict generalisability and country comparisons. Also, our effect estimates for some countries only investigate subgroups of hospitalised cases (e.g., France), which may lead to a systematic underestimation of the effect estimates, since these individuals likely have an increased risk of severity. However, the qualitative implications apply across different geographic regions as well as different data sources.

In conclusion, we found estimates in the range of two and three indicating that populations with comorbidities, such as cerebrovascular and cardiovascular diseases, hypertension, COPD, and renal disease are most at risk of dying from COVID-19. We also provided evidence synthesis for the effects of comorbidities on the severity of COVID-19 and effect modification of these effects by age in order to target public health measures towards groups at risk. The detailed analyses on effect modification revealed that effects of comorbidities on disease severity increase for several comorbidities with young age, which has important implications for the planning of vaccine strategies as well as non-pharmacological interventions targeting risk groups.