The effect of corticosteroids, antibiotics, and anticoagulants on the development of post-COVID-19 syndrome in COVID-19 hospitalized patients 6 months after discharge: a retrospective follow up study

Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 which causes the Coronavirus disease (COVID-19) has taken the world by storm. The impact this virus has had on the global economy, education, travel, and healthcare has been astounding [1‐3]. Although physicians initially had difficulty treating this disease, a more or less standardized treatment has been established. Corticosteroids and anticoagulants play an important role in this treatment and target key elements in the disease pathophysiology [4]. As higher incidences of venous thromboembolism (VTE) have been observed for COVID-19 hospitalized patients, varying from 2.6 to 15% for pulmonary embolisms (PE) and 4.6–12% for deep vein thrombosis (DVT), researchers have been prompted to investigate the underlying mechanism [5]. Although this mechanism has not yet been fully elucidated, COVID-19 is thought to cause an exaggerated inflammatory response which in turn leads to endothelial damage and activation of the coagulation cascade. Additionally, micro clotting has been observed in COVID-19 infected patients, hindering oxygen exchange [6]. Furthermore, the immobility of hospitalized patients further increases the risk of thrombotic complications, hence the administration of anticoagulants [7, 8]. Aside from thrombotic complications, COVID-19 patients have been observed with higher levels of inflammatory indices such as C-reactive protein, neutrophils, and interleukins which in turn cause excessive release of pro inflammatory cytokines. These cytokines cause significant damage to the respiratory system leading to pulmonary infections, respiratory failure, and organ damage via immune and inflammatory mediated pathways [9, 10]. Corticosteroids target these inflammatory pathways and have played a vital role in improving clinical outcomes and mortality in patients [11‐13]. Another commonly used drug group in the treatment of COVID-19 patients are antibiotics. These drugs are primarily implemented to treat secondary infections and prevent superinfections which has accounted for a significant portion of COVID-19 deaths. That said, some COVID-19 hospitalized patients in severe health states have also been treated empirically with antibiotics, despite the lack of evidence for a beneficial effect [14].

Although healthcare workers have mainly been focused on the treatment of the acute phase, i.e., the viral infection and the associated health symptoms of COVID-19. However it has now become apparent that after the initial infection a certain proportion of patients experience COVID-19 related symptoms for a prolonged period [15]. Due to the lack of a universally accepted definition among the scientific community and the ever-changing availability of information, these post-COVID conditions have been identified by various names. Long haul COVID, chronic COVID, post-acute COVID-19, long COVID, and post-COVID-19 syndrome are a few of the commonly used names. In this study, we have adopted the definitions of COVID conditions as described in the rapid guideline on post-COVID-19 conditions developed in collaboration with the National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the Royal College of General Practitioners (RCGP). Post-COVID-19 syndrome is defined as “signs and symptoms that develop during or after an infection consistent with COVID-19, present for more than 12 weeks and are not attributable to alternative diagnoses” [16].

As these post-COVID conditions are still in their infancy little is known about the underlying disease pathophysiology and epidemiology. The incidence rate of post-COVID-19 conditions varies widely per study, ranging from more than 30 to 76% after 6 months of symptom onset [17‐21]. This variation can be attributed to differences in follow-up length, the definition of the post COVID condition, and the population sample [15].

While much research has been done regarding the safety and efficacy of corticosteroids, antibiotics, and anticoagulants on the treatment of the acute phase of COVID-19 and its concomitant manifestations, little is known regarding the impact these medications have on the development of post-COVID-19 syndrome. No studies were identified looking into a possible association. Given the extent to which these drugs are prescribed, it is therefore imperative to investigate a possible interplay between these drugs and post-COVID-19 syndrome. Identifying the association between pharmacotherapy and the development of post-COVID-19 syndrome allows healthcare providers to make better-informed treatment choices and could contribute to overall patient well-being. Therefore, the aim of this study was to assess the effect of corticosteroids, anticoagulants, and antibiotics on the development of post-COVID-19 syndrome.

A total of 123 patients met the inclusion criteria of which, 33 patients (26.8%) had developed and were still affected by post-COVID-19 syndrome 6 months after hospital discharge (Table 1). The univariate analysis shows no statistically significant difference between the use of corticosteroids for patients who have and have not developed post-COVID-19 syndrome (p = 0.14). The same results can be seen for patients treated with anticoagulants (p = 0.34) or antibiotics (p = 0.96) (Table 2).

The univariate analysis showed no significant difference between the individual exposure groups (corticosteroids, antibiotics, or anticoagulants) and development of post-COVID-19 syndrome. While the multivariate analysis showed that corticosteroid treatment in patients hospitalized for COVID-19 was associated with a significantly smaller chance (OR 0.32, 95% CI 0.11–0.90, p = 0.03) of developing post-COVID-19 syndrome. Anticoagulant treatment in patients hospitalized for COVID-19 was associated with a smaller chance (OR 0.55, 95% CI 0.18–1.71, p = 0.30) of developing post-COVID-19 syndrome although this effect was not found to be significant. While antibiotic treatment in patients hospitalized for COVID-19 was associated with a greater chance (OR 1.26, 95% CI 0.47–3.39, p = 0.65) of developing post-COVID-19 syndrome compared to patients not treated with antibiotics, it was not statistically significant. Combinations of drug treatments showed no significant changes in lessening the chance of developing post-COVID-19 syndrome.

Patients treated with corticosteroids were associated with significantly lower incidences of post-COVID-19 syndrome. While patients treated with anticoagulants were also observed benefitting from a protective effect from developing post-COVID-19 syndrome, this effect was not significant. Antibiotic treatment on the other hand seemed to increase incidences of post-COVID-19 syndrome, although not significantly.

Although information regarding post-COVID-19 syndrome disease pathophysiology is scarce, corticosteroids’ effect on this disease may be explained by the hyperactivation of (chronic) inflammatory and immunological pathways post-COVID-19 syndrome induces and the anti-inflammatory and immunomodulating mechanism of action of corticosteroids. Among others, Corticosteroids decrease the production of pro-inflammatory cytokines and chemokines, stimulate the release of anti-inflammatory cytokines, and suppress lymphocyte activation and production of immunoglobulins, which play important roles in the disease progression [15, 28].

Patients infected with COVID-19 have been observed developing micro clots which in turn obstruct capillaries, hinder oxygen exchange, and could cause post-COVID-19 related symptoms. This in turn may be a potential explanation for the seemingly protective effect against post-COVID-19 syndrome of anticoagulants [6]. In contrast to corticosteroids and anticoagulants, antibiotics seemed to increase the chances of developing post-COVID-19 syndrome. As antibiotics are not part of Medisch Spectrum Twente’s COVID-19 treatment protocol, we can infer that patients who had received antibiotics were primarily treated for secondary infections which in turn suggests a graver patient health state. This is in line with our regression model which also shows a possible trend for higher chance of developing post-COVID-19 syndrome with increasing disease severity. However, this finding was not significant. Furthermore, some studies have better identified the role of the gut microbiome in COVID-19 patients, which show that antibiotics cause a dysbiosis in the gut microbiome which is closely involved in immune system regulation through the gut–lung axis and gut-brain axis amongst others. An imbalance can lead to more pro-inflammatory mediators and immune cell activation which in turn perpetuates the disease [29‐32].

Besides the underlying disease mechanisms, the significance of these results may be explained by the discriminatory ability of the aforementioned drugs. When patients are admitted to MST due to COVID-19, anticoagulants are administered as per hospital protocol, whereas corticosteroids are only administered when certain patient criteria are met. These criteria, such as respiratory rate and oxygen requirement are directly linked to disease activity and therefore have a higher discriminatory ability.

Seeing as post-COVID-19 conditions had only just started to emerge at the commencement of this study, no treatment or predisposing factors for these conditions were known. We can therefore infer that the COVID-19 hospitalized patients were treated as per hospital protocol and thus received similar medical treatment, explaining why no differences were found in administered drug treatment among patients.

The current study has several limitations. Firstly, the included sample size was limited which has direct implications on the power of our study. Secondly, drug class effects were measured for each drug group without taking into account possible dose variations or treatment duration as patients were treated as per hospital protocol. Thirdly, comorbidities were grouped into having a direct or indirect influence on COVID-19. Due to the relatively small sample size, it was necessary to include limited disease groups so as to not skew the data. For this reason, based on literature review and expert opinion it was decided to only include a select few disease groups as these were considered to be the most impactful on COVID-19 severity.

This study provides more insight into the effect of commonly used drug treatments for COVID-19 hospitalized patients on the development of post-COVID-19 syndrome. Although corticosteroids are primarily used for the treatment of COVID-19 hospitalized patients fitting certain respiratory criteria, this study shows corticosteroids reducing the probability of developing post-COVID-19 syndrome related symptoms after the acute infection. The observed protective effect is a new and unexpected finding which may have implications for daily practice in healthcare in relation to post COVID-19 syndrome prevention. Although the results indicate the added value of using corticosteroids for the prevention of post-COVID-19 syndrome, it is equally important not to overuse these drugs given the immunosuppressive effects and the development of infections. For this reason, more studies are needed to not only substantiate these findings but also to find an optimal treatment dose and length for corticosteroid use.

COVID-19 hospitalized patients in MST underwent the same treatments as per hospital protocol. No distinction was made between patients with predisposing factors for post-COVID-19 syndrome. Corticosteroids have shown a significant protective effect on the development of post-COVID-19 syndrome in this study. Further research is required to validate these findings and to yield improved prevention and management strategies for post-COVID-19 syndrome.