Patients older than 70 years of age are at increased risk for severe forms of COVID-19 and for dying from the infection.1,2,3 The presence of multiple preexisting conditions, such as cardiovascular and respiratory diseases, diabetes, and renal failure, frailty, and an impaired immune response related to aging make the elderly more vulnerable to COVID-19.2,3
The use of a number of drugs, including corticosteroids and low-molecular-weight heparins, has resulted in improved management of patients with COVID-19; however, these drugs have well-defined indications for use during COVID-19 and may result in adverse reactions, particularly in the elderly population.
Depending on their known immunomodulatory properties, the use of corticosteroids in the treatment of COVID-19 has been debated since the beginning of the pandemic.4
In July 2020, the New England Journal of Medicine published preliminary data from the RECOVERY study, marking an initial turning point in the natural history of COVID-19.5 Indeed, the RECOVERY study shows that dexamethasone treatment is significantly associated with a reduction in 28-day mortality in COVID-19 patients on oxygen supplementation, including patients on invasive mechanical ventilation.5
In September 2020, leading health care authorities, including the European Medicines Agency (EMA) and the World Health Organization (WHO), revised their guidelines for the management of corticosteroid therapy in COVID-19 accordingly, approving the use of 10 mg/day of dexamethasone for 10 days in patients with respiratory failure.4
While marking a major breakthrough, RECOVERY did not provide data on the safety of such therapy. Nonetheless, the World Health Organization has suggested that dexamethasone treatment is not associated with an increase in adverse events, except for an increased incidence of hyperglycemia and hypernatremia.6
Frail elderly patients with multiple diseases and on polypharmacy are particularly susceptible to developing adverse events related to drugs, including dexamethasone. First and foremost is the hyperglycemia, with increased need for hypoglycemic therapy if the patients have diabetes. In addition, the use of high-dose corticosteroids can lead to a hydro-electrolyte imbalance, favoring the risk of hypernatremia, but at the same time water retention, edema, and hypertensive crisis.6 A common finding is also that of hypokalaemia, which exposes the patient to further adverse events such as arrhythmias.7
Electrolyte alterations and related dehydration, in association with the clear presence of an inflammatory state reactive to the ongoing infection, may also favor the onset of delirium, one of the most frequent complications of hospitalization in elderly patients.8 In addition, exposure to steroid treatment increases the risk of bacterial and fungal infections, another common complication of elderly hospitalized patients.9,10
Finally, dexamethasone not only increases the risk of gastrointestinal bleeding, but it is also a moderate inducer of CYP3A4 and therefore interacts with the metabolism of several drugs including warfarin, leading to difficulties in INR control and exposing the patient to both thrombotic and hemorrhagic risk.4,6
In conclusion, the use of corticosteroids, although representing a fundamental therapy during respiratory failure in patients with COVID-19, must be accompanied by strategies aimed at preventing possible complications related to these therapies, such as the control of hydro-electrolyte balance and blood pressure, the prevention of hemorrhagic risk, through the use of gastroprotectors, and an adequate review of hypoglycemic therapy in diabetic patients.
The rationale of the use of low-molecular-weight heparins in the course of COVID-19 is based on the knowledge that the infection promotes a hyperinflammatory and prothrombotic state, such as to expose the patient to an increased risk of venous and pulmonary thromboembolism.11,12
Several observational studies have shown that there is a clear benefit in terms of reduced mortality when low-molecular-weight heparins are used in patients with COVID-19.12 However, it is difficult to deduce definitive indications because of the differences between the populations considered and the different treatment dosages, which vary between a prophylactic, “intermediate” or therapeutic dose. The Italian Medicines Agency (AIFA) recommends the use of a prophylactic dose in patients with reduced mobility, whereas it places indications for intermediate or therapeutic dosages in severe cases of COVID-19 and in patients at high thrombotic risk.12
Although low-molecular-weight heparins may benefit patients with COVID-19, these drugs should be used with caution in the elderly. First, the dosage of low-molecular-weight heparins should be adjusted according to the patient’s renal function. This is particularly important in frail, low-body-weight elderly patients who may have inapparent renal insufficiency (decreased renal function with normal creatinine levels).
In addition, the risk of bleeding is higher in the elderly population: cases of spontaneous epistaxis, gastrointestinal bleeding, and cerebral hemorrhage have been documented in elderly patients with COVID-19 treated with low-molecular-weight heparins.13-15
For these reasons, it is important to use a low-molecular-weight heparin dosage that does not increase bleeding risk. JAMA recently published a study evaluating the efficacy of administering an intermediate dose of low-molecular-weight heparins to prevent thrombotic events in patients admitted to the intensive care unit because of COVID-19. The results are clear: the intermediate dose does not appear to have an advantage over the standard prophylactic dose in preventing venous thromboembolism, whereas it is associated with more major bleeding events.11
Although more precise data are needed, in the elderly patient with COVID-19, a risk-benefit assessment should certainly be performed, preferring the administration of enoxaparin at a prophylactic dose for bed restraint, especially if concomitantly treated with corticosteroids, except in carefully evaluated cases.
- World Health Organization (WHO). Numbers at a glance. 2021 https://www.who.int/emergencies/diseases/novel-coronavirus-2019?gclid=EA...
- Williamson E, Walker A, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430-6.
- Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020;323:1775-6. CDI
- Agenzia Italiana del Farmaco (AIFA). Corticosteroidi nella terapia dei pazienti adulti con COVID-19. 2020. https://www.aifa.gov.it/documents/20142/1123276/Corticosteroidi_06.10.20...
- REcovery collaborative group, horby p, lim w, et al. dexamethasone in Hospitalized Patients with COVID-19. N Engl J Med.2021;384:693-704.
- World Health Organization (WHO). Corticosteroids for COVID-19. https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-20...
- Mark D, Coggins C. Steroid-related risks. Today’s Geriatr Med 2014;7:8.
- Zazzara M, Penfold R, et al. Probable delirium is a presenting symptom of COVID-19 in frail, older adults: a cohort study of 322 hospitalised and 535 community-based older adults. Age Ageing 2021;50:40-8. CDI
- Obata R, Maeda T, et al. Increased secondary infection in COVID-19 patients treated with steroids in New York City. Jpn J Infect Dis 2020;DOI:10.7883/yoken.JJID.2020.884.
- Riche C, Cassol R. Is the frequency of candidemia increasing in COVID-19 patients receiving corticosteroids ? J Fungi 2020;6:286. CDI
- INSPIRATION Investigators, Sadeghipour P, Talasaz A, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA 2021;DOI:10.1001/jama.2021.4152. CDI
- Agenzia Italiana del Farmaco (AIFA). Uso delle eparine nei pazienti adulti con COVID-19. 2020. https://www.aifa.gov.it/documents/20142/1123276/Eparine_Basso_Peso_Molec...
- Dell’Era V, Dosdegani R, et al. Epistaxis in hospitalized patients with COVID-19. J Int Med Res 2020;DOI:10.1177/0300060520951040. CDI
- Martin T, Wan D, et al. Gastrointestinal bleeding in patients with coronavirus disease 2019: a matched case-control study. Am J Gastroenterol 2020;115:1609-16. CDI
- Azpiazu Landa N, Velasco Oficialdegui C, et al. Ischemic-hemorrhagic stroke in patients with COVID-19. Rev Esp Anestesiol Reanim 2020;67:516-20.
Maria Beatrice Zazzara1, Graziano Onder2, Luca Pellizzari3
1 Centre for Diseases of Aging, Agostino Gemelli Foundation University Hospital, Rome
2 Director Department of Cardiovascular, Endocrinometabolic and Aging Diseases, National Institute of Health, Rome
3 Geriatrics A, Civile Maggiore Hospital, Verona, Italy.