“Showing Promising Recovery Results from Respiratory Failure in COVID-19 Patients - Contagionlive.com” plus 3 more

Showing Promising Recovery Results from Respiratory Failure in COVID-19 Patients - Contagionlive.com
[Full text] Beware of Steroid-Induced Avascular Necrosis of the Femoral Head in th | DDDT - Dove Medical Press
The Cardiac Implications of COVID-19 - News-Medical.net
COVID‐19 and cardiovascular problems in elderly patients: Food for thought - Wiley

Showing Promising Recovery Results from Respiratory Failure in COVID-19 Patients - Contagionlive.com

Posted: 03 Mar 2021 08:18 AM PST

Patients with severe COVID-19 dealing with respiratory failure can have extended hospital stays and experience higher mortality rates. As such, an urgent need to aid these patients in respiratory failure is a priority in COVID-19 clinical care.

COVID-19-related respiratory failure is caused by selective infection of the alveolar type II cell (ATII) by the SARS-CoV-2 virus. The ATII cells are vulnerable because of their (ACE2) surface receptors, which serve as the route of entry for the virus. These specialized cells manufacture surfactant that coats the lung and is essential for oxygen exchange. Loss of surfactant causes collapse of the air sacs (alveolae) in the lung and results in respiratory failure.

Biopharmaceutical company, NeuroRx, in collaboration with Relief Therapeutics, have developed aviptadil, previously known as RLF-100, (Zyesami), a therapy targeting the lungs for patients in COVID-19 respiratory distress. Aviptadil contains a vasoactive intestinal polypeptide (VIP), a natural occurring peptide in the body that has been shown to protect the lungs from SARS-CoV-2. VIP has shown to block coronavirus replication in the ATII cell, block cytokine synthesis, block viral-induced cell death (cytopathy), and upregulate surfactant production.

Aviptadil is being studied in 2 clinical trials looking at intravenous and inhaled administration. Last week, NeuroRx announced results from its phase 2b/3 trial for aviptadil for the treatment of respiratory failure in critically ill COVID-19 patients.The company reports the investigational therapy demonstrated multidimensional benefit around its primary endpoint of recovery from respiratory failure with discharge from hospital and ICU (without relapse) by day 28 in patients with critical COVID-19 who were treated with high flow nasal oxygen.

Although not envisioned at the start of this clinical trial, high flow nasal oxygen has become the predominant form of treatment in COVID-19 respiratory failure, with mechanical ventilation reserved for those whose blood oxygen levels cannot be maintained on this less invasive modality.

"We started off giving it [aviptadil] to the people who were critically ill with COVID-19—people who were on ventilators, high-flow oxygen. And we are now just starting studies where it will be given in an inhaled form for people who are less sick," NeuroRx CEO and Chairman Jonathan Javitt, MD, MPH, told Contagion. "Most pulmonary drugs are best given in inhaled form but once someone has COVID distress and is on a ventilator there is a lot of debris in the lungs and reasons to give it intravenously."

The first trial was originally approved as a 28-day study. However, in December, NeuroRx added a 60-day endpoint based on the recognition that critically ill patients with COVID-19 are frequently maintained in the ICU with advanced technologies beyond this time.

Nonetheless, at 28 days, the trial did demonstrate positive results. The cohort of patients treated with aviptadil demonstrated a 35% higher likelihood of recovery from respiratory failure with continued survival compared to a patient group treated with placebo (Hazard Ratio 1.53; P=.08). In tertiary care hospitals, aviptadil-treated patients were 46% more likely to recover and return home before day 28 (Hazard Ratio controlling for age and severity 1.84; P=.058).

At day 28, a highly significant 10-day difference in median time to recovery and hospital discharge has emerged in aviptadi-treated patients compared to those treated with placebo (P<.006). Should these trends continue through day 60, the company said they have the potential to reach statistical significance.

Contagion spoke to NeuroRx CEO and Chairman Jonathan Javitt, MD, MPH, about the significance of the Zyesami brand name, the mechanism of action, and the details about the 2 trials.

[Full text] Beware of Steroid-Induced Avascular Necrosis of the Femoral Head in th | DDDT - Dove Medical Press

Posted: 03 Mar 2021 12:44 PM PST

Search Strategy and Selection Criteria

We searched the ScienceDirect, PubMed, MEDLINE, and Wiley (between January 2003, and August 2020) for articles published from the inception of each database. We used the search terms "SARS" or "COVID-19" in combination with the terms ("ARDS" or "respiratory system") and ("steroid" or "glucocorticoid" or "steroid-induced") with ("necrosis of the femoral head" or "necrosis"). We largely selected articles published in the past 15 years, but we did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant.

Introduction

The recent outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic. It was found that the amino acid sequence of the spike (S) protein of SARS-CoV-2 was 76·47% similar to that of severe acute respiratory syndrome-related coronavirus (SARS-CoV), but its affinity for angiotensin-converting enzyme 2 (ACE2) was 10 to 20 times higher than that of the latter, resulting in rapid transmission between people.¹ Huang et al reported that fever (98%) and cough (76%) were the initial features of the disease. 55% of the patients developed dyspnea after an average of 8 days of illness onset, and 29% of the patients developed ARDS 9 days after illness onset.² The pathological results showed that ARDS played an important role in the death of COVID-19 patients. Further, autopsy revealed bilateral diffuse alveolar injury with exudation of fibrous mucus and a mononuclear inflammatory infiltrate dominated by lymphocytes in the lung interstitium, which were related to the cytokine storm induced by overactivation of the immune system. These findings were very similar to those observed in SARS-CoV infection.³ Corticosteroids have been widely used in the treatment of severe acute respiratory syndrome (SARS). During the SARS epidemic of 2003, corticosteroids were considered to improve the patient's condition in the early stages by reducing fever, reducing lung inflammatory infiltration, and improving oxygenation; however, long-term use (especially at high doses) is associated with potentially serious adverse events.⁴ In a follow-up study, 23.1% (18 of 78) of Chinese patients with SARS developed steroid-induced avascular necrosis of the femoral head (SANFH) which was mainly due to the administration of high-dose glucocorticoids during the treatment of SARS.⁵ However, most of the studies ignored the influence of other confounding factors when analyzed the relationship between steroid and osteonecrosis of the femoral head(ONFH) retrospectively. There are many factors to be looked for, such as hemoglobinopathies (especially sickle cell anemia), autoimmune diseases, hyperlipidemia, excessive alcohol intake and abuse of traditional Chinese medicine.⁶ For example, the steroid dose is positively correlated with the incidence of osteonecrosis in systemic lupus erythematosus patients. The rate of osteonecrosis increased when prednisone-equivalent > 20 mg/d, each 10 mg/d increase was associated with a 3.6% increase.⁷ In addition, prior osteoporotic status and vitamin D deficiency of patients can not be ignored. Gangji confirmed that ONFH is associated with low bone mineral density.⁸ Inoue reported that the serum concentration of 1.25 (OH) 2D3 in 18 patients with idiopathic ONFH (16.7 ± 7.9 pg/mL) was significantly lower than that in the control group (26.9 ± 13.7 pg/mL) (P < 0.01), suggesting the possibility of bone metabolism abnormalities due to abnormal vitamin D3 metabolism as a background of ONFH.⁹ It has also been suggested that SARS itself may be an independent risk factor for ONFH.¹⁰

The prognosis of untreated SANFH is poor; it often leads to subchondral collapse in a short time. Timely diagnosis and treatment can preserve the function of the hip joint to the maximum extent only if detected in the early stages. Hormones are a double-edged sword. In today's global outbreak, whether corticosteroid therapy should be used, the dosage and duration of treatment, and ways for the prevention, early detection, and timely intervention of SANFH are some important issues that need to be addressed. We hope that this review can provide a reference for health care providers in COVID-19 endemic countries and regions, especially with respect to the pros and cons of corticosteroid use in the treatment of patients with COVID-19.

Mechanism of Action of Glucocorticoids

The inflammation and cytokine storm caused by the immune response are responsible for the fatal pneumonia after SARS-CoV infection.¹¹ Cytokines such as interferon gamma (IFN-γ), tumour necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) can cause tissue damage.¹² It is well known that corticosteroids do not directly inhibit viral replication, but their main effects are anti-inflammatory and immunosuppressive. Glucocorticoids can inhibit the "cytokine storm" by inhibiting the expression of proinflammatory proteins such as IL-1, IL-2, IL-6, TNF-α, and IFN-γ and the migration of leukocytes to the sites of inflammation.¹³ Glucocorticoids can also affect lipid metabolism. If the emulsification of very low-density lipoprotein cholesterol in the blood is not complete, it will combine with the lipoprotein globules which can form fat emboli resulting in blockage of the peripheral blood vessels and, consequently, ischaemic necrosis of the bone tissue in the vascular supply area. At the same time, the free fatty acids produced by hydrolysis of the fat emboli damage the capillary endothelial cells, cause diffuse vasculitis, and trigger intravascular coagulation, all of which aggravate the ischaemic necrosis of bone tissue.¹⁴ Glucocorticoids can also regulate the local blood flow by regulating the response of the blood vessels to vasoactive substances, which leads to constriction of the internal artery of the femoral head resulting in femoral head ischaemia.¹⁵ Fu et al found that the expression of microRNA 596 (miR-596) in the bone marrow of patients with steroid-induced femoral head necrosis (FHN) was upregulated, which could hinder the repair of the osteonecrotic bone by inhibiting the proliferation and osteogenic differentiation of the bone marrow stromal cells (BMSCs).¹⁶ Some basic studies have found that microRNA-17-5p (miR-17-5p) and miR-210 are related to the pathogenesis of SANFH.^17,18 Du et al confirmed for the first time that four sensitive single-nucleotide polymorphisms (SNPs), namely, rs3740938, rs2012390, rs1940475, and rs11225395 of MMP8 from the MMP (matrix metalloproteinases)/TIMP (tissue inhibitors of MMP) system were significantly correlated with the increased risk of steroid-induced FHN in a study conducted in northern China.¹⁹ Wang et al considered that −1031CT/CC and −863 AC genotypes may be risk factors for FHN in patients with SARS.²⁰

Pros and Cons of Glucocorticoid Therapy

There is no specific drug for the treatment of COVID-19. Fever, cough, and dyspnoea are the most common symptoms of COVID-19. Symptomatic supportive treatment is still the most effective treatment. ARDS is a serious complication of COVID-19 and the use of glucocorticoids in the treatment of severe COVID-19 pneumonia and ARDS is controversial. Herein, we compiled a table including opinions (Table 1) and research details in the treatment of COVID-19 pneumonia and ARDS, and present the points in favour of and against the use of glucocorticoids.

Table 1 Main Characteristics and Findings of the Studies About COVID‐19 Patients Using Steroids

Favor

It is well known that corticosteroids are beneficial in the treatment of ARDS because they reduce inflammation and improve the functioning of the lung and extrapulmonary organs. Experiments on animals have also shown that inhibition of inflammation can improve the prognosis of animals infected with SARS-CoV.³⁶ Russell et al summarised the clinical evidence indicating that corticosteroids can be used in patients with SARS-CoV infection.³⁷ A large number of retrospective studies have also shown that the corticosteroids prescribed to the vast majority of SARS patients may contribute to the regulation of the inflammatory response and treatment of lung injury.³⁸ Chen et al, through a retrospective study of 401 patients with severe SARS, found that the appropriate application of glucocorticoids in patients with severe SARS can significantly reduce mortality and shorten the length of hospital stay.³⁹ A total of 2141 patients with influenza A (H1N1) viral pneumonia from 407 hospitals in China received five kinds of low-dose corticosteroids (25–150 mg/day methylprednisolone or equivalent) which significantly reduced the mortality in patients with PaO₂/FiO₂ < 300 mmHg.⁴⁰ The genome structure, transmission, and pathogenesis of SARS-CoV-2 are similar to those of SARS-CoV. In view of the fact that there is no conclusive evidence at present and there is an urgent need in clinical practice, the National Health Commission of China suggests that methylprednisolone should be used appropriately within a short period of time (3–5 days) onset of pneumonia and at a dose not exceeding 1–2 mg/kg/day. This method may achieve a good therapeutic effect in patients with a strong inflammatory response and acute progression of the disease observed by lung imaging.⁴¹ Extensive inflammation, which is caused by excessive activation of proinflammatory cytokines and chemotaxis of T lymphocytes to the inflammatory site, is the possible mechanism of the chest tightness and dyspnoea in COVID-19. Short-term and low-dose corticosteroid treatment can quickly relieve the symptoms of chest tightness and dyspnoea.⁴² Some scholars believe that this treatment should not be limited to severely ill patients because the early use of corticosteroids can reduce the risk of ARDS in viral infections.⁴³ The utilisation rate of glucocorticoids in COVID-19 patients reported by many hospitals in China was 28.0% to 44.9%,^44–46 and even 70% in some critically ill patients.⁴⁷ This was due to their experience of treating patients with similar medications during the SARS-Co-V epidemic. A retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia at the Wuhan Jinyintan Hospital showed that methylprednisolone treatment may be beneficial to patients with ARDS.⁴⁸ Recent multicentre studies have shown that Early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS.⁴⁹ Although the World Health Organisation (WHO) does not recommend the routine use of glucocorticoids in patients with COVID-19, some scholars believe that the uncertain clinical evidence should not be the reason for abandoning corticosteroids in the treatment of COVID-19. At the very least, corticosteroids can be prescribed to the right patients at the right time. For example, in the context of cytokine storms, if tocilizumab is ineffective, steroid immunosuppression can be considered.⁵⁰ The results of a systematic review and meta-analysis by Yang et al revealed that patients with a severe illness were more likely to need corticosteroid treatment.⁵¹ Therefore, it is suggested that in the treatment of patients with COVID-19, corticosteroids should not be administered to patients with a mild illness but can be used in moderate doses in patients with a severe illness to inhibit the immune response and relieve symptoms.

Opposition

During the SARS outbreak, systemic corticosteroids were widely used. However, a systematic review of the published literature on their application in SARS concluded that the treatment was not beneficial. In Stockman's meta-analysis on the use of steroids in SARS, the idea of using corticosteroids to treat ARDS was conjectured, for 25 studies were inconclusive and only four were conclusive, all of which showed that corticosteroid use was harmful.⁵² Moreover, corticosteroids may damage the innate antiviral immune response. If given before virus replication is controlled, they may delay virus clearance leading to aggravation of the disease and complications of corticosteroid treatment in survivors.^53,54 In Wuhu, corticosteroid therapy is widely used in patients with COVID-19, but there is no evidence of any clinical benefits from its use in patients who do not have ARDS.⁵⁵ In the preliminary data of a COVID-19 retrospective cohort study in China, corticosteroids were used more frequently in patients who died (48%) than in patients who survived (23%).⁵⁶ Some people think that most of the patients in the above studies are critically ill patients with ARDS, and the ability of steroids to improve the (poor) prognosis in such cases is overestimated.⁵⁷ Moreover, health care providers tend to use corticosteroids for the most critical patients. Therefore, the presence of a selection bias and confounding factors may result in a biased conclusion. In the absence of solid scientific evidence, the WHO and Centers for Disease Control and Prevention (CDC) recommend that corticosteroids should not be routinely used in the treatment of viral pneumonia or ARDS in patients with COVID-19 unless otherwise indicated, such as during asthma, exacerbation of chronic obstructive pulmonary disease, or septic shock.³⁷ Zha et al reported that 11 out of 31 patients with COVID-19 received corticosteroid treatment (40 mg methylprednisolone was administered once or twice a day within 24 hours of admission for an average of 5 days). Cox proportional hazard regression analysis showed that there was no correlation between corticosteroid treatment and the virus clearance time, hospital stay, or symptom duration.⁵⁵ In cases where the advantage is uncertain, the complications are definite. In one study, 39% patients with SARS developed FHN within a few months of glucocorticoid treatment.⁵⁸ Furthermore, in another study, some patients who received corticosteroids for less than 4 weeks or received fewer corticosteroids, too, developed FHN.⁵⁹ But some scholars believe that SARS virus itself is an independent factor for the occurrence of femoral head necrosis.¹⁰ Ksiazek shown that SARS virus may directly cause ONFH through S protein.⁶⁰ In addition, we believe that the strong systemic inflammatory response to release a large number of inflammatory mediators, patients with varying degrees of hypoxemia in the course of the disease can also lead to ONFH. COVID-19 patients may also suffer these pathological processes. So, we think it is irrational to deny the positive therapeutic effect of glucocorticoids. At least for those critically ill patients, saving their lives is the most important thing.

In addition, when evaluating the effect of steroid therapy, we should not ignore the role of other confounding factors. Vitamin D3, for example, may have some extra-skeletal effects, especially on the immune system and lung function.⁶¹ The main complication of COVID-19 is ARDS mediated by a variety of mechanisms that may be aggravated by vitamin D deficiency and tapered down by activation of the vitamin D receptor.⁶² Anweiler found bolus vitamin D3 supplementation during or just before COVID-19 was associated in frail elderly with less severe COVID-19 and better survival rate, indicating Vitamin D3 supplementation may be effective for COVID-19 treatment.⁶³

Of course, in addition to causing SANFH, other complications caused by hormones can not be ignored. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing's syndrome, mental disorders and immunosuppression are also serious side effects in the treatment of systemic corticosteroid.⁶⁴ Although high-dose glucocorticoid pulse therapy has a rapid anti-inflammatory effect, it also increases the neutrophil/lymphocyte ratio and D-dimer level, increasing the risk of thromboembolism.⁶⁵ For newly diagnosed diabetic patients, frequent use of glucocorticoids may exacerbate hyperglycemia.⁶⁶ Obata et al found that the bacterial infection rate (25%/13.1%, P = 0.041) and fungal infection rate (12.7%/0.7%, P < 0.001) during hospitalization in steroid group were significantly higher than those in non steroid treatment group.²² There have also been reports about glucocorticoid caused bacterial endocarditis, strongyloides or amebic infections that can progress to catastrophic complications in patients with COVID-19 pneumonia.^67,68

Glucocorticoid Usage

The sequelae of SARS are closely related to the dosage of the hormone, duration of hormone use, sensitivity of patients to the hormone, and method of administration.⁶⁹

Maximum Daily Dose

In one study, logistic regression analysis showed that there was a correlation between the maximum daily dose of glucocorticoids and FHN, suggesting that adequate control of the maximum daily dose is necessary.⁷⁰ Motomura et al treated rabbits with 1 mg/kg, 5 mg/kg, 20 mg/kg, and 40 mg/kg methylprednisolone; the incidence of osteonecrosis was 0%, 42%, 70%, and 96%, respectively.⁷¹ By comparison (5 mg/kg/day vs 1 mg/kg/day), Marsh et al found that osteonecrosis only occurred in the 5 mg/kg/day group.⁷² Massardo et al reported that a dose of prednisone greater than 40 mg/day was positively correlated with osteonecrosis,⁷³ and the incidence rate increased by 3.6% for every 10 mg increase in the dose.⁷

Cumulative Dose

In a retrospective study of 539 SARS patients treated with corticosteroids, the increased incidence of FHN was associated with the total dose of corticosteroids.⁷⁴ Griffith et al reported that the risk of FHN was 0.6% in patients receiving less than 3 g of prednisolone equivalent dose and 13% for doses greater than 3 g.⁷⁵ Zhao et al observed a nonlinear relationship between the cumulative dose and osteonecrosis. When the total dose of methylprednisolone was less than 5 g, the risk of osteonecrosis was still relatively low. However, as the total dose increased from 5 g to 10 g, the risk of osteonecrosis increased. The risk seemed to be the highest when the total dose was about 10 g to 15 g. It is considered that a low cumulative dose of corticosteroids (methylprednisolone < 5 g) is relatively safe for patients with SARS. Doctors should avoid using high-dose corticosteroids, especially those with cumulative doses > 10 g.⁷⁶ A study by Rademaker et al suggested that 700 mg prednisolone was the threshold for the occurrence of femoral head necrosis.⁷⁷ Michael et al suggested that cumulative doses > 2000 mg of methylprednisolone, > 1900 mg of hydrocortisone, > 1340 mg of hydrocortisone equivalent, and > 13,340 mg of corticosteroid therapy were risk predictors of osteonecrosis.⁷⁸

Duration of Medication

Zhao et al reported that the incidence of osteonecrosis was closely related to the duration of treatment in 1137 patients with SARS. The rate ratio (RR) of osteonecrosis was 1.29 (95% CI 1.09–1.53, P = 0.003) for every 10 days of treatment. The relationship was nonlinear. They also asserted that it was important to reduce the risk of osteonecrosis by modifying the duration of corticosteroid treatment.⁷⁶

Individual Differences

Li et al conducted a comprehensive investigation on the bone and joint complications of patients with SARS and found that approximately 30% of patients had osteonecrosis, but the remaining patients (about 70%), who were infected with the same type of pathogens, did not show any complications with the same corticosteroid regimen,⁷⁹ indicating that there were differences in patients' susceptibility levels. Shigemura et al found that age was a risk factor, and the risk of osteonecrosis in adolescents and adults was significantly higher than that in children.⁸⁰ Zhao et al found that there was no significant difference in the risk based on sex (RR 0.01, 95% CI 0.03–0.06, P = 0.582).⁷⁶ Kerachian et al suggested that the difference in the incidence rate may depend on the duration of medication, dosage, or some potential diseases.¹⁵

Timing of Medication

The timing of glucocorticoid administration is very important for the prognosis of critically ill patients. Premature administration of glucocorticoids can inhibit the initiation of immune defence mechanisms, thus increasing the viral load and eventually leading to adverse consequences. Timely administration of glucocorticoids in the early stage of the inflammatory cytokine storm can effectively prevent the occurrence of ARDS.⁸¹ The clinical features of this period are the rapid progress of inflammatory infiltration and a deterioration in the level of oxygenation. In other words, if there is a significant progression of the lung lesions within 48 hours in mildly ill patients, glucocorticoid treatment can be considered to prevent untoward developments in these patients.⁸²

Righteous Usage

With the increase in treatment doses and duration of glucocorticoids, the probability of developing obvious side effects is also increasing. Therefore, short-term and low-dose treatments should be used. Zhao et al considered that a cumulative dose of methylprednisolone < 5 g and course of treatment < 30 days were associated with a relatively low risk of osteonecrosis.⁷⁶ According to Shanghai's experience in treating COVID-19 patients, the initial dose of methylprednisolone was 40–80 mg/day for 3 days which was gradually reduced to 20 mg/day. The total treatment duration was less than 7 days. The safety of this dose was satisfactory.⁸² However, it has also been reported that even low-dose or short-term glucocorticoid therapy can cause FHN,⁸³ and the above protocol was not followed up. Yang et al found that intermittent treatment is less likely to cause osteonecrosis in mice than continuous dexamethasone treatment. This "steroid vacation" method may be used for reference in clinical use.⁸⁴

Post Glucocorticoid-Use Plan

Diagnosis

Early diagnosis is necessary for timely treatment because the treatment options for advanced disease are limited and many patients of FHN are young and active individuals. Regular hip monitoring via magnetic resonance imaging (MRI) should be carried out in high-risk patients as it has a sensitivity of 93 to 100%.⁸⁵ Zhao et al emphasised the importance of regular screening via MRI. It was found that in 23 patients with a confirmed diagnosis of FHN, if MRI was only performed 2 to 3 months after hormone treatment, the diagnosis in 21 patients would be missed.⁸⁶ The reported onset time of FHN after glucocorticoid use is from 3 weeks to 3 months.^87,88 Diffusion-weighted MR images revealed that the diffusion of FHN was significantly enhanced, which can provide additional information to aid diagnosis.⁸⁹ Because the clinical manifestations appear later than the imaging examination findings, 78.82% of glucocorticoid-induced FHN patients complain of pain within 3 years after the commencement of steroid treatment and 10.41%, within 6 years or more. The diagnosis of glucocorticoid-induced FHN mainly depends on imaging examination. MRI should be performed 3, 6, and 12 months after steroid administration.⁹⁰ Ren et al suggested that ten main metabolites containing phosphatidylcholine are closely related to the early changes of steroid-induced FHN. If the clinical symptoms and imaging changes are not obvious, the ten metabolites can be used to monitor steroid-induced FHN 1 week later.⁹¹ Sun et al pointed out that plasminogen activator inhibitor type 1 (PAI-1) is a sensitive haemogram for screening high-risk and susceptible populations.⁹² In addition, serum levels of complement 3 (C3), C4, inter-alpha-trypsin inhibitor heavy chain H4, and α-2 macroglobulin may also be potential biomarkers for diagnosing FHN.⁹³ Wei et al found that serum miR-423-5p in patients with steroid-induced FHN was significantly increased, suggesting a potential role in its diagnosis.⁹⁴

Treatment

Without treatment or intervention, FHN may become an irreversible process. Some medications such as lipid-lowering drugs, anticoagulants, vasodilators, and traditional Chinese medicines can reduce the chances of developing necrosis. Levodopa can reduce osteocyte apoptosis and promote the repair of necrotic zones by promoting the synthesis and release of insulin-like growth factor-1 (IGF-1).⁹⁵ Alendronate sodium can prevent and delay the progression of FHN by inhibiting the bone resorption capacity of osteoclasts and accelerating the apoptosis of osteoclasts.⁹⁶ Pilose antler extract can regulate the expression of 11β-hydroxysteroid dehydrogenase (11 β-HSD) in rabbits' femoral heads and osteoblasts, and promote the proliferation of osteoblasts.⁹⁷ Camporesi et al conducted a 7-year follow-up of patients with SANFH. The results showed that hyperbaric oxygen (HBO) treatment for 6 weeks significantly improved the clinical symptoms in SANFH patients. The HBO environment increases the oxygen concentration in the blood and reduces bone marrow oedema. In addition, it also promotes angiogenesis as well as the function of osteoblasts and osteoclasts and provides the necessary preconditions for the treatment of SANFH.⁹⁸ Koren et al considered HBO to be an effective method for the treatment of Association Research Circulation Osseous I and II (ARCO I and II) FHN in a study in which the patients were followed up for 11.1 ± 5.1 years.⁹⁹ But the high cost of HBO treatment may be an important prohibitive factor. Experiments on animals have revealed that pulsed electromagnetic field stimulation can prevent SANFH in rats, and its mechanism may be related to the decrease in blood lipid levels and increase in transforming growth factor beta-1 (TGFβ-1) expression.¹⁰⁰ Ludwig et al reported that extracorporeal shock wave therapy (ESWT) of 1-year duration significantly reduced pain and improved hip joint function, which was suitable for patients with ARCO I to III FHN. ESWT induces neovascularization and improves the blood supply to the femoral head by enhancing the expression of vascular endothelial growth factor (VEGF) in the femoral head.¹⁰¹ Liu et al retrospectively studied the long-term efficacy of combined therapy (alendronate sodium, ESWT, and HBO) in 37 patients with SANFH from 2003 to 2015. After 12 years of follow-up, it was found that comprehensive treatment can delay or prevent the development of SANFH after SARS. The combined treatment had different effects on FHN patients with different ARCO stages, and the greatest benefits were seen in patients with FHN ARCO I.¹⁰² Xie et al found that although most patients received ESWT, HBO, or traditional Chinese medicine to promote local blood circulation, these methods had no obvious short-term effects on the recovery of the femoral head.⁵ At present, significant progress has been made in the discovery of new ideas for treatment. Yang et al reported that the expression of gene COL5A2 was low in patients with SANFH; hence, COL5A2 may be a promising target in the treatment of SANFH.¹⁰³ Alpha‑2‑macroglobulin (A2MG) is involved in many mechanisms of SANFH including coagulation, hyperlipidaemia, and free radical and MMP degradation.⁹³ The results of real-time quantitative polymerase chain reaction (RQ-PCR) in a study showed that the level of serum A2MG in SANFH patients was significantly lower than that in the control group (P < 0.05). Immunohistochemical staining and Western blotting showed that the expression of A2MG in the necrotic area of patients with SANFH was significantly reduced (P < 0.05). Therefore, A2MG may become the new target in the treatment of SANFH.¹⁰⁴

Conclusion

Even though there is a debate on the pros and cons of using steroid, from the perspective of orthopaedics, it is an indisputable fact that long-term and high-dose steroid use leads to ONFH. Therefore, we call for judicious use of corticosteroids in the treatment of COVID-19 patients and do not recommend it as a routine treatment. For patients who have received corticosteroid treatment, bisphosphonates, anticoagulants, vasodilators, and traditional Chinese medicine combined with ESWT, HBO, and other physical therapies can be considered. We reiterate the importance of regular screening in high risk patients, especially those on long-term steroids. MRI is the best tool for early detection of SANFH, and clinicians must take efforts to improve aware ness regarding the prevention of SANFH. A high index of suspicion is necessary for patients complaining of bone and joint pain at typical sites. Patients suspected of having SANFH should be referred to orthopaedic doctors in the early stages, and clinicians should try to delay the progression of osteonecrosis to prevent FHN from affecting the daily life of patients.

Abbreviations

COVID-19, coronavirus disease 2019; SARS, severe acute respiratory syndrome; ARDS, acute respiratory distress syndrome; CoV, coronavirus; SANFH, steroid-induced avascular necrosis of the femoral head; ONFH, osteonecrosis of the femoral head; IFN-γ, interferon gamma; TNF, tumor necrosis factor; IL-1, interleukin-1; IL-6, interleukin-6; BMSCs, bone marrow stromal cells; miR, microRNA; HBO, hyperbaric oxygen; ARCO, Association Research Circulation Osseous; ESWT, extra-corporeal shock wave therapy; MMP, matrix metalloproteinases.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Role of the Funding Source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure

The authors report no conflicts of interest in this work.

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The Cardiac Implications of COVID-19 - News-Medical.net

Posted: 03 Mar 2021 07:27 AM PST

Although COVID-19 is primarily a respiratory condition, many patients may suffer from cardiovascular consequences which range from arrhythmia to heart failure, especially in those with pre-existing cardiovascular diseases and advanced age. Understanding the mechanisms behind why cardiovascular consequences are higher in COVID-19 compared to flu is important in bettering our understanding of the disease and how to treat it effectively.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection typically results in either asymptomatic or mild-moderate COVID-19 severity in the vast majority of people. However, in specific age groups (especially those over 65) and those with pre-existing health conditions (including cardiovascular diseases, diabetes, hypertension, etc), the risk of severe disease is much higher and can require intensive care unit admission in hospital, or in some cases death.

COVID-19

Image Credit: Andrii Vodolazhskyi / Shutterstock.com

Cardiovascular/cardiac implications in COVID-19

In severe disease, multi-organ system failure and acute respiratory distress syndrome (ARDS) can lead to death. At the center of the most severe clinical manifestation of COVID-19 is the presence of substantially elevated cytokines (cytokine-release syndrome) which include granulocyte colony-stimulating factor (GCSF), interferon-inducible protein 10, macrophage inflammatory protein-1A and tumor necrosis factor (TNF)-alpha. In addition, those who have myocardial injury also show substantially elevated interleukin-6 (IL-6) levels, suggesting the severity of disease corresponds to the levels of circulating cytokines.

As discussed, the severity of the disease may be related to the levels of cytokines circulating in patients which can lead to an array of multi-organ damage, including to the heart and cardiovascular system. Specifically, cytokines acting on the heart can lead to stress cardiomyopathy and/or cytokine-related myocardial dysfunction in the most severe cases of COVID-19.

A key component that is implicated in cardiovascular dysfunction in COVID-19 is the renin-aldosterone-angiotensin system (RAAS). SARS-CoV-2 binds to ACE2 receptors in the body which in turn leads to a downregulation of ACE2 receptors. This downregulation of ACE2 can lead to decreased rates of the conversion of angiotensin II (ATII) to angiotensin I (ATI) which leads to elevated levels of ATII that can have a direct effect on the cardiovascular system such as increased sympathetic activity, vasoconstriction, aldosterone secretion (causing renal sodium and water reabsorption), pulmonary vascular permeability, and fibrosis.

COVID-19 in patients with cardiovascular disease

One of the biggest risk factors for severe COVID-19 and fatality from COVID-19 is cardiovascular disease comorbidity. For example, out of nearly 45,000 patients in China (case-fatality rate of 2.3%), the highest mortality rates were in patients with cardiovascular disease (10.5%), followed by diabetes (7.3%) and hypertension (6%), and these effects were similarly observed in Italy.

A majority of patients with cardiovascular disease tend to be older (over the age of 65), where most of the deaths from COVID-19 occur. Furthermore, 2 or more comorbidities are usually present in many patients with cardiovascular disease, including hypertension and diabetes which increase the risk of severe disease and death substantially, combined with advanced age. Patients with heart failure and diseases such as ischaemic heart disease may suffer from potentially severe and devastating cardiac implications with COVID-19.

The causes of mortality in hospitalized COVID-19 patients with pre-existing cardiovascular disease can be attributed to several different factors, including those mentioned previously. Several studies have shown that elevated troponin levels are associated with severe disease and mortality from COVID-19. Elevated troponin levels are associated with myocarditis, systemic infection and cytokine storm, arrhythmias and ischemia. Thus, troponin and cytokine measurements may serve to be crucial prognostic markers in disease outcomes.

Patients with pre-existing cardiovascular diseases (especially heart failure) are at an increased risk of severe disease and mortality from COVID-19 (especially older patients), but COVID-19 may also cause the development of new cardiovascular implications (including cardiomyopathy/myocarditis) in patients without pre-existing cardiovascular diseases.

These may be related to cytokine storm levels causing systemic damage (severe disease), or perhaps even direct SARS-CoV-2 infection of cardiac tissues. Whilst this is rare in healthy younger individuals, older patients with other comorbidities may be at an increased risk of developing new cardiac implications from COVID-19.

For example, patients with COVID-19 have a higher incidence of arrhythmias such as long-QT syndrome and torsades des pointes (found in many COVID-19 patients who die) which may be caused by metabolic abnormalities including cytokine storms, hypoxemia and acidosis. Many of these patients also have elevated troponin levels, thus serum measurements of troponin and other cytokines are an excellent prognostic tool in patients with severe COVID-19, and for assessment of cardiac conditions such as myocarditis.

Management of pre-existing comorbidities (health conditions) such as the aggressive treatment of heart failure, cardiac and cardiovascular diseases is important in reducing the risk of severe COVID-19 complications and mortality. These include antiarrhythmics (for arrhythmias/atrial fibrillation/tachycardia), vasopressors/diuretics (heart failure/cardiogenic shock), statins/heparin/beta-blockers (coronary syndromes) and thrombolysis (in pulmonary embolism).

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Flu vs COVID-19

Compared to flu, COVID-19 has a higher case mortality rate (CMR) in addition to a higher prevalence of complications in COVID-19 compared to flu, especially in patients with pre-existing cardiovascular disease. However, this information must be taken with caution as testing for seasonal flu and reporting to health authorities is done in a limited way compared to COVID-19 and different health authorities have different ways of reporting death from both diseases.

Despite that, many countries have used these statistical parameters to compare between COVID-19 and flu. In China, official statistics place COVID-19 to have almost 15 times higher CMR compared to flu. Furthermore, deaths in patients with cardiac abnormalities/cardiovascular diseases and COVID-19 are substantially higher than the same existing comorbidities in flu. It is important to note that cardiac diseases predispose more severe disease and risk of death (primarily from myocarditis) in both flu and COVID-19, but the rates are higher in COVID-19 compared to flu.

Summary

In summary, people with pre-existing cardiovascular and cardiac diseases are at an increased risk of more severe disease and mortality from COVID-19 as they would be from flu also. However, compared to flu, COVID-19 has a higher death rate for patients with cardiovascular diseases.

Such patients should be very cautious in preventing getting infected (e.g., shielding), and should ensure they stay on top of medications and treatments, especially in the context of heart failure. Cytokine storms and troponin levels may be important pathological and prognostic markers in severe COVID-19 and could serve to be important treatment targets.

References

1 INTRODUCTION

COVID‐19 has been declared a global pandemic by the World Health Organization.¹ The global number of infections, as of December 23, 2020, stood at approximately 79 million, with over 1.7 million deaths. The level of contagiousness of SARS‐CoV‐2 appears to be higher than that of other coronavirus outbreaks, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). This contagiousness may explain the rapid spread of the virus and the danger it poses, especially to the weakest groups of the population, such as the elderly. In Italy, as of December 9, 2020, there had been more than 60 000 deaths, with a lethality rate of 3.5%, second only to that of Mexico and Iran, and on a par with Great Britain. A high risk of death is present in patients with comorbidities; and age is emerging as the strongest predictor of death related to COVID‐19,² which highlights the vulnerability of elderly patients to emerging diseases. The demographic projections of the United Nations indicate that in three decades, the number of people over 65 years will more than double that of children younger than 5 years.³ In Italy, the lethality rate according to age group, as described by the Istituto Superiore di Sanità (ISS) document, "Cumulative Data of the Integrated Surveillance of the Istituto Superiore di Sanità," goes from 0.19% in those aged 40‐49 years, to 2.97% in those aged 50‐59 years, 10.23% in those aged 60‐69 years, 16.17% in those aged 70‐79 years, 19.03% in those aged 80‐89 years, and about 25% in those aged ≥90 years. According to the ISS infographic, "Characteristics of Patients Who Died Positive for SARS‐CoV‐2 Infection in Italy," updated on December 2, 2020, the average age of patients who have died with a positive result for SARS‐CoV‐2 is approximately 80 years and is 30 years higher than the average age of patients who have contracted the infection. With aging, age‐associated health conditions, particularly non‐communicable diseases (such as cardiovascular disease, neoplasms, and metabolic and autoimmune diseases) combined with treatments for these diseases and immune senescence, can substantially influence responses to infectious diseases and vaccines.⁴ It is therefore essential to identify these patients to ensure their protection through effective prevention, treatment, and monitoring procedures. Initially, COVID‐19 disease was identified as a disease involving the respiratory tract, with the possibility of progressing to severe interstitial pneumonia and acute respiratory distress syndrome (ARDS) (R. Costa, A. Castagna, & G. Ruotolo, Personal Considerations). Ever increasing data highlight the possibility that in addition to the lungs, the heart is also a possible target of the coronavirus. In fact, the complications of COVID‐19 that lead to death are mainly respiratory failure (94.1%), acute kidney damage (23.6%), superinfections (19.3%), and acute myocardial damage (10.8%) and cardiovascular diseases seem to represent a multiplier of the risk of death in case of infection with COVID‐19.^{2, 5, 6}

2 COVID‐19, ARTERIAL HYPERTENSION, AND THE AGED

The COVID‐19 pandemic and earlier coronavirus outbreaks have been associated with ARDS as well as worse outcomes in older patients.^{7, 8} Cardiovascular disease and the presence of hypertension are consistently reported as more common factors among patients with COVID‐19 who have had severe disease, been hospitalized in intensive care, received mechanical ventilation, and/or died compared to COVID‐19 patients who have had mild disease.⁹ Acute respiratory infections are associated with an elevated risk of cardiovascular death, especially in the weeks immediately following infection, and particularly in elderly patients and those with preexisting cardiovascular disease. The severity of pneumonia in these patients is linked with an increased risk of death. COVID‐19 and other coronaviruses show tropism for angiotensin‐converting enzyme 2 (ACE2) on type II pneumocytes. This tropism, the close anatomical juxtaposition of type II pneumocytes and the pulmonary vascular network, and a severe multifaceted inflammatory reaction, is likely to drive the generalized pulmonary hypercoagulable state seen in patients with COVID‐19.^{10, 11} SARS‐CoV‐2 as well as other coronaviruses can utilize angiotensin‐converting enzyme 2 (ACE2) protein for entry into cells.^12-15 ACE2 is a type I integral membrane protein that performs many important physiological functions: it is a counter‐regulator to the angiotensin II activity generated through ACE1 and is protective against the harmful activation of the renin‐angiotensin‐aldosterone system; and it degrades angiotensin II into angiotensin (1‐7), which exerts vasodilatory, anti‐inflammatory, antifibrotic, and antigrowth effects.¹⁶ In studies performed in humans, tissue samples from 15 organs showed that ACE2 is widely expressed, including in the heart and kidneys, as well as in the lung, where it plays a protective role; the lung is also the main site of entry for SARS‐CoV‐2 in the human host,^12-16 that is, the lung alveolar epithelial cells.^{17, 18} It has also been shown that the binding of glycoprotein with viral peaks to the ACE2 receptor leads to its downregulation with compromise of a pulmonary protective pathway and consequent lung damage during SARS‐CoV infection, contributing to viral pathogenicity.¹⁸ Downregulation of ACE2 causes excessive angiotensin (ANG) II production by the ACE enzyme correlated with ANG receptor type 1a (AT1R) stimulation and increased pulmonary vascular permeability, facilitates initial infiltration of neutrophils in response to bacterial endotoxin,^{19, 20} and can cause an uncontested accumulation of angiotensin II and local activation of the renin‐angiotensin‐aldosterone system (RAAS). Experimental data on rats showed that ACE2 expression decreases dramatically with aging²¹; this could provide an explanation for how the differential levels of ACE2 in the heart and lung tissues of the elderly versus the young, together with comorbidities and an impaired immune system, may favor the different spectrums of disease virulence observed among patients with COVID‐19. The interaction between SARS viruses and ACE2 has led to a debate on the potential use of RAAS blockers in the context of the pandemic, as these drugs are able to influence the expression of ACE2, being able to promote the virulence of the disease.^22-24 Contrary to available animal models, there are few human studies regarding the effects of RAAS inhibition on ACE2 expression. Data on the effects of RAAS inhibitors on lung‐specific ACE2 expression are lacking, and further mechanistic studies in humans are also lacking. It is necessary to better define the unique interaction between SARS‐CoV‐2 and the RAAS network.²⁵ Moreover, to date, no meta‐analysis of randomized and controlled studies has ever shown an excess of infectious and/or inflammatory pathologies, or mortality, with ACE inhibitors or with sartans.^26-29 Therefore, in relation to their respective positions, the European Society of Cardiology (https://www.escardio.org/Councils/Council‐on‐Hypertension‐(CHT)/News), the American Heart Association (https:/www.heart.org/en/about‐us/coronavirus‐covid‐19‐resources), the Italian Society of Cardiology (https://www.sicardiologia.it/public/Documento‐SIC‐COVID‐19.pdf), the Italian Society of Arterial Hypertension (https://siia.it/), and the Italian Society of Pharmacology (https://www.sifweb.org) believe that the suspension, albeit temporary, of ACE inhibitors or sartans in all patients who are taking them in order to prevent future SARS‐CoV‐2 infection is not supported by convincing scientific evidence. In patients with active infection, in whom there are clear indications for the continuation or initiation of treatment with ACE inhibitors or sartans, no definitive epidemiological data are available, nor that derived from animal models or from controlled clinical studies to support the decision to renounce, even temporarily, the use of these drugs, an event that could cause clinical instability and adverse health events.²³

3 COVID‐19, COMORBIDITIES, CARDIOVASCULAR DISEASE, AND COAGULOPATHIES IN THE ELDERLY

Italian data also indicate a high risk of death in COVID‐19 patients with comorbidities.³⁰ The development of vascular inflammation may also contribute to a hypercoagulable state and endothelial dysfunction in such patients. It is known that multi‐organ damage is more likely in patients with sepsis if they develop coagulopathy and that inhibition of thrombin synthesis can have a positive impact in reducing mortality. The International Society on Thrombosis and Haemostasis has provided recommendations³¹ based only on some evidence indicating that a markedly increased D‐dimer value, particularly in patients who develop D‐D with thrombotic phenotype, is associated with high mortality in SARS‐CoV‐2‐infected patients. Chronic cardiovascular disease may become unstable in the setting of viral infection as a consequence of imbalance between infection‐induced increase in metabolic demand and reduced cardiac reserve. The clinical manifestations of COVID‐19 can range from the asymptomatic positive subject to subjects with mild symptoms (such as fever, altered taste or smell, and dry cough), or to more severe forms, such as bilateral pneumonia, systemic inflammation, altered endothelial function, coagulopathy, activation platelet, ARDS, and multi‐organ failure. The troponin increase can be present in up to 25% of hospitalized patients,³² in some cases secondary to myocardial infarction, in others to myocarditis, venous thromboembolism, disseminated intravascular coagulation, specifically referred to as COVID‐19 Induced Coagulopathy (CIC).³³ Thrombo‐embolic episodes can in turn be caused by hypoxia secondary to SARS‐Cov19 infection, through the triggering of circulating immune complexes. In some patients with aberrantly activated hemocoagulation cascade, positivity was found for antibodies of the IgG and IgA class anticardiolipin and anti‐B2‐glycoprotein, suggesting that these antibodies may play a role in the abnormal activation of the hemocoagulation cascade.³⁴ The most severe cases of COVID‐19‐associated interstitial pneumonia evolve with inflammatory alveolar edema (non‐cardiogenic pulmonary edema), reduced lung compliance with reduced gas exchange, and severe hypoxemia, meeting the criteria for ARDS³⁵; these are cases in which mechanical ventilation is necessary.³⁶ The development of ventilation‐perfusion mismatch, with consequent intrapulmonary shunt (Qs/Qt), secondary to the presence of poorly ventilated lung regions, favors the severe hypoxemia found in these patients.³⁷ The advanced manifestations of SARS‐Cov‐2 infection have different characteristics from classical ARDS, which is particularly relevant for pulmonary circulation. These would consist of increased hypercoagulability, with phenomena of vascular thrombosis in situ, attenuated hypoxic pulmonary vasoconstriction, and pulmonary vascular remodeling.³⁸ The combination of diffuse pulmonary immunothrombosis related to SARS‐Cov19 infection, a pathophysiological model of pulmonary intravascular coagulopathy, and age‐related changes in immunity, may explain the cardiovascular mortality in these patients. In some deceased patients, an increased capillary neoangiogenesis due to vascular intussusception, different from angiogenesis by budding by marked increase in the capillary surface, observed in other forms of ARDS, such as that of H1N1,³⁹ would have been highlighted as an autopsy finding, and favored from the expression of pro‐angiogenic genes and from the high local blood flow.⁴⁰ Direct viral damage at the endothelial level, both at the level of the pulmonary and peripheral circulation, is certainly decisive in the activation of coagulation.⁴¹ Hypoxia can change the basal anti‐inflammatory and antithrombotic phenotype of the endothelium towards a pro‐inflammatory and pro‐coagulant phenotype through the expression of pro‐coagulating factors induced by hypoxia, as reported in other forms of ARDS.⁴² Fever, diarrhea, and dehydration, often present in COVID‐19, can aggravate the picture described above. These data suggest that their identification in critically ill patients, who already have several risk factors for thrombosis, may be important in recommending an early start of anticoagulation therapy. Moreover, the use of low molecular weight heparin in addition to protecting critically ill patients from thromboembolism has been shown to possess anti‐inflammatory properties: based on the immunothrombosis model, which highlights a bidirectional relationship between the immune system and thrombin generation, blocking thrombin from heparin can dampen the inflammatory response.⁴³ During COVID‐19, extrapulmonary complications have been highlighted, including cardiac involvement, which can reach affect 20% of cases.^{32, 44} An acute cardiovascular syndrome has recently been defined, with clinical pictures accumulated by the occurrence of acute myocardial damage. The prevalence rates of acute myocardial damage and troponin increase are far higher in COVID‐19 patients admitted to intensive care^{45, 46} and in those who do not survive.⁴⁴ Furthermore, in patients with acute myocardial injury and troponin increase, the death rate is high, in the order of 50%‐60%.^{32, 47} The increase in troponin is considered a marker of disease severity and poor prognosis, probably as it expresses the presence of systemic damage in the COVID‐19 patient.⁴⁸ Therefore, the prognostic significance of a slight increase in this marker may be uncertain, especially in intubated and elderly patients. Some authors suggest extensively evaluating troponin to identify patients at greater risk early,⁴⁹ but there is no unanimous agreement on this aspect.⁵⁰ ProBNP and CK‐MB were also considered markers of myocardial damage. NT‐proBNP is postulated to increase the risk of heart failure in patients with COVID‐19.⁵¹ A meta‐analysis also showed the possibility that NT‐proBNP was independently associated with mortality after adjustment to troponin and creatine kinase myocardial band.⁵² In cases with an infectious outcome, the median time to onset of acute myocardial damage is 14.5 days. A slight progressive increase in troponin was observed in these patients up to Day 16, after which it rapidly increased.⁴⁴. In other circumstances, troponin, which is normal on admission, has been observed to increase in the week before death⁵³ Still other authors have shown an early increase in the marker of myocardial damage from the early stages of the disease⁵⁴ These data reinforce the hypothesis that the increase in troponin, while representing the presence of myocardial damage, would seem to be mainly evidence, in patients with COVID‐19, of the severity of the generalized (systemic) disease.⁴⁸ The mechanisms of myocardial damage could be manifold. A possible mechanism could be direct heart damage secondary to the stimulation of the angiotensin 2 converting enzyme (ACE2), present on vascular endothelial cells and myocytes, which would act as a receptor for SARS‐Cov‐2.⁶ A second mechanism could be macro‐ and microcirculatory thrombosis, which can also be correlated to a state of hypercoagulability observed in some patients.⁵⁵ A further hypothesized mechanism is that related to the systemic inflammatory response mediated by the release of cytokines, the so‐called "cytokine storm."⁶ Cytokine storm and cytokine release syndrome are life‐threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune‐cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.⁵⁶ A complex, interconnected network of cell types, signaling pathways, and cytokines is involved in cytokine storm disorders. Interferon‐γ, interleukin (IL)‐1, IL‐6, tumor necrosis factor (TNF), and IL‐18 are key cytokines that often have elevated levels in cytokine storm and are thought to have central immunopathologic roles. Serumcytokine levels that are elevated in patients with COVID‐19‐associated cytokine storm include those of IL‐1β, IL‐6, IP‐10, TNF, interferon‐γ, macrophage inflammatory protein 1α and 1β, and vascular endothelial growth factor.^{45, 57} Higher IL‐6 levels are strongly associated with shorter survival.⁵⁸ Left ventricular dysfunction can present in different forms. Ventricular stress dysfunction, known as Takotsubo syndrome and so far highlighted in a few cases by SARS‐Cov‐2 infection, presents on echocardiography with the typical contraction of the left ventricle with systolic apical ballooning and was confirmed on coronary angiography, which did not highlight significant coronary stenosis. Several pathophysiological mechanisms involved in the genesis of myocardial damage in COVID‐19 appear to be involved in the development of the syndrome in these patients, especially those related to microcirculatory dysfunction, excessive sympathetic stimulation, and cytokine storm.⁵⁹ Currently there are just over 10 clinical cases of myocarditis related to SARS‐Cov‐2 infection,⁶⁰ some with evidence of marked depression of contractility^60-65 and others with preserved function; one case has buffering pericardial effusion.⁶⁶ Myocardial dysfunction secondary to dysregulation of the cytokine system, also common to other serious pathological conditions, such as septic shock and myocardial infarction, could develop in patients with COVID‐19. The mechanisms of cytokine‐induced ventricular dysfunction are unknown; it is possible, however, that an excess of pro‐inflammatory mediators, such as IL‐6, interfere with the activity of calcium channels, resulting in a contractile depression of myocytes.⁵⁵ Also, nitric oxide and mitochondrial dysfunction could play a role in the development of myocardial contractile dysfunction,⁵⁵ which can be diffuse or regional and reversible. From a phenotypic point of view, left ventricular dysfunction due to dysregulation of the cytokine system does not have characteristic morphological elements, such as the apical ballooning of stress‐induced ventricular dysfunction, but can lead to widespread or regional impairment of myocardial function and can be reversible. Furthermore, in a series on 105 consecutive patients,⁶⁷ 30% of whom were intubated and mechanically ventilated, it was observed that the right ventricle underwent dilation and hypokinesia in about 31% of cases; and some of them showed pulmonary embolism. In multivariate analysis, right ventricular dilation was the only variable significantly associated with mortality. Finally, in a recent series of patients with COVID‐19 pneumonia, the independent predictors of in‐hospital mortality were troponin I values, arterial oxygen saturation at the entrance, mean pulmonary arterial pressure, and tricuspid annular plane systolic excursion.⁶⁸ Further revealing information capable of predicting mortality risk independently and incrementally in these patients may also derive from the longitudinal strain of the right ventricle.⁶⁹

4 COVID‐19 AND ARRHYTHMIAS

Although the data on the prevalence are scant and the exact contribution of COVID‐19 to cardiac arrhythmias remains uncertain, heart rhythm disturbances and sudden cardiac death are among the manifestations of COVID‐19. Patients with SARS‐Cov‐2 infection may have arrhythmias due to a variety of mechanisms, which are mutually interrelated and inter‐facilitated. Palpitations were reported as a major symptom related to SARS‐Cov‐2 infection in patients without fever or cough. Abnormal heart rate has been described in approximately 6%‐7% of hospitalized individuals with suspected COVID‐19.⁷⁰ Sinus tachycardia is the most frequently encountered COVID‐19‐associated arrhythmia.⁷¹ Prolonged QTc intervals have also been reported.⁷² In an Italian multicentric, cross‐sectional, retrospective analysis of 431 consecutive hospitalized COVID‐19 patients who died or were treated with invasive mechanical ventilation, the electrocardiogram was abnormal in 93% of the patients and atrial fibrillation/flutter was detected in 22% of the patients. Electrocardiogram signs suggesting acute right ventricular pressure overload were detected in 30% of the patients.⁷³ High prevalence of arrhythmia might be, in part, attributable to metabolic disarray, hypoxia, or neurohormonal or inflammatory stress in the setting of viral infection in patients with or without prior CVD.^{74, 75} In addition to acquired arrhythmias, it is believed that patients with inherited arrhythmogenic cardiomyopathies, such as short QT and long QT syndrome, Brugada syndrome, and catecholaminergic polymorphism, are believed to be more susceptible to pro‐arrhythmic effects of SARS‐Cov‐2, such as stress, fever, use of antiviral drugs, and electrolyte disturbance,⁷⁶ a condition that must be taken into account in the overall treatment of these patients.

5 CONCLUSIONS

Diseases with pandemic potential, transmitted by vectors and favored by climate change, can put global health at risk, especially the health of the most fragile sections of the population, such as the elderly, who suffer from multimorbidity and who make up an increasing proportion of the population. The pandemic underway, at the root of an unprecedented crisis, forces us to think now about the best way to manage the care of the sick elderly, for the good of all, also in consideration of the costs and stresses for the health systems. Outlining the principles of effective immunity in the elderly will allow us to develop new strategies for wider disease prevention and control in older populations. The protection of this segment of the population will be a key issue, probably of primary interest to all. Biomarkers appear to be extremely useful as an indication of what is happening from a pathophysiological point of view in the heart, allowing us to better stratify the prognosis of our patients affected by COVID‐19, especially in the most severe cases and those with comorbidities.

ACKNOWLEDGEMENTS

No funders had a role in writing this review or in the decision to submit for publication.

CONFLICT OF INTEREST

The authors report no competing interests.

AUTHOR CONTRIBUTIONS

Conceptualization: R.C., A.C., and G.R. Data curation: R.C., A.C., and G.R. Formal analysis: R.C., A.C., and G.R. Writing and original draft preparation: R.C., A.C., and G.R. Writing, review, and editing: R.C., A.C., and G.R. Supervision: G.R. All the authors agreed on the final text.

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