Covid-19: Cardiology

Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts

Nicin L, Abplanalp WT, Mellentin H et al

European Heart Journal, 2020, Apr 15 ehaa311   doi: 10.1093/eurheartj/ehaa311

Angiotensin-converting enzyme 2 (ACE2) has been identified as a potential receptor for SARS coronavirus and is also considered the main receptor for SARS-CoV-2 (Covid-19). SARS-CoV-2 binds to ACE2 via its glycosylated outer membrane spike proteins. Although SARS-CoV-2 mainly invades alveolar epithelial cells, it can also cause myocardial injury, as assessed by increased troponin T and NT-proBNP levels accompanying increased cardiovascular symptoms in Covid-19-infected patients. It is unclear whether elevated biomarkers of cardiac injury (or long-term effects on the cardiovascular system) are directly caused by viral infection of cardiac tissue or are secondary to hypoxia and systemic inflammation. 

The situation may be aggravated by findings showing that ACE inhibitors, which are often used to treat cardiovascular diseases, augment the expression of the SARS-CoV-2 receptor ACE2 in lung cells. This is probably mediated by an effect on angiotensin II, which is known to reduce ACE2 expression. Thus, ACE inhibition decreases angiotensin II, leading to an indirect up-regulation of ACE2. The effect of angiotensin II receptor blockers (ARBs), which primarily target the angiotensin receptor 1, is unclear. The effect of the two different treatments on the expression of ACE2 in the heart requires further investigation.

With this aim, the authors used single nuclei RNA sequencing to determine the expression of ACE and ACE2 in the different cell types of the human heart. 

Their data provide novel insights into the cell type-specific expression and regulation of ACE2 in the heart. Patients with varying heart disease aetiology show augmented expression of ACE2 levels particularly in cardiomyocytes. Treatment with ACE inhibitors tends to be associated with increased ACE2 mRNA and unfavourable ACE/ACE2 ratios, which are believed to be a driver of cardiovascular pathologies. 

This study is limited by its small sample size and therefore is only hypothesis-generating. However, these novel data suggest that it will be important to monitor SARS-CoV-2-infected patients for cardiovascular complications and assess the impact of ARB/ACE inhibitor therapy.

Hypertension, the renin–angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for Covid-19: European Society of Hypertension Covid-19 Task Force Review of Evidence

Kreutz R, El-Hady Algharably EA, Azizi M et al

Cardiovascular Research 2020, Apr 15 cvaa097 doi: 10.1093/cvr/cvaa097

Systemic arterial hypertension is a major risk factor of mortality worldwide, and its importance is further emphasised in the context of the  novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as Covid-19. 

Patients with severe Covid-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of Covid-19 in relation to hypertension itself as well as its treatment with renin-angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). 

Here the European Society of Hypertension Covid-19 Task Force provides a critical review on the relationship of hypertension, RAS and risk of lung injury. The taskforce demonstrates lack of sound evidence that hypertension per se is an independent risk factor for Covid-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. The ESH taskforce also reviews in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with Covid-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney and other tissues. 

In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in Covid-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the Covid-19 pandemic.

Association of cardiac injury with mortality in hospitalized patients with Covid-19 in Wuhan, China

Shi S, Qin M, Shen B et al 

JAMA Cardiol Published online March 25, 2020. doi:10.1001/jamacardio.2020.0950

Covid-19 has resulted in considerable morbidity and mortality worldwide since December 2019. However, information on cardiac injury in patients affected by Covid-19 is limited. In this cohort study of 416 consecutive patients with confirmed Covid-19, cardiac injury occurred in 19.7% of patients during hospitalisation, and it was one independent risk factor for in-hospital mortality.

The authors set out to explore the association between cardiac injury and mortality in patients with Covid-19. This cohort study was conducted from January 20, 2020 to February 10, 2020 in a single centre at Renmin Hospital of Wuhan University, Wuhan, China. The final date of follow-up was February 15, 2020. All consecutive inpatients with laboratory-confirmed Covid-19 were included in this study. Clinical laboratory, radiological and treatment data were collected and analysed. Outcomes of patients with and without cardiac injury were compared. The association between cardiac injury and mortality was analysed.

A total of 416 hospitalised patients with Covid-19 were included in the final analysis; the median age was 64 years (range, 21 to 95 years), and 50.7% were female. Common symptoms included fever (80.3%), cough (34.6%) and shortness of breath (28.1%). A total of 82 patients (19.7%) had cardiac injury and in compared with patients without cardiac injury, these patients were older (median age 74 versus 60 years; p < 0.001); had more comorbidities (eg. hypertension in 59.8% versus 23.4%; p < 0.001); had higher leukocyte counts (median 9,400 versus 5,500 cells/µL) and levels of C-reactive protein (median 10.2 versus 3.7mg/dL), procalcitonin (median 0.27 versus 0.06ng/mL), creatinine kinase–myocardial band (median 3.2 versus 0.9ng/mL), myohemoglobin (median 128 versus 39µg/L), high-sensitivity troponin I (median 0.19 versus < 0.006µg/L), N-terminal pro-B-type natriuretic peptide (median 1,689 versus 139pg/mL), aspartate aminotransferase (median 40 versus 29U/L), and creatinine (median 1.15 versus 0.64mg/dL); and had a higher proportion of multiple mottling and ground-glass opacity in radiographic findings (53 of 82 patients [64.6%] versus 15 of 334 patients [4.5%]). Greater proportions of patients with cardiac injury required non-invasive mechanical ventilation (38 of 82 [46.3%] versus 13 of 334 [3.9%]; p < 0 .001) or invasive mechanical ventilation (18 of 82 [22.0%] versus 14 of 334 [4.2%]; p < 0.001) than those without cardiac injury. Complications were more common in patients with cardiac injury than those without cardiac injury and included acute respiratory distress syndrome (58.5% versus 14.7%; p < 0.001), acute kidney injury (8.5% versus 0.3%; p < 0.001), electrolyte disturbances (15.9% versus 5.1%; p = 0.003), hypoproteinaemia (13.4%] versus 4.8%; p = 0.01), and coagulation disorders (7.3% versus 1.8%; p  = 0.02). Patients with cardiac injury had higher mortality than those without cardiac injury (51.2% versus 4.5%; p < 0.001). 

In conclusion, cardiac injury is a common condition among hospitalised patients with Covid-19 in Wuhan, China, and it is associated with higher risk of in-hospital mortality.

Coronaviruses and the cardiovascular system: acute and long-term implications

Xiong T-Y, Redwood S, Prendergast B, Chen M 

European Heart Journal, 18 March 2020 ehaa231, https://doi.org/10.1093/eurheartj/ehaa231

The present COVID-19 outbreak emphasises the need for greater awareness of the immediate and long-term cardiovascular (CV) implications of viral infection and the significant gaps in knowledge that future research will need to address.

CV complications of influenza infection, including myocarditis, acute myocardial infarction and exacerbation of heart failure have been well-recognised during previous historical epidemics and make a significant contribution to mortality. Likewise, previous coronavirus outbreaks have been associated with a significant burden of CV comorbidities and complications. Furthermore, the severity of the primary respiratory syndrome and risk of adverse outcomes is increased in patients with pre-existing CV diseases. Hypotension, tachycardia, bradycardia, arrhythmia or even sudden cardiac death are common in patients with SARS. Electrocardiographic changes and troponin elevation may signal underlying myocarditis, and echocardiography frequently demonstrates sub-clinical left ventricular diastolic impairment. 

Outbreaks of viral respiratory illness threaten public health but the associated extra-pulmonary manifestations and their prolonged consequences are often overlooked. Pre-existing CVD may contribute to adverse early clinical outcomes of Covid-19 and infection may have longer-term implications for overall CV health. Inter-disciplinary management of severe cases (with priority for those with pre-existing CVD) and prolonged clinical follow-up are therefore essential.

Covid-19: Vaccines

Two Middle East respiratory syndrome vaccines: first step for other coronavirus vaccines?

Modjarrad K, Kim JH

Lancet Infectious Diseases April 20, 2020     https://doi.org/10.1016/S1473-3099(20)30317-0-2

Since the outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, the emergence and expansion of endemic and epidemic coronaviruses has been accelerating on a scale not seen for any other group of viruses with pandemic potential. In the past two decades alone, five new human coronaviruses have been discovered, three of which are highly pathogenic

The Covid-19 pandemic is just the latest example of the danger posed by zoonotic diseases, foreshadowed by the regional, but unabated, emergence of Middle East respiratory syndrome coronavirus (MERS-CoV). In recognition of its intrinsic threat to public health and as a prototypical member of the family Coronaviridae, in 2015 the World Health Organization prioritised MERS-CoV as a pathogen to which increased resources should be dedicated for countermeasure research and development. The newly established Coalition for Epidemic Preparedness Innovations followed suit with investments in the development of candidate MERS-CoV vaccines. In subsequent years, three vaccine candidates have completed initial clinical evaluation and are now ready for advanced testing.

In Lancet Infectious Diseases, two groups report results from phase I clinical trials of non-replicating viral vector MERS-CoV vaccines. Folegatti et al summarise the safety and immunogenicity of a chimpanzee adenovirus-vectored vaccine, ChAdOx1 MERS, and Koch et al do the same for a poxvirus-vectored vaccine, MVA-MERS-S. The two vaccines demonstrated tolerable safety profiles (no vaccine-related serious adverse events were reported for either vaccine) and induced humoral and cellular immune responses at peak, post-vaccination timepoints. ChAdOx1 MERS was administered as a single injection, whereas MVA-MERS-S was given as a two-dose regimen, with a 28-day interval between doses. Both products were tested in a dose-escalating design. Although the frequency and severity of adverse events were proportional to vaccine dose in both studies, only higher doses of ChAdOx1 MERS improved immunogenicity. A single dose of ChAdOx1 MERS also showed an earlier ascent and slower decay of antibody-mediated and cell-mediated immunity than two doses of MVA-MERS-S. While noting that binding antibody levels are reported differently between these studies, a single dose of ChAdOx1 MERS vaccine induced detectable antibody titres at day 180 (in 18 [75%] of 24 participants) and day 364 (13 [68%] of 19 participants) after vaccination, whereas with MVA-MERS-S only three (14%) of 22 vaccine recipients had detectable antibody titres at day 180.

Differences in the magnitude, kinetics and character of the elicited immune responses raise common concerns for the development pathway of outbreak vaccines against MERS-CoV and, more acutely, SARS coronavirus 2 (SARS-CoV-2). Interrogation of the humoral and cellular immune profiles of the vaccine candidates highlights the first point: what immune responses do coronavirus vaccines need to elicit to confer protection against infection or severe disease? Although the question is applicable to many viruses, the answer has been elusive among coronaviruses.

Without previous identification of a potential correlate of protection, it is difficult to ascertain the relevance of immunogenicity outputs. In addition, there remains a lack of consensus on the methodology by which immunogenicity outputs are measured. Although the two trials report similar assessments of humoral response (binding antibody, wild-type MERS virus, and pseudovirus neutralisation assays) it is difficult to know how these individual results compare between studies. Koch et al found a strong correlation between binding and neutralising antibody titres (Spearman’s correlation r = 0·86 [95% CI 0·6960 to 0·9427], p = 0·0001), whereas Folegatti et al did not (Spearman’s r = 0·28, p = 0·175). Does this represent an immunologically relevant difference between vaccine-induced responses or a methodological difference between laboratories? 

Some animal studies suggest that certain SARS-CoV and MERS-CoV vaccines might, upon viral challenge, be associated with eosinophilic pulmonary infiltrates. This finding underscores the importance of factoring safety into the design, monitoring and long-term follow-up of coronavirus vaccine trials – something that cannot be fully addressed in the two early-stage MERS vaccine trials under discussion, but which will undoubtedly be considered in future efficacy trials.

The experience with SARS and the emergence of MERS, particularly during the outbreaks of 2014-2015 in the Arabian and Korean peninsulas, were harbingers of the consequences of Covid-19, and similar pathogens, on all sectors of society – not only in overall morbidity and mortality, but also in the capacity to level economies and disrupt social order. If MERS has been eclipsed by its pandemic cousin, then the lessons learned have prepared the global vaccine research and development community for moving coronavirus vaccines forward at an accelerated pace, such that first-in-human Covid-19 vaccine trials are moving on unprecedented, shortened timelines. To stay ahead of these increasingly frequent outbreaks, the field must maintain momentum in advancing rapid, scalable and translatable vaccine strategies, not only for MERS-CoV, but even more urgently for SARS-CoV-2 and, ultimately, the next novel coronavirus that leaps from its animal host to humans.

Correlation between universal BCG vaccination policy and reduced morbidity and mortality for Covid-19: an epidemiological study

Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH

MedRxiv March 28, 2020   doi: 10.1101/2020.03.24.20042937

COVID-19 has spread to most countries in the world. Puzzlingly, the impact of the disease is different in different countries. These differences are attributed to differences in cultural norms, mitigation efforts and health infrastructure. The authors propose that national differences in Covid-19 impact could be partially explained by the different national policies respect to Bacillus Calmette-Guérin (BCG) childhood vaccination. 

BCG vaccination has been reported to offer broad protection to respiratory infections. The authors compared large number of countries BCG vaccination policies with the morbidity and mortality for Covid-19. 

Interestingly they found that countries without universal policies of BCG vaccination (Italy, the Netherlands, the US) have been more severely affected compared to countries with universal and longstanding BCG policies. Countries that have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. 

They also found that BCG vaccination also reduced the number of reported Covid-19 cases in a country. The combination of reduced morbidity and mortality makes BCG vaccination a potential new tool in the fight against Covid-19.

Note: This article is a preprint and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice. www.medrxiv.org

Connecting BCG vaccination and Covid-19: additional data

Dayal D, Gupta S 

MedRxiv April 19, 2020   doi: 10.1101/2020.04.07.20053272

The reasons for a wide variation in severity of coronavirus disease 2019 (Covid-19) across the affected countries of the world are not known. Two recent studies have suggested a link between the BCG vaccination policy and the morbidity and mortality due to Covid-19.

In this study the authors compared the impact of Covid-19 in terms of case fatality rates (CFR) between countries with high disease burden and those with BCG revaccination policies presuming that revaccination practices would have provided added protection to the population against severe Covid-19. They found a significant difference in the CFR between the two groups of countries. 

According to the authors this data further supports the view that universal BCG vaccination has a protective effect on the course of Covid-19, probably preventing progression to severe disease and death. 

Clinical trials of BCG vaccine are urgently needed to establish its beneficial role in Covid-19 as suggested by the epidemiological data, especially in countries without a universal BCG vaccination policy, they argue. 

Note: This article is a preprint and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice. www.medrxiv.org

Covid-19: Drug treatment

Hydroxychloroquine and azithromycin as a treatment of Covid-19: results of an open-label non-randomized clinical trial

Cao B, Wang Y, Wen D et al 

Int J Antimicrob Agents 2020, March 20   doi: 10.1016/j.ijantimicag.2020.105949 [Epub ahead of print]

Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese Covid-19 patients. In this study the authors evaluated the role of hydroxychloroquine on respiratory viral loads.

French confirmed Covid-19 patients were included in a single arm protocol from early March to March 16, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another centre and cases refusing the protocol were included as negative controls. Presence and absence of virus at day 6-post inclusion was considered the endpoint.

Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at day 6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.

Despite its small sample size the survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in Covid-19 patients and its effect is reinforced by azithromycin.

A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19

Cao B, Wang Y, Wen D et al 

N Engl J Med 2020, March 18   doi: 10.1056/NEJMoa2001282 [Epub ahead of print]

No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.

The authors conducted a randomised, controlled, open-label trial involving hospitalised adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of ≤ 94% while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of < 300mmHg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400mg and 100mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary endpoint was the time to clinical improvement, defined as the time from randomisation to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomisation; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% versus 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by one day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.

In hospitalised adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. 

(Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others).

A systematic review on the efficacy and safety of chloroquine for the treatment of Covid-19

Cortegiani A, Ingoglia G et al

J Crit Care 2020 March 10   doi: 10.1016/j.jcrc.2020.03.005 [Epub ahead of print]

COVID-19 is a public health emergency of international concern. As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patients contracting the severe form of the disease. 

The aim of this systematic review was to summarise the evidence regarding chloroquine for the treatment of Covid-19. PubMed, EMBASE, and three trial registries were searched for studies on the use of chloroquine in patients with Covid-19. The researchers included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (the virus causing Covid-19) in vitro.

The conclusions were that there is rational, pre-clinical evidence of the effectiveness and evidence of safety from long-time clinical use for other indications to justify clinical research on chloroquine in patients with Covid-19.

However, clinical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or be ethically approved as a trial as stated by the World Health Organization. 

Safety data and data from high-quality clinical trials are urgently needed.

Pharmacologic treatments for coronavirus disease 2019 (Covid-19): a review

Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB 

JAMA 2020, April 13  doi: 10.1001/jama.2020.6019 [Epub ahead of print]

The pandemic of coronavirus disease 2019 (Covid-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection.

No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in-vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomised trials. Oseltamivir has not been shown to have efficacy and corticosteroids are currently not recommended. 

Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with Covid-19.

The Covid-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for Covid-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.