Care of patients with pulmonary arterial hypertension during the coronavirus (COVID-19) pandemic
The COVID-19 pandemic presents many unique challenges when caring for patients with pulmonary hypertension. The COVID-19 pandemic has altered routine standard of care practice and the acute management particularly for those patients with pulmonary arterial hypertension, where pulmonary arterial hypertension-specific treatments are used. It is important to balance the ongoing care and evaluation of pulmonary arterial hypertension patients with “exposure risk” to COVID-19 for patients coming to clinic or the hospital. If there is a morbidity and mortality benefit from starting pulmonary arterial hypertension therapies, for example in a patient with high-likelihood of pulmonary arterial hypertension, then it remains important to complete the thorough evaluation. However, the COVID-19 outbreak may also represent a unique time when pulmonary hypertension experts have to weigh the risks and benefits of the diagnostic work-up including potential exposure to COVID-19 versus initiating targeted pulmonary arterial hypertension therapy in a select high-risk, high likelihood World Symposium Pulmonary Hypertension Group 1 pulmonary arterial hypertension patients. This document will highlight some of the issues facing providers, patients, and the pulmonary arterial hypertension community in real-time as the COVID-19 pandemic is evolving and is intended to share expected common clinical scenarios and best clinical practices to help the community at-large.
Could pulmonary arterial hypertension patients be at a lower risk from severe COVID-19?
The COVID-19 pandemic now impacts over 1.2 million individuals worldwide with higher risk comorbidities including age, cardiac and pulmonary diseases. Pulmonary hypertension (PH) centres prepared for the worst for their high-risk pulmonary arterial hypertension (PAH) patients. However, providers have been surprised thus far by the paucity of hospitalised PAH–COVID-19 patients, generally tolerable symptoms in those affected, and their relatively early recovery.
In late March 2020, experts from over 32 U.S. PH Centres responded to a Pulmonary Hypertension Association (PHA) query. Only 13 COVID-19 cases were reported, with one death (Table 1), prompting us to ask, why have there been so few catastrophic COVID–PAH patient events? At the outset of the pandemic, PAH patients were warned to self-isolate, something that they may be more accustomed to than the general population, and that may be the simple answer. However, paradoxically could the pre-existing pulmonary vasculopathy and/or PAH-specific medications somehow be protective for these otherwise high-risk patients? Could PH-specific medications (endothelin receptor antagonists (ERA), phosphodiesterase-5 (PDE5) inhibitors, inhaled nitric oxide (iNO) and prostacyclins) protect against some cardiopulmonary manifestations of COVID-19? Might there be an altered pulmonary endothelial response due to lack of ability to mount a florid inflammatory response, relative hypoxemia and possible effect on viral replication, efficacy of the nitric oxide/cyclic GMP pathway, antiplatelet effect of prostacyclins and/or use of anticoagulants in WSPH Group 1 PAH patients?
Rethinking COVID-19 ‘pneumonia’ – is this primarily a vaso-occlusive disease, and can early anticoagulation save the ventilator famine?
As the COVID-19 pandemic rampages around the globe, it remains an enigma as to how a fraction of those infected can turn critically ill with severe hypoxemia – the scale of this problem so massive that hospitals in seriously affected cities see their ventilator capacity overwhelmed. As of 25 April 2020, there are approximately 2.6 million infections with more than 180,000 deaths worldwide.1 The main driver of mortality and morbidity with COVID-19 has been the acute respiratory syndrome that occurs in 12–32% of patients2–4 after the initial upper respiratory tract symptoms. While it is widely suspected that an abnormal host response such as a ‘cytokine storm’ is the driving force in those precariously ill,5 there are peculiarities in radiological findings and ventilator mechanics that are atypical of the usual viral pneumonia and acute respiratory distress syndrome (ARDS). Increasingly, published data and anecdotal observations indicate that the pathogenesis may lie primarily in the pulmonary vasculature with the newly observed tendency for thrombi formation.
In the eye of the storm: the right ventricle in COVID-19
The Coronavirus disease of 2019 pandemic caused by the SARS-CoV-2 virus continues to inflict significant morbidity and mortality around the globe. A variety of cardiovascular presentations of SARS-CoV-2 infection have been described so far. However, the impact of SARS-CoV-2 on the right ventricle is largely unknown. Due to its pathophysiologic relevance, the right ventricle finds itself in the eye of the storm of corona virus disease of 2019, placing it at higher risk of failure. Increased afterload from acute respiratory distress syndrome and pulmonary embolism, negative inotropic effects of cytokines, and direct angiotensin converting enzyme 2-mediated cardiac injury from SARS-CoV-2 are potential mechanisms of right ventricle dysfunction in coronavirus disease of 2019. Early detection and treatment of right ventricle dysfunction may lead to decreased mortality and improved patient outcomes in coronavirus disease of 2019.
COVID-19 and the pulmonary vasculature
Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19) present in a number of ways, from asymptomatic carriers to respiratory failure with acute respiratory distress syndrome (ARDS)-like features. Early observational studies documented that virtually all hospitalised patients had parenchymal abnormalities on computed chest tomography. Interestingly, vascular thickening was also shown to be a predominant imaging finding in COVID-19 compared to non-COVID-19 pneumonia (observed in 59% vs. 22%, p < 0.001),1 implying a potential tropism of the virus for the pulmonary vasculature. This is not surprising since its functional receptor from the host cells, the angiotensin-converting enzyme 2 receptor, is largely present on the surface of pulmonary vascular cells. Accordingly, diffuse endothelial inflammation, dysfunction and apoptosis resulting from direct viral infection of the endothelial cells have been reported within the lungs and other organs. Several lines of evidence also suggest that COVID-19 impacts the pulmonary circulation clinically. For example, patients with severe COVID-19 commonly present an atypical form of ARDS with significant dissociation between relatively well-preserved lung mechanics and severe hypoxemia for which the loss of hypoxic vasoconstriction lung perfusion regulation has been proposed as a possible explanation.2 Systematic assessment of thrombotic complications also revealed a high incidence of confirmed venous thromboembolic events amongst patients hospitalised in the ICU, likely exacerbating ventilation–perfusion mismatch.3 Disseminated intravascular coagulation, a condition characterised by the generation of microthrombi in different organs including the pulmonary circulation, was also diagnosed in 71% of the non-survivors of COVID-19, and pulmonary microthrombi were observed at lung dissection from critically ill COVID-19 patients. Consistently, high levels of D-dimers were repeatedly shown to be associated with mortality amongst COVID-19 patients in line with the immuno-thrombosis model of severe sepsis and ARDS, and anticoagulant therapy with heparin has been reported to be associated with decreased mortality, especially so in patients with significant sepsis-induced coagulopathy or markedly elevated D-dimer levels.4 Whether these observations could be related to the non-anticoagulant properties of heparin, including its anti-inflammatory, antiviral, and protective effects on the pulmonary endothelium remains elusive. Given the increased risk of bleeding and previous negative trials of endogenous anticoagulants in sepsis, this retrospective study requires further validation before the efficacy and best dosage, as well as characteristics of patients most suitable for systemic anticoagulation beyond the traditional prevention and management of venous thromboembolism are confirmed.
Virtual echocardiography screening tool to differentiate hemodynamic profiles in pulmonary hypertension
This study validated a novel virtual echocardiography screening tool (VEST), which utilised routinely reported echocardiography parameters to predict hemodynamic profiles in pulmonary hypertension (PH) and identify PH due to pulmonary vascular disease (PHPVD). Direct echocardiography imaging review has been shown to predict hemodynamic profiles in PH; however, routine use often overemphasises Doppler-estimated pulmonary artery systolic pressure (PASPDE), which lacks discriminatory power among hemodynamically varied PH subgroups. In patients with PH of varying subtypes at a tertiary referral centre reported echocardiographic findings needed for VEST, including left atrial size, E:e’ and systolic interventricular septal flattening, were obtained. Receiver operating characteristic analyses assessed the predictive performance of VEST vs. PASPDE in identifying PHPVD, which was later confirmed by right heart catheterisation. VEST demonstrated far superior discriminatory power than PASPDE in identifying PHPVD. A positive score was 80.0% sensitive and 75.6% specific for PHPVD with an area under the curve of 0.81. PASPDE exhibited poorer discriminatory power with an area under the curve of 0.56. VEST’s strong discriminatory ability remained unchanged when validated in a second cohort from another tertiary centre. We demonstrated that this novel VEST using three routine parameters that can be easily extracted from standard echocardiographic reports can successfully capture PH patients with a high likelihood of PHPVD. During the COVID-19 pandemic, when right heart catheterisation and timely access to experts at accredited PH centres may have limited widespread availability, this may assist physicians to rapidly and remotely evaluate PH patients to ensure timely and appropriate care.
Understanding the current status of patients with pulmonary hypertension during COVID-19 outbreak: a small-scale national survey from China
Pulmonary hypertension is a chronic disease developing progressively with high mortality. Pulmonary hypertension patients need persistent medical care; however, limited reports focused on them when there was an outbreak of coronavirus disease 2019 in China. This national survey was aimed to evaluate the overall condition of pulmonary hypertension patients during this period. A questionnaire regarding the living condition of pulmonary hypertension patients during coronavirus disease 2019 was designed by pulmonary hypertension diagnostic experts in Wuhan Asia Heart Hospital. Pulmonary hypertension patients and their family members were invited to participate in this survey online. One-hundred twenty pulmonary hypertension patients and 23 family members participated in the survey; 64.8% (n = 87) participants came from Hubei, and others were from 15 other provinces; 98.6% (n = 141) participants were in home quarantine; 65.8% (n = 79) were pulmonary arterial hypertension associated with congenital heart disease; and 76.7% (n = 92) patients proclaimed their heart function was well maintained at class I or II. One (0.8%) patient was confirmed severe acute respiratory syndrome coronavirus 2 infection. Two (1.7%) patients were hospitalised due to heart function worsening. Nearly 70% (n = 100) participants implied shortage in medications during coronavirus disease 2019 outbreak. A total of 24.2% (n = 29) patients indicated that medications were discontinued due to the insufficient supply. Most of the participants stayed optimistic on either coronavirus disease 2019 outbreak or their pulmonary hypertension disease, and 61.7% (n = 74) patients would go to the hospital for follow-up immediately after outbreak. These preliminary data show pulmonary hypertension patients are able to avoid severe disease when they are in home quarantine. Medication supplement is important for pulmonary hypertension patients when their heart function is well maintained. In addition, there might be increasing requirements of medical care for pulmonary hypertension patients after the outbreak.
Letter to the Editor regarding “Could pulmonary arterial hypertension patients be at lower risk from severe COVID-19?”
It was with great interest and some concern we read the recently published paper “Could pulmonary arterial hypertension (PAH) patients be at lower risk from severe COVID-19.”1 In this paper, the authors quote an electronic survey of the Pulmonary Hypertension Association (PHA) centres conducted in March 2020, which only yielded 13 confirmed cases of COVID-19 in known PAH patients. Based on these results, they speculate that PAH patients may have an attenuated COVID-19 course due to potential protective features of PAH-targeted therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitor (PDE) inhibitors or prostanoids). We are concerned about the possible detrimental effects misinterpretation of this message could have to the PAH community. These assumptions were based on little data at an early stage of the pandemic in the US, and the resulting speculations could mislead and put PAH patients at higher risk. SARS-CoV2 and its related illness can have devastating effects on those with pre-existing medical conditions including PAH, and assuming protective effects of their medical therapy may lead PAH patients to altering their behavior by providing a false sense of security.
Management of hospitalised patients with pulmonary arterial hypertension and COVID-19 infection
The novel coronavirus SARS-CoV2 that causes coronavirus disease 2019 (COVID-19), has approximately afflicted over 2 million people worldwide,1 including approximately a million cases with over 50,000 deaths in the United States2 as of 27 April 2020. Pulmonary arterial hypertension (PAH), a chronic, progressively fatal condition, requires complicated medical management.3 Patients with PAH are very sensitive to the changes in their cardiopulmonary status and any disruption in treatment or development of additional cardiac or pulmonary pathology can trigger a rapid course of decline leading to death. Furthermore, all-cause hospitalisation itself is a risk factor for disease progression in PAH.4 A recently published small case series suggested that 86% of critically ill COVID-19-infected patients had heart failure and chronic kidney disease as the most common underlying medical conditions.5 These conditions are commonly seen in patients with PAH and increase the risk for PAH patients to develop severe disease. Many PAH patients are on complicated regimens, including oral, inhaled or continuous intravenous therapies, some of which may be difficult to deliver during an acute illness. In this brief communication, we will highlight the in-patient management of COVID-19-infected PAH patients.
The course of COVID-19 in a 55-year-old patient diagnosed with severe idiopathic pulmonary arterial hypertension
We describe a 55-year-old woman with severe idiopathic pulmonary arterial hypertension (mean pulmonary artery pressure 71 mmHg, pulmonary vascular resistance 30 WU at diagnosis five months ago), who was diagnosed with SARS-CoV-2 infection (COVID-19) and experienced a relatively mild course with symptoms resembling a common cold. To date, information about the clinical course of COVID-19 in pre-existing pulmonary arterial hypertension is lacking, and it is thus unknown whether pulmonary arterial hypertension belongs to the risk factors of severe COVID-19 disease.
Impact of SARS-CoV-2 pandemic on pulmonary hypertension out-patient clinics in Germany: a multi-centre study
Pulmonary hypertension is frequently underdiagnosed, and referral is delayed with subsequent impact on outcomes. During the SARS-CoV-2 pandemic, restrictions on daily life and changes in hospitals' daily routine care were introduced in Germany. This multi-centre study provides evidence for a negative influence of these restrictions on patient care in pulmonary hypertension expert referral centres.