Case Report & Editorial: Home Nitric Oxide Therapy for COVID

Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive Idiopathic Pulmonary Arterial Hypertension and COVID-19 Infection
Roham T. Zamanian 1,2*, Charles V. Pollack Jr.3, Michael A. Gentile 4, Moira Rashid 5, John Christian Fox 6, Kenneth W. Mahaffey 1, and Vinicio de Jesus Perez 1,2
  • 1Stanford University School of Medicine, Stanford, California
  • 2Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, California
  • 3University of Mississippi School of Medicine, Jackson, Mississippi
  • 4Vero Biotech, Atlanta, Georgia
  • 5Private Practice, Long Beach, California and University of California Irvine Emergency Medicine, Orange, California
  • Corresponding Author: Roham T. Zamanian zamanian@stanford.edu
Figure 1.
Serial 6-minute-walk distance (6MWD), EmPHasis-10 (E10) score, World Health Organization (WHO) symptom class, and inhaled nitric oxide (iNO) dose over the course of a patient’s coronavirus disease (COVID-19) infection.
To the Editor:
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is associated with significant pulmonary morbidity and acute respiratory distress syndrome (ARDS)-like illness (1). The unprecedented global COVID-19 pandemic is impacting the well-being of vulnerable patients, particularly the elderly and those with underlying cardiopulmonary diseases (2). Because no specific antiviral therapy is currently approved for COVID-19, treatment is supportive (at times intensive) and has severely stretched global hospital staffing and equipment capacity. Here, we report on outpatient management of a patient with concomitant idiopathic pulmonary arterial hypertension (iPAH) and COVID-19 using inhaled nitric oxide (iNO).
Case
A 34-year-old female with vasoreactive iPAH (Table 1), who was historically stable on nifedipine (60 mg extended release daily), tadalafil, and macitentan, presented through a telehealth visit with progressive dyspnea and fatigue in the setting of a recent positive COVID-19 PCR test. The patient reported a recent 2-week trip to Egypt, including a Nile cruise, flying round-trip from the United States through Germany to Egypt. Upon her return, the patient initially noticed onset of anosmia followed by a low-grade fever for which she sought medical care. Five days later, she was contacted by the county health authority, advised of the positive test result, and asked to self-quarantine. On the same day, she contacted her PAH care center and was immediately evaluated.
EDITORIAL:
Home Nitric Oxide Therapy for COVID
Alvarez RA, Berra L, Gladwin MT.
Am J Respir Crit Care Med. 2020 Jul 1;202(1):16-20.
nfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of cardiopulmonary and vascular complications, ranging from upper respiratory tract symptoms to severe acute respiratory distress syndrome (ARDS), as well as shock, acute kidney injury, and thromboembolic complications (12). Although SARS-CoV-2 initially infects the upper respiratory tract epithelia, some of the most serious complications of the disease appear to arise through vascular inflammation and injury. Although further mechanistic and epidemiological studies are needed, case reports, imaging studies, and autopsy series have suggested the possibility that the SARS-CoV-2 virus, once in the lower respiratory tract, may directly infect endothelial cells, leading to a cascade of consequences including vasoplegia, vascular thromboses, pulmonary edema, endothelial sloughing, and abnormal regulation of pulmonary perfusion (23). Regardless of the mechanisms, it is clear that patients often develop severe respiratory failure with hypoxemia that may be refractory to oxygen supplementation and often requires invasive mechanical ventilation. Because of the rapidity with which the virus spread, many healthcare systems were stressed by the sudden increase in coronavirus disease (COVID-19) cases, with the accompanying increased need for hospital beds, ICU beds, ventilators, and even oxygen. A high percentage of mechanically ventilated patients develop multi-organ failure syndrome, characterized by pressor-dependent shock and a high associated mortality. Even those who survive with the assistance of mechanical ventilation may require prolonged hospitalizations (4). These concerted adverse sequalae of SARS-CoV-2 infection create major strains on health care system resources.
It is with this backdrop that, in this issue of the Journal, Zamanian and colleagues (pp. 130–132) present an interesting and compelling case of a patient with pulmonary arterial hypertension (PAH) who was treated remotely in an ambulatory setting with inhaled nitric oxide (iNO) (5). This patient with well-controlled vasoreactive PAH lived in a remote area more than 300 miles away from their center and experienced symptoms of worsening breathlessness after being diagnosed with COVID-19. Considering her concerns about traveling the long distance to their center to receive care, and with recognition of her prior confirmed responsiveness to iNO, they established a plan to support her with an ambulatory iNO system while monitoring her symptoms, vital signs, and functional capacity remotely. The patient had rapid and sustained improvement in her 6-minute-walk distance, as assessed by her caregiver, and symptom score, and she recovered over several days without having to engage emergency department or hospital care.
Figure 1.
Summary of major therapeutic properties of inhaled nitric oxide gas (NO). From top left: inhaled NO gas is known to be a selective pulmonary vasodilator. NO can improve right heart function and decrease pulmonary vasoconstriction in subjects with acute and chronic pulmonary hypertension. Middle left vignette: breathing NO gas is shown to improve ventilation and provide bronchodilation in mild asthmatic subjects. Bottom left vignette: NO gas in the alveolar space improves oxygenation by increasing blood flow to ventilated lung units (i.e., improvement of ventilation perfusion matching). Top and middle right vignettes: in vitro and in vivo data showed that NO gas can act as an antiinflammatory and antithrombotic agent. Bottom right vignette: NO donors and NO gas showed antibacterial and antiviral properties in in vitro studies and early clinical investigations. The extent of benefits of these six therapeutic pathways of NO gas in coronavirus disease (COVID-19) infection are now under investigation. Some of those studies testing NO therapeutic properties are highlighted in Table 1.
Related paper in Lancet:
Lancet. 2020 395(10234): 1417–1418.
Endothelial cell infection and endotheliitis in COVID-19
Zsuzsanna Varga,a Andreas J Flammer,b Peter Steiger,c Martina Haberecker,a Rea Andermatt,c Annelies S Zinkernagel,d Mandeep R Mehra,e Reto A Schuepbach,c Frank Ruschitzka,b and Holger Mocha
Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.12
SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells.3 Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro.4 Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix).
Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient’s condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8.
Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B ). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested.
Pathology of endothelial cell dysfunction in COVID-19
(A, B) Electron microscopy of kidney tissue shows viral inclusion bodies in a peritubular space and viral particles in endothelial cells of the glomerular capillary loops. Aggregates of viral particles (arrow) appear with dense circular surface and lucid centre. The asterisk in panel B marks peritubular space consistent with capillary containing viral particles. The inset in panel B shows the glomerular basement membrane with endothelial cell and a viral particle (arrow; about 150 nm in diameter). (C) Small bowel resection specimen of patient 3, stained with haematoxylin and eosin. Arrows point to dominant mononuclear cell infiltrates within the intima along the lumen of many vessels. The inset of panel C shows an immunohistochemical staining of caspase 3 in small bowel specimens from serial section of tissue described in panel D. Staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections, indicating that apoptosis is induced in a substantial proportion of these cells. (D) Post-mortem lung specimen stained with haematoxylin and eosin showed thickened lung septa, including a large arterial vessel with mononuclear and neutrophilic infiltration (arrow in upper inset). The lower inset shows an immunohistochemical staining of caspase 3 on the same lung specimen; these staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections. COVID-19=coronavirus disease 2019.
Patient 2 was a woman, aged 58 years, with diabetes, arterial hypertension, and obesity. She developed progressive respiratory failure due to COVID-19 and subsequently developed multi-organ failure and needed renal replacement therapy. On day 16, mesenteric ischaemia prompted removal of necrotic small intestine. Circulatory failure occurred in the setting of right heart failure consequent to an ST-segment elevation myocardial infarction, and cardiac arrest resulted in death. Post-mortem histology revealed lymphocytic endotheliitis in lung, heart, kidney, and liver as well as liver cell necrosis. We found histological evidence of myocardial infarction but no sign of lymphocytic myocarditis. Histology of the small intestine showed endotheliitis (endothelialitis) of the submucosal vessels.
Patient 3 was a man, aged 69 years, with hypertension who developed respiratory failure as a result of COVID-19 and required mechanical ventilation. Echocardiography showed reduced left ventricular ejection fraction. Circulatory collapse ensued with mesenteric ischaemia, and small intestine resection was performed, but the patient survived. Histology of the small intestine resection revealed prominent endotheliitis of the submucosal vessels and apoptotic bodies (figure C).
We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs.3 Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D).
The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis.5 Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state.6
Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7891011 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.
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