Pulmonary arterial hypertension post COVID-19: A sequala of SARS-CoV-2 infection?

It has been suggested that pulmonary arterial hypertension (PAH) could be a potential sequela of coronavirus disease 2019 (COVID-19) in particular in those with hypertension; however, development of PAH after the course of COVID-19 in normotensive individuals are rarely reported. Here, we report a patient who developed PAH two months post-COVID-19. The patient was a 55-year-old female and normotensive, tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), developed mild respiratory distress syndrome and necessitated continuous positive airway pressure during the treatment in the hospital. After two months discharged from the hospital with RT-PCR negative for SARS-CoV-2, the patient presented with exertional dyspnea, dry cough, fatigue and episodes of syncope during exertion. Based on clinical presentation, electrocardiography, computed tomography, and transthoracic echocardiography assessment, PAH diagnosis was made. To our knowledge, this is a rare PAH case and this highlights the possible of PAH as sequala that might present in post COVID-19 patients.

Pulmonary arterial hypertension (PAH) is a chronic fatal disease that requires immediate and proper medical treatment since it could cause cardiopulmonary collapse [9,10]. Heart failure and chronic kidney disease are the most common underlying medical conditions of PAH [11]. It has been reported that COVID-19 patients are at risk of developing cardiac or pulmonary complications due to pulmonary hypertension [9]. To date, the pathophysiology and effects of COVID-19 in PAH are unclear. In this case report, we report the case of a severe COVID-19 patient, had no PAH underlying medical conditions, who later developed PAH after two months discharged from the hospital.

Case presentation
A 55-year-old female, with no previous PAH comorbidities, initially presented with fever, shortness of breath, dry cough, chest pain, nausea, and generalized body aches for seven days. On presentation in the hospital, the blood pressure was 100/70 mmHg, pulse was 105 bpm, respiratory rate of 22/min, and oxygen saturation was 77%. On examination, there were bilateral coarse crackles in both lower lung fields. Based on the history and examination findings, a COVID-19 was suspected. The patient was admitted to the COVID-19 isolation unit and was started on oxygen by a simple face mask (5 L). The patient was started on intravenous (IV) azithromycin (500 mg/day) and ceftriaxone (75 mg/kg/day IV) along with enoxaparin sodium (40 mg for each 12 hours subcutaneously), dexamethasone (6 mg/day IV), vitamin C and Zinc. The baseline lab testing and a chest X-ray (CXR) were ordered. Moreover, a nasopharyngeal swab was collected for SARS-CoV-2 RT-PCR.
Two months after discharge, she visited the outpatient department with complaints of exertional dyspnea, dry cough, and fatigue for one month. She also reported an episode of exertional syncope. Her vitals revealed blood pressure of 140/90 mmHg, pulse rate 90 bpm, respiratory rate of 18/min, and oxygen saturation of 88% without any oxygen support. On examination, her jugular venous pressure raised 13 cm of H 2 O; left parasternal heave, and wide splitting of the second heart sound was noted. All the relevant blood tests were ordered along with a CXR, electrocardiography (ECG), and a SARS-CoV-2 RT-PCR. The ECG suggested right axis deviation, and the blood test results are presented in Table 1. A RT-PCR for SARS-CoV-2 was negative which ruled out reinfection. The lung CXR demonstrated right atrial enlargement and some fibrotic changes (Fig. 1A). A high-resolution CT-scan revealed massive fibrosis, diffuse symmetrical ground glass opacities involving both lung fields along with septal thickening and traction bronchiectasis most consistent with post-COVID-19 changes (Fig. 1B).
To further investigate the cause of patient problem, transthoracic echocardiography was ordered which showed right ventricular systolic blood pressure (RVSP) 59 mmHg, tricuspid regurgitant jet velocity (TRV) 4.5 m/s, pulmonary artery diameter was 31 mm with normal left side heart parameters. Based on echocardiographic findings and clinical presentation of the patient, the diagnosis of PAH group 3 was made in accordance with the European Society of Cardiology (ESC) and European Respiratory Society (ERS). The patient was commenced on epoprostenol infusion (25 ng/kg/min, repeated every week), montelukast 10 mg/day, oxygen therapy, and spironolactone 100 mg/day. In addition, all routine vaccinations including pneumococcal and influenza vaccines offered to the patient, and a follow-up visit was scheduled with a multidisciplinary team consisting of a pulmonologist, pulmonary rehabilitation team, and a cardiologist. Partial improvement was recorded in the subsequent visit (improved exercise tolerance, oxygen saturation, and decreased pulmonary arterial pressure to 45 mmHg).

Discussion
In this report, we aimed to highlight the possible relation of COVID-19 and PAH. Two months after recovering from COVID-19, the patient developed PAH with exertional dyspnea, dry cough, and fatigue as well as an episode of exertional syncope. One of the possible explanations is COVID-19 could cause pulmonary vasoconstriction that increased the pulmonary vascular resistance (PVR) [12]. The patient responded well to the initial treatment on her subsequent follow-up visit. This patient should be evaluated further for severe hypoxemia, thrombotic complications i.e. venous thromboembolic events, pulmonary micro-thrombi, vascular thickening, right ventricular hypertrophy and failure as they would be the predominant findings in patient developing PAH with COVID-19 [13].
It has been suggested that having history of hypertension increases the chances of PAH in patients with COVID-19 infection [14]. Therefore, patients with hypertension are at greater risk of developing PAH. One the biggest concern that need to addressed is did the patient have no PAH underling conditions that were potentially masked by the COVID-19? The patient reported in the present study was unique since that patient had no known comorbidities including hypertension. Assessment at the presentation and monitoring during COVID-19 infection revealed that the blood pressure ranged within normal limits. On physical examinations at both first presentation and during monitoring in the hospital suggested there were no signs of lower extremity deep vein thrombosis (DVT) and no sign of heart problems. Therefore, echocardiography and assessment of biomarkers for heart diseases were not advised. However, the D-dimer level was in the normal range (Table 1). Similarly, there was no evidence of rheumatologic diseases or other chronic illnesses on history and physical examination. We acknowledge that those assessments are critical to ensure that PAH in this patient was genuinely associated with COVID-19. However, due to the nature of the case, some of the underlying conditions of PAH could not confirmed.
Besides the above-mentioned limitation, PAH in case was diagnosed using a transthoracic echocardiography. The golden standard test to diagnose PAH is using right heart catheterization where PAH is defined with mean pulmonary artery pressure ≥25 mmHg, pulmonary artery wedge pressure <15 mmHg and pulmonary vascular resistance >3 units. However, transthoracic echocardiography results had enough parameters to suggested that the patient likely had PAH. Although direct association of SARS-CoV-2 infection and PAH is unable to be elucidated in this patient, this case highlights and informs the possible another sequala of COVID-19.

Conclusion
To our knowledge, this is a rare case of PAH that has not been previously reported. It is uncertain that either PAH is a risk factor of severe SARS-CoV-2 infection or vice versa. Further study is warranted to improve our understanding on the relationship between PAH and COVID-19 and therefore to be able to predict and to prevent PAH in COVID-19 patients.

Consent for publication
Written informed consent for publication was sought from the patient.

Funding
This study received no external funding.

Authors' contributions
AWK conceived and designed the study. AWK, IU, KSF, MJT were responsible for data collection and acquisition of data. AWK, IU, KSF, MJT, HH analyzed and/or interpreted the data. IU, HH wrote the initial manuscript. IU, HH critically revised the manuscript. All authors have read the final manuscript.

Declaration of competing interest
The authors declare no conflicts of interest.