Covid-19-induced pulmonary hypertension in children, and the use of phosphodiesterase-5 inhibitors

Respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first occurred in Wuhan, China, in December 2019 and was declared as a pandemic by WHO. The interaction between the 2019 coronavirus disease (COVID-19) and pulmonary hypertension (PH) in children is not widely known. Phosphodiesterase-5 inhibitors (PDEI), one class of drugs used to treat PH, including sildenafil, can suppress angiotensin type I (AT-1) receptor expression. Furthermore, it reduces proinflammatory cytokines and infiltrates the alveolar, inhibits endothelial and smooth muscle transition, mesenchymal cells in the pulmonary artery, and prevents clotting and thrombosis complications. Sildenafil has shown positive effects by diverting the blood flow to the lungs in such a way that ventilation is adequate and can also be anti-inflammatory.


Introduction
Coronavirus disease 2019 (COVID- 19) is a respiratory tract infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).In addition, the virus can mutate rapidly and is a zoonotic pathogen that can exist in humans and animals with a diverse range of clinical presentation, from asymptomatic, mild to severe symptoms, and death. 1 This respiratory-tract infection, currently declared as a pandemic, was caused by the newly recognized coronavirus emerged in Wuhan, China, in December 2019. 1,2As of March 19, 2020, there were 209,839 cases with more than 170 countries affected.About 8,778 deaths were reported, with a fatality rate of 4.18%.Furthermore, the incidence in children is lower than adults, and most children, who were confirmed to be positive, contracted the infection from their families.The incidence in children aged 10-19 years was 549 per 72,314 cases or 1% of all cases, while in children aged under 10 years, the incidence was 416 per 72,314 (0.9%) cases.The reported data showed that the mortality rate ranges from 0.3 per 1000 cases in patients under 18 years old. 3 Although most people who were confirmed positive had only mild symptoms or were without any complication, about 14% had severe illness needing hospitalization and oxygen support, and 5% needed to be admitted to an intensive care unit. 1 In severe cases, infection causes serious acute respiratory disease syndrome (ARDS), sepsis including septic shock, multi-organ failure, including renal failure, or acute heart failure. 3ld age and comorbidities are reported as predictors of death, and D-dimer >1 μg/L when admitted to a health facility is associated with higher case fatality rate. 4e symptoms in children are usually not as severe as adults and generally include cough and fever, which can resolve independently.Furthermore, the signs and symptoms in children are difficult to distinguish from other respiratory diseases.The respiratory tract disease becomes dangerous if it attacks the lungs or causes inflammation of the lungs or pneumonia.[7] SARS-CoV-2 is an enveloped single-stranded RNA virus (ssRNA) and is the seventh strain of coronavirus that can infect humans.This virus is different from other coronaviruses known to cause mild respiratory infections (229E, OC43, NL63, and HKU1).However, it is much the same as the SARS-CoV and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which may lead to severe respiratory infections. 8,9Furthermore, it is suspected that SARS-CoV-2 emerged from bats because it has 89-96% nucleotide similarity to the bat coronavirus.Similar to the case with SARS and MERS, SARS-CoV-2 probably moved from bats to an intermediate host (possibly pangolins, with 91% nucleotide similarity) and was later transmitted to humans. 10e SARS-CoV-2 virus spreads predominantly through droplets produced by sneezing or coughing, and indirectly through infected objects or surfaces.Transmission can be from symptomatic or asymptomatic patients, and the incubation period for the virus is about 2-14 days (5 days on average).Furthermore, the main symptoms experience by the patients includes fever, cough, and dyspnea.Other symptoms include myalgia, anorexia, malaise, painful swallowing, nausea or vomiting, nasal congestion, headaches, and diarrhea.In severe cases, the patient may develop severe pneumonia, ARDS, sepsis, septic shock, and multiple organ dysfunction syndromes (MODS). 11Although the clinical manifestations are predominantly respiratory symptoms, patients may experience severe cardiovascular disorders, including pulmonary hypertension (PH). 12

Pathogenesis of COVID-19
The pathogenesis of SARS-CoV-2 remains unknown, but it is probably not much different from the more widely known SARS-CoV. 13In humans, SARS-CoV-2 primarily infects cells in the airways coating the alveoli.Furthermore, it links to the receptors and enter the cell.The glycoprotein in the envelope spike of the virus binds to the cellular receptor in the form of ACE2 on SARS-CoV-2.Inside cells, the virus clones the genetic material and synthesizes the required proteins, forming new virions appearing on the cell surface. 14,15VISED Amendments from Version 1 We have included detailed of COVID-19 and pulmonary hypertension in children, elaborated them with adult patients.We also have added some prospective studies on how to diagnosis pulmonary hypertension.We added the doses sildenafil in children and outcomes based on clinical trials.Finally, we add the association between pulmonary hypertension and COVID-19 pathomechanism and how sildenafil therapy effects the pulmonary hypertension in children.
Any further responses from the reviewers can be found at the end of the article In the case of SARS-CoV-2, it is assumed that when the virus enters the cell, the viral RNA genome is discharged into the cell cytoplasm and translated into two polyproteins and structural proteins.Subsequently, the viral genome will begin to replicate.The glycoproteins in the newly formed viral envelope enter the membrane of the endoplasmic reticulum or Golgi cells.Therefore, the formation of the nucleocapsid, composed of RNA genome and nucleocapsid proteins, occurs.The virus particles grow into the endoplasmic reticulum and Golgi apparatus.[18] In SARS-CoV, it has been reported that the S protein is the main predictor of virus penetration into host cells.Furthermore, its entry into a cell begins with the fusion of the viral membrane and the plasma membrane of the cell. 16,18n this process, the S2' protein has a vital role in the proteolytic cleavage process, which mediates the membrane fusion process.In addition to membrane fusion, there is clathrin-dependent and clathrin-independent endocytosis, mediating SARS-CoV into host cells. 18rus and host factors contribute to infection.The infection severity is determined by the cytopathic effects of the virus and its capability to defeat the immune response.Immune system disorders leads to tissue damage in SARS-CoV-2.The inadequate immune response causes viral replication and tissue damage.In contrast, an excessive immune response could result in tissue damage. 19,20e immune response induced by SARS-CoV-2 is also not fully known, but can be examined using SARS-CoV mechanisms.When the virus gets into the cell, the viral antigen is presented to antigen presenting cells (APC).The presentation of viral antigens mainly depends on the major histocompatibility complex (MHC) class I molecules.However, MHC class II also plays a role.Antigen presentation also stimulates humoral and cellular immune response mediated by virus-specific T and B cells.In the humoral immune response, IgM and IgG are formed against SARS-CoV.IgM to SARS-CoV disappears by the end of week 12, but IgG can last long. 13,19,20ruses have mechanisms to evade the host immune response.SARS-CoV may produce double-membrane vesicles without pattern recognition receptors (PRRs) and duplicate in these vesicles in such a way that the host cannot recognize them, and can also inhibited the IFN-I line. 13,19e role of ACE2in COVID-19 has been extensively discussed and researched because SARS-COV-2 uses this transmembrane receptor to cross cell membranes, and its expression is positively associated with infectivity.The enzyme that converts ACE and ACE2 has a balancing effect and leads to pulmonary and systemic effusions.ACE converts angiotensin to angiotensin-II via activation of the angiotensin-II type 1 receptor pathway, causing a proliferative response and prothrombotic vasoconstriction.In the other hand, ACE2 converts angiotensin-II to angiotensin (1-7) heptapeptide, which reverses angiotensin-II action with its antithrombotic effects and antiproliferative vasodilator.Subsequently diminishing the part of ACE2 in COVID-19 seriousness because of its suggestions for viral infectivity, which can be excessively shortsighted, as this receptor has been demonstrated to be engaged with the pathogenesis of the different instruments causing lung and cardiovascular harm.Moreover, ACE2 has an endothelial assurance impact by turning around the impacts of ACE angiotensin II.Studies have revealed that ACE2 overexpression decline atherosclerosis by protecting endothelial capacity and lessening the incendiary reaction through diminished articulation of MCP-1, VCAM-1, and E-selectin brought about by angiotensin II.This endothelial defensive impact is the reason for the antithrombotic impact.[23][24] Despite the fact that angiotensin II is the primary substrate of ACE2, it can also degrade angiotensin I into angiotensin and play a role in peptide hydrolysis.[23][24] ACE2 not only plays a crucial role in the cardiovascular system, but also serves as a receptor for the coronavirus, which binds directly to the virus surface peak protein.SARS-CoV-2 enters the cells through the ACE2 receptor, which is mostly found in the lugs (especially in alveolar type II cells).ACE2 is also present in large quantities in the heart.In addition, ACE2 was also reported to be found on intestinal epithelium, vascular endothelium, and kidney; this is the basis for multiorgan dysfunction mechanism that occur in SARS-CoV-2. 8,12fection of SARS-CoV-2 begins when the viral surface spike protein bound to the ACE2 receptor after being activated by transmembrane protease serine 2 (TMPRSS2). 12The unification of the viral spike protein and ACE2 receptor will downregulation the activity on the cell surface.it can cause the enzyme protective effect disappeared.[24][25] The increased oxygen demand due to systemic infections and hypoxia from COVID-19 can cause an imbalance between oxygen demand and supply, which will lead to myocardial injury.The mechanism of myocardial injury due to COVID-19 is not fully recognized, and myocardial traces may result from viral myocarditis and/or an ischemic process.Previous studies indicate that in35% of patients with COVID-19, the genome is identified in the heart, raising the suspicion that the virus can directly infect the myocardium and cause myocarditis and myocardial damages.SARS-CoV-2 can have a similar mechanism as SARS-CoV because they have homologous genomes. 10,12 inflammatory responses, ACE2 is involved in regulating the innate immunity, and its expression reduces the release of cytokines.The protein spike of SARS-CoV binding to ACE2 will reduce the regulation and develop lungs injury by activating the angiotensin II type 1 receptor by angiotensin II. 22ACE2 expression modification on the surface of pneumocytes is dynamic and vital to oversee inflammation of neutrophil during infection.Thus, in the first stages of infection, diminished ACE2 expression would not affect development of the inflammatory response into deactivated aggression.Latent recovery of ACE2 will help reduce inflammatory infiltrate, preventing excessive injury. 233][24] The reduced ACE2 expression results in diffuse endothelial dysfunction, leading to severe lung impairment concomitant with inflammatory infiltrates and also edema, extensive thrombosis, and homeostasis changes in vascular. 24,26VID-19 develops a cytokine storm, an uncontrolled systemic inflammatory response due to the deliverance large amounts of proinflammatory cytokines (IFN-α, IFN-γ, IL-1β, IL-2, IL-6, IL-7, IL-10, IL-12, IL-18, IL-33, TNF-α, TGFβ, CCL2, CCL3, CCL5, CXCL8, CXCL9, and CXCL10), Granulocyte-colony stimulating factor (GCSF), monocyte chemoattractant protein 1, and macrophage inflammatory protein 1α, which contribute to myocardial injury, acute respiratory distress syndrome (ARDS), lungs damage and fibrosis.This results in functional disability, disease severity and dysfunction in various organs.Some research have reported high levels of proinflammatory cytokines in severe COVID-19 patients. 11,13,15stemic hyper-inflammation and cytokine storms can eventually lead to an increase of coagulation cascade activation.The hypercoagulation state will intensify the risk of thrombosis and thromboembolism in both the veins and arteries. 11,13,16Furthermore, coagulation disorder often found in patients with severe COVID-19 and usually has a poor prognosis.Increased D-dimer, prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), and thrombocytopenia are common parameters in coagulopathy. 27,288][29] In patients with mild manifestations of COVID-19, proinflammatory chemokines and cytokines, as well as venous thromboembolism do not upgrade, even at the time of symptoms. 30

Pulmonary hypertension (PH) in children
If not recognized and treated early, pediatric pulmonary hypertension (PH) is a rare condition with a significant morbidity and fatality rate.Multiple investigations have established the rarity of sustained pediatric PH, with an estimated prevalence of 20 to 40 cases per million in Europe.The prevalence of pulmonary arterial hypertension (PAH), a kind of PH that affects the precapillary pulmonary arterioles, ranges from 3.0 to 3.7 cases per million children. 31 the last 20 years, there has been an increasing realization that juvenile PH is a distinct entity with its own pathogeneses, presentation, and management, despite some similarities to adult PH.A mean pulmonary arterial pressure (mPAP) greater than 20 mm Hg in children older than 3 months is considered pediatric PH.PAH is defined as an increased mPAP more than 20 mm Hg and pulmonary vascular resistance index (PVRi) (>3 Wood units (WU) m2) with normal left heart pressures.It is a subset of PH caused by anomalies in the precapillary arterioles.Because mildly increased mPAP (20-24 mm Hg) has been found to independently predict poor survival in adult patients with PH, these definitions, which were published by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, use a cutoff for a normal mPAP of 20 instead of the previously used 25 mm Hg. 32 Sustained PH was projected to affect 4-10 cases per million children per year in all categories, with a prevalence of 20-40 cases per million in Europe (Spain, the Netherlands), and 5-8 cases per million children per year in the United States (26-33 per million children).The majority of the children (2845 out of 3262) were newborns with "transient" PAH and either persistent PH of the newborn (PPHN) or repairable cardiac shunt abnormalities.Other forms of PAH (IPAH, PAH-CHD, PAH associated with connective tissue disease (CTD), and pulmonary veno-occlusive disease (PVOD) were found in 27% of the remaining children, while a significant proportion (34%) had PH associated with developmental lung disease, such as bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH), and congenital pulmonary vascular abnormalities (CPVA). 32cause the causes of PH are so varied, a systematic and complete diagnostic approach is required to arrive at an accurate diagnosis and treatment strategy.Furthermore, IPAH is a diagnosis made "by exclusion," meaning it can only be made after all other causes of PH have been ruled out.Despite this, recent registries have revealed that the majority of youngsters do not receive a thorough examination.For determining the definitive diagnosis and type of PAH, performing acute vasodilator test (AVT), and giving relevant data for risk stratification, right heart catheterization (RHC) remains the gold standard.This requirement must be weighed against the hazards it entails.RHC-related major problems in children with PH have been documented to be 1-3% of the time, and are often linked to clinical state and early age (newborns and young infants).As a result, cardiac catheterization in paediatric PAH is strongly advised to be performed in experienced paediatric PH centers with strategies to avoid these potential complications and the ability to manage complications such as PH crisis with aggressive interventions such as extracorporeal life support (ECLS).A kid may be too unwell to safely undergo cardiac catheterization in rare cases (e.g., World Health Organization Functional Class (WHO FC) IV).When there is a high suspicion of PAH and non-invasive imaging is positive, it is best to stabilize first and then begin appropriate PH therapy under careful surveillance, most typically in an intensive care unit setting.When the patient is adequately stabilized, RHC can be performed more safely. 32

Pulmonary hypertension (PH) in COVID-19
The COVID-19 and PH incidence in adults was 2.1 cases per 1000 patients.Meanwhile, there are few reports of this in children.Some contributing factors to its incidence with PH in children include the rarity of this disease and non-universal testing.However, drugs for treating PH may protect children against infection. 312][33][34][35][36][37] Deficiency or downregulation of ACE2, an enzyme that physiologically counteracts the renin-angiotensin-aldosterone (RAS) system, degrades and attenuates its effects on endothelial damage, vasoconstriction, and fibrosis.In the lungs of children, ACE2 expression and transmembrane serine protease 2 (TMPRSS2) are suppressed.The sequence of events that leads to ventilation/perfusion mismatch, hypoxia, vasoconstriction, and PH is known as endothelial dysfunction.It's crucial to start the chain of events that leads to a ventilation/perfusion mismatch, hypoxia, and other problems.Increased pulmonary artery pressure causes an increase in RV afterload, which causes RV vasoconstriction and PH.An rise in pulmonary artery pressure leads to increase of RV afterload, causing RV dysfunction and heart failure. 33Hemodynamic status in patients with ARDS is comparable with expansion in the diastolic pneumonic slope (the contrasts between the pressing factor of diastolic aspiratory corridor and aspiratory supply route wedge) >7 and pneumonic vascular obstruction (PVR) >3 Wood units.ARDS and consequent interstitial fibrosis are the outcome of significant lung injury.ARDS-related hypoxia causes pulmonary vasoconstriction and acute PH.Although the exact mechanism is unknown, a hypercoagulable condition and intravascular thrombosis may result from a systemic inflammatory response caused by cytokine storm and endothelial destruction.Hyperinflammation, fibrosis, and thrombosis all contribute to the development of PH and consequent RV dysfunction.SARS-CoV-2 produces endothelial dysfunction, diffuse microangiopathy, and microthrombosis, resulting in a ventilation-perfusion mismatch; intrapulmonary right-to-left shunting exacerbates hypoxia, resulting in a vicious loop that leads to pulmonary vascular remodeling. 33This is regular for this pre-capillary PH type. 38,39 PH is the increase of the mean pulmonary arterial pressure (PAPm) ≥ 25 mmHg at rest, or ≥30 mmHg during activity compared with normal PAPm (<15 mmHg) and PVR index >3 units of Wood units measured using right heart catheterization.PH is a pathological condition that can complicate most cardiovascular and respiratory system diseases. 43

Use of sildenafil to manage PH in children with COVID-19
During the pandemic, each child with a history of PH or newly diagnosed PH must be examined for COVID-19 when symptoms occur (fever, respiratory distress, or hypoxemia).If an antigen test shows a negative results, nevertheless the clinical COVID-19 is suspected, an antibody screening must be conducted. 31High-resolution CT (HRCT) capable for measuring changes in pulmonary blood volume and show prominent abnormalities according to "Pruning" of blood vessels and evaluate pulmonary vascular dysfunction.HRCT findings are highly related with increased pulmonary vascular resistance. 44o date, the literature related to PH therapy in children, especially clinical trials, is very limited.Generally, the treatment for PH in children follows the PH management algorithm in adults with some adjustment. 45Current pharmacological therapies used for the treatment of PH include the prostacyclin class (epoprostenol), prostacyclin analogues (beraprost, iloprost, treprostinil), endothelin receptor antagonists (bosentan), nitric oxide (NO), phosphodiesterase-5 inhibitor (sildenafil), and combinations of these preparations. 46e therapy of PH that occurs with COVID-19, in addition to medicine, oxygen should be given if the oxygen saturation <92%.Inhaled nitric oxide (iNO) is well known to treat ARDS and PH.Phosphodiesterase-5 inhibitors (PDEI), especially sildenafil, may reduce angiotensin type I (AT-1) receptors and degrade proinflammatory cytokines and infiltration of inflammatory cell in alveoli. 31osphodiesterase 5 (PDE5) inhibitors, like NO, increase cGMP levels in smooth muscle, causing pulmonary vasodilation.PDE5 inhibitors were initially used to wean patients off iNO after surgery, but they are now widely applied as firstline therapy in the treatment of PAH, along with other drugs. 31ere are currently many studies examining the effect of sildenafil for treating the PH in COVID-19, but mainly for adults and only a few reports of cases for children.Sildenafil is a potent inhibitor of phosphodiesterase-5, which can accumulate and increase the activity of cyclic guanosine monophosphate (cGMP) that works synergistically with NO. 47 PDE5 inhibitors, when given alone or in combination with prostacyclins, have been demonstrated to ameliorate symptoms in young patients with PH.The PDE5 inhibitor sildenafil improved the functional class and maximal aerobic capacity of pediatric PAH patients in the STARTS-1 trial, a double-blind, multicenter, placebo-controlled trial.The European Medicines Agency approved sildenafil for use in Europe based on the results of the STARTS study. 31The Food and Drug Administration (FDA) has recommended sildenafil for the treatment of PH since 2005.To date, this medicine is the most frequent medication in pediatric patients with secondary PH. 48,49Sildenafil is preferred because of the oral packaging in such a way that it is easy to administer.Sildenafil is commonly given three times a day and is entered as 1 mg/kg each dose in tablets, 10 mg for children between 10 to 20 kg, and 20 mg for children weighing more than 20 kg.The intravenous dose is half the amount given orally. 31The usual dose of sildenafil for children is 0.5-1 mg/kg, given 3-4 times a day.Administration of sildenafil in high doses can cause side effects such as erection and systemic hypotension. 48veral pilot studies on the safety of sildenafil have been and are being carried out.In one phase 3 study at Tongji Hospital, the 0.1 g/day was administered for 14 days (in COVID-19 patients between February 9 to November 9, 2020). 50urthermore, another study conducted in Brazil on children with positive COVID-19, admitted to ICU and receiving nitric oxide and/or sildenafil (0.5-2 mg/kg/dose each 4-6 hours with a maximum of 20 mg/dose every 8 hours) in patients with persistent hypoxemia showed encouraging results. 51A survey conducted to 300 respondents in China, there were 120 respondents from children to adults aged 32.3+11.5 years with PH.The medications given were bosentan, ambrisentan, tadalafil, and sildenafil.Bosentan and ambrisentan are widely used because they are cheap.There were 69 respondents (57.5%) that received sildenafil and showed good clinical results. 52

Conclusion
There is currently evidence of options for PH management in children.Sildenafil appears to be effective in improving pulmonary vascular hemodynamics.However, it has been shown that no single type of drug has been proven to be better than others.Furthermore, oral sildenafil is an interesting and effective therapy because it is easy to administer, has minimal side effects, and is less expensive than other therapeutic options.Randomized clinical trials with large sample sizes from various research centers are necessary to ensure the safety and optimal dosage of sildenafil in children with COVID-19.

Underlying data
No data are associated with this article.
The pathogenesis of pulmonary arterial hypertension is involving the role of remodelling that occurs in all layers of the pulmonary arterial wall.There are increasing of proliferative and apoptotic pathway activities, thickening of smooth muscle cell layer, increasing growth of endothelial cells and changes of vasoactive substances homeostasis.TGF-β has a role in proliferation, transformation, apoptosis, deposition of matrix extracellular protein, as profibrotic cytokine and induction of the secretion of proinflammatory cytokine.There is the activity of elastase proteolytic enzyme and matrix metalloproteinase (MMP) in the pulmonary arterial wall that induces the secretion of mitogenic growth factors from extracellular matrix protein.The adventitial fibroblast proliferation is increase beyond the smooth muscle cells proliferation, the dramatic increase in collagen synthesis, fibronectin and tropoelastin mRNA occurs, followed by increased deposition of these proteins.Fibroproliferative changes in the adventitial layer correlate with the narrowing of vascular lumen and progressive decrease in response to the vasodilation.Tissue inhibitor of metalloproteinase (TIMP) is an endogenous inhibitor of MMP.MMP expression and activity is increased in experimental pulmonary arterial hypertension.Imbalance of MMP-TIMP causes deposition of ECM and fibrosis of pulmonary artery wall.
An enzyme homolog known PDE5 contributes to it being easier for cGMP and/or cAMP to break down.Since PDE5 inhibitors restrict this enzyme's activity, systemic and pulmonary pressure are reduced.Furthermore, because pulmonary vascular resistance decreased compared with systemic vascular resistance, PDE5 inhibitors are more selective for pulmonary vasodilators.Since it improves pulmonary pressure, cardiac index, exercise capacity, and functional class-all indicators of the severity of the disease-sildenafil has emerged as the preferred treatment option for pulmonary arteriaI hypertension.
I propose that the author will continue on conducting the meta-analysis of pulmonary arterial hypertension treatment especially in COVID 19 infection.

Reviewer Expertise: Pulmonary Arterial Hypertension in Congenital Heart Disease Therapy
We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.In summary, this literature review is quite relevant for the current pandemic situation and it is worth indexing.But it would be better if minor revision to cite the literature regarding the mechanism of pulmonary hypertension that could be happening in Covid-19 infection which could be treated using phosphodiesterase-5 inhibitors.
Is the topic of the review discussed comprehensively in the context of the current literature?
The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com the topic of the review discussed comprehensively in the context of the current literature?Yes Are all factual statements correct and adequately supported by citations?Yes Is the review written in accessible language?Yes Are the conclusions drawn appropriate in the context of the current research literature?Yes Competing Interests: No competing interests were disclosed.

Version 1 Reviewer
Report 26 May 2022 https://doi.org/10.5256/f1000research.57403.r138090© 2022 Mishra A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Ajay Kumar Mishra Department of Cardiovascular Medicine, St Vincent Hospital, Worcester, MA, USA In this review, the authors have discussed COVID 19 pulmonary hypertension in children and the use of phosphodiesterase-5 inhibitors I have the following recommendations: Authors have given many details on COVID 19 per se and much fewer details on pulmonary hypertension, and pulmonary hypertension in children 1.In the literature review, it was not very clear what the correlation between pulmonary hypertension and the Covid-19 virus is.Particularly the pathomechanism of Covid-19 for the pathogenesis of pulmonary hypertension.So it would be a good point after the discussion of therapy of sildenafil, which is established as a drug of choice for pulmonary artery hypertension if there was an explanation of how the virus can cause pulmonary hypertension based on the literature.