COVID-19 in Cyanotic Congenital Heart Disease

Congenital heart disease (CHD) is the most prevalent congenital defect in newborn infants. Due to the various types of heart abnormalities, CHD can have a wide range of symptoms. Cardiac lesions comprise a range of different types and accordingly varying severities. It is highly helpful to classify CHD into cyanotic and acyanotic heart diseases. In this review, we are investigating the course of Coronavirus disease 2019 (COVID-19) in cyanotic CHD patients. The infection may directly or indirectly affect the heart by affecting the respiratory system and other organs. The effect on the heart that is pressure- or volume-overloaded in the context of CHD is theoretically more severe. Patients with CHD are at a higher risk of mortality from COVID-19 infection or suffering worse complications. While the anatomic complexity of CHD does not seem to predict the severity of infection, patients with worse physiological stages are more susceptible such as cyanosis and pulmonary hypertension. Patients with CHD exhibit continuous hypoxemia and have lower oxygen saturations because of a right-to-left shunt. Such individuals run the danger of rapidly deteriorating in the event of respiratory tract infections with inadequate oxygenation. Additionally, these patients have a higher risk of paradoxical embolism. Hence, critical care should be given to cyanotic heart disease patients with COVID-19 in comparison to acyanotic patients and this is through proper management, close observation, and adequate medical therapy.

sequencing in patient cohorts with CHD throughout the past 40 years of genetic study into heart illnesses.
Although the discovery of disease gene mutations' penetrance is well known, this research has yielded three noteworthy insights: frst, human CHD mutations afect a heterogeneous set of molecules that orchestrate cardiac development; second, CHD mutations frequently alter geneprotein dosage; and third identical pathogenic CHD mutations cause a variety of distinct malformations, and this suggests that higher-order interactions are responsible for specifc CHD phenotypes.

Types of Congenital Heart Diseases.
Tere are very few misdiagnoses made nowadays since clinical and echocardiographic diagnoses are so precise, but there are still signifcant diagnostic challenges with the classifcation and, consequently, with the inclusion as specifc lesions. Tese lesions comprise a range of diferent types and accordingly varying severities. CHD lesions include isolated ventricular septal defect, patent ductus arteriosus, atrial septal defects of the fossa ovalis (secundum) type, isolated partial anomalous pulmonary venous connection, atrioventricular septal defects, pulmonic stenosis, bicuspid aortic valves, coarctation of the aorta, and mitral incompetence [6].
Te classifcation of numerous lesions is inconsistent, and hence the classifcation of CHD into three types of lesions based on severity is, therefore, highly helpful. Te frst category presents severe CHD that encompasses cyanotic and acyanotic heart diseases. Most patients who present extremely unwell during the newborn period or early infancy fall into this category ( Figure 1). Cyanotic heart disease includes tetralogy of fallot including pulmonary atresia, absent pulmonary valve, and hypoplastic right or left heart. Although right-to-left shunting, insufcient pulmonary blood fow, or common mixing lesions can be used to categorize cyanotic heart lesions, many defects contain several physiologic problems [6]. Te "fve T's" of cyanotic CHD which include transposition of the great arteries, tetralogy of fallot, truncus arteriosus (also known as "truncus"), total anomalous pulmonary venous connection, and anomalies of the tricuspid valve remain a helpful mnemonic [7]. Acyanotic heart diseases include atrioventricular septal defect, a large ventricular septal defect, and a large patent ductus arteriosus [6]. Te second category presents moderate CHD which comprises mild or moderate aortic stenosis or aortic incompetence, pulmonic stenosis or incompetence, and complex forms of ventricular septal defect. Te third category presents mild CHD, most patients fall within this category, and this is due to their lack of symptoms, potential lack of substantial murmurs, and frequent early spontaneous resolution of their lesions. Tis category includes small ventricular septal defect, small patent ductus arteriosus, mild pulmonic stenosis, and others [6].

Noncardiac Cyanosis-Inducing
Etiologies. Some patients present as suspects of cyanotic heart defect as their presentation resembles that of Cyanotic heart disease; however, upon cardiological examinations, a heart defect is excluded. Serological markers reveal increased blood methemoglobin (MHb) levels and decreased activity of NADH-dependent MHb reductase which causes methemoglobinemia [8]. Methemoglobinemia, an uncommon yet easily detected condition, may resemble cyanotic CHD. A permanent or temporary enzyme shortage may be caused by toxic substances, particularly nitrate absorption. Methemoglobinemia with subsequent hemoglobin disorders or congenital enzyme defciencies has a dismal prognosis. Te preferred therapeutic and diagnostic tool is methylene blue [9]. As a matter of physiology, hemoglobin loses its capacity to transport molecular oxygen and carbon dioxide when the ferrous (Fe 2 ) iron component of hemoglobin is oxidized to the ferric (Fe 3 ) state to generate MHb. Cyanosis, compromised aerobic respiration, metabolic acidosis, and in extreme situations, mortality, are all efects of increased MHb levels. To convert MHb back to hemoglobin, erythrocytes contain reduced glutathione, reduced NADPH-MHb reductase, and cytochrome-b5-MHb reductase. When these enzyme systems are overworked, methemoglobinemia becomes fatal [10]. Individuals develop cyanosis as the MHb content rises. Te typical symptoms include confusion and tachypnea, followed by anxiety, light-headedness, headache, and tachycardia. Patients may have acidosis, seizures, arrhythmias, and eventually coma and death if the MHb levels rise. For a given MHb concentration, patients with the underlying cardiac, pulmonary, or hematologic disease may have more severe symptoms [11].

COVID-19/SARS-CoV-2
2.1. Overview. Te novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 outbreak, also known as COVID-19, which was initially discovered in China in December 2019 [12]. Te COVID-19 pandemic was formally classifed as a public health emergency of international concern by the World Health Organization in January 2020, as a result of the SARS-CoV-2 virus' quick spread over the world. Coronaviruses belong to the Nidovirales order's Coronaviridae family of enclosed, positive single-stranded RNA viruses with genomes that range in size from 26 to 32 kb [13]. Tere are currently four identifed genera of the virus, namely, alpha (α), beta (β), gamma (c), and delta (δ) [14]. Te novel SARS-CoV-2, on the other hand, is a member of the genus coronavirus and has an RNA genome size of 29.9 kb [15]. Research has shown that the SARS-CoV-2 virus is primarily spread between humans by inhalation or contact with droplets that are infectious, with an incubation period of 2 to 14 days [16][17][18]. A wide variety of clinical symptoms, ranging from asymptomatic to symptomatic, are associated with SARS-CoV-2 infection, including respiratory symptoms, fever, shortness of breath, cough, dyspnea, viral pneumonia, and in more severe cases, pneumonia, severe acute respiratory syndrome, heart failure, renal failure, and even death [19]. However, respiratory failure, septic shock, renal failure, hemorrhage, and heart failure are the leading causes of death associated with COVID-19.
Individual diferences in the clinical presentation of new SARS-CoV-2 infection range from asymptomatic presentations to severe respiratory distress syndrome and multiorgan failure. Consequently, it is difcult to make an accurate COVID-19 diagnosis. Te epidemiological history, clinical signs, and confrmation by a range of laboratory detection techniques are the main components of the usual clinical diagnosis of COVID-19 ( Figure 2) [20].

COVID-19
Pathophysiology. Te three phases of COVID-19 represent its pathogenesis. Viral entry into the respiratory epithelium initiates the frst phase, which is followed by cellular proliferation. Te initial immune response is characterized by moderate symptoms and is characterized by the activation of monocytes and macrophages. Pulmonary vasodilatation and enhanced vascular permeability mark the start of the subsequent phase. Following leukocyte migration, fuid extravasation and pulmonary edema occur. Alveolar injury, hypoxia, heart damage, and stress are thus provoked. Te excessive infammatory response leads to a large cytokine storm in the last phase, which is its defning feature [21].

COVID-19 in Patients with Cyanotic Congenital Heart Disease
Te SARS-CoV-2 infection may directly or indirectly afect the heart by afecting the respiratory system and other organs. In the context of COVID-19, there are three processes that result in cardiac involvement: (1) direct damage brought on by direct viral entry into cardiac cells, (2) hypoxiainduced myocardial ischemia, and (3) an exaggerated, heightened infammatory response characterized by endothelial overactivation and microvascular thrombi [2,22]. Te efects of this infection on a heart that is pressure-or volume-overloaded in the context of CHD could theoretically be more severe. Furthermore, there are no established  A sample should be obtained from the patient by means of a long swab that is inserted into the nostrils and is adequately swept against the walls of the nasopharynx. Following sample collection, RNA extraction is performed followed by any of the analytical laboratory methods (RT-qPCR, RT-LAMP, NGS, CRISPR, and ddPCR). Alternatively, a sample can be collected from the patient's serum. Blood is then treated to obtain antigens and/or antibodies present which then can be analyzed via ELISA, lateral fow of chemiluminescence immunoassay. Recreated from [20] via BioRender.  risk factors for COVID-19 severity in CHD patients [23]. Patients with CHD frequently exhibit genetic abnormalities, although it is unclear how these syndromes may afect the patient in this case. Physicians should prioritize emergency measures by learning how CHD afects the course and outcome of COVID-19 [23]. Patients with CHD are thought to be at a higher risk of mortality from COVID-19 infection or sufering worse complications. In a study conducted by Bromberg et al., adults with CHD had comparable COVID-19 mortality rates to the general population. While the anatomic complexity does not seem to predict the severity of infection, patients with worse physiological stages are more susceptible, such as cyanosis and pulmonary hypertension [24]. Te study yielded a conclusion that male sex, diabetes, cyanosis, pulmonary hypertension, renal insufciency, and prior hospital admission for heart failure were all risk factors for poor prognosis in COVID-19 and COVID infection-related mortalities [24,25]. Te most typical symptom in these patients is cough, followed by edema, fever, dyspnea, cyanosis, restlessness, and poor feeding in infants. Laboratory results show that some patients exhibit extremely increased C-reactive protein or erythrocyte sedimentation rate. Others develop mild lymphopenia, and some develop thrombocytopenia during their hospital stay. Low oxygen saturation levels also seem to be an alarming laboratory fnding [23].
Clinicians are in constant search for an association between CHD patients' contraction of COVID-19 and adverse outcomes of infection. For this sake, some researchers consider hospitalization for COVID-19 requiring noninvasive or invasive ventilation and/or inotropic support, as well as a death outcome to be defning features of a problematic and complicated disease course [26]. Cyanotic lesions, such as unrepaired cyanotic abnormalities or Eisenmenger syndrome, were among the congenital heart anomalies that posed a particularly high risk and are considered the most important predictors of a complicated disease course [26]. Due to a right-to-left shunt as well as severe aberrant pathobiology of the pulmonary tissue and pulmonary vascular bed, individuals with cyanotic heart disease, including those with Eisenmenger syndrome, exhibit persistent hypoxemia and frequently have much lower resting oxygen saturations. In the event of respiratory tract infections with reduced oxygenation, such patients hold a risk of rapidly deteriorating. An increase in right-to-left shunting caused by an increase in pulmonary vascular resistance and an infammatory-mediated decrease in systemic vascular resistance exacerbates pre-existing hypoxemia in the case of a severe COVID-19 infection [27]. Additionally, the risk of paradoxical embolism is higher for these patients. A worse result in these individuals may also be caused by the potential increased prothrombotic risk brought on by preexisting hemostatic problems, venous stasis, endothelial damage, and infammatory response [28]. D-dimer may aid in the early identifcation of these high risk patients and assist in outcome prediction. Additionally, preliminary fndings show that anticoagulant medication appears to be related to decreased mortality in the subgroup satisfying sepsis-induced coagulopathy criteria or with noticeably raised D-dimer levels in patients with severe COVID-19 [29]. Te main risk factor is venous stasis, which is frequently visible in the cavopulmonary circuit due to the lack of a pump for both pulmonary blood fow and systemic venous return; therefore, these patients should be given long-term anticoagulation [30]. Even lesser levels of pulmonary involvement can be anticipated to cause the patients status to worsen. To avoid stroke from an air embolism, air flters should be installed on all venous cannulas in patients with (residual) right-to-left shunts [31].
Oxygen saturation levels of less than 90% at rest or during activity may be typical in adults with CHD patients with cyanotic heart disease. Cyanosis can be remarkable when the fngers and toes are clubbed. In addition to the present measurements, treatment decisions must be based on the pre-COVID-19 baseline oxygen saturation [31]. Instead of absolute values of oxygen saturation, thresholds for oxygen dosing or switching to mechanical ventilatory assistance must be based on variables such as respiratory rate and lactate levels. Venesections should not be performed since chronic cyanosis causes an adaptive increase in hemoglobin levels that are needed in this situation ( Figure 3) [31].

Impact of COVID-19 on Pediatric Patients with Congenital
Heart Disease. According to recent advances, the COVID-19 infection and the pandemic's collateral damage present a burden on pediatric patients with CHD. Most infected pediatrics have mild to moderate illnesses, and laboratory and radiographic data show signifcant interindividual variation. However, cardiac involvement in children with COVID-19 who are healthy has been observed and is related to a number of factors [2]. Children can develop myocarditis, arrhythmias, cardiogenic shock, and catastrophic multisystem infammatory syndrome. Children who have been infected have reported cases of asymptomatic, mild, moderate, severe, and critically sick cases. Patients with CHD, especially those with cyanotic abnormalities, are more likely to need intensive care unit (ICU) hospitalization and artifcial respiratory assistance. COVID-19 may aggravate hypoxemia and impair tissue perfusion in these patients. Additionally, patients with complex CHD who also have pulmonary hypertension, immunodefciencies (such as DiGeorge syndrome), and other concomitant diseases such as reduced myocardial contractility are at risk of developing severe and critical COVID-19 illness [2].

Vaccination for COVID-19 in Congenital Heart Disease
Patients. Until today, there are not enough data on the COVID-19 vaccine's acceptability, immunogenicity, and safety in adults with CHD. In a study conducted by Fusco et al. on COVID-19 vaccination in adults with CHD has revealed that COVID-19 vaccinations, had it been Pfzer-BioNTech BNT162b2 vaccine, Moderna, or AstraZeneca-ChAdOx1, have acceptable immunogenicity and seem safe in adults with CHD. However, the most susceptible patients in the study displayed a reduced antibody response. Patients in this study reported symptoms after the frst and second doses. Symptoms duration was always limited, there were no allergic responses, and the most frequent symptoms were headaches, fever, muscle soreness, gastrointestinal disturbances, exhaustion, and dizziness [32]. To this end, studies provided comforting information about the vaccinations' good safety profle, with the majority of side efects being brief and mild, similar to what has previously been documented in the general population worldwide [33]. It appears that vaccination avoidance based on worries about vulnerability due to the underlying heart disease is not justifed. Vaccine administration is a low-risk action. As noted before, regardless of prior viral infection, adults with CHD patients with advanced physiological stages may have reduced antibody responses; however, this does not diminish the positive efect of these patients receiving COVID-19 vaccines [32].

Specifc Considerations for Severely Afected Adults with
Congenital Heart Disease Patients. When handling severely impacted adults with CHD patients with complicated underlying lesions, a detailed study of the underlying anatomy and pathophysiology is necessary, and they should be admitted to secondary or tertiary adults with CHD centers. Many adults with CHD patients are prone to developing arrhythmias, which frequently require immediate management to avoid decompensation [34]. Some concerns are relevant for adults with CHD patients who are hospitalized in critical care units. For instance, common prior surgical procedures (Blalock-Taussig-Tomas shunts and subclavian fap) can alter blood pressure readings, so measures should be performed from the contralateral side. Chronic arterial occlusion typically prevents central venous access because of prior critical care stays, numerous operations, and pacemaker leads. Large catheters, such as those used for hemofltration, may have trouble ftting through a persistently tiny right superior vena cava due to a persistently small right superior vena cava.
Patients with Down syndrome are more likely to develop lung infections and acute respiratory distress syndrome which are frequently linked to CHD and immunological abnormalities ( Figure 3) [35].
In a study conducted by Sachdeva et al. on the outcome of COVID-19-positive children with heart disease and grown-ups with CHD, researchers aimed at identifying risk factors that might be associated with mortality in those patients. A total of 94 patients were included, and they were presented with either symptomatic or asymptomatic COVID-19 infection. In this study, researchers classifed the types of heart diseases into obstructive, acyanotic, and cyanotic CHD and acquired heart disease in children. 31 patients had acyanotic CHD, and 39 patients were cyanotic, with >80% of the patients being unoperated. Based on the occurrence of cyanotic episodes, refractory heart failure, persistent shock, or the need for ventilatory support, the degree of sickness upon presentation was divided into severe and nonsevere illness [36]. Children with CHD are known to have poorer prognosis with common respiratory viral and bacterial infections, and pneumonia are the most prevalent noncardiac cause of mortality in these children [36,37]. Furthermore, COVID-19 pneumonia in a child with CHD can result in hypercapnic vasoconstriction, worsening V/Q mismatch, embolic events, worsening pulmonary Key issues for critical care management of COVID-19 patients with Congenital Heart Disease Cyanotic heart disease General Considerations Admit to secondary or tertiary adults with Congenital Heart Disease center. Blood pressure readings affected by some surgical procedures. In this case, measurements should be taken from the contralateral side. Central venous access may be difficult due to chronic vascular occlusion or anomalous veins. Arrhythmias are frequent and can lead to rapid deterioration. Compare ECG with baselines.
Impairment of lung function is prevalent in adults with Congenital Heart Disease patients and should be expected to negatively infuence disease course.
Patients with Down syndrome are at higher risk for pulmonary infections and Acute Respiratory Distress Syndrome.
Oxygen saturations <90% at rest or with exercise are the norm. Treatment guided by oxygen saturation compared with baseline, respiratory rates and lactate levels. Hemoglobin levels should not be lowered by venesections.
Increased risk for thromboembolic complications as well as bleeding. Expected to deteriorate with even milder degrees of pulmonary involvement. Air filters on all venous cannulas in patients with right-to-left shunts to prevent stroke. hypertension, and progressive hypoxia. According to this study, children with cyanotic CHD are probably more prone to experience this combined impact, which will decrease tissue oxygenation and perfusion, hence, making these patients face a fatal battle against COVID-19 infection. [38]. Literature has some studies that contradict the former fndings. Some studies concluded that children and young adults with an underlying cardiac condition rarely had to be hospitalized for coronavirus illness. Cardiovascular risk factors were not linked to an increased chance of hospitalization; however, extracardiac comorbidities were linked. Te severe acute respiratory syndrome of coronavirus did not seem to be associated with the traditional cardiac risk factors for more severe acute respiratory infections in children. For instance, in these studies, most patients who required treatment had ventricular dysfunction, or had persistent, substantial cardiac abnormalities that afected hemodynamics, reported having mild or asymptomatic infections [39]. Te patients with palliated single ventricle CHD and those with residual cyanotic CHD who are among the people most at risk for developing severe respiratory infections did not require hospitalization for the severe acute respiratory syndrome of coronavirus infection during the study period. When comorbidities were examined individually as risk factors, only chronic lung disease and immune suppression showed statistically signifcant correlations with hospitalization. Tis conclusion may be partially explained by the limited sample size of these studies, which reduces the sensitivity to identifying possible risk factors in cardiac patients [39].
To this end, according to the anatomical and physiological stage classifcation, patients with complex CHD, such as Fontan patients, cyanotic congenital heart defects (unrepaired or palliated), single ventricles, and pulmonary atresia, should be regarded as having high risk of complications from COVID-19 infection because of a decreased functional reserve. When patients are admitted, the treatment plan should address indicators of end-organ damage, symptomatic support, and management of respiratory failure. Patients with mild illness can be handled with noninvasive measures of additional oxygen support [40]. However, patients with severe COVID-19 disease frequently require intubation to improve oxygenation and ventilation because they have symptoms resembling acute respiratory distress syndrome. Tis can be difcult for Fontan patients because increased intrathoracic pressure brought on by positive pressure ventilation has detrimental efects on intrapulmonary and intracardiac hemodynamics, resulting in lower preload and, ultimately, decreased systemic cardiac output. Positive end expiratory pressure (PEEP) should be kept within the range to maintain the lung's functional residual capacity and prevent atelectasis and hypoxia-related vasoconstriction if intubation is necessary [40]. . When looking at the hospitalization of these patients, and according to recent research by the American Heart Association, people who were hospitalized with COVID-19 infection and had a congenital heart defect were more likely to experience serious sickness along with a complicated disease course or die than those who did not have a congenital heart problem. Individuals with congenital cardiac defects who contracted COVID-19 were also more likely to need ventilator support or treatment in an ICU [41]. Patients who had a heart defect and other medical issues were older than 50, or were male were among those who were most at risk for developing the most severe COVID-19 sickness [42]. In a study conducted by Diaz et al., the researchers attempted to describe patient characteristics in those with and without CHDs during hospitalization for COVID-19. At the time of the COVID-19 hospitalization, the results of the study revealed that patients with CHDs were considerably more likely to have obesity, acute pulmonary hypertension, venous thromboembolism, acute ischemic stroke, acute arrhythmia, myocardial damage, and heart failure but not respiratory failure. Patients with CHDs were much more likely to be admitted to the ICU and had a signifcantly longer median length of stay than patients without CHDs [43]. Furthermore, it is important to identify the risk factors associated with the increased mortality rates in these hospitalized patients. Studies had implied that physical symptoms such as anorexia, nausea, vomiting, diarrhea, chest discomfort, myalgia, and fever have no bearing on a patient's mortality. However, the mortality rates of COVID-19 cardiovascular patients were signifcantly correlated to symptoms such as headache, loss of consciousness, oxygen saturation below 93%, and the requirement for mechanical ventilation [44].

Materials and Methods
We performed a comprehensive and updated search on the severity of SARS-CoV-2 infection in patients with cyanotic CHD. Our search included some studies and reports published in the literature. Our search relied mostly on PubMed, Medline, and Google Scholars. Te keywords used for the search included congenital heart disease, cyanosis, COVID-19, and SARS-CoV-2. Upon our search, studies handling the association between COVID-19 and CHD were retrieved, and their conclusions were compiled in our review. Te studies are tabulated (Table 1), which shows the objectives, methodologies, and results of each study. Additionally, many narrative reviews were also retrieved to complement and support the information presented in our review.

Discussion
According to the literature presented above, the comorbidities and the complexity of the heart defects were thought to be the main risk factors for poor outcomes in the case of COVID-19. Patients with cyanotic heart disease are at a particularly high risk when challenged with the infection. Upon infection with COVID-19, the existing cyanotic CHD manifests itself dramatically. Patients with cyanotic heart disease exhibit continuous hypoxemia and frequently have considerably lower resting oxygen saturations because of a right-to-left shunt as well as severe abnormal pathobiology   between January 1, 2020, and December 10, 2020. We used poisson regression to describe and compare epidemiologic characteristics, heart-related conditions, and severe outcomes between these two groups Adults with CHD appear to be at greater risk for more severe CHD, including greater risk of ICU admission and longer length of hospital stays  [27]. Tese patients are at an increased risk for rapid health deterioration in the setting of respiratory tract infections with inadequate oxygenation [27]. Importantly, patients have a higher risk of paradoxical embolism [28]. Tis risk stems from the concomitant prothrombotic risk due to pre-existing hemostasis issues, venous stasis, endothelial damage, and infammatory response may also result in a worse outcome [28]. Despite all these fndings, a study conducted by Sabatino et al. aimed to evaluate the clinical traits and prognoses of COVID-19afected CHD patients [45]. Te cohort study showed that patients with CHD experienced a mild COVID-19 clinical course in contrary to the high case-fatality rates observed in earlier studies on patients with cardiovascular comorbidities [45]. However, this study had several limitations but was reassuring and comforting for CHD patients [45]. Along the course of COVID-19 pandemic, the approach to the vulnerable patients given their diferent presentations was problematic. Professionals in charge of particularly high risk groups, such as adult patients with CHD, were forced to make difcult choices during the initial onset of the COVID-19 pandemic [46]. During the early weeks of the pandemic, preexisting cardiovascular illnesses were discovered to be a key indicator of a poor prognosis in cases of infection with the novel SARS-CoV-2 [46]. It was not known for a long time whether this link held true for the predominantly adult individuals with CHD. A prospective multicenter European registry published in March 2023 attempted to assess the changes in risk stratifcation of adults with CHD patients [46]. By contrasting the results of two surveys given to experts in the feld of adults with CHD at two diferent points during the pandemic, at the start and soon after the frst outcome data on adults with CHD patients with COVID-19 were available, they determined changes in risk stratifcation of adults with CHD patients during the pandemic [46]. Te overall risk perception was lower in the second survey than it was in the frst when assessing the signifcance of general and adults with CHDspecifc risk factors for a complicated disease course in the case of COVID-19 among the patients [46]. Tis was true even for risk factors related to physiological stage, which have been linked to poor prognostic outcomes in adults with CHD patients with COVID-19 [24,46].
Tis implies that the same risk factors that suggest poor outcomes in COVID-19 cases as are seen in the general population similarly infuence the outcomes of adults with CHD patients [46]. Although COVID-19 individuals with cyanotic heart illnesses were at risk for a worst outcome in general, the anatomical complexity of CHD per se did not appear to be related to the increased mortalities and morbidities in case of COVID-19 infection [46]. Te prognosis of patients in later waves of the pandemic was improved by the knowledge gathered during the frst wave, and hence, approach to the patients has changed signifcantly along to pandemic [46].

Conclusion
Te COVID-19 pandemic has acutely afected patients with the underlying medical conditions. However, the efects of this infection in the context of CHD could conceivably be more severe, particularly in patients with cyanotic CHD. Based on the anatomical and physiological stage classifcation of the cardiac status, physicians should have specifc considerations when handling a cyanotic patient. However, more studies need to address the clinical presentation of cyanotic CHD patients in particular and investigate the changes of this presentation along the various waves of COVID-19 pandemic. Tis would allow for a better healthcare provision and better treatment outcomes.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Lama A Ammar and Joseph E Nassar have contributed equally to this work.