Covid-19 Transmission, Risks Factors and Disease Characteristics in Asthmatics Patients

Asthma is a chronic disease characterized airflow limitation and is one of the most common chronic diseases in Saudi Arabia, with the prevalence rate of 11.3% among physician-diagnosed respiratory disease [1]. The Saudi Thoracic Society initiated the Saudi Initiative for Asthma (SINA) in the year 2008 to ensure best practices in pulmonary and respiratory medicine arein use. The updated 2021 guidelines apart from integrating recommendation around new medication, and evidence-based treatment updates, also included the coronavirus disease 2019 (COVID-19) management guidelines wherein the recommendations were stratified as per different age groups; adults (> 18 years), adolescents (13–18 years), children (5–12 years and < 5years) [2]. The novel coronavirus pandemic of 2019 had global implications on healthcare management, although in Saudi Arabia, a similar challenge was posed by the Middle East respiratory syndrome coronavirus (MERS-CoV) when the first case was detected in September 2012, in a 60-year-old from Bisha, Saudi Arabia [3]. Though MERS (1139 cases, 431 deaths) and severe acute respiratory syndrome (SARS; 8273 cases, 775 deaths) pandemic occurred in the past in the year 2013 and 2003 respectively, the numbers being registered in the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been much more and world continue to fight multiple waves of increasing severity till date. The COVID-19 pandemic has affected over 46 countries internationally, as the virus continues to mutate, and new strains are being isolated from different parts of the world. The major challenge in COVID-19 management continues to be an asymptomatic transmission, wherein a China CDC study found 80.9% of the asymptomatic or mild pneumonia cases to have released large amounts of viruses in early infection stage. Further, epidemiological data indicate the disease spectrum of SARS-CoV-2 to be different from the previous SARS and MERS [4]. A summary of host and reservoir for SARS-CoV-2 with the information has been detailed in Table I.

The COVID-19 pandemic began in December 2019, when a series of cases resembling viral pneumonia were recorded from Wuhan in China. The health authorities issued an epidemiological alert on 31^st December 2019 as 59 suspected cases with symptoms of fever, and dry cough were transferred to a designated hospital even as all the pneumonia of unknown origin were found to have a shared history of exposure to the Huanan seafood market. Further, of the 59 suspected cases, 41 were confirmed to be affected by the 2019-nCoV, latter called SARS-CoV-2 by testing the respiratory specimen by next-generation sequencing (NGS) and real-time polymerase chain reaction (RT-PCR). Further, chest radiography of the confirmed cases revealed abnormalities in all, and 98% exhibited bilateral involvement. The chest-CT findings among non-ICU patients included bilateral ground-glass opacity and subsegmental areas of consolidation. Further, all patients had pneumonia. As on Jan 2020, 15% of the 41 confirmed cases died, as the time between hospital admission and development of acute respiratory distress syndrome (ARDS) was found to be as short as 2 days [5].

The origin of coronaviruses; both SARS and MERS have been linked to bats and transmitted to humans through market civets and dromedary camels, and whole genome sequencing analysis of a SARS-CoV-2 revealed presence of human angiotensin-converting enzyme 2 (ACE2) receptor which enable virus to infect and replicate inside human cells using the [6,7]. The findings around pathogenicity of coronavirus in humans became highlighted only after the SARS epidemic of 2002 and 2003 in China, followed by MERS which emerged in the Middle Eastern countries in 2012 [8, 3]. The need to study the present coronavirus involved in the COVID-19 pandemic arises as it becomes one of the notorious infectious diseases to have arrived in recent times, and the risk of such outbreaks in the future continues to remain high. The existing virologic, epidemiologic, data establishes that the SARS-CoV-2 would have evolved from a beta-coronavirus even as the warning issued by a group of Scientists studying coronaviruses in the year 2007 which was ignored earlier. The warning clearly read “The presence of a large reservoir of SARS-CoV-like viruses in horseshoe bats is a time bomb. The possibility of the re-emergence of SARS and other novel viruses should not be ignored” [9]. Global reservoirs of coronaviruses have been identified in the America, the Africa, the Middle East, and the South East Asia including China [10].

These highlight the need for understanding transmission and risks involved in SARS-CoV-2pandemic, to ensure minimal damage to human life, and effective control measures can be devised in place. Aggressive monitoring of the hotspots has also been recommended by scientists to predict and prevent viral emergence and limiting zoonotic interaction is also a key. The COVID-19 pandemic has posed a broad challenge to the scientific and medical community towards identifying symptoms, devising rapid diagnostic methods, follow-up, in addition to managing the rising medical crisis. Furthermore, since this virus affects the respiratory system individuals with pre-existing respiratory health conditions including chronic obstructive pulmonary disease (COPD) and asthma, were categorized as high-risk with possibility of severe disease consequences [11, 12].

Global burden of the SARS-CoV-2 continues rise with multiple nations suffering from burden of waves of infection burden apart from insurgence of multiple variants. This is closely followed by India with number of infected at 2,96,36,638 and 379,652 deaths indicating a death rate of 1.3%. However, there are regions which have reported less than a lakh case including China Mainland (91,471), Afghanistan (93,765), Singapore (62,339), Australia (30,274) to name a few. In terms of death per million (DPM), the highest ranking is Peru at 5665 (9.4% deaths), followed by Hungary at 3107 (3.7% deaths). The United Kingdom and the USA also report DPM of over 1000 at 1875 (2.8% deaths), and 1850 (1.8% deaths), respectively. Developing nations however, recorded low DPM for COVID-19, with India at 273, Nepal at 287; while China has a record low DPM at 3. In terms of Middle East, Saudi Arabia records a DPM of 215 (1.6% deaths), and the United Arab Emirates (UAE) at 173 (0.3% deaths) [13].

In case of Saudi Arabia, the number of confirmed cases stands at 468,175 and deaths at 7,606 until December 2021. The government of Saudi Arabia implemented early protective measures from the standard recommendations of social distancing, use of personal-protective-equipment, and stay-at-home to cancellation of the international Haj 2021. The rapid action could also be attributed to the fact that viral epidemics have been a part of the Saudi history from the Spanish flu of 1919, H1N1, MERS and now COVID-19, with the first case being reported on March 2^nd, 2020, from the Kingdom. The state is also providing free medical treatment to their citizens affected by COVID-19 in both public and private sector healthcare institutes [14].

Scientific evidence around epidemiology and transmission aspects of the SARS-CoV-2 have indicated old age, male gender, pre-existing comorbidi-ties, including diabetes, hypertension, heart disease, obesity, chronic lung disease, immunodeficiency, as well as pregnancy, to be the possible risk factors for COVID-19 progression [15]. The early months of the pandemic only painted a critical picture of the affected with patients in intensive care, struggling to breathe an in need for artificial ventilation. However, transmission studies further identified the benign nature of the infection in many individuals indicating “asymptomatic” presence [16]. Studies have also found the viral load and transmission risk to be comparable between the asymptomatic and the severely symptomatic and the only diagnostic distinguishing to be achieved through longitudinal testing [17, 16]. 41.1% and 44.8% of asymptomatic transmission was noted in a study from Italy which reported results from the two-pilot time sampling involving 85.9%, and 71.5% of Vo municipality population. Further, the authors reported none of the asymptomatic to develop symptoms in the two-week sampling window [18].

Controversy around susceptibility of adolescents, and youth towards SARS-CoV-2 has been recorded, as old age has been a documented risk factor. Many studies have reported low susceptibility among adolescents and data analysis from the Department of Health website of the US (six states) experiencing surges found prevalence to be significantly higher among adolescents (10–19 years) and youth (15–24 years) (p < 0.00001) [19] than older aged people. Recent studies have also indicated susceptibility to COVID-19 to be independent of age according to mathematical modeling outcomes on data from Japan, Spain, and Italy; but disease severity and mortality to be age dependent [20].

Disease manifestation in severe cases have been noted to include signs of dyspnea, blood oxygen saturation of ≤ 93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300 mmHg, respiratory frequency ≥ 30/min, within 24–48 hours of time span [21]. Studies have evaluated the occurrence of dysphagia in COVID-19 due to neuromuscular complications, prolonged bed rest, and endotracheal intubation [22]. Studies have reported one-third of the hospitalized patients to exhibit neurological symptoms including loss of taste and smell due to cranial nerve manifestation, with a frequency of 5.6%, and 5.1% respectively [23]. Hypernatremia has also been recorded as a manifestation of COVID-19 wherein studies records show development of first-time therapy-resistant hypernatremia (plasma sodium concentration ≥ 150 mmol per liter) among critically ill between age groups of 57–84 years in medical ventilation [24]. In terms of oral manifestation, dysgeusia has been recorded which includes ulcer, pustule, vesicle, depapillated tongue, plaque, pigmentation, hemorrhagic crust, necrosis, swelling, and spontaneous bleeding; with tongue involvement being 38%, the labial mucosa at 26%, and the palate at 22% respectively. Further, oral lesions have also been recorded to be symptomatic among 68% of the cases [25]. Gastrointestinal symptoms have also been recorded among patients at frequency between 16% to 33% and has been associated with severe disease stage [26]. Ocular presentations of COVID-19 have also been reported in a case series from China, 31.6% of hospitalized patients exhibited ocular symptoms including conjunctival hyperemia, chemosis, epiphora, and increased secretions [27]. Skin manifestations of COVID-19 have also been recorded which include pseudo-chilblains, rashes with macules and papules, urticaria, vesicular, and vaso-occlusive lesion [28]. Neurological manifestations recorded include myalgia, headache, hyposmia, altered sensorium, apart from certain uncommon ones like intracerebral hemorrhage, ischemic stroke, acute myelitis, and encephalo-myelitis [29].

Studies have also recorded multiple comorbidities to increase disease severity including arterial hypertension (OR = 2.01, 95% CI: 1.3–3.2), diabetes (RR = 2.96, 95% CI: 2.31–3.79), obesity (OR = 3.0, 95% CI: 1.22–7.38), asthma (OR: 1.39, 95% CI: 1.13–1.71), and COPD (OR = 1.36, 95% CI: 1.15–1.60) [30, 31, 32, 33, 34].

The most common symptoms of COVID-19 have been summarized in Table II.

Literature search was done to include research, longitudinal, observational, and case reports pertaining to the novel coronavirus disease of 2019. The keywords used for the search included “COVID-19”, “SARS-CoV-2”, “pandemic”, “asthma”, “coronavirus”, “respiratory disease”, and search engines including PubMed, Google Scholar, Scopus, and the Web of Science was used to select publications between the years 2019 to 2021.

The initial viral interaction in the nasal mucosa among humans occurs by binding of the spike (S) protein with the ACE2 receptor and enters principally via the upper airway epithelium., followed by cleavage of viral S protein by host TMPRSS2 (transmembrane serine protease 2), which aids in viral entry [35]. In terms of respiratory distress, the most common COVID-19 presentations include acute respiratory failure, disorders of the airway, lung parenchymal, and pulmonary vascular region [36]. Studies have also suggested the shunt physiology to be accompanied with severe abnormalities in the ventilation-perfusion (V/Q) matching with disordered hypoxic vasoconstriction [37]. Further, radiographic comparison between Computerized Tomography scans of COVID-19 affected, and other viral pneumonia has shown peripheral distribution of opacities, ground-glass and fine reticular appearance with vascular thickening to be prominent in the former [38]. Further, the infected epithelial cells have been shown to express high levels of inflammatory cytokines including C-X-C motif chemokine 10 (CXCL-10), and interferons [39]. An enhanced Th2 immune response and the elaboration of cytokines contribute to the induction of allergy and asthma. Studies have found the infected alveolar epithelium cells to produce pro-inflammatory chemicals including interleukins (IL-6, IL-8, IL-29), and chemokines (CCL5, CXCL9, CXCL10, and CXCL11) [40]. Interferon-γ, a Th1 cytokine, acts in conjunction with Th2 (IL-4, IL-13, and IL-5) in maintaining chronic allergic inflammation. The mechanisms leading to an enhanced Th2 response are still controversial. Th2-dominated immune responses may result from immune suppression of T-regulatory cells as well as Th1 cells. Understanding early-life immune mechanisms responsible for atopic diseases, specifically how cytokines of T-regulatory cells act to balance the Th1 and Th2 immune response, continues to be a fruitful area of research. The incidence of deep vein thrombosis has also been recorded to be high among hospitalized cases with studies reporting a frequency of up to 20% among the intensive care unit admission [41]. Evidence also indicates risk of potential sequela to the COVID-19 respiratory problems including fibrotic lung disease, pulmonary vascular disease, chronic cough, and bronchiectasis [42]. Recommendations from the British Thoracic Society include chest radiography to be done 3 months’ post hospital discharge of all COVID-19 patients and those with history of severe disease, persistent symptoms, and radiological abnormalities should be investigated further [43].

Studies have also evaluated COVID-19 disease outcome by stratifying comorbidities and one such from China found COPD (HR = 2.681 (1.424–5.048) 95% CI), diabetes (HR = 1.59 (1.03–2.45) 95% CI), hypertension (HR = 1.58 (1.07–2.32) 95% CI) and malignancy (HR = 3.50 (1.60–7.64) 95% CI) to be the risk factors of reaching the composite end-points and comorbid COVID-19 patients were found to exhibit poor clinical outcomes [44]. Studies have also evaluated the impact of COPD and smoking on COVID-19 disease outcome, and found COPD to be an increased risk factor for poor outcome (OR = 5.01; 3.06–8.22; 95% CI), mortality (OR = 4.36; 1.45–13.10; 95% CI), severe COVID-19 disease (OR = 4.62; 2.49–8.56; 95% CI), and ICU admission (OR = 8.33; 1.27–54.56; 95% CI). Further, smoking was also found to significantly increase risk of severe COVID-19 (OR 1.65; 1.17–2.34; 95% CI) [45].

The presence of asthma, a chronic airway disease has been increasing since the year 1950, and more than 300 million people worldwide have been reported to be affected: by both allergic and non-allergic causes. It is a heterogeneous disease characterized by persistent cough, wheezing, and dyspnea; affecting the lower respiratory tract [46, 47]. Further, the management of asthma includes long-term exposure to systemic corticosteroids which increases risk of other disease conditions including hypertension, diabetes, and impaired humoral immunity [48]. In studying the relation between asthma exacerbation in COVID-19, published reports till date are divided in the findings, which continues to be intriguing as Coronaviridae have been associated with asthma exacerbation in up to 27% of the adults [49]. Since virus commonly trigger asthma exacerbations, asthma became listed as a risk factor for COVID-19 morbidity, as the symptoms presented also included the common acute asthma inclusions like shortness of breath and dry cough. Further, recommendations indicate benefit from use of oral steroids for patients with asthma with weak response to bronchodilators, although the same is not recommended to treat COVID-19 lung disease due to risk of increased viral replication [50]. A study conducted on 150 COVID-19 patients indicated IL-6 an indicator of death. Significant difference in levels of white blood cell counts, platelets, albumin, total bilirubin, blood urea nitrogen, blood creatinine, myoglobin, cardiac troponin, C-reactive protein (CRP) and interleukin-6 (IL-6) was found between the deceased group and the survivors [51].

Reports from Saudi Arabia indicated the prevalence of asthma to be 2.9%, 0%, and 7.7%, among patients with mild, moderate, and severe COVID-19 [52]. In a Brazilian retrospective study including 51,770 COVID-19 cases, the prevalence of moderate to severe asthma was found to be 1.5%, while in a Spanish study, the prevalence was noted to be 3.7% among the fatal cases, and 5.5% among the discharged cases [53, 54].

Studies have also focused on documenting the clinical course of COVID-19 among asthma patients using big data analytics and artificial intelligence. One such analysis including 71182 patients with asthma, found the frequency of COVID-19 to be 1.41%, and much higher than the recorded 0.86% among the general population. Further, the cohort majorly included older adults (55 vs 42 years), and female gender (66% vs 59%), apart from smoking, hypertension, diabetes, and obesity. This study found increased risk of COVID-19 hospitalization among asthma patients to be linked with age and comorbidity-related factors. Further, use of inhaled corticosteroids (ICS) and biologics to have a protective impact against severe disease as low rate of hospitalization was noted among both, and specifically 0.23% for biologics [55]. Another clinical study involving 1526 COVID-19 patients, found 14% to be asthmatics, and wherein the condition (OR = 0.96; 0.77–1.19; 95% CI), and use of ICS (RR = 1.39; 0.90–2.15; 95% CI) did not increase the risk of hospitalization in an adjusted model [56]. Multiple reports from China including one by Zhang J.J. et al., [57] involving 140 patients, and Chen N. et al., [58] involving 99 cases, did not find asthma or allergic disease as a risk factor or pre-existing comorbidity in COVID-19. Few studies however, have reported finding the presence of comorbid asthma among hospitalized COVID-19 patients. These include one report from 106 patients from the Chest Diseases Department of Strasbourg University Hospital, wherein 23 patients were found to have asthma. Further, no significant difference between patients with and without asthma was noted with respect to need of maximal oxygen flow, length of hospital stays, need for non-invasive ventilation or the intensive care transfer; and SARS-CoV-2 did not induce severe asthma exacerbation [59]. Another UK study involving 16749 hospitalized patients found asthma to be the fourth-common comorbidity at 14%, after chronic cardiac disease (29%), uncomplicated diabetes (19%), and non-asthmatic chronic pulmonary disease (19%) [60]. The inconclusive association between COVID-19 and asthma has been reported in observational studies from different parts of the world including multiple reports from China, where the pandemic began. Few studies which have reported increased asthma prevalence among COVID-19 patients indicate underreporting, and under diagnosis to be the cause for inconclusive evidence. The data reported from the Center for Disease Control and Prevention found 27.3% of COVID-19 positive hospitalized patients to have listed asthma as a comorbidity from several hospitals across US [61].

Several Study reports also indicate asthma to be protective in COVID-19, wherein studies have found eosinophils to be reduced in SARS-CoV-2 infected peripheral blood, and it is speculated that increased eosinophils in the airway of asthmatics might be protective against the exaggerated inflammatory response in COVID-19 [57&62]. Another study involving 951 COVID-19 asthmatics found pre-existing eosino - philia (AEC ≥ 150 cells/μL) to be protective from COVID-19-associated admission, and development of eosinophilia during hospitalization to be associated with decreased mortality (mortality rate 9.6% vs 25.8%; OR = 0.006, 95% CI: 0.0001–0.64) [63]. Other protective factors against SARS-CoV-2 among patients with allergic asthma has been reported to be the asthma treatment, overproduction of mucus, and the T2 immune response [64, 65, 66]. Besides, the respiratory epithelial cells of asthma patients have been found to have reduced expression for ACE2 receptors which may contribute to protection from SARS-CoV-2 infection [64 & 67]. A study from Saudi Arabia involving 1519 confirmed cases of COVID-19 found 71.6% of the cases to be hospitalized, 4.7% to be admitted to intensive care and 9.3% of people with COVID-19 did not show symptoms. The study did not specifically clarify the symptoms associated with them. The study did not add details about the development and severity of cases [68].

In terms of management, it has been noted that there is a concern in the medical community on the use of nebulizers in hospitals to treat patients with asthma, especially those with COVID-19, as it can cause possible transfer of contaminated droplets to the uninfected and the medical staff [69]. Further, there is a consensus among the medical community to treat asthma by replacing nebulizers with metered-dose inhalers (MDIs) without negatively affecting patient outcome and also avoid COVID-19 transmission [70].

The literature review and the citations in this review highlights that asthmatic were exposed to SARS-CoV-2, but there was no serious impact on disease severity or outcome of the disease through appropriate medical intervention. It has been reported among majority with uncontrolled asthma and other chronic disease when exposed to SARS-CoV-2, there will likely be worsening of COVID-19 severity and the need for intensive care may arise.

However, this review is limited with respect to the number of available literatures studied to generate this review article. There are information on COVID-19 and asthma however conflicting reports are abundant. Further investigations and examination for various laboratory signs and clarification on ACE2 and TMPRSS2 expression and their involvement in COVID-19 and asthma is needed. This review is one of the few comprehensive literature studies on the impact of SARS-CoV-2 infection on patients with asthma.