key: cord-1003469-md2x29zp authors: Fung, Monica; Otani, Iris; Pham, Michele; Babik, Jennifer title: Zoonotic coronavirus epidemics: SARS, MERS, and COVID-19 date: 2020-12-11 journal: Ann Allergy Asthma Immunol DOI: 10.1016/j.anai.2020.11.021 sha: 41aac06a28ffff3801195d643b37509710e2e121 doc_id: 1003469 cord_uid: md2x29zp OBJECTIVE: To review the virology, immunology, epidemiology, clinical manifestations, and treatment of the three major zoonotic coronavirus epidemics: severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19). DATA SOURCES: Published literature obtained through PubMed database searches and reports from national and international public health agencies. STUDY SELECTIONS: Studies relevant to the basic science, epidemiology, clinical characteristics, and treatment of SARS, MERS, and COVID-19 with a focus on patients with asthma, allergy, and primary immunodeficiency. RESULTS: Whereas SARS and MERS each caused less than a thousand deaths, COVID-19 has caused a worldwide pandemic with nearly 1 million deaths. Diagnosing COVID-19 relies of nucleic acid amplification tests, and infection has broad clinical manifestations that can affect almost every organ system. Asthma and atopy do not appear to predispose patients to COVID-19 infection, but their effects on COVID-19 clinical outcomes remain mixed and inconclusive. It is recommended that effective therapies, including inhaled corticosteroids and biologic therapy, be continued to maintain disease control. There are no reports of COVID-19 among patients with primary innate and T-cell deficiencies. The presentation of COVID-19 among patients with primary antibody deficiencies is variable, with some experiencing mild clinical courses while others experiencing fatal. The landscape of treatment for COVID-19 is rapidly evolving, with both antivirals and immunomodulators currently with demonstrated efficacy. CONCLUSION: Further data is needed to better understand the role of asthma, allergy, and primary immunodeficiency on COVID-19 infection and outcomes. There are four common coronaviruses that cause mild upper respiratory illness in humans. Over theorized that bats are the natural reservoir of the virus and the pangolin, an endangered and The duration and degree of infectivity of an individual with COVID-19 depends on multiple Cardiac Manifestations 186 Arrhythmias have been described in 7-17% of hospitalized patients 84, 93 and cardiac injury 187 (defined by elevation in troponin level) in 7-28%. 94 Multiple studies have shown that there is no 188 association between the use of ACE inhibitors and angiotensin receptor blockers and the risk of 189 SARS-CoV-2 acquisition or the risk for more severe disease. 95-98 190 191 Head and Neck Manifestations 192 Disorders of taste (dysgeusia, ageusia) and smell (hyposmia, anosmia) are quite common in 193 COVID-19, ranging anywhere from 34-89% of patients. [99] [100] [101] These symptoms can manifest 194 before other respiratory symptoms and can be present without nasal congestion, raising the 195 possibility that disorders of taste and smell may at least be in part a direct effect of the virus 196 rather than solely due to nasal inflammation and obstruction. 100 Ocular symptoms have been 197 described in 1-32% of patients, with conjunctivitis being most common. 102-106 198 199 Neurologic Manifestations 200 Neurologic findings have been described in 36-57% of hospitalized patients. [107] [108] [109] The most 201 common symptoms were dizziness, headache, and impaired consciousness; stroke was seen in Rash has been reported from <1% to 20% of patients, depending on the study. 53, [124] [125] [126] The 222 most common morphologies reported are erythematous, urticarial, and vesicular rashes. Chilblain-like lesions (known colloquially as "COVID toes") have been described commonly in 224 patients during the COVID-19 pandemic. 127, 128 However, more recent data argues against a 225 casual link; rather, these lesions may be due to lifestyle changes (e.g. spending more time 226 barefoot) during shelter-in-place. 129, 130 227 228 Inflammatory Syndromes The increased levels of inflammatory markers in patients with severe COVID-19 (discussed 230 more below) have raised the possibility that some manifestations of critical illness in COVID-19 231 may be due to cytokine storm. However, recent data suggests that the levels of inflammatory 232 cytokines are similar in critically ill patients with and without COVID-19. 131, 132 Nevertheless, the inflammatory syndrome has recently been described in children, which has similarities to 236 Kawasaki disease but is thought to be a distinct entity. 133 Chest radiographic findings are abnormal in 60% and chest CT scans in 86% of patients 247 hospitalized with COVID-19. 53 The most common chest CT findings are ground glass opacities 248 (83-87%) that are usually bilateral (78-80%) and in a peripheral distribution (75-77%). 139, 140 249 Consolidations, septal thickening, and crazy paving are also common. Typical CT findings are 250 shown in Table 1) . Studies have found asthma prevalence in COVID-19 positive patients to be lower than the study. 145 Data regarding the effect of asthma on COVID-19 outcomes shown in Table 1 are mixed and 278 conflicting. Severe asthma was associated with increased risk of COVID-19-related death in one 279 study reviewing a health analytics platform with records of 40% of England's patients, 149 but 280 asthma was not necessarily associated with increased mortality in other studies. 147,150-152 281 Interestingly, in at least two studies where asthma was associated with worse clinical outcomes, 282 non-allergic asthma accounted for the increased risk for worse outcomes (severe COVID-19, be risk factors for hospitalization among asthmatic patients. 154 Another study from UK Biobank 288 found that asthma was a risk factor for COVID-19 hospitalization among women but not men. 155 Among pregnant women, those with moderate to severe COVID-19 were more likely to have 290 asthma than those with mild COVID-19. 156 It has been hypothesized that reduced ACE2 expression could be protective against COVID-19 293 infection, 157 although data remain limited and conflicting. Asthma, allergic rhinitis, and increasing 294 severity of allergic sensitization have been associated with reductions in ACE2 expression in 295 airway epithelial cells. 158, 159 Asthma has been associated with lower ACE2 expression and a 296 lower risk of developing severe COVID-19 compared to COPD. 160 IL-13, a cytokine implicated in 297 the pathogenesis of multiple atopic conditions including asthma, 161 was found to reduce ACE2 298 and increase TMPRSS2 expression in airway epithelial cells. 158 Conversely, asthma has also been associated with increased ACE2 expression in bronchial 301 biopsy, bronchoalveolar lavage, and blood. 162 Additionally, a study comparing 330 asthmatic 302 and 79 healthy control patients as well as a study comparing 77 asthmatic patients and 17 303 healthy control patients found that ACE2 expression was similar between asthmatics and non-304 asthmatics. 163, 164 Notably, there was higher ACE2 expression among asthmatic patients who 305 were male, African American, or had diabetes mellitus, and the authors have suggested that a 306 higher level of monitoring may be needed for these patients. 163 Indeed, African American race 307 and diabetes mellitus were implicated as risk factors for hospitalization in asthmatic patients 308 with COVID-19 154 and noninsulin-dependent diabetes mellitus was observed with a significantly 309 higher prevalence in asthmatics with COVID-19. 165 study of 1562 patients, ICS use did not appear to affect risk for hospitalization among 315 asthmatics in Chicago. 167 There has been a case series of inhaled ciclesonide initiation 316 temporally correlating to improvement in 3 hospitalized COVID-19 patients. 168 In vitro, a 317 combination of glycopyrronium, formoterol, and budesonide appeared to inhibit viral replication 318 in infected nasal and tracheal epithelial cells 169 Table 2) . In a study specifically investigating risk factors for hospitalization, ICU stay, and mortality among 332 asthmatics with COVID-19, both ICS and biologic use did not differ between COVID-19 positive 333 asthmatic patients who needed general versus ICU level of care. SABA-only use was 334 associated with lower risk for hospitalization. 154 recommending continued treatments that are effective for atopic patients, including type 2 338 biologics, given the current lack of evidence that type 2 biologics increase infectivity or mortality 339 and the risk of losing disease control if type 2 biologics were to be stopped. 172 proinflammatory cytokines that help propagate anti-viral responses. 176 There have been few 361 specific reports of COVID-19 in patients with known innate system immune deficiencies. From children younger than 2 years of age that ranged from an asymptomatic child with STAT1 GOF coinfection was treated with steroids in the ICU but recovered. 175, 177 There was also a report of a 367 young child in Italy who became infected with SARS-CoV-2 and developed mild myocarditis and 368 recovered. 175 survivors. 179 Patients in the group with elevated IL-6 levels (>20 pg/mL) and lower CD8+ T cell 382 counts (<165 cells/μL) were older, had more comorbidities, increased need for mechanical 383 ventilation and ICU admission, and increased incidence of death. 179 (28%) required ICU admission and 2 (6%) died. 175 The diagnoses of these children included In the few reports describing COVID-19 in adult patients with CVID, X-linked agammaglobulinemia (XLA) and autosomal-recessive agammaglobulinemia (ARA), patients 416 with more severe B cell defects appeared to experience a milder clinical course. 175,177,182-184,187- 189 Out of the patients described in these reports, there were 10 patients who were 418 asymptomatic (one with ARA, one with XLA, and one with hypogammaglobuinemia). 175,177,182- 419 184, [187] [188] [189] In the international study with 94 PID patients, 26% had mild disease and were treated 420 outpatient and the most commonly reported PID in that group was predominantly antibody 421 deficiency with 14 patients. 175 There are also reports of patients with XLA who had COVID-19-422 related pneumonia but not needing mechanical ventilation. 175, 177, 187 These cases suggest that B-423 cells are important, but not strictly required to overcome infection. In the literature there have been about a dozen reported fatalities following a SARS-CoV-2 426 infection described in patients with inborn errors of immunity, predominantly in those with 427 antibody deficiencies. 175, 183, 184 In the international collaboration study, nine patients in that cohort 428 (7 adults and 2 children) died. All adult patients with PID who died due to SARS-CoV-2 infection 429 had pre-existing comorbidities which included cardiomyopathy, chronic kidney disease, 430 malignancies, chronic lung disease. 175 Their PID diagnoses were mostly antibody deficiencies -431 6 patients with CVID (4), IgG deficiency (1), IgA and IgG2 deficiency (1) -and one patient with a 432 syndromic disease. 175 The two children with X-CGD also had concomitant Burkholderia sepsis 433 and HLH and another child had XIAP deficiency who had severe gut graft versus host disease 434 following HSCT, septic shock and HLH. There have also been two case reports of death in other 435 CVID patients including one patient who was a 59-year-old female with chronic bronchitis and 436 CVID on immunoglobulin replacement and the other a 42-year-old male with asthma, morbid 437 obesity, and CVID who was off of intravenous immunoglobulin (IVIG) for at least 6 months. swabs remained positive throughout his month-long hospitalization before he died. 184 184, [188] [189] [190] [191] Immunoglobulin replacement has been 447 speculated to potentially be beneficial given its immunomodulatory effects and also potential to 448 provide antibodies that may be cross-reactive with COVID-19 but there is limited data. 192 There 449 are many other factors present as well that may increase mortality including age and 450 comorbidities. These reports are small and additional studies and randomized controlled trials are needed to 453 examine the susceptibility to, clinical course, and optimal treatment of SARS-CoV-2 infections in 454 patients with PID. There are current efforts between allergists and immunologists internationally 455 to gather further data through surveys and databases and there have been joint society 456 statements which state that there is no current data pointing to whether there is a general 457 increased risk of severe COVID-19 in PID. 175, 193, 194 There may be certain types of PID that are at 458 higher risk of contracting an infection and developing a more severe course, though, and 459 clinician contribution to these studies and the publication of data will be helpful in informing infection, and most also show an increased risk of adverse effects. [204] [205] [206] [207] The FDA has revoked the proteases of SARS-CoV-2 and were used previously to treat SARS and MERS. 12 However, 520 randomized control trials have shown no benefit of either lopinavir/ritonavir 210 or 521 darunavir/cobicistat. 211 Corticosteroids should not be used in patients who do not require 522 oxygen. Immunomodulators The RECOVERY trial, a RCT of over 6000 hospitalized patients in the United Kingdom, showed 526 a significant mortality benefit for the use of dexamethasone versus placebo, in particular those 527 who were mechanically ventilated or on supplemental oxygen; there was no mortality benefit 528 (and a trend towards harm) among patients who did not require oxygen. 212 Although there are 529 some caveats to the study, the IDSA Guidelines now recommend dexamethasone for 530 hospitalized patients requiring oxygen. 209 Convalescent plasma is believed to have both antiviral (via neutralizing antibodies) and 533 immunomodulatory effects (via neutralization of cytokines/complement and other effects). 213 Observational data suggests possible benefit of convalescent plasma 214, 215 and minimal risk of 535 harm, 216 although RCT data is limited. 217 More trials are underway and the IDSA guidelines 536 currently recommend using convalescent plasma only in the context of a clinical trial. 209 537 However, the FDA has issued EUA for convalescent plasma despite the current lack of robust Tocilizumab is an antibody against the IL-6 receptor that has been used in hopes of dampening 541 the inflammatory response in severe cases of COVID-19. However, a meta-analysis of 7 542 retrospective studies 219 and preliminary data from a RCT 220 both showed no clinical benefit. demonstrates the similarities and differences among these infections. Additional data is needed 557 to better understand the impact of COVID-19 on patients with asthma, allergy and PID. 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