key: cord-0945202-bjyzrmsb
authors: Gulati, Aishwarya; Pomeranz, Corbin; Qamar, Zahra; Thomas, Stephanie; Frisch, Daniel; George, Gautam; Summer, Ross; DeSimone, Joeseph; Sundaram, Baskaran
title: A Comprehensive Review of Manifestations of Novel Coronaviruses in the Context of Deadly COVID-19 Global Pandemic
date: 2020-05-11
journal: Am J Med Sci
DOI: 10.1016/j.amjms.2020.05.006
sha: 2b89006a7439074f374e466857f675baf0a4d79e
doc_id: 945202
cord_uid: bjyzrmsb

Since December 2019, the global pandemic caused by the highly infectious novel coronavirus 2019-nCoV (COVID-19) has been rapidly spreading. As of April 2020, the outbreak has spread to over 210 countries, with over 2,400,000 confirmed cases and over 170,000 deaths [1]. COVID-19 causes a severe pneumonia characterized by fever, cough, and shortness of breath. Similar coronavirus outbreaks have occurred in the past causing severe pneumonia like COVID-19, most recently, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). However, over time, SARS-CoV and MERS-CoV were shown to cause extra-pulmonary signs and symptoms including hepatitis, acute renal failure, encephalitis, myositis, and gastroenteritis. Similarly, sporadic reports of COVID-19 related extrapulmonary manifestations emerge. Unfortunately, there is no comprehensive summary of the multi-organ manifestations of COVID-19, making it difficult for clinicians to quickly educate themselves about this highly contagious and deadly pathogen. What's more, is that SARS-CoV and MERS-CoV are the closest humanity has come to combating something similar to COVID-19, however, there exists no comparison between the manifestations of any of these novel coronaviruses. In this review, we summarize the current knowledge of the manifestations of the novel coronaviruses SARS-CoV, MERS-CoV, and COVID-19, with a particular focus on the latter, and highlight their differences and similarities.

The current global pandemic due to the highly contagious COVID-19 infection is rapidly spreading in many countries with a high number of deaths. Many communities and countries have enforced restrictions, permitting only essential activities. Health systems around the globe are currently preparing to manage the surge of the influx of critically ill patients. During this phase, care providers, administrators, and policymakers work in concert to understand and combat this deadly pandemic. The current knowledge about COVID-19 is limited but rapidly evolving. During this outbreak, the medical community used evidence gleaned from past outbreaks of SARS-CoV and MERS-CoV to predict COVID-19's behavior, clinical presentation and treatment. In addition, coronaviruses are known to cause signs and symptoms of multi-organ system damage, many of which are subtle and can go unnoticed by trained medical professionals. Furthermore, frontline healthcare personnel lack a comprehensive review of the numerous clinical pulmonary and extra-pulmonary manifestations of deadly coronaviruses making self-education time consuming.

We have attempted to summarize the manifestations of COVID-19 and other coronaviruses in many organs with the goal of consolidating knowledge to address the current pandemic. We hope that this review will provide information that would help to manage patients, evaluate manifestations in different organs, predict complications and prognosis, allocate resources in the appropriate domains, and provide opportunities for research.

We searched the published literature for multiple combinations of different organs, and names for infectious conditions of those organs and novel coronaviruses. We only included articles written in the English language and published after 2002. We included both animal and human research studies. The search methodology resulted in nearly 2000 articles. During the further review, we limited the number of articles by eliminating articles that lacked direct relevance. We populated tables with disease manifestations in various organs (Tables 1-8) .

Coronaviruses (CoVs) are a large family of single-stranded RNA viruses that infect humans primarily through droplets and fomites. Before December 2019, there were six known human coronaviruses, including the alpha-CoVs, HCoV-NL63 and HCoV-229E, and the beta-CoVs, HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome-COV (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) [2] . The recently identified COVID-19 is a beta-CoV that infects both humans and animals. All three of these novel viruses (SARS-CoV, MERS-CoV and COVID-19) originate from zoonotic transmission. Bats may have served as the source of SARS-CoV and COVID-19 based on sequence similarity with bat coronaviruses. Camels are suspected to have been the zoonotic host for transmission of MERS-CoV.

The SARS-CoV outbreak spanned from 2002 to 2003 infecting 8098, causing 774 deaths resulting in a 5-10% mortality and a 43% mortality in the elderly [3, 4] . The MERS-CoV outbreak was first reported in Saudi Arabia in 2012 [4] . It then spread to Europe, Asia, Africa, and North America and infected 2494 people, causing 858 death [5] . The MERS-CoV caused severe pneumonia with an ICU admission rate of 40-50% and an in-hospital ICU death rate of 75% [6, 7] . In December 2019, the city of Wuhan in Hubei Provence, China, reported a small outbreak of a novel coronavirus, COVID-19. The fatality rate is highest in adults >85 years old (10-27%), followed by 65-84 years (3-11%) with 50% of ICU admission among persons >65 years. The World Health Organization (WHO) declared COVID-19 as a pandemic on March 11, 2020. received corticosteroids, ribavirin, and intravenous immunoglobulin (IVIG) [17] . In a small case series, antiviral therapy was not beneficial [18] . MERS-CoV also induces overexpression of inflammatory cytokines/chemokines [19] .

A dry cough is a common symptom in COVID-19 infection, present in up to 68% of patients [20] ( Table 1) . Sore throat and sputum production are uncommon (5% or less) [21] . The presence of dyspnea is predictive of ICU admission [21] . In early descriptions of hospitalized patients in China, all patients had an abnormal chest computed tomography [20, 22] . Ground glass opacities are common (56%), followed by consolidation and interstitial abnormalities [21] . In a large Chinese study, the course was complicated by ARDS in 3.4% patients, 6.1% required mechanical ventilation, and the case fatality rate was 1.4-2.1% [21] . Other studies noted a higher incidence of ARDS among hospitalized patients (29%), and higher mortality (15%) [20, 22] . Respiratory failure tends to have a delayed onset, occurring approximately one week after the onset of symptoms. Patients with critical illness were on average older (median age 66 vs 51 non-critically patients) and had more comorbidities [20] . Patients who received invasive mechanical ventilatory support were more likely to be male and obese [23] . Histopathology of the lung shows diffuse alveolar damage, denuded alveolar lining cells, and interstitial fibrosis [24] . There is also evidence of a higher incidence of thromboembolism in COVID-19 patients and an association between elevated D-dimer levels and mortality [25] . Additionally, preliminary evidence suggests that heparin use may result in lower 28-day mortality rates when compared to in COVID-19 patients not receiving this therapy [26] .

Currently, it is speculated that respiratory compromise due to COVID-19 is driven by cytokinemediated injury of the lung and that interventions to reduce the activity of specific inflammatory mediators may improve outcomes [27, 28] . COVID-19 also uses angiotensin-converting enzyme 2 (ACE2) receptor to enter into cells so therapies targeting this receptor may serve as a potential treatment option [29] [30] [31] [32] . There is no standard of care for the prevention or treatment of respiratory compromise in COVID-19 yet. Medications including glucocorticoids, IL-6 antagonists, Janus kinase inhibitors, antivirals, and chloroquine/hydroxychloroquine are currently being studied as possible therapeutic options [33] .

Patients may present with cardiac arrhythmia, failure, and myocarditis[34-37] ( 

There are rare case reports describing acute myocarditis in MERS-CoV patients, presenting with severe chest pain and subsequent heart failure with elevated high-sensitivity TnI and pro-brain natriuretic peptide levels (pro-BNP) [22, 43] (Table 1) . Few reports also note sinus tachycardia and diffuse T-wave inversion on electrocardiography and global left ventricular dysfunction on echocardiography [43] .Rarely pericarditis may also ensue [6] .

ACE2, the functional receptor of COVID-19 is expressed in the myocardium. Whether the use of the renin-angiotensin-aldosterone system (RAAS) inhibitors alters COVID-19 infection by upregulating ACE2 is under investigation. Similar to MERS-CoV and SARS-CoV, COVID-19 also causes acute cardiac injury in a subset of patients with corresponding elevated high-sensitivity cardiac troponin-I (hs-cTnI) levels [22, 44] (Table 1) 

Hepatitis in SARS-CoV is a well-recognized common complication, although it is a diagnosis of exclusion. Approximately 60% of patients with SARS-CoV had a degree of liver impairment with elevated ALT and or AST, hypoalbuminemia, and hyperbilirubinemia [53] ( 

Several studies report patients with MERS-CoV and elevated liver enzymes, as well as hypoalbuminemia [59, 60] ( noted in the acute phase, including IFN-g, TNF-a, IL-15, and IL-17 [65] . Future investigations may clarify the role of inflammatory response in causing the liver injury.

The few available studies show that as many as 51% of patients with COVID-19 have abnormal liver function on admission (elevated liver enzymes, bilirubin and LDH levels) [66] ( 

Gastrointestinal involvement in SARS-CoV was common and occurred at different stages of the disease; rarely, patients reported only GI symptoms [68-70]. The most common gastrointestinal presentation was loss of appetite (up to 55%) and watery diarrhea (up to 76%) [69, 71] ( 

Patients may present with GI symptoms, pain, and fever [16, 77, 78] (Table 3) 

There is increasing recognition of gastrointestinal symptoms in COVID-19 patients (up to 50%) 

Renal impairment in SARS-CoV seems multifactorial and could include secondary sepsis, comorbidities, rhabdomyolysis, treatment-related interstitial nephritis, and altered immune response ( 

MERS-CoV uses the exopeptidase dipeptidyl peptidase 4 (DPP4) or CD 26 as its cellular receptor, which is highly expressed in kidneys [100]. Renal involvement is as high as 41% and required dialysis more than SARS-CoV patients [4, 17, 60] (Table 4 ). Cha et al. reported (n=30 patients), 60% and 73% of patients with proteinuria and hematuria, respectively, approximately 27% of them developed acute kidney injury within 18 days. Patients with acute kidney injury were older and had elevated levels of albumin to creatinine ratios. Patients requiring renal replacement therapy had a higher mortality.

Preexisting chronic kidney disease is also a predictor of poor outcomes [16, 101, 102] . The virus has been detected in urine and renal tissue and causes apoptosis, suggesting direct viral pathogenicity complements the other mechanisms of renal injury [17, 61, 103].

Acute renal dysfunction in COVID-19 at the time of presentation is not uncommon [92, 104, 105]. The incidence of acute kidney injury either at presentation or later is as high as 15% with a high mortality rate of 60-90% [106, 107] ( Table 4) 

Patients with SARS-CoV presented with ischemic stroke, likely due to the hypercoagulable state and vasculitis induced during the illness [110] (Table 5) However, in one case report, tears from a female patient were analyzed by PCR and shown to be positive for SARS-CoV when other testing methods were negative. Still, risk of SARS-CoV transmission through tears remains low.

symptoms occur later in the course of the illness as weakness and neuropathy and less frequently hypersomnolence and ataxia (Table 5) 

Increasingly recognized sensory symptoms of COVID-19 infection include the sudden onset of anosmia, and, to a lesser extent, dysgeusia (Table 6) 

As many as 60% of patients with SARS-CoV had myalgia with up to 30% presenting with muscle weakness and increased creatinine phosphokinase (CPK) ( Table 6) [10, 34, [126] [127] [128] . However, there was no statistically significant difference in CPK levels between SARS-CoV patients with ARDS versus patients without ARDS [126] . Muscle weakness was typically symmetric and involves truncal and weakness of the proximal limbs and neck muscles with sparing of the facial and small hand muscles [128] .

Muscle atrophy may also be the result of steroid myopathy or critical illness myopathy (CIM) [128] . A variable degree of focal myofibril necrosis noted postmortem without evidence of viral particles suggests that muscle damage is likely the result of immune-mediated damage [128] . Cutaneous manifestations of SARS-CoV hasn't yet been reported in the literature to the authors' knowledge.

Myositis and muscle atrophy are less prevalent than SARS-CoV [61, 129] . Muscle weakness was common in patients with MERS-CoV (Table 6) 

Myalgia is also a common presenting symptom of COVID-19 infection, and 36% of patients develop muscle pain during their illness (Table 6 ) [130] . High creatinine kinase (CK) levels present in 14% to 33% of patients [22, 41, 106, 131] . Patients with suspected COVID-19 and muscle aches were more likely to have abnormal lung imaging findings [131] . Higher CK levels noted in ICU-level patients in a study compared to non-ICU patients, although it was not a statistically significant finding.

Rhabdomyolosis has been reported in patients with COVID-19 with MYO levels >12,000 ug/L and CK levels >11,000 U/L [132] .

The cutaneous manifestations of COVID-19 are not widely known beyond the dermatology community. From a series of 88 patients 20% developed cutaneous manifestations including erythematous rash, widespread urticaria, and chickenpox like vesicles [133] . The most common region involved was the trunk and pruritis was uncommon. Several recent case series have reported a viral exanthum similar to chilblains disease in patients with COVID-19 [134] . To date, there has been no correlation between cutaneous manifestations of COVID-19 and disease severity.

Reactive lymphocytosis and severe lymphopenia (<500 cells/mm3) are uncommon in patients with SARS (Table 7 ) [10, 135] . Patients with SARS-CoV infection often presented with a normal total leukocyte counts [135, 136] . There was no correlation between the degree of leukopenia and disease severity. However, patients with a high initial neutrophil count had worse outcomes [1]. Chng et al.

reported mild to moderate (<1000 cells/mm3) lymphopenia as a common finding in SARS-CoV (70-98% of patients), especially during the first ten days of illness. Initial hemoglobin levels were often normal but gradually decrease later [10] . Thrombocytopenia was present in up to half of the patients, although platelet count levels <100,000 cells/mm3 are rare, and they usually normalized later [137] . Prolonged activated partial thromboplastin time (aPTT) and elevated D-dimer levels were also common abnormalities (63% and 45%, respectively) [10] .

The pathogenesis of lymphopenia and thrombocytopenia in SARS has been controversial. In addition to traditional theories, vascular adhesion molecule-1, ligand, and severe cytokine storm may play a vital role [138, 139] . Thrombocytopenia could be due to the result of interplay between autoantibodies, immune complexes, increased consumption and decreased production of platelets [137] .

Most patients present with a normal total leukocyte count [17]. One-third of the patients may present with lymphopenia of <1500 cells/mm3 and severely low levels during the early stage of the illness 600 cells/mm3 or less (Table 7) 

Data regarding the hematologic manifestations of COVID-19 infection are emerging. Patients with severe disease may have higher total white cell counts ( Otherwise, similar to the other novel coronavirus infections, lymphopenia is a frequent finding, is present in a third of patients [21, 130] . Hence, lymphopenia may help as a reference index [130] . However, there may not be any differences in lymphocyte counts between mild and severe forms of COVID-19.

Neutrophilia may help to predict intensive care unit (ICU) admissions. Hemoglobin seems to be mostly unaffected by COVID-19 infection. DIC is a rare complication [21] . In general, mild thrombocytopenia is present in one-third of patients [21] . Patients requiring ICU admissions are seen to have higher levels of D-dimer [14] . A meta-analysis of 9 studies showed significantly higher PT and d-dimer levels in patients with more severe disease, indicating the likelihood of disseminated intravascular coagulation (DIC) or a highly inflammatory state [56] . The incidence of thromboembolic events in these patients is garnering a lot of attention. A study conducted by Llitjos et al found a 69% incidence of thromboembolic events, with a 56% incidence even in patients treated with therapeutic anticoagulation [57] . Increased levels of circulatory cytokines, ferritin, C-reactive protein and procalcitonin also seem to correlate with the severity of the disease [34, 58].

Although the data are limited for SARS-CoV in pregnancy, evidence suggests poorer clinical outcomes for pregnant women. Reports are available for twelve pregnant women in Hong Kong and two in the United States (Table 8 ) [142] . Among the twelve women in Hong Kong, pregnancy did not appear to impact the initial clinical presentation of SARS. Four of the seven women presenting in the first trimester miscarried, though this finding is confounded by treatment with the purported teratogen Ribavirin in six patients. When compared to matched controls (n=10), the rate of ICU admission was significantly higher in the pregnant group (60% vs. 17.5%, P = 0.012). Three pregnant women died, whereas no women died in the matched nonpregnant group (P = 0.01) [132] . Of the five women presenting in the second or third trimester of pregnancy, four delivered preterm, one spontaneously due to preterm labor and three iatrogenic due to worsening maternal status [133] .

There was no evidence of transplacental or intrapartum vertical transmission of SARS-CoV (Table 8 ) [143] [144] [145] . However, there may be hypoxia-induced placental blood flow alterations, consequent increased placental fibrin deposition, and thrombotic vasculopathy, resulting in intrauterine growth restriction in women who deliver after convalescence [143, 146] .

Pregnant women with symptomatic MERS-CoV infection may be at a higher risk of adverse events. There are nine reported cases of symptomatic MERS-CoV in pregnant women, and seven of them required ICU admission, five required mechanical ventilation, and three died (Table 8 ) [147] . One case report of a term delivery in a recovered patient and another report of a patient delivered preterm while in the active phase of infection showed negative viral testing in the infant [147, 148] . There are two reported cases of asymptomatic MERS-CoV infection in pregnant women, both identified via contact tracing. One was identified at six weeks gestation, and the other at 24 weeks. Both had healthy term deliveries [149] . Based on available epidemiologic data, it is unclear whether pregnant women with MERS-CoV have worse outcomes, though three deaths among eleven reported cases are concerning compared to an 8.9%

death rate reported in a non-pregnant female population [150] .

Unlike SARS-CoV and MER-CoV, the risk of severe COVID-19 disease in the pregnant population compares favorably to the general population[120]. Recently, a WHO mission group studied 147 pregnant women with COVID-19, 65 confirmed and 82 presumed, of whom 8% had severe disease, and 1% were critical with multi-organ failure ( Table 8 ). As the rate of adverse events seemed less compared to the general population (13.8% severe and 6.1% critical), the mission concluded that pregnant women might not be at increased risk [151] . However, this determination may evolve with more data.

There are a few case reports and mini case series discussing the late trimester pregnancy and COVID-19. A study on thirty-eight third trimester pregnant women did not show any severe pneumonia requiring mechanical ventilation or maternal deaths, despite co-morbid conditions. There were also no fetal or neonatal deaths [152] . Another study (thirteen women in the second and third trimesters) reported one ARDS and septic shock case with a stillbirth at 34 weeks of gestation [153] . Other reports on women with gestational ages of 25 to 39 weeks raise concern for an increased risk of preterm rupture of membranes and preterm delivery [153] [154] [155] . However, in contrast, a retrospective study of sixteen pregnant women infected with COVID-19 compared with 45 non-infected pregnant women showed no differences in preterm labor or preterm delivery, though the youngest gestational age included was only 35 weeks. Also, there was no difference in birth weight between the two groups [152] . Pathophysiology in obstetric patients could be due to naturally suppressed cell-mediated immunity and physiologic respiratory changes [142] . A noteworthy observation by Abbas et al has been an increasing incidence of hydatiform moles with the onset of the pandemic. The majority of these cases were primigravidae without other risk factors. They suggest an immune mediated mechanism triggered by the virus and recommend COVID testing in all women with hydatiform moles [65].

Currently, there is no evidence of vertical transmission of COVID-19, as confirmed by negative viral PCR in thirty neonates [152] . One study of six women showed no detectable virus in amniotic fluid, cord blood, and breastmilk, nor on a neonatal throat swab [155] . There is a paucity of data regarding COVID-19 infection in the first and second trimesters.

A study investigating the possibility of sexual transmission of COVID-19 found no virus in the vaginal discharge of 35 COVID-19-infected non-pregnant patients, possibly due to the lack of ACE2 expression in the vagina [156] .

The current COVID-19 pandemic is the third major global illness due to a novel coronavirus.

Understanding COVID-19 along with the other known novel coronaviruses places the newest coronavirus in context. We presented the similarities and differences in pathogenesis, manifestations, and outcomes with respect to a spectrum of extra-pulmonary orgran systems. Increasing knowledge about COVID-19 literature will aid in earlier recognition and more effective therapy.

Arabi 

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 PNS symptoms: 8.9%, most common hypogeusia (5.6%) and hyposmia (5.1%)

 Skeletal muscle symptoms