ABSTRACT
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 extrapulmonary 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 multiorgan manifestations of COVID-19, making it difficult for clinicians to quickly educate themselves about this highly contagious and deadly pathogen. What is 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.Key Indexing Terms
INTRODUCTION
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 (CoV) are known to cause signs and symptoms of multiorgan 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 extrapulmonary manifestations of deadly CoVs making self-education time consuming.
We have attempted to summarize the manifestations of COVID-19 and other CoVs 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.
Methods
We searched the published literature for multiple combinations of different organs, and names for infectious conditions of those organs and novel CoVs. 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 (Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8).
Table 1Pulmonary manifestations of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | ||||
|---|---|---|---|---|
| Study | Lee et al (2003) N = 138, confirmed cases Retrospective study | Lang et al (2003) N = 3, confirmed cases Clinicopathologic study | Liu et al (2004) N = 53, confirmed cases Retrospective study | Peiris et al (2003) N = 75, confirmed cases Prospective study |
| Clinical features |
| Fever (3/3) Dyspnea (3/3) Mildly productive cough (1/3) Death within 9-15 days of illness |
|
|
| Key findings on investigations | CXR
|
|
| Initial CXR abnormal: 71%
|
| Histopathology |
|
| N/A | N/A |
| Key study findings and message |
| Severe immunological damage to lung tissue causes clinical features |
|
|
| MERS | ||||
| Study | Assiri et al (2013) N = 47, confirmed cases Retrospective study | Arabi et al (2014) N = 12, (11 confirmed cases, 1 probable) Case series | Al-Abdley et al (2019) N = 33, confirmed cases Retrospective study | Almekhlafi et al (2016) N = 31, confirmed cases Retrospective study |
| Clinical features |
|
|
|
|
| Key findings on investigations | CXR abnormality (100%) – ARDS pattern | CXR, CT: lobular to bilateral extensive ARDS pattern | N/A | CXR abnormality (96.4%) |
| Key study findings and message |
| 100% invasive mechanical ventilation, mean duration 100 days |
|
|
| COVID-19 | ||||
| Study | Huang et al (2020) N = 41, confirmed cases Retrospective study | Wang et al (2020) N = 138, confirmed cases Retrospective study | Guan et al (2020) N = 1099, confirmed cases Retrospective study | Zhang et al (2020) N = 1, confirmed cases Clinicopathologic study |
| Clinical features |
|
|
|
|
| Key findings on investigations | Abnormal chest CT (100%); (98% bilateral) |
|
| CT: Patchy bilateral ground glass opacities |
| Histopathology | N/A | N/A | N/A |
|
| Key study findings and message |
|
|
| Histopathologic findings consistent with diffuse alveolar damage |
ARDS, acute respiratory distress syndrome; CXR, chest x-ray; ECMO, extracorporeal membrane oxygenation; GGO, ground glass opacities; ICU, intensive care unit; MERS-CoV, middle east respiratory syndrome coronavirus; RR, respiratory rate; SARS-COV, severe acute respiratory syndrome coronavirus; URT, upper respiratory tract.
Pathogens
CoVs are a large family of single-stranded RNA viruses that infect humans primarily through droplets and fomites. Before December 2019, there were 6 known human CoVs, 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 3 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 CoVs. Camels are suspected to have been the zoonotic host for transmission of MERS-CoV.The SARS-CoV outbreak spanned from 2002 to 2003 infecting 8,098, 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 2,494 people, causing 858 death.5
The MERS-CoV caused severe pneumonia with an intensive care unit (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 declared COVID-19 as a pandemic on March 11, 2020.PULMONARY MANIFESTATIONS
SARS-CoV
Patients infected with SARS-CoV initially had features of atypical pneumonia. Cough was a common presenting symptom in up to 74% of patients
8
, 9
, 10
(Table 1). Other symptoms suggestive of an upper respiratory tract infection (e.g., rhinitis) were less frequent.11
Approximately 50% of patients developed hypoxia during hospitalization, and up to 26% progressed to acute respiratory distress syndrome (ARDS) requiring mechanical ventilation.8
,12
The elderly and patients with multiple comorbidities had particularly high (more than 15.7%) mortality.12
,13
Unilateral, focal, peripheral areas of consolidations on imaging were identified in upwards of 78% of patients.10
Histopathology revealed diffuse serous, fibrinous and hemorrhagic inflammation. SARS-CoV RNA has been detected in type II alveolar cells, interstitial cells and bronchial epithelial cells, suggesting infection of both proximal and distal epithelium of the lung.13
Most patients received antibacterial antibiotics, with or without the use of ribavirin and corticosteroids.9
, 10
, 11
Angiotensin-converting enzyme 2 (ACE2) serves as a functional receptor to SARS-CoV.
13
,14
SARS-CoV also disrupts the urokinase pathway, which controls fibrin levels through extracellular remodeling, and is associated with pulmonary hemorrhage and fibrosis.15
SARS-CoV also triggers the production of high levels of proinflammatory cytokines contributing to excessive inflammation in the lungs. Hence, anticytokine and chemokine immunotherapy may be effective for minimizing collateral damage.12
MERS-CoV
Common presenting symptoms of MERS include dyspnea in up to 92% and cough in 83% of patients
16
,17
(Table 1). In a study including 47 patients, all patients presented with an abnormal chest radiograph, 89% needed ICU admissions, and 72% required mechanical ventilation. The case fatality rate was 60%, and the rate increased with age.16
Most patients received antibiotics, and a small minority received corticosteroids, ribavirin and intravenous immunoglobulin.17
In a small case series, antiviral therapy was not beneficial.18
MERS-CoV also induces overexpression of inflammatory cytokines and/or chemokines.19
COVID-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 1 week after the onset of symptoms. Patients with critical illness were on average older (median age 66 versus [vs.] 51 noncritically 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 cytokine-mediated injury of the lung and that interventions to reduce the activity of specific inflammatory mediators may improve outcomes.
27
,28
COVID-19 also uses 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 and/or hydroxychloroquine are currently being studied as possible therapeutic options.33
CARDIOVASCULAR MANIFESTATIONS
SARS-CoV
Patients may present with cardiac arrhythmia, failure and myocarditis
34
, 35
, 36
, 37
(Table 1). A study on 121 hospitalized SARS-CoV patients found that tachycardia was the most frequent acute presentation followed by hypotension, bradycardia, reversible cardiomegaly and transient paroxysmal atrial fibrillation.34
Case reports have described acute onset myocarditis in patients with SARS-CoV; however, on autopsy, the virus was absent in the myocardium, suggesting myocardial damage may be indirectly related to the illness.38
,39
Another report described several fatal cases of SARS-CoV patients with acute heart failure and, rarely, myocardial infarction in the setting of septic shock with elevated myocardial enzymes.40
,41
Chronic cardiometabolic damage may also ensue in some, even 12 years after recovery with dysregulated lipid metabolism.42
MERS-CoV
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 probrain natriuretic peptide levels
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
COVID-19
ACE2, the functional receptor of COVID-19 is expressed in the myocardium. Whether the use of the renin-angiotensin-aldosterone system 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 levels
22
,44
(Table 1). CK-MB and high-sensitivity cardiac troponin-I were higher in ICU patients, suggesting that myocardial injury is more likely present in patients with severe disease.45
,46
As many as 7% of deaths in COVID-19 patients have been attributed to myocardial injury.47
Other cardiac manifestations include acute myocardial infarction, fulminant heart failure and dysrhythmias.48
In some studies, arrhythmia with COVID-19 infection was as high as 17%.20
,45
It is also important to note various drug interactions and the arrhythmogenic potential of medications often used in these patients. Additionally, patients with preexisting cardiovascular disease and hypertension have been seen to suffer from more severe disease requiring critical care.48
Presenting symptoms range from mild chest pain with preserved ejection fraction to profound cardiovascular collapse requiring extracorporeal membrane oxygenation. Echocardiography may show a regional wall motion abnormality or global hypokinesis with or without pericardial effusion.
49
,50
Initial electrocardiogram may show low voltage QRS complexes in the limb leads, ST segment elevations in leads I, II, aVL, V2-V6 and PR elevation and ST depressions in aVR.49
,50
There should be a low threshold for SARS-CoV-2 testing in patients presenting with signs of myopericarditis even in the absence of fever and respiratory symptoms.Proposed mechanisms of cardiac injury in patients with COVID-19 include overexpression of ACE2 in patients with chronic cardiovascular disease, cytokine storm triggered by an imbalanced response by type 1 and type 2 helper cells, hypoxemia resulting in myocardial damage, plaque rupture, coronary vasospasm, or direct vascular injury.
22
,45
,51
There may be a complex interplay between the accelerated immunologic dysregulation of the cytokines and T cells and the underlying cardiovascular or related metabolic conditions. Virally-induced systemic inflammation may also promote coronary plaque rupture and have a procoagulant effect necessitating the intensification of medical therapy.52
HEPATOBILIARY MANIFESTATIONS
SARS-CoV
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 alanine aminotransferase and/or aspartate aminotransferase, hypoalbuminemia and hyperbilirubinemia
53
(Table 2). ACE2 receptors are also found on the hepatic endothelial cells.54
On histopathology, SARS-CoV patients had a large number of virus particles in the hepatic parenchymal cells.38
,39
,55
Elevated levels of IL-1, IL-6 and IL-10 in patients with SARS-CoV hepatitis support coexisting acute inflammatory response.56
Hepatic cell damage and cell-cycle disruption was seen on hepatic biopsy with apoptosis, mitotic arrest with eosinophilic bodies and balloon-like hepatocytes.22
Unfortunately, hepatic damage potentially due to antivirals use complicates our understanding of the etiology of hepatitis in patients with SARS-CoV.57
Hepatic involvement may indicate a poor prognosis, particularly in patients with high LDH levels.58
Yang et al reported long-standing hyperglycemia (due to pancreatic injury) as an independent predictor for adverse outcomes in patients with SARS-CoV.58
Table 2Cardiovascular manifestations of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | |||||
|---|---|---|---|---|---|
| Study | Booth et al (2003) N = 144, confirmed cases Retrospective study | Li et al (2003) N = 46, confirmed cases Prospective study | Pan et al (2003) N = 15, confirmed cases Retrospective study | Ding et al (2004) N = 8 (4 confirmed cases, 4 control) Clinicopathologic study | Yu et al (2006) N = 121, confirmed cases Retrospective study |
| Clinical features | • Chest pain (10%) • ↑HR (46%) | • No chest pain or overt CHF on admission • ↓HR (non-ICU) ↑HR (ICU) •CHF exacerbation | • Sudden cardiac arrest (100%) • MI and arrhythmia (33%) | • Chest pain |
|
| Key findings on investigations |
|
|
| N/A |
|
| Histopathology | N/A | N/A | N/A |
| N/A |
| Key study findings and message |
| Possibly reversible subclinical diastolic impairment seen in SARS patients | Proposed causes of SCD:
| ACE2 expressed in heart, but virus not detected |
|
| MERS | |||||
| Study | Alhogbani (2016) N = 1 confirmed case Case report | Almekhlafi et al (2016) N = 31, confirmed cases Retrospective study | Garout et al (2018) N = 52, confirmed cases Retrospective study | ||
| Clinical features | CHF | ↑HR (67.7%) | Pericarditis | ||
| Key findings on investigations |
| N/A | N/A | ||
| Key study findings and message | MERS-CoV may cause myocarditis and acute heart failure |
| No association of ECMO need with outcomes | ||
| COVID-19 | |||||
| Study | Huang et al (2020) N = 41, confirmed cases Retrospective study | Wang et al (2020) N = 138, confirmed cases Retrospective study | Zheng et al (2020) Review | Bhatraju et al (2020) N = 24, confirmed cases Retrospective study | Fried et al (2020) N = 4, confirmed cases Case reports |
| Clinical features |
|
|
|
|
|
| Key findings on investigations |
|
| N/A |
|
|
| Key Study findings and message | ↑BP more common in ICU patients (P = 0.018) | ICU patients more likely to have pre-existing hypertension, develop arrhythmias, acute cardiac injury (P < 0.001) | Proposed mechanism of cardiac injury:
|
|
|
BNP, B-type natriuretic peptide; BP, blood pressure; HR, heart rate; CHF, congestive heart failure; CK, creatine kinase; CKMB, creatine kinase myocardial band; CXR; chest x-ray; ECMO, extracorporeal membrane oxygenation; Hb, hemoglobin; ICU, intensive care unit; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MERS-CoV, middle east respiratory syndrome coronavirus; RBBB, right bundle branch block; SARS-COV, severe acute respiratory syndrome coronavirus; TnI, troponin-I.
MERS-CoV
Several studies report patients with MERS-CoV and elevated liver enzymes, as well as hypoalbuminemia
59
,60
(Table 2). The degree of hypoalbuminemia also helps to predict disease severity.60
Hepatic findings may resemble SARS-CoV-related changes.61
However, MERS-CoV utilizes dipeptidyl peptidase-4 to infect cells, which is highly expressed in the liver.62
,63
In transgenic mice, the liver injury occurred within the first week after infection resulting in hepatic necrosis and infiltration of Kupffer cells and macrophages.64
Similar to other coronavirus infections, high concentrations of inflammatory cytokines are 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.COVID-19
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 lactate dehydrogenase levels)
66
(Table 2). Patients with abnormal LFTs present with a high degree of fever, and their degree of hepatic dysfunction correlates with length of hospitalization.66
New reports suggest that the liver dysfunction in patients with COVID-19 may be related to damage to the cholangiocytes lining the biliary epithelium, likely due to the higher expression of ACE2 receptors on those cells.67
Patients with preexisting metabolic fatty liver disease have been seen to have an about 6-fold higher chance of severe disease in the presence of coexisting obesity.Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv [Preprint]. February 4, 2020. https://doi.org/10.1101/2020.02.03.931766
21
GASTROINTESTINAL MANIFESTATIONS
SARS-CoV
Gastrointestinal (GI) involvement in SARS-CoV was common and occurred at different stages of the disease; rarely, patients reported only GI symptoms.
68
, 69
, 70
The most common GI presentation was loss of appetite (up to 55%) and watery diarrhea (up to 76%)69
,71
(Table 3). Patients also complained of nausea, vomiting (14-22.2%) and abdominal pain (3.5-12.6%).72
The association between symptoms and outcomes had been mixed. Leung et al found that patients with diarrhea had a higher likelihood of requiring ICU admission and ventilatory support.68
Others found that GI symptoms at presentation conferred a better prognosis.69
Others found no association between diarrhea and the development of ARDS or the requirement of ventilatory support.70
The mechanism of GI symptoms is unclear, but SARS-CoV particles have been detected in saliva (100%), feces (97%) and mucosal epithelial and lymphoid tissue of affected patients with associated depletion of lymphoid tissue.72
Table 3Hepatobiliary manifestation of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Study | Duan et al (2003) N = 154, confirmed cases Retrospective study | Ding et al (2004) N = 8 (4 confirmed cases, 4 control) Clinicopathologic study | Chau et al (2004) N = 3, confirmed Case report | Zhao et al (2004) N = 169, confirmed cases Retrospective study | Yang et al (2005) N = 168, confirmed cases Retrospective study | Zhan et al (2006) N = 12 (6 confirmed cases, 6 controls) Clinicopathologic study | Yang et al (2010) N = 539 (520 confirmed cases) Prospective study | |
| Clinical Features | Hepatic dysfunction | Hepatic dysfunction | Hepatic dysfunction | Hepatic dysfunction | Hepatic dysfunction | Diabetes:
| ||
| Key findings on investigations |
|
|
| ↑ ALT:
| ↑ blood glucose | |||
| Histopathology | N/A |
|
| N/A | Nonspecific inflammation | Spleen:
| ACE2 receptors found in pancreatic islet cells | |
| Key study findings and message |
| Liver may also be target of infection besides lungs | Liver damage likely by virus directly | Total protein remained normal despite albuminemia |
|
|
| |
| MERS | ||||||||
| Study | Saad et al (2014) N = 70, confirmed cases Retrospective | Al-Hameed et al (2016) N = 8, confirmed cases Prospective study | Alsaad et al (2017) N = 1, confirmed cases Clinicopathologic | |||||
| Clinical Features | Hepatic dysfunction (31.4%) | Hepatic dysfunction later during ICU stay (62.5%) | N/A | |||||
| Key findings on investigations |
|
| N/A | |||||
| Histopathology | N/A | N/A | Liver:
| |||||
| Key study findings and message | Albumin <35 g/L at diagnosis predictor of severe infection (P = 0.026) | 41% developed multiorgan failure | Portal and lobular hepatitis, viral particles not identified in liver on EM | |||||
| COVID-19 | ||||||||
| Study | Fan et al (2020) N = 148, confirmed cases Retrospective study | Chai et al (2020) N = 4 (healthy) Clinicopathologic | Huang et al (2020) N = 41, confirmed cases Retrospective study | Wang et al (2020) N = 138, confirmed cases Retrospective study | ||||
| Clinical features | Hepatic dysfunction at admission (50.7%) | Preexisting chronic liver disease (2%) | Pre-existing chronic liver disease (2.9%) | |||||
| Key findings on investigations | ↓ CD4+ and CD8+ T cells in patients with hepatic dysfunction | N/A | ↑ AST (37%)(62% ICU, 25% non-ICU) | ↑ LDH | ||||
| Histopathology | N/A | ACE2 expression in cholangiocytes (59.7%) and hepatocytes (2.6%) | N/A | N/A | ||||
| Key study findings and message |
|
| Cytokine storm possible associated with disease severity | AST, ALT, T.bil, LDH higher in ICU patients (P < 0.001, P = 0.007,P = 0.02, P < 0.001) | ||||
ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase; MERS-CoV, middle east respiratory syndrome coronavirus; RT-PCR, reverse transcriptase polymerase chain reaction; SARS-COV, severe acute respiratory syndrome coronavirus; T. Bili, total bilirubin.
A significant mode of spread in community outbreaks was fecal-oral transmission.
70
,73
,74
Patients with diarrhea also had a higher rate of positive serological and nasopharyngeal secretion tests.75
The virus remained stable in stool up to 2-4 days, and may even be detectable as late as 4 weeks.70
,73
,76
MERS-CoV
Patients may present with GI symptoms, pain and fever
16
,77
,78
(Table 3). Patients with GI symptoms have delayed MERS-CoV serological clearance.60
,79
MERS-CoV RNA in stool has been detected in about 15% of patients, much lower than SARS-CoV, and may not correlate with the presence of GI symptoms.79
,80
While the virus replicates in the intestinal tract, isolation of the virus from feces and fecal-oral transmission are rare.81
, 82
, 83
COVID-19
There is increasing recognition of GI symptoms in COVID-19 patients (up to 50%).
84
Patients may present only with GI symptoms.20
,84
Loss of appetite and diarrhea have been the most commonly reported symptom (in up to 78.6% cases), and less often vomiting (up to 5%), and abdominal pain (up to 2%) (Table 3).20
, 21
, 22
,84
Vomiting has been shown to be a more common presenting symptoms in children. The GI features seem to worsen with overall disease severity and the presence of abdominal pain has been associated with about 4 times higher odds of severe COVID.22
,24
The delayed recognition of GI symptoms and lack of awareness may lead to a delay in seeking medical care.22
Patients who present later during their illness were more likely to suffer from hepatic dysfunction but without a difference in mortality, ICU days or time to discharge.22
Patients with obesity are at significantly higher risk for severe disease requiring critical care and invasive mechanical ventilation. Compared with patients with a BMI <25 kg/m2, patients with BMI >35 kg/m2 have been seen to have 7 times the odds for requiring invasive mechanical ventilation.25
,26
COVID-19 virus enters enteric epithelial tissue through ACE 2 and transmembrane protease, serine 2, but the exact mechanism of GI symptoms is not known.
85
The virus is detectable in stool in up to half of COVID-19 patients,86
,87
and the feces remains positive for as much as 4 weeks.87
ACE 2 and viral protein have been detected in GI epithelial cells, and infectious virus particles were isolated from feces.88
Fecal polymerase chain reaction (PCR) testing has been shown to be as accurate as PCR detection from a sputum sample, and in some cases, fecal PCR is positive before sputum PCR.88
It remains unclear if the fecal-oral route is a significant mode of transmission.RENAL MANIFESTATIONS
SARS-CoV
Renal impairment in SARS-CoV seems multifactorial and could include secondary sepsis, comorbidities, rhabdomyolysis, treatment-related interstitial nephritis, and altered immune response (Table 4). In most SARS-CoV patients, acute renal damage was not common at presentation.
89
However, acute renal failure was noted in 5-15% of patients and more often developed subsequently 7-20 days after presentation.89
, 90
, 91
, 92
Choi et al reported a 6% incidence of acute renal failure in a study of 267 patients, more commonly in elderly diabetics. A large study with 536 patients stated that patients with ARF had hyponatremia and hypoalbuminemia at the time of admission.75
,91
Patients with renal dysfunction had mortality rates around 90%.75
,90
,91
,93
,94
Patients with hypouricemia and chronic renal replacement therapy also had poor outcomes.95
, 96
, 97
Table 4Gastrointestinal manifestations of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Lee et al (2003) N = 138, suspected Retrospective study | Donnelly et al (2003) N = 1425, confirmed cases Retrospective study | Peiris et al (2003) N = 75, confirmed cases Prospective study | Leung et al (2003) N = 138, confirmed cases Retrospective study | Choi et al (2003) N = 267 (227 confirmed cases) Retrospective study | Shi et al (2005) N = 14, (7 confirmed cases, 7 suspected) Clinicopathologic study | Kwan et al (2005) N = 240, confirmed cases Retrospective Study | ||||||||
| Clinical Features |
|
| Watery diarrhea (73%) (1% on admission)
| Watery diarrhea (38.4 % within first week, 20.3% on presentation)
|
|
|
| ||||||||
| Key findings on investigations | • ↑ baseline albumin • ↓ K+ | N/A | Viral RNA in stool (97%) (14.4 ± 2.2 days from onset) | • ↓ K+ • Viral RNA in stool (16%) • No viral isolation from stool • Colonoscopy (1) grossly within normal limits | ↓ K+ (41%) | N/A | K+ nadir lower in diarrheal patients than nondiarrheal (P < 0.05) | ||||||||
| Histopathology | N/A | N/A | N/A |
| N/A |
| N/A | ||||||||
| Key study findings and message | GI symptoms were less common | GI symptoms less common at presentation | 21%: concomitant fever, diarrhea, and radiological worsening |
|
| GI symptoms may be due to:
| GI symptoms more common in:
| ||||||||
| MERS | |||||||||||||||
| Study | Assiri et al (2013) N = 47, confirmed cases Retrospective study | Corman et al (2015) N = 37, confirmed cases Clinicopathologic study | Alenazi et al (2017) N = 130, confirmed cases Clinicopathologic study | Zhou et al (2017) Human intestinal epithelial cell culture, hDDP4 transgenic mice Clinicopathologic | Al-Abdley et al (2019) N = 33, confirmed cases Clinicopathologic study | ||||||||||
| Clinical features |
| N/A | GI symptoms in
| N/A |
| ||||||||||
| Key findings on investigations | N/A |
| N/A | N/A | RNA positive stool (57%) did not correlate with presence of GI symptoms | ||||||||||
| Key study findings and message | GI symptoms are frequent at presentation |
| MERS-CoV high in healthcare environment |
| Diarrhea may be associated with prolonged viral detection (p 0.069) | ||||||||||
| COVID-19 | |||||||||||||||
| Study | Wang et al (2020) N = 138, confirmed cases Clinicopathologic study | Guan et al (2020) N = 1099, confirmed cases Retrospective study | To et al (2020) N = 12, suspected cases Clinicopathologic study | Xie et al (2020) N = 19 suspected (9 confirmed cases) Clinicopathologic study | Pan et al (2020) N = 204, confirmed cases Retrospective study | Wu et al (2020) N = 74, confirmed cases Clinicopathologic study | |||||||||
| Clinical features |
|
| Diarrhea (11.1% of confirmed) |
| Diarrhea/Vomit/Stomachache (44.6%) | ||||||||||
| Key findings on investigations | N/A | N/A |
| RNA positive stool samples: 88.9% of confirmed (overall 42%) | ↑ALT, AST ↑ PT ↓monocyte count |
| |||||||||
| Key study findings and message | ICU patients more likely to have anorexia and abdominal pain (P < 0.001, P = 0.02) | GI symptoms less common |
|
|
| ||||||||||
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CXR, chest x-ray; EM, electron microscopy; F, female; GIT, gastrointestinal tract; HAI, healthcare associated infection; HAI, healthcare associated infection; MERS-CoV, middle east respiratory syndrome coronavirus; SARS-COV, severe acute respiratory syndrome coronavirus; TI, terminal ileumx.
On microscopy, acute tubular necrosis has been observed in these patients.
91
Viral detection in the urine at the onset was rare but gradually increased with the disease progression and remained detectable up to 30 days after symptom onset.76
,98
Xu et al reported that 6 patients who died of SARS-CoV had testicular damage, which was also likely secondary to the immune response.99
MERS-CoV
MERS-CoV uses the exopeptidase dipeptidyl peptidase 4 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
COVID-19
Acute renal dysfunction in COVID-19 at the time of presentation is not uncommon.
92
,104
,- Volunteers A–n
- Li Z
- Wu M
- et al.
Caution on kidney dysfunctions of 2019-nCoV patients.
medRxiv [Preprint]. March 27. 2020; https://doi.org/10.1101/2020.02.08.200212
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). Other researchers report albuminuria or proteinuria on admission in 44-63% patients, hematuria in 27%, elevated urea and creatinine in 13-27% and 14-19%, respectively, and low eGFR in 13%.104
,- Volunteers A–n
- Li Z
- Wu M
- et al.
Caution on kidney dysfunctions of 2019-nCoV patients.
medRxiv [Preprint]. March 27. 2020; https://doi.org/10.1101/2020.02.08.200212
105
There may also be imaging evidence of active renal edema and inflammation.104
Since renal dysfunction is early, an immunopathology response or direct viral injury may be contributing along with other systemic factors.- Volunteers A–n
- Li Z
- Wu M
- et al.
Caution on kidney dysfunctions of 2019-nCoV patients.
medRxiv [Preprint]. March 27. 2020; https://doi.org/10.1101/2020.02.08.200212
20
,92
Similar to other novel CoVs, renal involvement, acute or chronic, tends to associate with an adverse prognosis.22
,105
,107
The COVID-19 virus has been detected in renal tissue and in the urine.39
,70
,108
Due to the presence of ACE2 receptors in the Leydig cells and seminiferous tubules, it is also reasonable to speculate that testicular injury may be a consequence of COVID-19 infection.109
- Fan C
- Li K
- Ding Y
- et al.
ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-nCoV infection.
medRxiv [Preprint]. February 13. 2020; https://doi.org/10.1101/2020.02.12.20022418
NEUROLOGIC MANIFESTATIONS
SARS-CoV
Patients with SARS-CoV presented with ischemic stroke, likely due to the hypercoagulable state and vasculitis induced during the illness
110
(Table 5). Case reports mentioned the detection of SARS-CoV in the cerebral spinal fluid (CSF) of patients who subsequently developed seizures.111
,112
Tsai et al studied 4 patients with SARS-CoV who developed neuropathy and myopathy. Since they did not find CSF evidence of viral invasion, they attributed these findings to critical illness polyneuropathy and myopathy.113
Table 5Renal manifestations of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Study | Booth et al (2003) N = 144, confirmed cases Retrospective study | Choi et al (2003) N = 267 (227 confirmed cases) Retrospective study | Zou et al (2004) N = 165, confirmed cases Retrospective study | Chan et al (2004) N = 669, (323 tested positive) Clinicopathologic study | Huang et al (2004) N = 78, probable Retrospective study | Ding et al (2004) N = 8 (4 confirmed cases, 4 control) Clinicopathologic study | Chu et al (2005) N = 536, confirmed cases Retrospective study | |||
| Clinical features | Renal dysfunction | ARF (6%) during course of hospitalization | Renal dysfunction | N/A | ARF (17%). 7.2 ± 4.3 days after admission | N/A | ARF (6.7%) within 5-48 days of onset (median 20) | |||
| Key findings on investigations |
| ↑ Cr | ↑ Cr ↑ Urea |
| ↑ Cr | N/A | Cr normal at presentation, then ↑ | |||
| Histopathology | N/A | N/A | N/A | N/A | N/A | Virus detected in distal convoluted renal tubule | Acute tubular necrosis, no evidence of glomerular pathology | |||
| Key study findings and message | ↑ Urea > ↑ Cr associated with mortality (P = 0.003, P = 0.02) | ↑ Cr associated with mortality (P < 0.001, univariate) | ↑ Cr, ↑ Urea associated with poor prognosis (P = 0.001, P = 0.003) | Virus can persist >30 days after symptom onset in urine |
| ACE2 expressed and virus detected in kidneys |
| |||
| MERS | ||||||||||
| Study | Assiri et al (2013) N = 47, confirmed cases Retrospective study | Arabi et al (2014) N = 12 (11 confirmed cases, 1probable) Case series | Saad et al (2014) N = 70, confirmed cases Retrospective study | Cha et al (2015) N = 30, confirmed cases Retrospective study | Yeung et al (2016) Ex-vivo organ culture Nonhuman primate model Clinicopathologic | Alsaad et al (2017) N = 1, confirmed cases Clinicopathologic study | ||||
| Clinical feature | Coexisting chronic renal disease (49%) |
| ARF (42.9%) |
| N/A | |||||
| Histopathology | N/A | N/A | N/A | N/A | Smad7 and FGF2 expression elevated in kidneys of infected animals |
| ||||
| Key study findings and message | Chronic renal disease was a common comorbidity | Renal features may be due to:
| Acute kidney injury is a common complication |
| MERS-CoV induced apoptosis via upregulation of Smad7 and FGF2 expression | Tissue trophism in kidneys | ||||
| COVID-19 | ||||||||||
| Study | Wang et al (2020) N = 138, confirmed cases Retrospective study | Cheng et al (2020) N = 701, confirmed cases Retrospective study | Wang et al (2020) N = 205, confirmed cases Clinicopathologic | Li et al (2020) N = 193, confirmed cases Retrospective study | Zhou et al (2020) N = 191, confirmed cases Retrospective study | |||||
| Clinical Features |
|
| N/A |
|
| |||||
| Key findings on investigations | ↑ Cr |
| No viral detection in urine (72 samples) |
| ↑ Cr | |||||
| Key study findings and message |
|
| No viral shedding in urine | AKI associated with severe outcome (P < 0.001) |
| |||||
ACE2, Angiotensin-converting enzyme 2; AKI, acute kidney injury; ARF, acute renal failure; BUN, blood urea nitrogen; CKD, chronic kidney disease; CPK, creatine phosphokinase; Cr, creatinine; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; MERS-CoV, middle east respiratory syndrome coronavirus; SARS-COV, severe acute respiratory syndrome coronavirus; RRT, rapid response team.
Ocular manifestations have not been widely reported in patients with SARS-CoV infection. However, in 1 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.
MERS-CoV
MERS-CoV causes both central and peripheral neurological abnormalities. Neurological symptoms occur later in the course of the illness as weakness and neuropathy and less frequently hypersomnolence and ataxia (Table 5).
114
,115
In a study of 4 patients with neurological symptoms conducted by Kim et al, MERS-CoV was not detected in the CSF, however, patients developed Guillain-Barre’ syndrome, Bickerstaff's encephalitis, critical illness myopathy, viral myopathy or toxin associated myopathy and neuropathy.114
Algahtani et al also report a case of cerebrovascular accident attributable to disseminated intravascular coagulation (DIC) and viral-induced autoimmune response.115
The authors are not aware of evidence describing the ocular manifestations of MERS-CoV or the ability to isolate the virus in tear samples.COVID-19
Increasingly recognized sensory symptoms of COVID-19 infection include the sudden onset of anosmia, and, to a lesser extent, dysgeusia (Table 6).
40
Patients with pre-existing neurological diseases may also have a higher risk for encephalopathy and altered mental status.41
As many as 36.4% patients have neurological symptoms, and these are seen more commonly in patients with severe disease.42
Acute cerebrovascular accidents, altered mental status, and myopathy occurred in approximately one-third of patients. In an observational series of 58 COVID-19 positive patients, Helms et al documented confusion and agitation as the most common neurologic symptoms. Corticospinal tract signs were also evident in nearly two-thirds of patients including increased deep tendon reflexes, ankle clonus and bilateral extensor plantar reflexes.43
One recent case report described acute hemorrhagic necrotizing encephalopathy in a patient with COVID-19 infection.44
Guillain-Barré syndrome has been observed after the onset of COVID-19 in a few patients presenting with lower-limb weakness and paresthesia as well as facial diplegia and ataxia.45
Neurological involvement is present in more severely affected patients, and patients with central neurologic symptoms also had severe lymphopenia, thrombocytopenia and uremia.42
Patients with myopathy have a higher inflammatory response and a higher association with hepatic and renal disease.42
Table 6Neurological manifestations of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Study | Hung et al (2003) N = 1, confirmed cases Case report | Lau et al (2004) N = 1, confirmed cases Case report | Tsai et al (2004) N = 4, confirmed cases Case reports | Tsai et al (2005) N = 664, probable Retrospective study | |||||
| Clinical features | Seizures (4 limb twitching) starting day 5, lasting up to 30 min | Seizures (GTCS) started on day 22 |
|
| |||||
| Key findings on investigations | CSF:
| CSF:
|
| ||||||
| Key study findings and message | Symptoms may be due to direct viral pathogenicity | Symptoms likely due to critical illness polyneuropathy and/or myopathy |
| ||||||
| MERS | |||||||||
| Study | Algahtani et al (2016) N = 2, confirmed cases Case report, review | Kim et al (2017) N = 23, confirmed cases Retrospective study | |||||||
| Clinical features |
|
| |||||||
| Key findings on investigations | CSF and nerve conduction studies normal | ||||||||
| Key study findings and message |
|
| |||||||
| COVID-19 | |||||||||
| Study | Mao et al (2020) N = 214, confirmed cases Retrospective study | Filatov et al (2020) N = 1, suspected Case report | Bagheri et al (2020) N = 10069, with olfactory dysfunction Cross-sectional | Poyiadji et al (2020) N = 1, confirmed cases Case report | Helms et al (2020) N = 58, confirmed cases Retrospective study | ||||
| Clinical features |
| Altered mental status |
| Acute necrotizing encephalopathy |
| ||||
| Key findings on investigations | N/A |
| N/A |
| Brain MRI:
| ||||
| Key study findings and message |
| Can present with encephalopathy acutely or during hospitalization |
| Cytokine storm (known in influenza, other viral infections, more common in pediatrics) | Mechanism unknown, may be due to critical illness–related encephalopathy, cytokines, medication-induced or direct viral pathogenicity. | ||||
ARDS, acute respiratory distress syndrome; CK, creatine kinase; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; CVA, cerebrovascular accident; EEG, electroencephalogram; GTCS, generalized tonic clonic seizures; MERS-CoV, middle east respiratory syndrome coronavirus; MRI, magnetic resonance imaging; NCCT, noncontrast computed tomography; PNS, peripheral nervous system; SARS-COV, severe acute respiratory syndrome coronavirus.
Patients who underwent magnetic resonance imaging showed leptomeningeal enhancement with bilateral frontotemporal hypoperfusion.
43
Electroencephalography showed mostly nonspecific changes with findings consistent with encephalopathy.43
CSF analysis may show oligoclonal bands or elevated IgG levels, however, the significance of these findings is uncertain.Ocular manifestations of COVID-19 are garnering increasing attention. Animal studies show ACE2 and transmembrane serine protease 2, both established receptors for this virus, are expressed in the conjunctiva, although to a lesser extent than in the kidneys and lungs, and lesser in females.
46
A study reported conjunctivitis in as many as 31.6% patients, and more commonly in patients with severe disease.47
It has also been reported as the sole initial presentation.48
SARS CoV-2 has been isolated from conjunctival swabs in patients with ocular symptoms and reportedly detected for as many as 27 days after symptom onset.49
Interestingly, an animal model has also shown that the conjunctival route may lead to systemic infection as well, but viral replication in the conjunctiva and chances of virus release into the bloodstream are very low.50
MUSCULOCUTANEOUS MANIFESTATIONS
SARS-CoV
As many as 60% of patients with SARS-CoV had myalgia with up to 30% presenting with muscle weakness and increased creatinine phosphokinase (Table 6).
10
,34
,117
, 118
, 119
However, there was no statistically significant difference in creatinine phosphokinase levels between SARS-CoV patients with ARDS vs. patients without ARDS.117
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.119
Muscle atrophy may also be the result of steroid myopathy or critical illness myopathy 119
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.119
Cutaneous manifestations of SARS-CoV hasn't yet been reported in the literature to the authors’ knowledge.MERS-CoV
Myositis and muscle atrophy are less prevalent than SARS-CoV.
61
,120
Muscle weakness was common in patients with MERS-CoV (Table 6).114
Pathologic specimens mimic SARS-CoV specimens with myopathy and inflammatory cells in the areas of myofibril atrophy.61
Similar to SARS-CoV, cutaneous manifestation of MERS-CoV infection is rare and has not been widely reported.COVID-19
Myalgia is also a common presenting symptom of COVID-19 infection, and 36% of patients develop muscle pain during their illness (Table 6).
121
High creatinine kinase (CK) levels present in 14% to 33% of patients.- Li LQ
- Huang T
- Wang YQ
- et al.
2019 novel coronavirus patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis.
J Med Virol. 2020; ([Epub ahead of print])https://doi.org/10.1002/jmv.25757
22
,41
,106
,122
Patients with suspected COVID-19 and muscle aches were more likely to have abnormal lung imaging findings.122
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.123
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.
124
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.- Recalcati S
Cutaneous manifestations in COVID-19: a first perspective.
J Eur Acad Dermatol Venereol. 2020; https://doi.org/10.1016/j.jaad.2020.03.036
125
To date, there has been no correlation between cutaneous manifestations of COVID-19 and disease severity.- Alramthan A
- Aldaraji W
Two cases of COVID-19 presenting with a clinical picture resembling chilblains: first report from the Middle East.
Clin Exp Dermatol. 2020; ([Epub ahead of print])https://doi.org/10.1111/ced.14243
HEMATOLOGY MANIFESTATIONS
SARS-CoVa
Reactive lymphocytosis and severe lymphopenia (<500 cells/mm3) are uncommon in patients with SARS (Table 7).
10
,126
Patients with SARS-CoV infection often presented with a normal total leukocyte counts.126
,127
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 10 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.128
Prolonged activated partial thromboplastin time and elevated D-dimer levels were also common abnormalities (63% and 45%, respectively).10
Table 7Musculoskeletal Manifestation of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Lee et al (2003) N = 138, confirmed cases Retrospective study | Donnelly et al (2003) N = 1425, confirmed cases Retrospective study | Choi et al (2003) N = 267 (227 confirmed cases) Retrospective study | Chen et al (2005) N = 67, confirmed cases Retrospective study | Leung et al (2005) N = 8, probable Clinicopathologic study | Yu et al (2006) N = 121, confirmed cases Retrospective study | ||||||||
| Clinical features | Myalgia: 60.9% | Myalgia: 50.8% | Myalgia: 50% | Myalgia/arthralgia: 13.4% | N/A | Myalgia: 71% | ||||||||
| Key findings on investigations | ↑ CK (32.1%) | N/A | N/A | ↑ CK (20.9%) | ↑ CK | ↑CK (26%) | ||||||||
| Histopathology | N/A | N/A | N/A | N/A |
| N/A | ||||||||
| Key study findings and message | High peak CK predictive of ICU admission and death (univariate, P = 0.04) (Association with CK on admission had P = 0.06) | Myalgia commonly reported | No significant difference in CK levels in probable and confirmed patients | No difference in reporting of myalgia/arthralgia in patients with ARDS vs. without |
|
| ||||||||
| MERS | ||||||||||||||
| Study | Omrani et al (2013) N = 3, confirmed cases Retrospective study | Saad et al (2014) N = 70, confirmed cases Retrospective study | Kim et al (2017) N = 23, confirmed cases Retrospective study | Alsaad et al (2017) N = 1, Clinicopathologic | ||||||||||
| Signs and symptoms | Myalgia or arthralgia: 20% | Myalgia or arthralgia: 26.9% | N/A | |||||||||||
| Labs | ↑ CK | N/A | Electromyogram in 1 normal | N/A | ||||||||||
| Histopathology | N/A | N/A | N/A |
| ||||||||||
| Key study findings and message | Mild/asymptomatic cases may contribute to spread more than recognised | Myalgia/arthralgia common nonrespiratory symptom | Neuromuscular complications during MERS treatment may be underdiagnosed |
| ||||||||||
| COVID-19 | ||||||||||||||
| Study | Huang et al (2020) N = 41, confirmed cases Retrospective study | Chen et al (2020) N = 99, confirmed cases Retrospective | Wang et al (2020) N = 138, confirmed cases, Retrospective study | Guan et al (2020) N = 1099, confirmed cases Retrospective study | Li et al (2020) N = 1994, confirmed cases Meta-analysis, 10 studies | Zhang et al (2020) N = 645, confirmed cases Retrospective study | ||||||||
| Clinical features | Myalgia or fatigue: 44% | Myalgia: 11% | Myalgia: 34.8% | Myalgia or arthralgia: 14.9% | Myalgia or fatigue: 35.8% (11-50%) | Myalgia:11% | ||||||||
| Key findings on investigations | ↑ CK (33%) | ↑ CK (13%) (associated with ↑ myocardial enzymes) | ↑CK | ↑ CK> = 200 U/mL: 13.7% | ↑ CK: 13-33% | ↑ CK | ||||||||
| Key study findings and message | No difference in level of CK in ICU and non-ICU patients | Muscle ache less commonly reported | Higher CK in ICU patients (P = 0.08) | Muscle ache less commonly reported |
|
| ||||||||
ARDS, acute respiratory distress syndrome; CK, creatine kinase; ICU, intensive care unit; MERS-CoV, middle east respiratory syndrome coronavirus; SARS-COV, severe acute respiratory syndrome coronavirus.
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.
129
,130
Thrombocytopenia could be due to the result of interplay between autoantibodies, immune complexes, increased consumption and decreased production of platelets.128
MERS-CoV
Most patients present with a normal total leukocyte count.
17
One-third of the patients may present with lymphopenia of <1,500 cells/mm3 and severely low levels during the early stage of the illness 600 cells/mm3 or less (Table 7).16
,17
Hemoglobin levels are usually normal in patients with MERS-CoV.131
Mild thrombocytopenia was frequently present in critically ill patients with MERS-CoV and indicates poor prognosis.17
,131
Patients with a fatal form had developed DIC.17
,132
However, there is a paucity of studies explaining the pathogenesis.COVID-19
Data regarding the hematologic manifestations of COVID-19 infection are emerging. Patients with severe disease may have higher total white cell counts (Table 7) (median 6100 cells/mm3).
20
,21
Otherwise, similar to the other novel coronavirus infections, lymphopenia is a frequent finding, is present in a third of patients.21
,121
Hence, lymphopenia may help as a reference index.- Li LQ
- Huang T
- Wang YQ
- et al.
2019 novel coronavirus patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis.
J Med Virol. 2020; ([Epub ahead of print])https://doi.org/10.1002/jmv.25757
121
However, there may not be any differences in lymphocyte counts between mild and severe forms of COVID-19. Neutrophilia may help to predict ICU admissions. Hemoglobin seems to be mostly unaffected by COVID-19 infection. DIC is a rare complication.- Li LQ
- Huang T
- Wang YQ
- et al.
2019 novel coronavirus patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis.
J Med Virol. 2020; ([Epub ahead of print])https://doi.org/10.1002/jmv.25757
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 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
OBSTETRICS MANIFESTATIONS
SARS-CoV
Although the data are limited for SARS-CoV in pregnancy, evidence suggests poorer clinical outcomes for pregnant women. Reports are available for 12 pregnant women in Hong Kong and 2 in the United States (Table 8).
133
Among the twelve women in Hong Kong, pregnancy did not appear to impact the initial clinical presentation of SARS. Four of the 7 women presenting in the first trimester miscarried, though this finding is confounded by treatment with the purported teratogen Ribavirin in 6 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).123
Of the 5 women presenting in the second or third trimester of pregnancy, 4 delivered preterm, 1 spontaneously due to preterm labor and 3 iatrogenic due to worsening maternal status.124
- Recalcati S
Cutaneous manifestations in COVID-19: a first perspective.
J Eur Acad Dermatol Venereol. 2020; https://doi.org/10.1016/j.jaad.2020.03.036
Table 8Hematological manifestations of SARS-CoV, MERS-CoV and COVID-19.
| SARS (only studies with large study population included) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Study | Lee et al (2003) N = 138, confirmed cases Retrospective study | Wong et al (2003) N = 157, confirmed cases Retrospective | Chng et al (2005) N = 185, confirmed cases Retrospective study | Yang et al (2013) Review | |||||
| Key findings on investigations |
|
|
|
| |||||
| Histopathology | N/A | Lymphopenia in lymphoid organs on postmortem, including splenic white pulp | N/A | N/A | |||||
| Key study findings and message | Neutrophilia associated with ICU care or death (P = 0.02) | ↓ CD4+, CD8+ cells at presentation associated with ICU care or death (P = 0.029, 0.006) | White count and ANC associated with ICU admission (univariate) `(P = 0.034, 0.021) | Mechanism of thrombocytopenia:
| |||||
| MERS | |||||||||
| Study | Assiri et al (2013) N = 47, confirmed cases Retrospective study | Arabi et al (2014) N = 12, (11 confirmed cases, 1 suspected) Case series | |||||||
| Clinical features | Preexisting malignancy (2%) | ||||||||
| Key findings on investigations |
|
| |||||||
| Key study findings and message | Hematological manifestations common, lymphopenia most common | Lymphopenia commonly seen | |||||||
| COVID-19 | |||||||||
| Study | Chen et al (2020) N = 99, confirmed cases Retrospective study | Wang et al (2020) N = 138, confirmed cases Retrospective study | Guan et al (2020) N = 1099, confirmed cases Retrospective study | Li et al (2020) N = 1994, confirmed cases Meta-analysis, 10 studies | Tang et al (2020) N = 449, confirmed cases Prospective study | Zhou et al (2020) N = 191, confirmed cases Retrospective study | |||
| Clinical features | N/A | Preexisting malignancy (7.2%) | Preexisting malignancy (0.9%) | N/A | N/A | Preexisting malignancy (1%) | |||
| Key findings on investigations |
|
|
|
| ↑D-dimer |
| |||
| Key study findings and message | Various hematological abnormalities commonly seen |
| More severe derangements in more severe disease |
|
|
| |||
ANC, absolute neutrophil count; aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; Hb, hemoglobin; ICU, intensive care unit; MERS-CoV, middle east respiratory syndrome coronavirus; PT, prothrombin time; SARS-COV, severe acute respiratory syndrome coronavirus; TPO, thyroperoxidase; WBC, white blood cell count.
There was no evidence of transplacental or intrapartum vertical transmission of SARS-CoV (Table 8).
134
, 135
, 136
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.134
,137
MERS-CoV
Pregnant women with symptomatic MERS-CoV infection may be at a higher risk of adverse events. There are 9 reported cases of symptomatic MERS-CoV in pregnant women, and 7 of them required ICU admission, 5 required mechanical ventilation, and 3 died (Table 8).
138
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.138
,139
There are 2 reported cases of asymptomatic MERS-CoV infection in pregnant women, both identified via contact tracing. One was identified at 6 weeks gestation, and the other at 24 weeks. Both had healthy term deliveries.140
Based on available epidemi