Table 3.

Summary of extrapulmonary manifestations of SARS-CoV-2.

Manifestation	Described frequency	Day of onset after fever or respiratory symptoms	Pathologic mechanism	Association with severe disease or mortality
Immunologic manifestations
Cytokine release syndrome	1. Not defined and not precisely described in observational studies 2. Likely mirrors proportion of severe and critical cases (19.9%)[3]	Day 7–19[4,9,59,82]	1. Increased pathogenic Th1 cells and CD14+CD16+ monocytes[13] 2. Reduced memory Th (CD3+CD4+CD45RO+) and regulatory (CD3+CD4+CD25+ CD127low+) Tcells[6] 3. Depletion of absolute numbers and functional exhaustion of CD4+ and CD8+ T cells[14,15,16]	Not precisely described. ARDS and multiorgan dysfunction accompany higher mortality, as described below
Induction of antiphospholipid antibodies	3 case reports/series, total n=9 [23,24,25]	Not reported	1. Unknown for SARS-CoV-2 2. APLs induced by other viruses were related to endothelial exposure of phospholipid-binding viral peptides[153]	Not known
Haematologic manifestations
Hypercoagulability	Venous thromboembolism in 10%–31% of patients[17,16,27,28,29,30,31]	Although D-dimer increases on Day 5–7,[82] venous thromboembolism was reported on Day 1–21[28,32,33,34,35,36]	1. Thromboinflammation with elevated cytokines, such as IL-6, causing endothelial injury[19] 2. Direct invasion of endothelial cells by the SARS-CoV-2 virus[21] 3. Complement-mediated endothelial injury[22] 4. Elevations in circulating prothrombotic factors, e.g., factor VIII, fibrinogen, prothrombotic microparticles[18,19,20] 5. Possible role of induced antiphospholipid antibodies[23,24,25]	Disseminated intravascular coagulation was seen in 71.4% of non-survivors vs. 0.6% survivors in one study[26]
Leucocytosis	1.9%–44.7%[11,51,55,56,57,58,63,64,68]	Peaks on Day 15–17[82]	1. Increased leucocyte mobilisation from hypercytokinaemia 2. Secondary bacterial or fungal infections	1. ICU-admitters had a higher WBC count on admission[82] 2. 46% of non-survivors had leucocytosis vs. 11% of survivors[9] 3. In a meta-analysis of 3600 patients, leucocytosis was associated with severe disease (27.7% vs. 9.3% in mild disease)[51]
Lymphopenia	26.1%–85%[4,9,16,29,49,50,51,52,53,54,55,56,57,58,59,60]	Nadir on Day 5-10[82]	1. Apoptosis induced by hypercytokinaemia[6,16] 2. Direct viral destruction via ACE-2 receptor[66] 3. Translocation into affected organs[67]	Lymphocyte count at baseline, lymphocyte count over time[4,9,11,16,54,55,57,61,62,63,64] as well as lymphocyte-to-leucocyte ratio[65] were associated with severe disease and mortality
Thrombocytopenia	Thrombocytopenia was seen in 11.4%–30% of patients[51,70,71]	Nadir on Day 17–19[70]	1. Reduction of platelet production from direct infection of bone marrow or cytokine storm 2. Increased platelet destruction from increased immune clearance 3. Increased platelet consumption from microthrombi or pulmonary damage[154]	In-hospital mortality of 92.1% was observed for patients with a nadir platelet count of <50×10[70]
Eosinopenia	52.9%–81.2%[11,54,68]	Not known	Not known	Not predictive of disease severity in a meta-analysis of 294 patients[155]
Neutrophilia	38%–60%[4,11,51,57,58,63,65,68]	Peaks on Day 15–17[82]	1. Increase mobilisation as a result of hypercytokinaemia[10] 2. Possible secondary bacterial infection	HR 1.14 for death or ARDS in bivariable analysis in one study of 201 patients[58]
Sickle cell crisis	Case series of 2 patients who presented with painful vaso-occlusive crisis and acute chest syndrome that preceded fever and respiratory symptoms[156]	Day −3 to 1[156]	Similar process to other viral infections	Not known
Cardiac manifestations
Acute cardiac injury	1. 17.7% from a total of 1,412 COVID-19 patients (10 cohort studies, sample sizes 41–416).[4,59,62,82,83,84,85,86,87,88] 2. In another meta-analysis of 1,527 patients, 8.0% of patients suffered acute cardiac injury[89]	Day 4–21, peaking on Day 15[9]	1. Hypercytokinaemia driving increased sympathetic activity and resulting in demand ischaemia[7,157] 2. Over-representation of patients with underlying cardiovascular diseases[86,88] 3. Myocarditis with direct invasion of ACE-2-expressing myocytes[98] 4. Endotheliitis and endotheliopathy impairing perfusion of submucosal cardiac vessels[21] 5. Hyperinflammation increasing atherosclerotic plaque vulnerability and rupture[21,158] 6. Hypercoagulability leading to pulmonary embolism or microthrombi and right heart strain[17,27,28,29,32]	Mean mortality rate is 54.4% in patients with acute cardiac injury compared to 9.0% in those without[86,87,88]
Heart failure	6.5%–23% of all patients[9,51,60]	Not known but likely parallels cardiac injury	1. Ischaemia secondary to endotheliitis and endotheliopathy[21] 2. Key cytokines implicated in SARS-CoV-2 hypercytokinaemia, such as IL-6, may promote myocardial dysfunction[159] 3. Downregulation of ACE-2 has been demonstrated in SARS-CoV and may reduce cardioprotection by angiotensin 1-7[160] 4. Myocarditis	Seen in 52% of non-survivors vs. 12% of survivors[9]
Myocarditis	12.5% of 112 patients[85] 7 case reports[92,93,94,95,96,97,98]	Not known	Direct invasion of myocytes via ACE-2[98]	Not known
Arrhythmias	10.9%–16.7% of patients[53,82] Rapid ventricular tachycardia and ventricular fibrillation causing haemodynamic instability were seen in 7.0% of 187 patients.[86] Reports of transient complete heart block[161] and Brugada syndrome[162]	Not known but likely parallels cardiac injury	1. Acute cardiac injury 2. Myocarditis 3. Electrolyte disturbance from acute kidney injury or diarrhoea 4. Contribution from medications such as hydroxychloroquine	Seen in 40% of severe cases vs. 1.2% of non-severe cases[53]
Gastrointestinal manifestations
Gastrointestinal symptoms (including nausea, diarrhoea, anorexia and abdominal pain)	1. 12.8%-65.9% of all patients[65,82,99,100,101,102,103,104] 2. In a meta-analysis of 4,243 patients, the pooled prevalence of the symptoms was: anorexia 26.8%, diarrhoea 12.5%, nausea and vomiting 10.2%, abdominal pain 9.2%[105]	Predate respiratory symptoms by up to 9 days before, up till 11 days after[65,82,99,100,101,102,103,104]	1. Enteric infection is proposed to be mediated by ACE-2 receptors, which are abundantly expressed in epithelial cells[109] 2. Small bowel endotheliitis in patients with mesenteric ischaemia.[21]	1. Higher mortality and need for ventilatory support reported in 181 patients with high comorbidity burden[163] 2. No difference in outcomes in another multicentre, cross-sectional study of 204 patients[109]
Acute liver injury	1. Elevated aspartate aminotransferase and alanine aminotransferase were observed in 10%–36.6% and 7.7%–33.3% of patients, respectively.[4,8,49,57,100,103,110,111,112,113,114,115] 2. Hyperbilirubinaemia was seen in 2.1%–18.2%.[49,57,110,113,114,116,117]	Day 4–11, peak on Day 10[114]	1. Direct virus-induced effect via ACE-2 receptors expressed in biliary, liver epithelial cells or endothelial cells 2. Systemic inflammation and immune injury 3. Sepsis from secondary bacterial infection 4. Ischaemia secondary to hypoxia, heart failure or hypotension 5. Drug-induced liver injury from lopinavir/ritonavir, remdesivir and tocilizumab	More common in severely ill patients[4,49,51]
Neurologic manifestations
Stroke	1. 5.7% in severely ill patients[37] 2. Case series and case reports in Table 1	Day −2 to 33, appear to peak on Day 9–15 [Table 1]	Ischaemic strokes may be related to mechanisms of hypercoagulability, endotheliopathy and over-representation of cardiovascular comorbidities, as outlined above	5.7% in severely ill patients vs. 0.8% in mild cases[37]
Meningoencephalitis	1. Isolated case reports[79,80] 2. Leptomeningeal enhancement on brain imaging was reported in 62% of severe patients with ARDS and encephalopathy[41]	Diagnosed on Day 3 and Day 9 in 2 case reports[79,80]	1. Direct SARS-CoV-2 invasion into CNS[79] 2. Para-infectious mechanism with blood-brain barrier breakdown due to cytokine storm[75,79]	Not known
Elevated creatine kinase and rhabdomyolysis	1. 28.6% and 16.7% of patients with severe and mild clinical disease, respectively[51] 2. 0.2% rhabdomyolysis[49]	Not known. Reports of rhabdomyolysis as initial presentation[81]	1. Direct viral invasion by binding to ACE-2 receptor in skeletal muscle 2. Immune response resulting in cytokine storms and damaging muscle tissues 3. Circulating viral toxins may directly destroy muscle cell membranes[25,37]	More common in severely ill patients[51]
Guillain-Barré syndrome and Miller Fisher syndrome	Estimated 0.4%–0.5% from an Italian case series of 5 Guillain-Barré syndrome patients, with approximately 1,000−1,200 COVID-19 patients admitted during the study period[77]	Day 3−10[75,77] (1 report preceding SARS-CoV-2 by 8 days)[76]	1. Post-infectious autoimmune mechanism with presentation 3-10 days after COVID-19 symptoms[77,79] 2. Para-infectious mechanism proposed in view of an early presentation of Guillain-Barré syndrome[76]	Not known
Non-specific findings including headache, giddiness, delirium and corticospinal tract signs	36.4% of 214 patients in China, including headache (13.1%), giddiness (16.8%) and drowsiness (7.5%).[37] Similarly, in 58 French patients with ARDS, ICU delirium (65%) and corticospinal tract signs (67%) were the main neurological findings. A high incidence of leptomeningeal enhancement and bilateral frontotemporal hypoperfusion was reported on imaging. SARS-CoV-2 was negative in the CSF of all 7 patients who underwent lumbar puncture.[41]	Not known	Possibly related to general unwell state, systemic inflammation or drugs	Delirium and corticospinal tract signs are common in severely ill patients in ICU[41]
Renal manifestations
Acute kidney injury	0.5%–7% of all patients and up to 17% of patients in cohorts with higher prevalence of cardiovascular diseases[4,9,49,53,57,82,86,103,121]	Day 11–17[82]	1. Direct viral cytopathic effect, mediated through the ACE-2 receptor and cellular transmembrane serine proteases expressed on podocytes and tubular epithelial cells.[122] 2. Severe AKI in later course of disease in tandem with ARDS and other organ dysfunction, likely related to hypercytokinaemia[9,82]	In critically-ill patients, rates of AKI increased up to 29%,[4,49,53,59,82] and AKI was observed in up to 50% of patients who eventually died[9,65,68,90]
Collapsing glomerulopathy	1 case report in a patient who presented with fever, vomiting and acute renal failure. SARS-CoV-2 was absent in the kidney.[164]	Presented with other symptoms	Patient was homozygous for the APOL1 genotype[164]	Not known
Olfactory, gustatory and auditory manifestations
Olfactory dysfunction	1. Studies using self-reported symptoms: 20%–68% 2. Studies using objective measures: 82.6%–98% [Table 2]	Day 2–7[125]; could precede respiratory symptoms	1. Reactive inflammation of the olfactory cleft causing conductive smell dysfunction[130,131] 2. Direct viral invasion of ACE-2-expressing olfactory epithelial cells[130,131]	9% of 54 patients needed ICU care, 4% died[125]
Gustatory dysfunction	1. Studies using self-reported symptoms: 24%−85% 2. Studies using objective measures: 49.3%−88% [Table 2]	Day 2-7[125]; could precede respiratory symptoms	1. Inactivation of ACE-2 receptors in the oral cavity resulting in sodium channel inactivation in the taste receptors[131] 2. Viral binding to sialic acid receptors in the taste pores[131] 3. Smell dysfunction altering taste perception[130,131]	Not known
Cutaneous manifestations
Maculopapular eruption	47% of cutaneous manifestations[133]	Day 3–8[134,136,138,140,142,144,146]	Non-specific and could be related to both virus and drugs	12% needed ICU or non-invasive ventilation[133]
Urticaria	19% of cutaneous manifestations[133]	Day −2 to 6[135,137,138]	Non-specific and could be related to both virus and drugs	11% needed ICU or invasive ventilation[133]
Vesicular eruption	9% of cutaneous manifestations[133]	Day −2 to 12[139]	Non-specific and could be related to both virus and drugs	1. 6% of patients needed ICU or invasive ventilation[133] 2. 3/22 patients died in one series[139]
Livedoid lesions or necrosis	6% of cutaneous manifestations[133]	Day 7–10 for livedo reticularis[156] Day 14–21 for skin necrosis[22]	Endotheliitis, endotheliopathy and hypercoagulability (outlined above). Transient processes may result in livedo, while fulminant intravascular coagulation may lead to fixed necrosis.	33% required ICU or invasive ventilation[133]
Chilblain-like lesions	19% of cutaneous manifestations[133]	Day 6–15 (median 10 days)[150]	Not known. Likely related to microangiopathic process and a continuous spectrum with livedo	1. Only 3% required ICU or invasive ventilation.[133] 2. Case reports of generally well patients.[148,149,151]
Other manifestations
Conjunctivitis	19 patients (1 observation study and 3 case series/reports)[165,166,167,168] Symptoms included conjunctival hyperaemia, chemosis, epiphora and increased secretions[167]	Was the only symptom in 7 patients and often preceded other symptoms[165,166,167,168]	Viral invasion of conjunctival cells that express ACE-2	Not known. Observed in asymptomatic as well as critically ill patients
Mediastinal lymphadenopathy	1%–6% of patients who received chest computed tomography in 2 small observational studies (described to be subcarinal and voluminous)[169,170]	Not clear and depended on time of imaging	Likely similar to other infection-associated lymphadenopathy	Not known
Spontaneous pneumomediastinum	3 case reports in patients with bilateral pneumonia (one received positive pressure ventilation)[171,172,173]	Day 10–12[171,172,173]	Not known	Not known
Arthralgia	2 case reports, one in a patient with fever and thrombocytopenia[174]; another in a patient with urticaria[135]	Presenting symptom in both patients	1. Not known for SARS-CoV-2 2. Possibly similar to other viral arthritides: mechanisms include complement activation and infiltration of inflammatory cells into synovium 3. Key cytokines in the cytokine release of SARS-CoV-2 (e.g. IL-6 and MCP1) have been implicated in pathogenesis of acute arthritis for other viruses[175]	Not known
Auditory manifestations	Tinnitus (11%) and hearing loss (4%) were reported among 54 patients with anosmia.[125] A study showed that the high frequency pure-tone threshold and the transient evoked otoacoustic emissions amplitudes were significantly worse in a group of 20 young patients with confirmed SARS-CoV-2 who were asymptomatic.[176] One patient with otitis media presented with otalgia along with bilateral pneumonia[177]	Not known for tinnitus and hearing loss. Report of otitis media was synchronous with other symptoms[177]	Postulated to be due to direct viral damage to the hair cells, organ of Corti, stria vascularis, or spiral ganglion[176]	Not known
Testicular pain	One patient presented with stabbing testicular pain and fever[178]	Same as other symptoms	Not known	Not known

ACE-2: Angiotensin-converting enzyme 2, AKI: acute kidney injury, APL: anti-phospholipid antibodies, ARDS: acute respiratory distress syndrome, CSF: cerebrospinal fluid, CNS: central nervous system, HR: hazard ratio, ICU: intensive care unit, IL-6: interleukin-6, MCP1: monocyte chemoattractant protein-1, SARS-CoV-2: severe acute respiratory syndrome coronavirus-2, Th1: T-helper 1, WBC: white blood cell count