1. Ashraf, Obaid MD
  2. Young, Meilin MD
  3. Malik, Khalid J. MD
  4. Cheema, Tariq MD


Coronavirus disease-2019 (COVID-19) creates severe respiratory distress and often a cascade of other systemic complications impacting several organ systems. The immune response includes a cytokine storm that creates many life-threatening problems including coagulopathies, arrhythmias, and secondary infections. This article discusses the multisystem responses to the physical insults created by this corona virus.


Article Content

CORONAVIRUS DISEASE-2019 (COVID-19) causing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified in Wuhan 2019 and has since swept the world as a pandemic.1 SARS-CoV-2 transmits primarily through respiratory droplets. As the disease progresses, it results in a series of complications, most notably in the critically ill patients. Patients with SARS-CoV-2 can have multiorgan complications, including but not limited to, cardiac injury, acute respiratory distress syndrome (ARDS), arrhythmias, thromboses, infarcts, and secondary infections, which have been reviewed and discussed in detail here in a system-wise fashion.2-4



Cytokine release storm

Cytokine release storm (CRS) is a hyperinflammatory and multiorgan disease process as a result of excessive cytokine release from uncontrolled immune system activation that may be fatal. The characteristic feature is a profound increase in proinflammatory cytokines.5-8 The etiology of CRS includes various infections, drugs, and critical illness. It is known to be an immune system-related disease and has been seen previously in chimeric antigen receptor (CAR) T-cell therapy, sepsis, organ transplantation, and viral infection.6-8 Hyperinflammation in SARS-CoV2 is unique in that there is extensive end-organ disease primarily focused in the lung that results in ARDS and a modest ferritin elevation. Hemophagocytosis from lung tissue has been identified in previous coronavirus-related severe acute respiratory syndrome (SARS); this is a central pathologic feature of cytokine storm.9 In addition, patients with SARS also shows evidence of high levels of interferon-[gamma] (IFN-[gamma]) and interleukin-18 (IL-18), which are particularly crucial in cytokine storm syndrome.10 Thus, the host's immune response and tissue-focused inflammation in the lung likely play an essential role in COVID-19. SARS-CoV-2 CRS is closely associated with secondary hemophagocytic lymphohistiocytosis (sHLH). The cardinal features of sHLH are unremitting fevers, cytopenias involving multiple cell lines, and hyerperferritinameia.11 The cytokine profile is very much similar in both SARS-CoV-2 CRS and sHLH, which is characterized by increased granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-[alpha], IL-2, IL-7, tumor necrosis factor-[alpha], IL-6, and IL-10.3,12


Two criteria have been used previously in the identification of CRS in other diseases: CAR T-cell therapy related and sHLH. For CAR T-cell therapy, called CARTOX criteria, there is a grading system based on the number of organ systems involved in the disease process.13 For sHLH, the Hscore scoring system generates a probability for the presence of sHLH.14 An Hscore greater than 169 is 93% sensitive and 86% specific for HLH. Although studied in other disease processes, the limitation in using these criteria for SARS-CoV-2 is the lack of validation.


In the clinical setting, current proposed criteria being used in SARS-CoV-2 CRS are the presence of any one of the following15:


1. Ferritin greater than 1000 [mu]g/L and increasing over 24 hours


2. Single ferritin above 2000 [mu]g/L if patient requiring high-flow oxygen therapy or mechanical ventilation


3. Lymphopenia (ie, <800 lymphocytes/[mu]L) and presence of 2 of the following:


* Ferritin greater than 700 [mu]g/L


* Lactate dehydrogenase greater than 300 IU/L


* D-dimers greater than 1000 ng/mL


* C-reactive protein above 70 mg/L and no evidence of bacterial infection



In regard to treatment, while corticosteroid is effective for CRS in other clinical settings, its use is being avoided as it might exacerbate SARS-CoV-2-associated lung injury and prolong viral shedding.16 For hyperinflammation, immunosuppression is beneficial. The pathogenesis and concern that overactive and unchecked immune response driving CRS has created tremendous interest in anticytokine therapy to counter such exaggerated immune responses.17 Previously, the use of anticytokine treatment has been studied in a phase 3 clinical trial with anti-IL-1 (anakinra) therapy in sepsis. This showed a mortality benefit in patients with hyperinflammation and was without increased adverse events.18 There is also interest in using an anti-IL-6 agent (tocilizumab) given the central role that IL-6 has in the CRS.19 Currently, there are anecdotal reports of improved oxygenation in patients with COVID-19, systemic inflammation, and hypoxic respiratory failure when an anti-IL-6 agent was used. In a 15-patient case series of individuals with SARS-CoV-2, patients were given tocilizumab at varying doses of 80 to 600 mg. There was evidence of either clinical stability or improvement in 10 patients, while 5 patients failed treatment with 2 having disease aggravation and 3 with death.20 Another case series of 21 patients with severe or critical COVID-19 illness treated with anti-IL-6 (tocilizumab) showed evidence of improved oxygenation (71%), fever reduction (100%), normalization of C-reactive protein (84.2%), and radiologic improvement (90.5%) in patients.21 There are large randomized controlled trials underway to better understand the efficacy, dosage, and safety of anti-IL-6 therapy.22 An additional therapeutic agent currently undergoing a clinical trial is baricitinib, an anti-Janus kinase inhibitor (anti-JAK) acting against JAK1 and JAK2, which are cytokine mediations that result in the inhibition of clathrin-mediated endocytosis and subsequent reduction in the host inflammatory response. There are no clinical data available yet, as it is currently under investigational use.23



COVID-19 pneumonia is noted to be the second stage of SARS-CoV-2 illness. It results from the impairment of gas exchange between the lungs and circulating blood, resulting in hypoxemia. Clinical manifestations include shortness of breath and hypoxia noted by pulse oximetry. Respiratory failure is the leading cause of mortality in patients with SARS-CoV-2 infection.24 There is currently a hypothesis of 2 phenotypes of respiratory failure in SARS-CoV-2 disease. In type 1, there is a dissociation between the severity of the hypoxemia and the maintenance of a relatively intact respiratory system. These patients have near-normal pulmonary compliance. Hypoxia is primarily due to a ventilation/perfusion mismatch. As the disease progresses, the patient develops a type 2 phenotype, which is identified by decreased pulmonary compliance as a result of the natural evolution of the disease.25 Type 2 phenotype occurs in the setting of advanced ARDS and benefits from lower tidal volume and prone positioning.26



COVID-19 severe illness has been noted in patients with underlying cardiovascular comorbid conditions. In one cohort of 191 patients from Wuhan, China, hypertension was present in 30% of patients (48% in nonsurvivors) and cardiovascular disease in 8% of patients (13% of nonsurvivors).27 This was replicated in another cohort of 138 hospitalized patients with COVID-19, with hypertension of 31% (58% in patients requiring an intensive care unit [ICU]) and cardiovascular disease in 15% (25% in patients requiring an ICU).2 The mechanism of these associations remains unclear.


Myocardial injury

As discussed previously, COVID-19 is associated with the hyperinflammatory response, which affects the myocardium and vascular system as well. Inflammation of the myocardium has a variety of presentations in the form of heart failure, myocarditis, arrhythmias, acute coronary syndrome, and sudden death.28-30 In addition, there have been reported cases of myocarditis, cardiac tamponade, pericarditis, and Takotsubo syndrome.24,31-36 The mechanism of injury is not known, but underlying pathogenesis includes small vessel thrombotic complications, microvascular dysfunction, or a variant of stress-induced cardiomyopathy.29,37,38 Please see chapter titled: Covid-19 and the cardiovascular system for a review of SARS-CoV-2 related cardiac diseases.



SARS-CoV-2 has noted to have a prothrombotic nature as patients with higher D-dimer and fibrinogen degradation products having worse outcomes.2,27 One study identified 71% of SARS-CoV-2 patients who died met criteria for disseminated intravascular coagulation, compared with only 0.6% among survivors, suggesting an activation of the coagulation cascade in severe critical illness.39 Additionally, studies have identified prothrombin time more than 3 seconds or activated partial thromboplastin time more than 5 seconds (hazard ratio 4.1, 95% confidence interval 1.9-9.1), as independent predictors of thrombotic complications.2,27


Venous thromboembolism

The incidence of venous thromboembolism (VTE) is 25% to 31% in patients with severe COVID-19 infection,40,41 with pulmonary embolism (PE) being the most frequent thrombotic complication (81%). A single-center study from France suggested that D-dimer levels more than 26 600 ng/mL had a greater than 95% detection rate for a pulmonary embolism. However, the study limitations include small sample size, single-center, and lack of validation.42 The exact mechanism contributing to the high burden of VTE in COVID-19 is unknown and possibly multifactorial. Viral infection causes direct endothelial cell injury resulting in excessive thrombin generation and fibrinolysis shutdown.43 Other contributory factors include stasis, critical illness, and systemic inflammatory response.44,45


In regard to VTE management, published guidelines in this regard have been endorsed by the International Society on Thrombosis and Hemostasis (ISTH).43 All hospitalized COVID-19 patients should receive a prophylactic dose of low-molecular-weight heparin, provided there being no evidence of bleeding, the platelet count being higher than 25 x 109/L, and fibrinogen levels being greater than 0.5 g/L. The dose should be adjusted for obesity based on institutional guidance. Fondaparinux is used as the alternative agent for patients with a history of heparin-induced thrombocytopenia. If pharmacotherapy is contraindicated, mechanical thromboprophylaxis (eg, pneumatic compression devices) is recommended.46


Therapeutic anticoagulation for documented VTE is recommended and should be continued unless the platelet count is less than 30 to 50 x 109/L or if the fibrinogen is less than 1.0 g/L. Pulmonary embolism response teams that are available at the institution should be involved to provide multidisciplinary care to VTE patients who have intermediate- or high-risk PE.47,48 During the COVID-19 pandemic, this should transition from in-person evaluation to e-consult using a telemedicine system. Anticoagulation and close monitoring are recommended for intermediate-risk (low- and high-risk) hemodynamically stable patients.49-51 In the setting of further deterioration, systemic fibrinolysis should be considered.52 For patients presenting with overt hemodynamic instability, systemic fibrinolysis should be administered, provided the absence of any contraindication to such therapy. Inferior vena cava filters should not be used indiscriminately.53 There is limited mortality benefit with the use of advanced VTE therapies, thus usage should be limited to selected cases.


The use of therapeutic anticoagulation in a critically ill patient without documented VTE is an area under study and is currently not recommended.43 It has been hypothesized there might be a benefit if there is ongoing pulmonary microthrombosis as part of SARS-CoV-2 infection, but there is no robust clinical data to support it at this time. One should not discount the risk of bleeding in a critically ill patient. In a small retrospective study, 11% of the patients at high risk of VTE also had a high risk of bleeding.54


Patients who recover from COVID-19 after hospitalization are at an increased risk for VTE for up to 90 days after discharge. This is also the case with any acute medical illness. An extended thromboprophylaxis should be considered in a patient who is considered high risk, which includes individuals with the following characteristics: age over 75 years, obese, active cancer, and D-dimer more than 2 times the upper normal limit. Therapies to consider include rivaroxaban 10 mg/day or apixaban 2.5 mg twice a day.55,56


Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is seen frequently in patients with a critical illness and its presence carries a poor prognostic factor. It is also seen in critical COVID-19 illness with an incidence of 71% in nonsurvivors of patients.57 The diagnosis of DIC is established using the ISTH DIC score calculator.39 It incorporates platelet count, prothrombin time, D-dimer, and fibrinogen. Overt DIC is diagnosed with a score of 5 or higher. Therefore, it is essential to daily monitor the parameters mentioned previously to identify DIC early and treat the underlying condition. The median time of onset of DIC is 4 days in patients with critical COVID-19 illness.57 Treatment is focused on treating the underlying condition. Bacterial superinfection should be treated aggressively. In the absence of bleeding, supportive care and transfusions with fresh frozen plasma, cryoprecipitate, or platelets should be performed to maintain fibrinogen level above 150 and platelet count above 30 000. In the presence of bleeding, blood products should be given to correct the abnormality or coagulopathy (elevated prothrombin and activated partial thromboplastin time, low platelet count, low fibrinogen, and elevated fibrin degradation product). Anticoagulation should be withheld. Systemic anticoagulation should only be considered if there is overt thromboembolism. Therapeutic anticoagulation in the setting of DIC has not been shown to have a mortality benefit.58


Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is defined by the production of specific antiphospholipid (aPL) antibodies that attack endothelial cells. This leads to dysregulation and activation of the coagulation cascade, which result in inflammation, vasculopathy, and thrombosis.59 In a recent correspondence by Zhang et al,60 3 severely ill COVID-19 patients with multisystem thrombosis were positive for aPL antibodies, which are consistent with APS. At present, there is scarce data on the presence of aPL antibodies in COVID-19 outside of the above-mentioned 3 patient case series. Currently, it is not recommended to routinely test all COVID patients for aPL antibodies. Testing should be undertaken only in the right clinical context or as part of research protocol testing. Anticoagulation should only be initiated after the clinical diagnosis of APS is made. However, the presence of aPL antibodies alone is not an indication for treatment with therapeutic anticoagulation.



Patients with severe critical illness commonly have neurologic complications and is also seen in patients with COVID-19 infection. There have been reports of viral invasion of the central nervous system with SARS-CoV-2 being detected in the brain or cerebrospinal fluid.61 In a retrospective study of 214 patients, neurologic symptoms were present in 36.4% of patients. The most common neurologic symptoms were dizziness (16.8%), headache (13.1%), and impaired consciousness (7.5%). Patients with severe COVID-19 illness have a higher rate of neurologic complications manifesting as acute cerebrovascular disease (5.7% severe vs 0.8% nonsevere), impaired consciousness (14.8% severe vs 2.4% nonsevere), and skeletal muscle injury (19.3% severe vs 4.8% nonsevere).62 Other reported complications include ataxia, seizure, meningitis, encephalitis, and encephalopathy61-65 and are reported to have a poorer prognosis.



The incidence of stroke in patients with COVID-19 is 2.8% to 5.0%,62,65 with ischemic stroke (5%) being more common than intracerebral hemorrhage (0.5%). In the setting of ischemic stroke, 45.5% had large vessel stenosis. The average presentation is 12 days after the SARS-CoV-2 infection. The risk factors associated with stroke include older age, hypertension, diabetes, prior cerebrovascular disease, elevated C-reactive protein, and elevated D-dimer.65 Thus, one should consider a stroke if there is evidence of acute focal neurologic deficit and should establish and follow an institutional protocol to manage such patients.


Guillain-Barre syndrome

Guillain-Barre syndrome is an areflexic paralytic state, which can be seen commonly after a respiratory or gastric illness. Limited case reports have reported patients with SARS-CoV-2 infection presenting primarily with ascending paralysis.66-68 This has implications concerning testing as well as appropriate isolation precautions, as patients may not present primarily with the typical constitutional and respiratory symptoms recognized and associated with COVID-19 infection. The exact prevalence is unknown at this time, and broad epidemiological data are needed.



When SARS-CoV-2 began to gain traction in China and around the world as a novel infection causing respiratory illness, symptoms were focused on respiratory complaints, such as cough and shortness of breath. However, as more individuals became infected, patients were also found to have digestive complaints, such as anorexia, nausea, vomiting, diarrhea, and abdominal pain. Presumed gastrointestinal (GI) manifestations have been reported to range from 3% to 50% of patients with which respiratory symptoms are absent.69 Beyond symptoms, SARS-CoV-2 has been found to cause injury to the GI tract, specifically hepatic and colonic.


Hepatic dysfunction

Acute liver failure is a syndrome defined by a rapid decline in hepatic function characterized by jaundice, coagulopathy (international normalized ratio >1.5), and hepatic encephalopathy (altered mental status) in patients without a history of liver disease.70 Previous studies have shown acute liver injury and damage in patients infected by the SARS and Middle East respiratory syndrome coronavirus (MERS-CoV). In conjunction with this, acute liver injury has been found in various series of cases of those infected with SARS-CoV-2. The reported incidence has ranged from 14.8% to 53%, noted by abnormal elevations in enzymes predominantly concentrated in the liver, aspartate transaminase, and alanine transaminase, and slightly elevated bilirubin levels. In severe cases, albumin was also noted to be decreased. The proportion of individuals developing liver injury was significantly higher in severe cases than in mild cases. In cases of death, due to SARS-CoV-2, the incidence of liver injury was found to be as high as 58.06% to 78%.71 However, the primary mechanism of liver injury is undetermined, with speculations being due to drug-induced, as some abnormalities were noted to arise after certain therapeutics were started, or due to direct cellular injury from immune reactions. Despite these abnormalities, clinically significant liver dysfunction and even acute liver failure in patients with severe infections were not seen or quantified. Thus, the relevance and significance of hepatic dysfunction in SARS-CoV-2 disease remain unknown.72


Hemorrhagic colitis

Although not frequently described, SARS-CoV-2 has been cited as a cause of acute hemorrhagic colitis with patients presenting with bloody diarrhea in case reports. In the patients who presented with GI symptoms and underwent investigation, including endoscopy evaluation, areas of erythema without ulceration were visualized. On biopsy, normal cellularity, intact crypts, and absence of changes consistent with ischemia or inflammatory bowel disease were seen. These findings pointed toward SARS-CoV-2 GI infection as being responsible for acute hemorrhagic colitis after all other causes were ruled out. Besides, patients were found to have SARS-CoV-2 RNA in fecal samples.69



Like other organ systems, the kidney is also affected in patients with SARS-CoV-2 infection, but the actual prevalence appears to be lower. In a Chinese cohort of roughly 1000 patients with 93.6% hospitalized, only 0.5% were found to have an acute renal injury. The mechanisms of renal involvement are postulated to be the result of cytokine damage, organ crosstalk, and systemic effects.


As previously mentioned, cytokine release syndrome or cytokine storm occurs in various diseases and syndromes and is well documented in SARS-CoV-2 infection. Acute kidney injury (AKI) may result from infrarenal inflammation, increased vascular permeability, volume depletion, and cardiomyopathy, causing cardiorenal syndrome type 1. Also, the inflammation may be further exacerbated by the use of invasive interventions, such as mechanical ventilation and extracorporeal membrane oxygenation.


The lung-kidney axis in ARDS was recently delineated in a retrospective study showing an increased incidence of stage 3 kidney disease in patients with ARDS without a known history of renal disease. Cytokine production from injured renal tubular epithelium promotes the upregulation of the proinflammatory cytokine IL-6. Increased IL-6 concentrations in AKI was associated with higher alveolar-capillary permeability and hemorrhage. In addition, ARDS results in renal medullary hypoxia, adding further insult to tubular cells. In patients with SARS-CoV-2 pneumonia with ARDS, 4.5%-7% of patients developed AKI. Also, acute myocarditis and cardiomyopathy with cardiorenal syndrome due to SARS-CoV-2 have been documented. These 2 processes contribute to renal vein congestion, hypotension, and renal hypoperfusion, resulting in reduced glomerular filtration rate.73


In addition to the direct and indirect effects of SARS-CoV-2 infection, superimposed infections resulting in septic shock can also occur in these patients. The mechanisms of AKI from septic shock is well known and further compounds to the injury of the renal system in the SARS-CoV-2 patients. In the setting of persisting renal injury with resultant failure, renal replacement therapy remains the standard for intervention when indicated. Long-term effects and development of chronic renal disease as a result of AKI from SARS-CoV-2 infection remains unknown.



Rhabdomyolysis is a life-threatening disorder that is due to the breakdown of damaged skeletal muscle. Causes include autoimmune myopathies, electrolyte abnormalities, substance abuse, and infection. Myoglobin is the protein responsible for oxygen storage in muscles, releases. Rhabdomyolysis manifests with as myalgia, fatigue, pigmenturia, and acute renal failure.74 Generalized muscle weakness, pain, and fatigue are known common symptoms of SARS-CoV-2, but a few case reports have noted rhabdomyolysis itself can also occur when patients report focal pain and weakness. The current hypotheses for the pathogenesis of rhabdomyolysis include direct viral invasion and muscle damage from the cytokine storm. Creatinine phosphokinase levels should be checked in suspicious cases. The normal treatment and management for rhabdomyolysis in aggressive fluid administration is to prevent AKI. However, fluid may worsen oxygenation in patients with ARDS and worsen renal function in the setting of cardiomyopathy.75



As SARS-CoV-2 has become more wide-spread, other symptom presentations are being recognized as a manifestation of a SARS-CoV-2 infection. From Thailand to France, skin lesions described as a persistent, painful, petechial rash may be an isolated indicator of infection.76 In Northern Italy, the first major European nation to be afflicted by SARS-CoV-2, one-fifth of a group of patients who were SARS-CoV-2 positive had skin manifestations. This has also been recognized in the United States. The rashes had variable presentations, from eruptions at symptom onset to posthospitalization. The trunk is the most commonly affected area and was described as red, urticarial, livedoid eruptions, or tiny bruises. These manifestations are suggestive of a vaso-occlusive process, but the mechanism is unknown. However, the development and cessation of the rashes are not correlated with disease severity.77



Due to SARS-CoV-2 being a novel infection, the overall long-term effects and complications after surviving SARS-CoV-2 infection remain unknown. The current acute complications are based on case reports, case series, and retrospective studies from various countries that have been afflicted the highest (China, Italy, the United States, etc). In general, individuals who survive after spending a long period on a ventilator are prone to delirium, lung damage, muscle atrophy, and weakness, etc. With SARS-CoV-2 being more infectious compared with other viral illness, normal routine use of physical and occupational therapists, spontaneous breathing and awakening trials, etc, to mitigate the adverse outcomes is challenging. However, one can expect the survivors to face a difficult and long uphill battle to be their normal cognitive and functional selves.




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anticoagulation; coronavirus; COVID-19; cytokine storm; D-dimer; SARS-CoV-2