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Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109, USAVeterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109, USAVeterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI 48105, USAVA Center for Clinical Management Research, University of Michigan, Ann Arbor, MI 48109, USA
as of May 1, 2022. Although respiratory manifestations are the most common driver of hospitalization, SARS-CoV-2 infection has a wide range of manifestations, including multisystem organ failure in severe cases (Fig. 1, Table 1). In this review, we discuss the prevalence, pathophysiology, clinical manifestations, treatment, and outcomes of nonpulmonary organ dysfunction from SARS-CoV-2.
Fig. 1Nonpulmonary critical organ dysfunctions due to COVID-19 infection.
21%–45% with troponin elevation; 10%–20% with symptomatic dysfunction
Troponin elevation more common in patients requiring >50% Fraction of inspired oxygen support
Troponin elevation has 2.7× risk in-hospital mortality and associated with 2× increase in major complications, including sepsis, acute kidney failure, multiorgan failure, pulmonary embolism, and major bleeding
Fatigue (31%) and myalgia (30%) more common in hospitalized COVID-19 cases; stroke 2%
Skeletal muscle injury (5%) and disturbances of consciousness more likely in severe than nonsevere COVID-19 infection; 50% delirium
In patients ≥60 y of age, the presence of any neurologic manifestations was significantly associated with increased mortality (OR 1.80, 95% CI 1.11–2.91); nonsignificant higher odds of mortality in all patients with neurologic manifestations compared with those without them (OR 1.39)
In a meta-analysis by Karakike and colleagues of 151 studies published between August 2020 and March 2021 including 218,184 patients hospitalized with COVID-19 (mostly in Asia, Europe, and North America), the prevalence of sepsis (inferred by SOFA scoring, acute organ dysfunction, or organ support) was 33% among ward-treated patients, 78% among intensive care unit (ICU)-treated patients, and 52% overall (Table 2).
Among ICU-treated patients, the most common organ supports were mechanical ventilation (60%), vasopressor therapy (50%), and renal replacement therapy (RRT; 20%).
151 studies; 218,184 patients Forty-seven studies reported results from Asia, mainly China (21 studies), 21 from North America, 7 from Central and South America, 73 across Europe, one from Australia, and 2 were international
104 studies published in 2020 and 47 published in 2021
Sepsis prevalence was 77.9% (95% CI, 75.9–79.8; I2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3–36.4; I2 = 99%; 86 studies) in the general ward Pooled prevalence of organ support: vasopressor use 9.5%; Noninvasive ventilation (NIV) 20.9%; IMV 62.4%; Extracorporeal membrane oxygenation 6.2%; Continuous renal replacement therapy/dialysis 19.9% Pooled prevalence of organ dysfunction: Septic shock 36.4%; lactate elevated (>2 mmol/L) 47.2%; renal dysfunction 28.6%; coagulopathy 17.7%, liver dysfunction 20.3%, CNS dysfunction 8.8%, acute respiratory distress syndrome (ARDS) 87.5%, mild ARDS 21.5%, moderate ARDS 43.7%, severe ARDS 32.1%
The majority COVID-19 patients hospitalized in the ICU meet Sepsis-3 criteria and present with infection-associated organ dysfunction. Awareness and systematic reporting of COVID 19 viral sepsis is crucial to understand prognostic and treatment implications
Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: the international viral infection and respiratory illness universal study registry.
16 countries; 168 hospitals (150 from the United States); 20,608 patients
Patient hospitalized from February 15, 2020, to November 30, 2020
Mean age 60.5 y, 54.3% men; 42.4% were admitted to the ICU Organ Support and Mortality: IMV Only 40.8%; IMV + vasopressors 53%; IMV + vasopressors + RRT 71.6%; ECMO 35%; No organ support 8.2%; All patients 19%
Prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation
In the Society of Critical Care Medicine (SCCM) VIRUS cohort of 20,608 adult hospitalizations for COVID-19 in 16 countries during February to November 2020, 15,001 (72.3%) patients required no organ support, 5005 (24.3%) required invasive mechanical ventilation (IMV), and 602 (2.9%) required vasopressor therapy and/or acute RRT without IMV. Of the 5005 who required IMV, 1749 (34.9%) required IMV only; 2032 (40.6%) required IMV and vasopressors; 655 (13.1%) required IMV, vasopressors, and RRT; 180 (3.6%) required IMV and RRT; and 389 (7.8%) underwent extracorporeal membrane oxygenation.
Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: the international viral infection and respiratory illness universal study registry.
Among 5837 patients in the Health Outcome Predictive Evaluation (HOPE) COVID-19 registry, an international registry of patients hospitalized from March to June 2020 in 8 countries, patients with COVID-19 who developed viral sepsis were older, admitted sooner after symptom onset, and had higher burden of comorbid disease.
SARS-COV-2 enters the human host by inhalation. Once viral particles are inhaled, a spike protein on the virus surface attaches to the angiotensin 1 converting enzyme 2 (ACE-2) receptor, then relies on transmembrane protease serine 2 (TMPRSS2) expressed on the surface of respiratory epithelium to enter the cell.
Once inside the host cell, the virus can replicate. The ACE-2 receptor and TMPRSS2 have been identified in lung alveolar epithelial cells, but also on many other cell types, suggesting that direct viral invasion may be a common mechanism of injury across organs. Beyond direct viral invasion, several other mechanisms may be implicated, including endothelial damage with thrombo-inflammation,
dysregulation of the immune response via high serum level of proinflammatory cytokines such as interleukin (IL) 6 and IL-1 beta, and tumor necrosis factor,
Mechanisms of specific organ dysfunctions are discussed further in sections specific to each organ.
Clinical Manifestations
Respiratory failure is the most common organ dysfunction in COVID-19, and other organ dysfunctions rarely occur without respiratory dysfunction. In the HOPE-COVID-19 registry, patients with COVID-19-related sepsis had higher levels of D-dimer, procalcitonin, CRP, troponin, transaminases, ferritin, LDH, and creatinine.
The parsimonious HOPE Sepsis Score identified the following risk factors for sepsis during COVID-19 hospitalization: current smoking, respiratory rate, SpO2, blood pressure, Glasgow Coma Scale, procalcitonin, troponin I, creatinine, and hemoptysis.
Hospital mortality for COVID-19 is strongly associated with the severity and number of acute organ dysfunctions. In the SCCM VIRUS cohort, in-hospital mortality among 5005 IMV-treated patients was 50% versus 8% among 15,001 patients without organ support.
Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: the international viral infection and respiratory illness universal study registry.
In-hospital mortality increased with additional organ supports from 41% among IMV-treated patients to 71.6% among patient receiving IMV, vasopressors, and RRT (n = 655).
Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: the international viral infection and respiratory illness universal study registry.
Although antibacterial therapy is crucial to the treatment of bacterial sepsis, anti-SARS-CoV-2 therapies such as antivirals and monoclonal antibodies are most effective in earlier phases of SARS-CoV-2 infection, before the onset of acute organ dysfunction.
There has been particular interest in regulating the hyperinflammatory response to SARS-CoV-2 and subsequent viral-induced immunosuppression.
However, timing of initiation is important, and patients should be initiated on these therapies promptly on meeting illness severity criteria. Research is ongoing to clarify the optimal dosing regimens and patient populations for these therapies.
Beyond corticosteroids and IL-6 inhibitors, many other therapies under investigation for treatment/mitigation of disease, including stem cell therapy,
Prof. Dr. Jörg L, Cantonal Hosptal B. High Dose Vitamin-D Substitution in Patients With COVID-19: a Randomized Controlled, Multi Center Study. 2021. https://clinicaltrials.gov/ct2/show/NCT04525820
The Impact of Fecal Microbiota Transplantation as an Immunomodulation on the Risk Reduction of COVID-19 Disease Progression With Escalating Cytokine Storm and Inflammatory Parameters. 2022.
ExThera Medical Europe BV, ExThera Medical C, Vivantes Klinikum N. Safety & Effectiveness Evaluation of Seraph 100 in Treatment of Pts With COVID-19. 2022. https://clinicaltrials.gov/ct2/show/NCT04547257
RRT for acute renal failure is the third most common organ support among patients with COVID-19. In a cohort of 3993 patients hospitalized with COVID-19 at 5 hospitals in New York during March to May 2020, 46% had acute kidney injury (AKI, defined by Kidney Disease Improving Global Outcomes criteria
In a separate cohort of 5449 patients hospitalized with COVID-19 at 13 hospitals in New York during March to May 2020, 37% had AKI, including 90% of IMV-treated patients. Renal failure and RRT were largely limited to patients with respiratory failure. Indeed, in the 13-hospital New York cohort, nearly all patients treated with RRT were also receiving IMV.
In the meta-analysis by Karakike and colleagues, the pooled prevalence of RRT among ICU patients with COVID-19 was 20%.
Histology and pathophysiology
The hypothesized mechanisms of COVID-19-related AKI are largely drawn from biopsy and autopsy studies. In a series of 10 patients with COVID-19-related renal failure requiring RRT, the most common histologic finding was acute tubular injury,
Several studies found evidence of live virus, suggesting direct kidney tropism through angiotensin-converting enzyme-2 receptors expressed on proximal tubule cells and podocytes.
Whether from direct viral invasion, hypoxia, or hypercoagulability, there may be indirect causes for renal injury including hemodynamic instability, mitochondrial dysfunction,
In a cohort of 182 patients hospitalized with COVID-19-associated AKI, serum creatine was similar, proteinuria was more common, and dialysis was more common than in non–COVID-19-related AKI.
The development of COVID-19-related AKI is associated with worse outcomes, particularly among patients requiring RRT. Although AKI is a marker of worse disease, the association persists after adjustment for illness severity, suggesting that renal injury may also directly contribute to worse outcomes. In the 13-hospital New York cohort, the development of AKI was associated with a 3.4-fold increased risk of in-hospital mortality in adjusted analysis, whereas RRT was associated with 6.4-fold increased risk.
In a single-center telephone follow-up of 300 patients who survived ICU hospitalization for COVID-19 during March to April of 2020 in New York, only 42% survived to 6 months postdischarge. At 6 months postdischarge, AKI recovered in 74% of survivors, including 77% who liberated from dialysis.
Treatment strategies for COVID-19-related AKI are similar to standard management of AKI from other causes. Management focuses on mitigating further renal injury through avoidance of nephrotoxic medications, renally dosing medications, and maintaining perfusion to the kidney. The threshold for initiating RRT is similar to non–COVID-19-related renal failure. Clotting of continuous renal replacement therapy (CRRT) filters has led to significant resource utilization. In a case series of 65 patients who received CRRT for COVID-19-related renal failure at a single U.S. hospital, 85% lost at least one filter, with a median filter life of only 6.5 hours.
Studies are underway testing interventions to mitigate progression of renal disease, including oral medications targeting inflammatory pathways (NCT05038488) and treatments such as CRP-apheresis (NCT04898062) (Table 3).
Table 3Organ-specific randomized control trials of therapeutics in COVID-19 infections
Partial list of active interventional phase 2–4 randomized control trials.
Organ Function
NCT Number
Name of Study
Cardiac
NCT04883528 NCT04365153
Protecting with ARNI against cardiac consequences of Coronavirus Disease 2019 with Drug: Sacubitril/Valsartan Oral Tablet [Entresto] Canakinumab to Reduce Deterioration of Cardiac and Respiratory Function in SARSCoV2 Associated Acute Myocardial Injury with Heightened Inflammation (completed)
Renal
NCT04402957 NCT04818216
LSALT Peptide vs Placebo to Prevent ARDS and Acute Kidney Injury in Patients Infected With SARS-CoV-2(COVID-19) Nicotinamide Riboside in SARS-CoV-2 (COVID-19) Patients for Renal Protection (NIRVANA)
Liver
NCT04816682
Silymarin, phase 4, Does Silymarin Mitigate Clinical Course of COVID-19 in Patients Admitted to an Internal Medicine Ward with Elevated Liver Enzymes?
Neuro
NCT04904536
An International, Investigator Initiated and Conducted, Pragmatic Clinical Trial to Determine Whether 40 mg Atorvastatin Daily Can Improve Neurocognitive Function in Adults With Long COVID Neurologic Symptoms; Statin TReatment for COVID-19 to OptimiseNeuroloGical recovERy (STRONGER)
Coagulopathy
NCT04650087 NCT04508023
COVID-19 Post-hospital Thrombosis Prevention Trial: An Adaptive, Multicenter, Prospective, Randomized Platform Trial Evaluating the Efficacy and Safety of Antithrombotic Strategies in Patients With COVID-19 Following Hospital Discharge A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic Coronavirus Disease 2019 (COVID-19) Infection (PREVENT-HD)
a Partial list of active interventional phase 2–4 randomized control trials.
The spectrum of cardiac manifestations of COVID-19 includes asymptomatic cardiac biomarker elevation and symptomatic cardiac dysfunction such as heart failure, arrhythmia, and sudden cardiac arrest. Biomarker elevation occurs in approximately 20% to 35% of patients hospitalized with COVID-19. In a meta-analysis of 35 studies of 22,473 patients hospitalized in 2020 with COVID-19, troponin was elevated in 21% of patients tested on admission.
Symptomatic cardiac dysfunction is present in approximately 10% to 20% of hospitalized patients. In a study of 748 patients hospitalized in Europe and Australia during January-October 2020, 141 (19%) had an acute cardiac complication, including cardiovascular death (7%), heart failure (5%), pulmonary embolism (5%), sustained supraventricular tachycardia or ventricular arrhythmia (4%), cardiac arrest (2%), myocarditis (2%), and acute coronary syndrome (1%).
SARS-COV-2 is hypothesized to cause cardiac injury via endothelial inflammation, immune activation, direct myocardial injury, acute right heart strain secondary to acute respiratory distress syndrome and/or pulmonary embolism, and hypoxic injury.
Cardiac biomarkers, including troponin and BNP, may be elevated in up to one-third of patients hospitalized with COVID-19. Cardiac arrhythmias, including atrial fibrillation, bradyarrhythmias, and ventricular arrhythmias, occur in a minority of patients. The extent to which arrhythmias are directly mediated by SARS-CoV-2 versus general acute illness is unclear. Myocarditis may be triggered by a variety of viral infections including SARS-CoV-2, but the prevalence of this manifestation is unknown.
Although not common, cardiac manifestations can be the presenting symptom of COVID-19. In a series of 28 patients hospitalized in Italy during February-March 2020 with COVID-19 and ST segment elevation myocardial infarction (STEMI), 24 of 28 patients had the STEMI as the first manifestation of SARS-CoV-2 infection.
In a meta-analysis of 11 studies of patients hospitalized with COVID-19 during 2020, troponin elevation was associated with 2.7-fold increased risk of in-hospital mortality
in adjusted analysis. In a study of 416 patients hospitalized with COVID-19 in China in 2020, cardiac biomarker elevation was associated with increased need for IMV.
In a meta-analysis of 3 studies of in-hospital cardiac arrest, SARS-CoV-2 infection was associated with lower rates of shockable rhythm (9.6% vs 19.8%, P < .001), lower rates of ROSC (33.9% vs 52.1%, P < .001), and higher 30-day mortality (77.2% vs 59.7%, P = .003).
Treatment of COVID-19-related cardiac injury is similar to the management of cardiac injury from other causes. As of May 1, 2022, 253 phase 2 to 4 interventional clinical trials were registered in clinicaltrials.gov to test interventions, prevent or mitigate cardiac complications, including trials of colchicine (NCT04510038), antiplatelet and anticoagulant triple therapy (NCT04333407), angiotensin receptor neprilysin inhibitors (NCT04883528) and anti-IL1b (NCT04365153) antibody therapy.
Liver Dysfunction
Prevalence
Liver enzymes elevations are common in patients requiring hospitalization for COVID-19 but severe liver dysfunction is a rare manifestation of COVID-19. In a study of 2073 patients hospitalized with COVID-19 in China during January to April 2020, 62% of patients had liver enzymes greater than the upper limit of normal (ULN), including 46% on admission. Liver dysfunction was hepatocellular in 40%, cholestatic in 3%, mixed in 12%, and other in 8%. However, liver injury (>2–3× ULN) occurred in only 14%, including 5% on admission.
Similar to other solid organs, the liver is susceptible to hypoxic, ischemic, thrombotic, congestive, and direct viral injury. Several therapies for COVID-19, such as remdesivir and tocilizumab can be hepatotoxic, making drug-induced liver injury a potential cause of liver injury during hospitalization. The ACE2 receptor, where the SARS CoV-2 enters the host is expressed in higher amounts on cholangiocytes than hepatocytes.
In series of 40 decedents, macrovesicular steatosis was the most common finding (75%), followed by lobular necroinflammation (50%), portal inflammation (50%), and cholestasis (38%).
Liver enzyme abnormalities in COVID-19 include hepatocellular, cholestatic, and mixed patterns of injury, with most cases being mild (1–2× the ULN). The 834-patient US cohort found that the most common liver abnormalities were AST (63%), ALT (34%), alkaline phosphatase (12%), and total bilirubin (3%).
Liver injury due to COVID-19 is associated with worse outcomes. In a meta-analysis of 26 studies of patients hospitalized with COVID-19 in China, baseline AST greater than ULN was associated with increased mortality (odds ratio [OR] = 3.82, P = .05), ICU admission (OR = 2.98, P = .06), and nonfatal complications (OR = 2.95, P = .08).
In study of 565 patients hospitalized with COVID-19 on general medicine wards in Italy during 2020, 58% had abnormal liver function, which was associated with higher rates of ICU transfer (20% vs 8%), AKI (22% vs 13%), need for IMV (14% vs 6%), and mortality (21% vs 11%).
The management of acute liver injury in COVID-19—including hepatocellular, cholestatic, and mixed liver injury—is consistent with current strategies for management of non–COVID-19-related liver injury, including maintaining perfusion, minimizing hepatotoxic medications, optimizing volume status, and ruling out of other causes of hepatic injury. As of May 1, 2022, there was one interventional clinical trial registered on clinicaltrials.gov targeted specifically at patients with elevated liver enzymes in the setting of COVID-19 (NCT04816682).
Neurologic Dysfunction
Prevalence and clinical manifestations
The neurologic manifestations of COVID-19 are varied but can cause severe debility.
A meta-analysis of 48 studies published in the 2020, including 2839 patients with severe/critical COVID and 7493 with nonsevere COVID-19, analyzed neurologic manifestations and their association with COVID-19 severity.
Severe COVID-19 was associated with skeletal muscle injury, delirium or impaired consciousness, and fatigue, and less alteration in smell or taste. Myopathy was associated with prolonged hospitalization,
In a retrospective cohort of 277 patients admitted with a stroke to a large NYC hospital in March to April 2020, 38% were SARS-CoV-2 positive. The COVID-19-positive patients were more likely to have a cryptogenic stroke cause, lobar stroke location, admission to the ICU, and in-hospital mortality.
The majority (68%) of COVID-19-positive patients with stroke had parenchymal abnormalities on chest imaging, although stroke has been reported as the presenting sign of COVID-19 in patients without respiratory symptoms.
A meta-analysis of 29 studies published in 2020 with 43,024 patients found a 2% pooled prevalence of stroke, which is higher than the prevalence in influenza (0.2%).
Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study.
In an international cohort of 2088 ICU-treated patients during January to April 2020, 82% were comatose, for a median of 10 days, and 54.9% experienced delirium, for a median of 3 days.
The expression of ACE2 receptor is significantly lower in the central and peripheral nervous system compared with other organs but is found in glial cells in the brain and spinal neurons. In vitro models of the human blood–brain barrier showed a negative impact of SARS CoV-2 spike protein, and brain endothelial cells showed a distinct proinflammatory response.
Endothelial dysfunction, coagulation abnormalities, direct viral transmission through olfactory nerve, hypoxic brain injury, and disruption of the blood–brain barrier
Encephalopathy from hypoxia, hyperinflammatory response, and hypercoagulability (leading to stroke) are indirect manifestations of COVID-19 infection on the central nervous system.
Outcomes
Similar to other acute organ dysfunction, neurologic dysfunction is associated with increased mortality. In a meta-analysis of 21 studies, 770 of 2982 patients with neurologic manifestations died. The pooled prevalence of mortality among patients with neurologic manifestations was 27% (95% CI 19%–35%).
COVID-19 infection is also associated with significant morbidity in ICU survivors. A multicenter Dutch prospective cohort with follow-up to 1 year post-ICU, physical symptoms were reported in 74.3%, mental symptoms in 26.2%, and cognitive symptoms in 16.2%.
The management and treatment of neurologic manifestations of COVID-19 mirror strategies used for non–COVID-19-associated symptoms/diseases. Given the known association of delirium and poor outcomes,
strategies to reduce delirium in mechanically ventilated patients is extremely important. In a large international cohort of 2088 ICU patients, of which 87.5% undergoing mechanical ventilation at some point in their hospitalization, benzodiazepine use was identified as a modifiable risk factor for the development of delirium while the family visitation was associated with decreased risk for delirium. This information should be considered for sedations protocols as well as hospital policies regarding visitation. The treatment of stroke follows guidelines for non–COVID-19 stroke but studies are underway to assess the safety, feasibility, and efficacy of thrombectomy for the management of acute ischemia strokes in patients with COVID-19 (NCT04406090). Early mobility and rehabilitation are crucial to reduce the morbidity associated with COVID-19 disease.
Hematologic Abnormalities (Coagulopathy)
Prevalence
Coagulation abnormalities are a common manifestation of severe and critical COVID-19. In a meta-analysis of 24 studies including 2570 patients with critical COVID-19, the pooled prevalence of clinically detected venous thromboembolism (VTE) was 31% and increased to 48% if using systematic screening (eg, for extremity swelling and/or elevated D-dimer).
A subsequent meta-analysis of 19 studies with 1599 patients receiving prophylactic anticoagulation reported pooled prevalences of VTE, deep vein thrombosis (DVT), and PE in 30.1%, 27.2% and 18.3%, respectively.
Vascular findings in CTA body and extremity of critically ill COVID-19 patients: commonly encountered vascular complications with review of literature.
In the abdomen and pelvis, hemorrhagic complications were more common than thrombotic complications, including hematomas of retroperitoneum and abdominal wall.
Vascular findings in CTA body and extremity of critically ill COVID-19 patients: commonly encountered vascular complications with review of literature.
Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial.
The balance of coagulation and fibrinolysis is deranged in SARS-CoV-2 infection (Fig. 2). Abnormal laboratories associated with coagulopathy in COVID-19 are summarized in Table 4. Although the exact mechanism is incompletely understood, endothelial dysfunction is widely regarded as the major driver of the prothrombotic state in COVID-19.
Vascular findings in CTA body and extremity of critically ill COVID-19 patients: commonly encountered vascular complications with review of literature.
However, in prospective cohort of 98 patients hospitalized in ICU with COVID-19 in the United States during 2020 to 2021 at a single US center, thromboelastographic parameters and conventional coagulation parameters suggested a relative consumptive coagulopathy.
Table 4Current and novel biomarkers of hypercoagulability in COVID-19 disease
Adapted from Gorog DA, Storey RF, Gurbel PA, et al. Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium. Nat Rev Cardiol. 2022;19(7):475-495.
Serologic Biomarkers
Current Summary of Evidence Supporting Usefulness
C-reactive protein
Strong evidence that levels are associated with disease severity, occurrence of VTE and mortality
IL-6
Strong evidence to guide prognosis but not for prediction of thrombosis
D-dimer
Strong evidence that levels are associated with disease severity and adverse outcomes, including mortality
aPTT/Anti-Xa
Not useful as a marker of COVID-19 severity or prognosis
Neuroendocrine tumors
Potential use in detecting severe vs nonsevere COVID-19 but not in predicting thrombotic risk
Complement factors
Potentially of use in detecting severe COVID-19, longer-term prognostic utility unknown
ACE2
Discrimination of COVID-19 severity not shown
Calprotectin
Potentially of use in detecting severe COVID-19 and assessing the risk of thrombosis
Overall, COVID-19 is associated with a prothrombotic profile that may be driven by excessive inflammation, endothelial activation, platelet activation, impaired fibrinolysis, immune-related molecular events, and systemic hypercoagulability.
Thromboembolism is associated with worse outcomes in COVID-19. In a meta-analysis of 42 studies with 8217 patients hospitalized with COVID-19, the pooled VTE rate in-hospital was 21% (31% among ICU-treated patients).
Pooled in-hospital mortality was 23% vs 13% among patients with versus without thromboembolism. The pooled odds of mortality were 74% higher for patients diagnosed with a thromboembolism (OR 1.74, P = .04).
Several high-quality randomized control trials (RCT)s have addressed the prevention of thrombotic complications in COVID-19. The current evidence supports prophylactic anticoagulation in critically ill patients but therapeutic anticoagulation in ward patients. An open-label trial
that randomized 1207 patients to therapeutic heparin anticoagulation versus heparin thromboprophylaxis was stopped for futility. Patients randomized to therapeutic anticoagulation had fewer organ-support free days (median 1 vs 4 days) and similar survival to discharge (62.7% vs 64.5%).
However, among noncritically patients, full-dose anticoagulation decreased the need for IMV and other organ supports (aOR = 1.27), without increasing major bleeding (1.9% vs 0.9%).
Similarly, a multicenter US trial evaluated the impact of therapeutic anticoagulation for patients hospitalized with COVID-19 with elevated D-dimer levels (>4× ULN) or sepsis-induced coagulopathy score of 4 or more. The study found that—among noncritically ill patients—the combined outcome of VTE, ATE, or mortality was lower (16.7% vs 36.1%, P = .004) among patients randomized to therapeutic-dose anticoagulation.
Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial.
Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial.
A multicenter RCT in Iran randomized 562 patients with critical COVID to intermediate-dose thromboprophylaxis (enoxaparin 1 mg/kg daily) vs standard thromboprophylaxis (enoxaparin 40 mg daily).
Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with covid-19 admitted to the intensive care unit: the inspiration randomized clinical trial.
Outcomes, including composite outcome of VTE or ATE, ECMO treatment, and 30-day mortality, were similar among patients randomized to intermediate versus standard enoxaparin dosing. At this time, it is unclear whether continuing anticoagulation after hospital discharge affects short-term or long-term outcomes. However, studies are underway evaluating posthospitalization direct oral anticoagulants to prevent or reduce long-term symptoms associated with COVID-19 infection (NCT04801940).
New biomarkers for tests of coagulation, fibrinolysis, and platelet activation are being studied to support its usefulness for prognostic, diagnostic and management decisions in COVID-19-related thrombosis
Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations.
; however, the exact biomarker of choice has yet to be determined. In all, the prevalence and severe prognostic implications of thromboembolism should make thrombotic risk assessment and VTE prevention a priority.
Summary
Although SARS-CoV-2 infection most commonly causes respiratory symptoms and impairment, it can also cause nonpulmonary organ dysfunction, most commonly shock, AKI, and hypercoagulability. Neurologic, cardiac, and, to a lesser degree, liver injury may also occur from SARS-CoV-2. Management of extrapulmonary organ dysfunction largely focuses on supportive care practices that are applicable regardless of the cause of organ injury. However, there is emerging evidence to support therapeutic anticoagulation in noncritically ill patients to mitigate risk for VTE.
Clinics care points
•
Severe COVID-19 respiratory infection is often accompanied with other organ injuries, which are independently associated with poor outcomes.
•
It is important for providers to assess for multi-organ involvement of COVID-19 infection, as each organ injury impacts patient morbidity and mortality.
•
At this time, non-pulmonary organ injury is managed with supportive care and follows best practices that are applicable regardless of the cause of injury.
•
There is emerging data that supports therapeutic over prophylactic anticoagulation in non-critically ill patients admitted to the general hospital ward.
Disclosure
The authors have no commercial or financial conflicts of interest. H.C. Prescott has grant funding from VA, United States, AHRQ, United States, and BCBSM, unrelated to this article.
References
Coronavirus World Map: tracking the global outbreak. the New York times.
Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: the international viral infection and respiratory illness universal study registry.
Prof. Dr. Jörg L, Cantonal Hosptal B. High Dose Vitamin-D Substitution in Patients With COVID-19: a Randomized Controlled, Multi Center Study. 2021. https://clinicaltrials.gov/ct2/show/NCT04525820
The Impact of Fecal Microbiota Transplantation as an Immunomodulation on the Risk Reduction of COVID-19 Disease Progression With Escalating Cytokine Storm and Inflammatory Parameters. 2022.
ExThera Medical Europe BV, ExThera Medical C, Vivantes Klinikum N. Safety & Effectiveness Evaluation of Seraph 100 in Treatment of Pts With COVID-19. 2022. https://clinicaltrials.gov/ct2/show/NCT04547257
Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study.
Vascular findings in CTA body and extremity of critically ill COVID-19 patients: commonly encountered vascular complications with review of literature.
Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial.
Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with covid-19 admitted to the intensive care unit: the inspiration randomized clinical trial.
Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations.
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