Data on the management of comorbidities in patients with COVID-19 is evolving rapidly. Tailor the management of COVID-19 to the patient’s comorbidities (e.g., decide which chronic therapies should be continued and which therapies should be temporarily stopped, monitor for drug-drug interactions). For more information, see the Best Practice topic: Management of coexisting conditions in the context of COVID-19.
Several studies found a high incidence of thrombolytic complications in patients with COVID-19, even when thromboprophylaxis had been given. The pooled prevalence of venous thromboembolism among intensive care patients receiving prophylactic or therapeutic anticoagulation was 31%. Thrombotic events occurred in 16% of patients with COVID in a large New York health system, and the risk appears to be higher than in other acute infections. It may be due to cytokine storm, hypoxic injury, endothelial dysfunction, hypercoagulability, and/or increased platelet activity.
Coagulopathy in COVID-19 has a prothrombotic character, which may explain reports of thromboembolic complications. Patients may be predisposed to venous thromboembolism due to the direct effects of COVID-19, or the indirect effects of infection (e.g., severe inflammatory response, critical illness, traditional risk factors).
Venous thromboembolism (pulmonary embolism or deep vein thrombosis) has been reported in 20% to 31% of patients with severe COVID-19 in the intensive care unit (including some patients who were on thromboprophylaxis), and may be associated with poor prognosis. Other studies have reported higher rates of 46% to 85%.
The risk factors with the most evidence for being predictive of venous thromboembolism are older age and elevated D-dimer levels.
Patients with very high D-dimer levels have the greatest risk of thrombosis and may benefit from active monitoring. If venous thromboembolism is suspected, perform a computed tomographic angiography or ultrasound of the venous system of the lower extremities.
Treat patients with a thromboembolic event (or who are highly suspected to have thromboembolic disease if imaging is not possible) with therapeutic doses of anticoagulant therapy as per the standard of care for patients without COVID-19. There are currently insufficient data to recommend either for or against using therapeutic doses of antithrombotic or thrombolytic agents for COVID-19. Patients who require extracorporeal membrane oxygenation or continuous renal replacement therapy, or who have thrombosis of catheters or extracorporeal filters, should be treated with antithrombotic therapy as per the standard institutional protocols for those without COVID-19.
Initial parenteral anticoagulation with a low molecular weight heparin or unfractionated heparin is preferred in acutely ill hospitalized patients; however, direct oral anticoagulants may be used provided there is no potential for drug-drug interactions (lead-in therapy with a parenteral anticoagulant is required for dabigatran and edoxaban). Warfarin can be used after overlap with initial parenteral anticoagulation. Parenteral anticoagulation with a low molecular weight heparin or fondaparinux is preferred over unfractionated heparin in critically ill patients. Direct oral anticoagulants are the preferred option in outpatients provided there is no potential for drug-drug interactions, with warfarin considered a suitable alternative. Anticoagulation therapy is recommended for a minimum of 3 months. Thrombolytic therapy is recommended in select patients with pulmonary embolism.
A high incidence (14.7%) of asymptomatic deep vein thrombosis was reported in a cohort of patients with COVID-19 pneumonia. An autopsy study of 12 patients revealed deep vein thrombosis in 58% of patients in whom venous thromboembolism was not suspected before death. These studies highlight the importance of having a high suspicion for venous thromboembolism in patients who have signs of coagulopathy, including elevated D-dimer level.
While these patients are at higher risk of thrombotic events, they may also be at an elevated risk for bleeding. In a small retrospective study, 11% of patients at high risk of venous thromboembolism also had a high risk of bleeding.
Antiphospholipid antibodies and lupus anticoagulant have been detected in a small number of critically ill patients. The presence of these antibodies can rarely lead to thrombotic events in some patients (especially those who are genetically predisposed) that are difficult to differentiate from other causes of multifocal thrombosis. In other patients, antiphospholipid antibodies may be transient and disappear within a few weeks. The significance of this finding is unknown, although it is thought that these antibodies may not be involved in the pathogenesis of venous thromboembolism in patients with severe COVID-19.
It has been suggested that a new term (e.g., COVID-19-associated pulmonary thrombosis, diffuse pulmonary intravascular coagulopathy, or microvascular COVID-19 lung vessels obstructive thrombo-inflammatory syndrome [MicroCLOTS]) be used rather than the term pulmonary embolism as it has been hypothesized that the pathophysiology is different; local thrombi are formed in the lung vessels due to a local inflammatory process rather than the classical emboli coming from elsewhere in the body.
COVID-19 is associated with a high inflammatory burden that can result in cardiovascular complications with a variety of clinical presentations. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. These complications can present on presentation or develop as the severity of illness worsens. It is uncertain to what extent acute systolic heart failure is mediated by myocarditis, cytokine storm, small vessel thrombotic complications, microvascular dysfunction, or a variant of stress-induced cardiomyopathy.
Acute myocardial injury (defined by elevated cardiac biomarkers) has been reported in 5% to 31% of patients, and is associated with severe outcomes and mortality in patients with COVID-19. Elevated cardiac biomarkers and emerging arrhythmia are associated with the development of severe disease and need for intensive care admission.
Prevalence of cardiac disease is high among patients who are severely or critically ill, and these patients usually require intensive care and have a poor prognosis and higher rate of in-hospital mortality. These patients are more likely to require noninvasive or invasive ventilation, and have a higher risk of thromboembolic events and septic shock compared with patients without a history of cardiac disease. The mortality of patients with cardiovascular disease was 22% in one retrospective study, compared with the mortality of the overall population in the study, which was 9.8%. Patients with underlying cardiovascular disease but without myocardial injury have a relatively favorable prognosis.
Predictors for myocardial injury include older age, presence of cardiovascular-related comorbidities, and elevated C-reactive protein. Elevated myocardial markers predict risk for in-hospital mortality.
The most frequent cardiovascular complications in hospitalized patients are heart failure, myocardial injury, arrhythmias, and acute coronary syndrome. Cases of fulminant myocarditis, cardiomyopathy, cardiac tamponade, myopericarditis with systolic dysfunction, pericarditis and pericardial effusion, ST-segment elevation (indicating potential acute myocardial infarction), cor pulmonale, and takotsubo syndrome have also been reported.
Perform an ECG and order high-sensitivity troponin I (hs-cTnI) or T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with symptoms or signs that suggest acute myocardial injury in order to make a diagnosis. Results should be considered in the clinical context.
Monitor blood pressure, heart rate, and fluid balance, and perform continuous ECG monitoring in all patients with suspected or confirmed acute myocardial injury.
There are limited data to recommend any specific drug treatments for these patients. Management should involve a multidisciplinary team including intensive care specialists, cardiologists, and infectious disease specialists. It is important to consider that drugs such as hydroxychloroquine and azithromycin may prolong the QT interval and lead to arrhythmias.
Guidelines for the management of COVID-19-related myocarditis are available.
Infection may have longer-term implications for overall cardiovascular health; however, further research is required. A study of 100 patients who had recently recovered from COVID-19 found that cardiovascular magnetic resonance imaging revealed ongoing myocardial inflammation in 60% of patients, independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis.
acute kidney injury
The overall incidence of acute kidney injury in patients with COVID-19 is approximately 10% to 17%; incidence is higher in patients with chronic kidney disease and those with severe or critical illness. The degree of acute kidney injury is closely associated with disease severity and prognosis. Approximately 5% to 7% of patients require renal replacement therapy. Patients have a poor prognosis, especially those who require renal replacement therapy. In a small UK cohort, 29% of hospitalized children met the diagnostic criteria for acute kidney injury, with most cases occurring in children admitted to the intensive care unit and in those with pediatric inflammatory multisystem syndrome.
Can develop at any time before or during hospital admission. Risk factors include age ≥65 years, Black ethnicity, history of acute kidney injury, chronic kidney disease, cardiovascular disease, hypertension, heart failure, hepatic disease, and diabetes. Causes include hemodynamic changes, hypovolemia, viral infection leading directly to kidney tubular injury, thrombotic vascular processes, glomerular pathology, or rhabdomyolysis. Direct kidney infection has been confirmed in an autopsy study of a single patient.
Patients should meet criteria for acute kidney injury for diagnosis. NHS England: acute kidney injury (AKI) algorithm external link opens in a new window Perform a urinalysis for blood, protein, and glucose to help identify the underlying cause. Imaging is recommended if urinary tract obstruction is suspected.
Stop any drugs that can cause or worsen acute kidney injury, if possible. Aim to achieve optimal fluid status (euvolemia) in all patients. Consider a loop diuretic for treating fluid overload only. Manage hyperkalemia according to local protocols. See local protocols for guidance on renal replacement therapy.
Specialist input may be required in some cases (e.g., uncertainty about cause, abnormal urinalysis results, complex fluid management needs, indications for renal replacement therapy), and some patients may require critical care admission. Continuous renal replacement therapy (CRRT) is recommended in critically ill patients with acute kidney injury who develop indications for renal replacement therapy; prolonged intermittent renal replacement therapy is recommended over hemodialysis if CRRT is not available or possible.
Monitor fluid status daily, as well as serum blood urea nitrogen, creatinine, and electrolytes at least every 48 hours (or more often if clinically indicated). Monitor patients for the development of, or progression to, chronic kidney disease for at least 2 to 3 years after acute kidney injury.
Acute kidney injury is associated with poor prognosis.
acute liver injury
The pooled prevalence of hepatic manifestations on admission is: elevated alanine aminotransferase (26.6%); elevated aspartate aminotransferase (37.2%); decreased albumin (45.6%); and elevated total bilirubin (18.2%). The incidence of acute hepatic injury was higher in Chinese populations and groups with a higher prevalence of preexisting chronic liver disease; the incidence was similar in younger and older patients. Hepatic complications such as acute hepatic injury have been associated with an increased risk of severe disease and mortality. The prevalence of elevated aspartate aminotransferase was significantly higher in patients with severe disease (45.5%) compared with nonsevere cases (15%).
Risk factors associated with severe liver injury include older age, preexisting liver disease, and severe COVID-19.
Medications used in the treatment of COVID-19 (e.g., lopinavir/ritonavir) may have a detrimental effect on liver injury.
Guidelines on the management of liver derangement in patients with COVID-19 have been published.
Patients with severe illness commonly have central or peripheral neurologic complications, possibly due to viral invasion of the central nervous system (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] has been detected in the brain and cerebrospinal fluid) or systemic illness.
Neurologic symptoms have been reported in 36% to 57% of patients in case series, and were more common in patients with severe illness. In a small retrospective study of patients in an intensive care unit, 44% of patients with neurologic symptoms had abnormal findings on brain magnetic resonance imaging.
Complications include acute cerebrovascular disease, impairment of consciousness, ataxia, neuralgia, seizures, musculoskeletal injury, corticospinal tract signs, meningitis, encephalitis, encephalopathy, encephalomyelitis, transverse myelitis, intracerebral hemorrhage, cerebral venous sinus thrombosis, rhabdomyolysis and other muscle disease, myasthenia gravis, and Guillain-Barre syndrome and other neuropathies. Patients may present with these signs/symptoms, or they may develop them during the course of the disease.
Ischemic stroke has been reported in 1.6% of adults with COVID-19 who visited the emergency department or were hospitalized. It appears to be more severe and result in worse outcomes (severe disability) in patients with COVID-19, with the median NIH Stroke Scale score being higher among those with COVID-19 compared with those without. Guidelines for the management of acute ischemic stroke in patients with COVID-19 infection have been published.
Patients may show cerebral changes on magnetic resonance imaging months after recovery, suggesting that long-term consequences may be possible.
cytokine release syndrome
Cytokine release syndrome may cause ARDS or multiple-organ dysfunction, which may lead to death. Elevated serum proinflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-2, interleukin-6, interleukin-8, interleukin-10, granulocyte-colony stimulating factor, monocyte chemoattractant protein 1) and inflammatory markers (e.g., C-reactive protein, serum ferritin) have been commonly reported in patients with severe COVID-19. This likely represents a type of virus-induced secondary hemophagocytic lymphohistiocytosis, which may be fatal. Interleukin-6, in particular, has been associated with severe COVID-19 and increased mortality.
One study found that patients who require admission to the intensive care unit have significantly higher levels of interleukin-6, interleukin-10, and tumor necrosis factor alpha, and fewer CD4+ and CD8+ T cells.
Anti-inflammatory/immunosuppressive treatments (e.g., tocilizumab, hydroxychloroquine/chloroquine, Janus kinase inhibitors) are being trialed in COVID-19 patients. See Emerging section for more information.
Cytokine release syndrome has been reported in children, although cases appear to be rare. See section below on pediatric inflammatory multisystem syndrome.
pediatric inflammatory multisystem syndrome
A rare, but severe condition, reported in children and adolescents approximately 2 to 4 weeks after the onset of COVID-19, likely due to a postinfectious inflammatory process. The syndrome has a strong temporal association with SARS-CoV-2 infection. Also known as PIMS, multisystem inflammatory syndrome in children (MIS-C), pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), as well as other variations.
The syndrome shares common features with Kawasaki disease and toxic shock syndrome, but case definitions vary. Most patients have fever, as well as features of shock, cardiac involvement (e.g., elevated cardiac markers, congestive heart failure, cardiac dysfunction, myocarditis, coronary artery dilatation or aneurysm, hypotension, pericardial effusion, mitral regurgitation), gastrointestinal symptoms (e.g., abdominal pain, vomiting, diarrhea), and significantly elevated inflammatory markers.
A systematic review of 8 studies from the US and Europe found that the median age of patients ranged from 7 to 10 years of age, and 59% of patients were male. In regards to ethnicity, 31% to 62% were Black and 36% to 39% were Hispanic. The proportion of patients with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) test result ranged from 13% to 69%, and the proportion with a positive serology test ranged from 75% to 100%. Gastrointestinal symptoms were prominent (87%), as were dermatologic/mucocutaneous (73%) and cardiovascular symptoms (71%). Respiratory, neurologic, and musculoskeletal symptoms were less frequent. Serum ferritin and D-dimer levels were elevated in at least 50% of patients, and C-reactive protein, interleukin-6, and fibrinogen levels were elevated in at least 75% of patients. Cardiac markers were elevated in the majority of patients. Thrombocytopenia was common. The mortality rate was 2%.
In a multicenter observational study in the UK, 78 cases were reported across 21 pediatric intensive care units. The median age was 11 years and 67% were male. Children from minority ethnic backgrounds accounted for 78% of cases. Fever, shock, abdominal pain, vomiting, and diarrhea were the common presenting features. Around 36% had evidence of coronary artery abnormalities. In terms of treatment, 46% required invasive ventilation and 83% required vasopressor support.
Management is mainly supportive and involves a multidisciplinary team (pediatric infectious disease, cardiology, rheumatology, critical care). Patients are commonly managed with intravenous immune globulin, vasopressor support, corticosteroids, immune modulators, anticoagulation, antiplatelet therapy, and respiratory support.
While an association between this syndrome and COVID-19 seems plausible based on current evidence, the association is not definitive and further research is required. It is not clear yet whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or whether this is a different syndrome, although increasing evidence suggests that they are two separate syndromes. The syndrome appears to occur in children who have not manifested the early stages of COVID-19, but appears similar to the later phase of COVID-19 in adults.
Guidelines for the management of shock in critically ill patients with COVID-19 recommend a conservative fluid strategy (crystalloids preferred over colloids) and a vasoactive agent. Norepinephrine (noradrenaline) is the preferred first-line agent, with vasopressin or epinephrine (adrenaline) considered suitable alternatives. Vasopressin can be added to norepinephrine if target mean arterial pressure cannot be achieved with norepinephrine alone. Dopamine is only recommended as an alternative vasopressor in certain patients (e.g., those with a low risk of bradycardia or tachyarrhythmias). Dobutamine is recommended in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressors. Low-dose corticosteroid therapy is recommended for refractory shock.
disseminated intravascular coagulation
Reported in 71% of nonsurvivors. Disseminated intravascular coagulation (DIC) is a manifestation of coagulation failure, and an intermediate link in the development of multi-organ failure. Patients may be at high risk of bleeding/hemorrhage or venous thromboembolism.
Coagulopathy manifests as elevated fibrinogen, elevated D-dimer, and minimal change in prothrombin time, partial thromboplastin time, and platelet count in the early stages of infection. Increasing interleukin-6 levels correlate with increasing fibrinogen levels. Coagulopathy appears to be related to severity of illness and the resultant thromboinflammation. Monitor D-dimer level closely.
Prophylactic-dose low molecular weight heparin should be considered in all hospitalized patients with COVID-19 (including those who are not critically ill), unless there are contraindications. This will also protect against venous thromboembolism. Anticoagulant therapy with a low molecular weight heparin or unfractionated heparin has been associated with a better prognosis in patients with severe COVID-19 who have a sepsis-induced coagulopathy (SIC) score of ≥4 or a markedly elevated D-dimer level. In patients with heparin-induced thrombocytopenia (or a history of it), argatroban or bivalirudin are recommended.
Standard guidance for the management of bleeding manifestations associated with DIC or septic coagulopathy should be followed if bleeding occurs; however, bleeding manifestations without other associated factors is rare.
acute respiratory failure
Reported in 8% of patients in case series.
Leading cause of mortality in patients with COVID-19.
Children can quickly progress to respiratory failure.
Retrospective reviews of pregnant women with COVID-19 found that women appeared to have fewer adverse maternal and neonatal complications and outcomes than would be expected for those with severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). Adverse effects on the newborn including fetal distress, respiratory distress, thrombocytopenia, and abnormal liver function have been reported; however, it is unclear whether these effects are related to maternal SARS-CoV-2 infection. Maternal deaths have been reported, as well as miscarriage (including a case in the second trimester), ectopic pregnancy, intrauterine growth restriction, oligohydramnios, perinatal death, preterm birth, and neonatal death. It is unclear whether these effects are related to COVID-19. While the rate of stillbirth increased during the pandemic in one center in London, it is unknown whether this is related to SARS-CoV-2 infection.
Approximately 3% of pregnant women require intensive care admission. The preterm birth rate is 20%, and the neonatal death rate is 0.3%. In the UK, 25% of births were preterm, 10% of women required respiratory support, 1% of women died, and 5% of babies tested positive for SARS-CoV-2. Almost 60% of women gave birth by cesarean section, although most cesarean births were for indications other than maternal compromise due to COVID-19. In Spain, severe adverse maternal outcomes occurred in 11% of pregnant women, and cesarean delivery was independently associated with an increased risk of maternal clinical deterioration and neonatal intensive care unit admission. In the US, cesarean delivery rates were higher in patients with COVID-19 compared with patients without in one cohort. Postpartum complications (fever, hypoxia, readmission) occurred in 13% of infected women compared with 4.5% of women without COVID-19.
Invasive pulmonary aspergillosis has been reported in critically ill patients with moderate to severe ARDS. A prospective observational study found that one third of mechanically ventilated patients with COVID-19 had putative invasive pulmonary aspergillosis.
Intubation for more than 7 days may be a risk factor. Other potential risk factors include older age, chronic obstructive pulmonary disease, immunosuppression, critical illness, or use of high-dose corticosteroids. Consider aspergillosis in patients who deteriorate despite optimal supportive care or have other suspicious radiologic or clinical features.
Prescribe appropriate antifungal therapy according to local guidelines.
Mild pancreatic injury (defined as elevated serum amylase or lipase levels) has been reported in 17% of patients in one case series. It is unknown whether this is a direct viral effect or due to the harmful immune response that occurs in some patients. Clinical acute pancreatitis has not been reported. Prior history of pancreatitis does not appear to be a risk factor for pancreatic inflammation in patients with COVID-19.
autoimmune hemolytic anemia
Warm or cold autoimmune hemolytic anemia (first episode) has been reported in 7 patients after the onset of COVID-19 symptoms and within the timeframe compatible with cytokine release syndrome. Four patients had indolent B lymphoid malignancy. It is unknown whether the hemolytic anemia is related to COVID-19 infection.
Cases of subacute thyroiditis have been reported in patients with COVID-19 who require intensive care. The first known case of subacute thyroiditis was reported in an 18-year-old woman. Subacute thyroiditis is a thyroid disease of viral or post-viral origin.
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