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 hospitalised 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 hypothesised 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 non-invasive 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 favourable 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 hospitalised 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 pre-existing 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%; 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 7% of patients require renal replacement therapy. Patients have a poor prognosis, especially those who require renal replacement therapy.
In retrospective studies in New York, 36.6% to 78% of hospitalised patients went on to develop acute kidney injury, and of these 14.3% to 35.2% required renal replacement therapy. Nearly 90% of patients on mechanical ventilation developed acute kidney injury, and 97% of patients requiring renal replacement therapy were on ventilators. Data from the UK indicate that approximately 31% of patients on ventilators (and 4% not on ventilators) require renal replacement therapy. Similarly, 31% of critically ill patients in a New York study required dialysis. In a small UK cohort, 29% of hospitalised 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 paediatric 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 haemodynamic changes, hypovolaemia, 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 (euvolaemia) in all patients. Consider a loop diuretic for treating fluid overload only. Manage hyperkalaemia 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 haemodialysis if CRRT is not available or possible.
Monitor fluid status daily, as well as serum urea, 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 pre-existing 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 non-severe cases (15%).
Risk factors associated with severe liver injury include older age, pre-existing 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 neurological 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.
Neurological 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 neurological 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 haemorrhage, cerebral venous sinus thrombosis, rhabdomyolysis and other muscle disease, 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.
Ischaemic stroke has been reported in 1.6% of adults with COVID-19 who visited the accident and emergency department or were hospitalised. 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 ischaemic 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., tumour 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 haemophagocytic 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 tumour necrosis factor alpha, and fewer CD4+ and CD8+ T cells.
Anti-inflammatory/immunosuppressive treatments (e.g., tocilizumab, hydroxychloroquine/chloroquine, Janus kinase inhibitors) are being trialled 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 paediatric inflammatory multisystem syndrome.
paediatric inflammatory multisystem syndrome
A rare, emerging inflammatory disease in children that has been temporally associated with COVID-19. It appears to be a post-infectious manifestation that occurs 4 to 5 weeks after infection (including in children who had initial asymptomatic or mild infection). It has been estimated that the risk is 2 per 10,000 children, based on French surveillance data. A small number of deaths have been reported. The long-term outcomes are unknown.
The syndrome shares common features with Kawasaki disease, toxic shock syndrome, bacterial meningitis, and macrophage activation syndromes. Common features include abdominal pain, other gastrointestinal symptoms, and cardiac inflammation (elevated troponin and pro-B-type natriuretic peptide levels). However, patients can present with a wide spectrum of signs, symptoms, and disease severity ranging from fever and inflammation to myocardial injury, shock, and coronary artery aneurysms. Gastrointestinal symptoms are prominent and were reported in 84% of children in one cohort (accompanied by fever in 100% of children and rash in 70.5%). Abnormal cardiac findings are common; 60% of children in one cohort had non-specific ST/T-wave abnormalities, and about one third had moderate or severe ventricular dysfunction on electrocardiogram at admission.
The largest case series reported so far included 186 patients in the US. The median age was 8.3 years (7% were <1 year, 28% were 1-4 years, 25% were 5-9 years, 24% were 10-14 years, and 16% were 15-20 years), and 62% were male. In regards to ethnicity, 31% were Hispanic or Latino, 25% were Black, and 19% were White. Around 73% of patients had previously been healthy, and 70% were positive for SARS-CoV-2 by molecular or serological testing. The majority (88%) were hospitalised with a median duration of 7 days, and 80% received intensive care. The most common organ systems involved were the gastrointestinal (92%), cardiovascular (80%), haematological (75%), mucocutaneous (74%), and respiratory (70%) systems. Some 8% of patients had coronary artery aneurysms, and Kawasaki disease-like features were noted in 40%. At least four inflammatory biomarkers were elevated in 92%.
In another US cohort of 100 patients (54% male; 40% Black and 36% Hispanic), all patients had subjective fever or chills, 97% of patients had tachycardia, 80% had gastrointestinal symptoms, 60% had rash, 56% had conjunctival injection, and 27% had mucosal changes. Myocarditis was documented in 53% of patients. Similar to the previous study, 80% of patients required intensive care, and the median hospital stay was 6 days. The mortality rate in both studies was 2%.
In a multicentre observational study in the UK, 78 cases were reported across 21 paediatric 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 diarrhoea 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.
A retrospective review at a centre in Bergamo province, Italy, reported a higher number of cases of Kawasaki-like disease during the COVID-19 epidemic, with a monthly incidence 30 times greater than the monthly incidence of the previous 5 years, and a clear starting point after the first case of COVID-19 was diagnosed. The clinical and biochemical features of these patients differ from the centre’s historical cohort of patients with Kawasaki disease. The authors conclude that there is a strong association between this syndrome and the COVID-19 epidemic.
A retrospective study in France and Switzerland identified 35 children with fever and acute heart failure possibly associated with this syndrome. The median age at admission was 10 years, and comorbidities were present in 28% of children. Gastrointestinal symptoms were prominent. Inflammation markers were suggestive of cytokine release syndrome and macrophage activation. Left ventricular ejection fraction was <30% in one third of patients. Some 88% of patients tested positive for SARS-CoV-2. All patients were treated with immunoglobulin, and some received corticosteroids. All patients recovered.
Another retrospective study in France identified 21 children with features of Kawasaki disease. Of these children, 57% had African ancestry. The median time from earlier onset of viral symptoms to the onset of Kawasaki-like illness was 45 days; 57% presented with Kawasaki disease shock syndrome and 76% presented with myocarditis. Approximately 90% of patients had positive molecular or serological tests for SARS-CoV-2. All patients had gastrointestinal symptoms early in the course of illness and elevated inflammatory markers. All patients were treated successfully and discharged.
A retrospective study in New York found that the median age of children was 10 years; 61% were male, 45% were Hispanic/Latino, and 39% were Black. Comorbidities were present in 45% of children. Fever and vomiting were the most common presenting symptoms, and depressed left ventricular ejection fraction was found in 63% of children. Inflammatory markers were elevated in all patients. All but one patient survived.
The Royal College of Paediatrics and Child Health in the UK has published a case definition, as well as guidance on how to manage these patients. Management is mainly supportive and involves a multidisciplinary team (paediatric infectious disease, cardiology, rheumatology, critical care). Patients are commonly managed with vasopressor support, corticosteroids, intravenous immunoglobulin, interleukin inhibitors, and anticoagulation. The World Health Organization and the US Centers for Disease Control and Prevention have also published case definitions.
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. 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.
Also known as multisystem inflammatory syndrome in children (MIS-C), paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), as well as other variations.
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. Noradrenaline (norepinephrine) is the preferred first-line agent, with vasopressin or adrenaline (epinephrine) considered suitable alternatives. Vasopressin can be added to noradrenaline if target mean arterial pressure cannot be achieved with noradrenaline 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 non-survivors. 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/haemorrhage 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 hospitalised 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 centre 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 caesarean section, although most caesarean 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 caesarean delivery was independently associated with an increased risk of maternal clinical deterioration and neonatal intensive care unit admission. In the US, caesarean delivery rates were higher in patients with COVID-19 compared with patients without in one cohort. Postnatal 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 radiological 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 haemolytic anaemia
Warm or cold autoimmune haemolytic anaemia (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 haemolytic anaemia 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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