Several studies have found a high incidence of thrombolytic complications in patients with COVID-19, even when thromboprophylaxis had been given. The pooled prevalence of venous thromboembolism, pulmonary embolism (with or without deep vein thrombosis), and deep vein thrombosis alone among all hospitalised patients was 26%, 12%, and 14%, respectively. These rates were higher in patients admitted to the intensive care unit compared with general wards.
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). Thrombotic events may be due to cytokine storm, hypoxic injury, endothelial dysfunction, hypercoagulability, and/or increased platelet activity.
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. Anticoagulation should be considered in these patients.
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. However, this has not become accepted practice.
COVID-19 is associated with a high inflammatory burden that can result in cardiovascular complications with a variety of clinical presentations. Inflammation in the myocardium can result in myocarditis, heart failure, arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. These complications can occur 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.
Cardiac injury has been reported in 24.4% of hospitalised patients, and the all-cause mortality in these patients was 72.6% compared with those without cardiac injury. Factors associated with the development of cardiac injury include older age, chronic obstructive pulmonary disease, and hypertension.
Cardiovascular complications have been reported in 14.1% of patients during hospitalisation, with an overall case fatality rate of 9.6%. Patients with pre-existing cardiovascular comorbidities or risk factors are at higher risk for cardiovascular complications and mortality. Complications include arrhythmias or palpitations (18.4%), myocardial injury (10.3%), angina (10.2%), acute myocardial infarction (3.5%), and acute heart failure (2%). Cases of fulminant myocarditis, cardiac tamponade, cor pulmonale, takotsubo syndrome, and pericarditis have also been reported.
Elevated cardiac biomarkers and emerging arrhythmia are associated with the development of severe COVID-19 and the 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.
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 pooled incidence of acute kidney injury is 28.6% among hospitalised patients from the US and Europe, and 5.5% among patients from China. The pooled incidence of renal replacement therapy is 7.7% in the US and Europe, and 2.2% in China. Among patients admitted to the intensive care unit, the incidence of renal replacement therapy is 20.6%. Risk factors associated with acute kidney injury include older age, male sex, cardiovascular disease, diabetes, hypertension, and chronic kidney disease. Acute kidney injury is associated with an increased risk of mortality with a pooled risk ratio of 4.6. Can develop at any time before or during hospital admission.
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.
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 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. However, most studies included minor symptoms such as headache and dizziness, which are classified as symptoms of COVID-19 in this topic rather than complications. 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. Neurological complications are rare in children.
Complications include acute cerebrovascular disease, impairment of consciousness, ataxia, neuralgia, seizures, corticospinal tract signs, meningitis, encephalitis, encephalopathy, encephalomyelitis, peripheral demyelinating lesions, peripheral neuropathy, intracerebral haemorrhage, cerebral venous sinus thrombosis, myopathy, myasthenia gravis, and Guillain-Barre syndrome (GBS) and other neuropathies. Patients may present with these signs/symptoms, or they may develop them during the course of the disease.
The mean age of patients with GBS was 55 years with a male predominance. Most patients had respiratory and/or severe symptoms of COVID-19, although it has also been reported in asymptomatic patients. A higher prevalence of the classic sensorimotor form and acute inflammatory demyelinating polyneuropathy have been reported, although rare variants have also been noted.
Stroke is relatively frequent among hospitalised patients (1.8% for any type of stroke, 1.6% for ischaemic stroke) relative to other viral respiratory infections, and has a high risk of in-hospital mortality (34%). Ischaemic stroke 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.
post-acute COVID-19 (long COVID)
While most patients recover within 2 weeks, approximately 10% of patients still have symptoms after 3 weeks, and some may have symptoms for months, according to data from the UK COVID Symptom Study in which people enter their ongoing symptoms on a smartphone app. The term ‘long COVID’ has been used to describe post-acute COVID-19 symptoms.
Nearly 90% of hospitalised patients who recovered from COVID-19 reported persistence of at least one symptom 2 months after discharge. Only 12.6% of patients had no related symptoms, 32% had one or two symptoms, and 55% had three or more symptoms.Prolonged illness can occur among young adults with no underlying comorbidities. In a survey study of symptomatic adults, 35% had not returned to their usual state of health 2 to 3 weeks after testing. Among those aged 18 to 34 years with no underlying chronic medical conditions, 20% had not returned to their usual state of health.
Symptoms vary widely, may relapse and remit, and can occur in those with mild disease only. Common long-term symptoms include cough, low-grade fever, and fatigue. Dyspnoea, chest pain, myalgia, headaches, rashes, gastrointestinal symptoms, neurocognitive difficulties, and mental health conditions have also been reported. Blood tests should be ordered selectively and for specific clinical indications after a careful history and examination. Other investigations may include chest x-ray, urine tests, and an electrocardiogram.
There are no definitive, evidence-based recommendations for the management of post-acute COVID-19 as yet; therefore, patients should be managed pragmatically and symptomatically (e.g., antipyretic for fever, breathing techniques for chronic cough, home pulse oximetry for monitoring breathlessness, pulmonary rehabilitation, staged return to exercise). Many patients recover spontaneously with holistic support, rest, symptomatic treatment, and a gradual increase in activity. Referral to a specialist may be required in patients where there is clinical concern along with respiratory, cardiac, or neurological symptoms that are new, persistent, or progressive.
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
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. Reported in 71% of non-survivors.
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.
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, Janus kinase inhibitors) are being trialled in COVID-19 patients. See the Emerging external link opens in a new windowsection for more information.
Cytokine release syndrome has been reported in children, although cases appear to be rare. See the section below on paediatric inflammatory multisystem syndrome.
paediatric 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 post-infectious inflammatory process. The syndrome has a strong temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Also known as PIMS, multisystem inflammatory syndrome in children (MIS-C), paediatric 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, diarrhoea), and significantly elevated inflammatory markers. Additional clinical and laboratory characteristics including thrombocytopenia, fatigue, headache, myalgia, sore throat, and lymphadenopathy have been suggested to refine the case definition.
A systematic review of 35 studies (783 cases) found that the median age of patients was 8.6 years of age, and 55% of patients were male. Comorbidities were reported in 20% of cases, with obesity being the most common. Cardiovascular symptoms (82% of patients were tachycardic and 61% were hypotensive) and gastrointestinal symptoms (71%) were prominent. Rashes were reported in 42% of patients. Respiratory symptoms were infrequent. The proportion of patients with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) or serology test result was 59%, and 41% had chest imaging abnormalities. Inflammatory markers were elevated in 83% of patients. Cardiac markers were also elevated in the majority of patients. Approximately 68% of patients required intensive care admission, 63% required inotropic support, and 28% of patients required respiratory support. The mortality rate was 1.5%.
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.
Management is mainly supportive and involves a multidisciplinary team (paediatric infectious disease, cardiology, rheumatology, critical care). Patients are commonly managed with intravenous immunoglobulin, vasopressor support, corticosteroids, immune modulators, anticoagulation, antiplatelet therapy, and respiratory support. A national consensus management pathway from the UK is available.
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. Immunologically, PIMS appears to be a distinct clinical entity from Kawasaki disease as neutrophilia and raised monocyte counts, features of Kawasaki disease, were not observed in one cohort.
Pregnancy outcome is usually good, although there are little data on exposure during early pregnancy. Risk factors for severe disease in pregnant women include pre-existing comorbidities (e.g., chronic hypertension, diabetes), high maternal age, and high body mass index. Pregnant women are more likely to need intensive care unit admission and invasive ventilation, especially those with a pre-existing comorbidity. Preterm birth is more common in pregnant women with COVID-19 compared with pregnant women without the disease. Caesarean delivery occurs in approximately 50% of cases, with the most common indication being severe maternal pneumonia or concern about sudden maternal decompensation. Perinatal deaths are rare, and occur in less than 1% of cases. Stillbirths have been reported. Maternal morbidity is similar to that of women of reproductive age.
Limited low-quality evidence suggests that the risk of infection in neonates is extremely low. Most infections are acquired in the postnatal period, although congenitally acquired infection has been reported. Unlike children who generally have asymptomatic infection, two-thirds of neonatal cases are symptomatic and a significant proportion require intensive care, although the overall prognosis appears to be excellent.
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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