post-intensive care syndrome
Early reports suggest that COVID-19 patients treated in the intensive care unit can present with post-intensive care syndrome, a spectrum of psychiatric, cognitive, and/or physical disability (e.g., muscle weakness, cognitive dysfunction, insomnia, depression, anxiety, post-traumatic stress disorder, delirium, encephalopathy) that affects survivors of critical illness, and persists after the patient has been discharged from the intensive care unit. Weakness affects 33% of patients who receive mechanical ventilation, 50% of patients with sepsis, and <50% of patients who remain in the intensive care unit for more than 1 week. Cognitive dysfunction affects 30% to 80% of patients. The risk can be minimised with medication management, physical rehabilitation, family support, and follow-up clinics.
The pooled incidence of venous thromboembolism, deep vein thrombosis, and pulmonary embolism among hospitalised patients was 14.7, 11.2%, and 7.8%, respectively. The prevalence was significantly higher in patients admitted to the intensive care unit, despite thromboprophylaxis. While venous thromboembolism appears to be frequent in hospitalised COVID-19 patients, one systematic review and meta-analysis found that the overall risk of venous thromboembolism did not significantly differ between COVID-19 and non-COVID-19 cohorts with similar disease severity, except for patients admitted to the intensive care unit. This suggests that severe disease that requires intensive care unit admission may be a risk factor for developing venous thromboembolism. Pulmonary embolism is rare in patients presenting to the accident and emergency department, but the incidence is approximately 9-fold higher than in the general non-COVID-19 population. COVID-19 patients with thromboembolic events have 1.93 times the odds of dying compared with patients without venous thromboembolism. Thromboembolic events are rare in children.
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. Male sex, obesity, mechanical ventilation, intensive care unit admission, severe parenchymal abnormalities, and elevated white blood cells have also been identified as risk factors for pulmonary embolism. 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.
The American Society of Hematology has published draft guideline recommendations on the use of anticoagulation in patients with COVID-19.
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 (mainly lupus anticoagulant) were detected in nearly half of patients in one meta-analysis and systematic review, with an increased prevalence in patients with severe and critical disease. However, there does not currently appear to be any association between this finding and disease outcomes (e.g., thrombosis, mortality).
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.
Cases of arterial thrombosis, cerebral venous thrombosis, splanchnic vein thrombosis, and acute limb ischaemia secondary to thrombosis have been reported. The prevalence of arterial thromboembolism appears to be substantial at 3.9%; however, evidence is limited.
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.
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. A Cochrane review found that the most common cardiovascular complications were cardiac arrhythmias, heart failure, and arterial and venous occlusive events. The most common arrhythmias reported during hospitalisation were supraventricular and ventricular arrhythmias. QT interval changes and ST-segment deviation have been reported. QT interval prolongation has been reported independent of whether the patient is taking drugs that prolong the QT interval.
Laboratory biomarkers may help identify those at greater risk of developing cardiovascular complications and of death. Elevated cardiac biomarkers and emerging arrhythmia are associated with the development of severe disease 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. The following test results may help inform the diagnosis: evolving ECG changes suggesting myocardial ischaemia; NT-proBNP level >400 nanograms/L; high levels of hs-cTnI or hs-cTnT, particularly levels increasing over time. Elevated troponin levels may reflect cardiac inflammatory response to severe disease rather than acute coronary syndrome. Seek specialist cardiology advice on further tests and imaging.
Monitor blood pressure, heart rate, and fluid balance, and perform continuous ECG monitoring in all patients with suspected or confirmed acute myocardial injury. Monitor in a setting where cardiac or respiratory deterioration can be rapidly identified.
Seek specialist cardiology advice on treatment and follow local treatment protocols. 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 some drugs 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 10.6%, which is higher than the incidence in hospitalised patients without COVID-19. Incidence varies widely across studies, with estimates of approximately 20% reported in some meta-analyses. Patients with acute kidney injury have a significantly increased risk of in-hospital mortality (odds ratio of 11.05). The mortality rate and incidence in patients in China was significantly lower than those in patients outside of China. Risk factors include older age ≥60 years, male sex, and severe infection. Presence of diabetes, hypertension, chronic kidney disease, and tumour history was associated with increased incidence of acute kidney injury at population level across different settings. Patients with a history of kidney transplant had a higher incidence of acute kidney injury; however, their risk of death was lower. Use of renin-angiotensin-aldosterone system blockade drugs is also significantly associated with an increased risk of acute kidney injury in hospitalised patients.
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, during, or after hospital admission. Causes include haemodynamic changes, hypovolaemia, viral infection leading directly to kidney tubular injury, thrombotic vascular processes, glomerular pathology, or rhabdomyolysis. May be associated with haematuria, proteinuria, and abnormal serum electrolyte levels (e.g., potassium, sodium). Direct kidney infection has been confirmed in an autopsy study of a single patient.
Follow local guidelines for assessing and managing acute kidney injury. 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 patients with chronic kidney disease for at least 2 years after acute kidney injury.
acute liver injury
Liver injury may be associated with pre-existing liver disease, viral infection, drug toxicity, systemic inflammation, hypoxia, or haemodynamic issues; however, the underlying mechanism is unclear. The overall prevalence has been reported as 25%, although there is no uniform definition of liver injury in these patients and prevalence depends on the definition used in studies. The overall prevalence may be as low as 9% when strict criteria for diagnosis are used. The prevalence of elevated alanine aminotransferase and aspartate aminotransferase was 19% and 22%, respectively. The prevalence of hypertransaminasaemia was higher in patients with severe disease compared with patients with non-severe disease. Another meta-analysis concluded that findings from the available evidence to date from observational studies and case reports indicate that transaminases and total bilirubin levels appear not to significantly change in patients with COVID-19.
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, remdesivir, tocilizumab) may have a detrimental effect on liver injury.
Guidelines on the management of liver derangement in patients with COVID-19 have been published.
Patients commonly have central or peripheral neurological complications, possibly due to viral invasion of the central nervous system, inflammatory response, or immune dysregulation. Neurological complications occur across the lifespan in the context of infection, with and without known comorbidities, and with all disease severities (including asymptomatic patients).
Neurological manifestations have been reported in 22% to 35% of patients across studies. Central nervous system manifestations were more common than peripheral nervous system manifestations. A retrospective electronic health records study of nearly 240,000 patients found that approximately one third of patients received a neurological or psychiatric diagnosis in the 6 months after diagnosis, and 13% received such a diagnosis for the first time. The risk was greater in patients with severe disease.
Neurological complications include, but are not limited to, acute cerebrovascular disease, impairment of consciousness, ataxia, seizures, corticospinal tract signs, meningoencephalitis, encephalopathy, encephalomyelitis (including acute disseminated encephalomyelitis), peripheral demyelinating lesions, peripheral neuropathies, cerebral venous sinus thrombosis, myopathy, acute transverse myelitis, myasthenia gravis, Guillain-Barre syndrome and other neuropathies, status epilepticus, dementia, catatonia, parkinsonian syndromes, mood/anxiety/psychotic/substance use disorders, and abnormal findings on brain magnetic resonance imaging.
Patients may present with these manifestations, or they may develop them during the course of the disease. Neurological complications tend to develop 1 to 2 weeks after the onset of respiratory disease.
Acute cerebrovascular disease (including ischaemic stroke, haemorrhagic stroke, cerebral venous thrombosis, and transient ischaemic attack) has been reported in 0.5% to 5.9% of patients. The most common type was ischaemic stroke (0.4% to 4.9%). Patients with severe disease are at an increased risk of ischaemic stroke compared with patients with non-severe disease. Stroke is relatively frequent among hospitalised COVID-19 patients relative to other viral respiratory infections, and has a high risk of in-hospital mortality. Risk factors include older age and male sex. Median time from onset of COVID-19 symptoms to stroke was 8 days. Stroke presents later in severe disease, and earlier in mild to moderate disease. Patients may present with ischaemic stroke during the convalescent phase of infection, including younger people <50 years of age with asymptomatic or pauci-symptomatic COVID-19. 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.
Guillain-Barre syndrome has been reported. Both post-infectious and pre-infectious patterns have been reported. The pooled prevalence among hospitalised and non-hospitalised patients was 0.15%. The mean age of patients 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. Patients had an increased odds for demyelinating subtypes. Clinical outcomes were comparable to those for contemporary or historical controls not infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Encephalitis has been reported in <1% of patients, but increases up to 6.7% in critically ill patients. Encephalitis is associated with poorer outcomes including admission to the intensive care unit, need for mechanical ventilation, and increased mortality rate (13.4%) compared with the general population of COVID-19 patients.
Patients with pre-existing neurological disorders may develop an exacerbation of their neurological symptoms and severe COVID-19.
Patients may show cerebral changes on magnetic resonance imaging months after recovery, suggesting that long-term consequences may be possible.
Neurological involvement is common in children and adolescents. In a case series of 1695 patients <21 years of age, 22% of patients had documented neurological involvement. Those with neurological involvement were more likely to have an underlying neurological disorder compared with those without, but a similar number were previously healthy. In the majority of cases, symptoms were transient. However, approximately 12% had life-threatening conditions including severe encephalopathy, central nervous system infection/demyelination, Guillain-Barre syndrome/variants, and acute fulminant cerebral oedema.
post-COVID-19 syndrome (long COVID)
Also known as post-acute COVID-19, post-acute COVID-19 syndrome, chronic COVID, long-haul COVID, post-acute sequelae of SARS-CoV-2 infection (PASC), and post-COVID conditions.
Definition: case definitions vary. The World Health Organization defines it as a condition that occurs in people with a history of probable or confirmed SARS-CoV-2 infection, usually occurring 3 months from the onset of symptoms and lasting for at least 2 months, that cannot be explained by an alternative diagnosis. The UK National Institute for Health and Care Excellence defines it as signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks, and are not explained by an alternative diagnosis. Ongoing symptomatic COVID-19 is defined as signs and symptoms from 4 weeks up to 12 weeks. The US Centers for Disease Control and Prevention defines post-COVID conditions as an umbrella term for the wide range of health consequences that are present more than 4 weeks after infection with SARS-CoV-2. The syndrome is not thought to be linked to disease severity or specific signs and symptoms during the acute phase of illness. Protracted symptoms are common after many viral and bacterial infections, including influenza. However, while the clinical features were also observed after influenza infection, the incidence appears to be higher after COVID-19. The neurological symptoms are similar to symptoms of other neurological conditions such as chronic fatigue syndrome and functional neurological disorder.
Epidemiology: frequency ranges from 4.7% to 80% across observational studies, and occurs between 3 to 24 weeks after the acute phase or hospital discharge. Potential risk factors include older age, age 40 to 49 years, female sex, obesity, severe clinical status, higher number of comorbidities, higher symptom load, hospital admission, and oxygen supplementation in the acute phase, although data is lacking. A study in the UK found that 38% of patients reported at least one persistent symptom, and 15% reported three or more persistent symptoms, lasting 12 weeks or more (a weighted population prevalence of persistent symptoms of 5.8% for one and 2.2% for three or more symptoms). Approximately 63% of patients report at least one symptom at 30 days after symptom onset/hospitalisation, with 71% reporting at least one symptom after 60 days, and 46% at 90 days or more in a systematic review and meta-analysis. The most commonly reported persistent symptoms were dyspnoea and fatigue. Persistent symptoms have been reported up to 12 months after discharge, but most people had a good and functional recovery during 1-year follow-up. Prolonged illness can occur among young adults with no underlying comorbidities, and in patients who had mild disease. Approximately 12% to 15% of patients who had mild symptoms still had symptoms up to 8 months later. The number of symptoms at follow-up was associated with the symptom load during the acute phase of infection and the number of comorbidities in non-hospitalised patients. Persistent symptoms have been reported in pregnant women and children, but appear to be less common in children compared with adults. The frequency and characteristics of this syndrome are still under investigation in children and adolescents.
Diagnosis: use a holistic, person-centred approach that includes a comprehensive clinical history (including history of suspected or confirmed acute COVID-19, nature and severity of previous and current symptoms, timing and duration of symptoms since the start of acute illness, and a history of other health conditions), and appropriate examination that involves assessing physical, cognitive, psychological, and psychiatric symptoms, as well as functional abilities. Refer patients with signs or symptoms that could be caused by an acute or life‑threatening complication (e.g., severe hypoxaemia, signs of severe lung disease, cardiac chest pain, multisystem inflammatory syndrome in children) urgently to the relevant acute services.
Signs and symptoms: symptoms vary widely, may relapse and remit or fluctuate, can change unpredictably, and can occur in those with mild disease only. Common long-term symptoms include persistent cough, low-grade fever, breathlessness, weakness, malaise, impairment of concentration, fatigue, pain, chest pain/tightness, palpitations, myalgia, arthralgia, headaches, vision changes, hearing loss, earache, tinnitus, sore throat, loss of taste/smell, impaired mobility, numbness in extremities, dizziness, tremors, memory loss, mood changes, skin rashes, gastrointestinal symptoms, neurocognitive difficulties, sleep disturbances, delirium (older people), and mental health conditions (e.g., anxiety, depression). Gastrointestinal sequelae including loss of appetite, nausea, acid reflux, and diarrhoea are common in patients 3 months after discharge. The most common symptoms at 1-year follow-up were fatigue, sweating, chest tightness, anxiety, and myalgia. Some of the symptoms may overlap with post-intensive care syndrome (see above). The inability to return to normal activities, emotional and mental health outcomes, and financial loss are common.
Investigations: tailor investigations to the clinical presentation, and to rule out any acute or life-threatening complications and alternative diagnoses. Investigations may include blood tests (e.g., full blood count, kidney and liver function tests, C-reactive protein, ferritin, thyroid function), oxygen saturation, blood pressure and heart rate measurements, exercise tolerance test, chest imaging, electrocardiogram, and psychiatric assessment. Approximately 50% of patients had residual abnormalities on chest CT and pulmonary function tests at 3 months. Around 9% of patients had deteriorating chest x-ray appearances at follow-up, which may indicate lung fibrosis. Persistently elevated D-dimer and C-reactive protein have also been reported.
Management: give advice and information on self-management including ways to self-manage symptoms (e.g., set realistic goals, antipyretic for fever, breathing techniques for chronic cough, home pulse oximetry for monitoring breathlessness, pulmonary rehabilitation, staged return to exercise); who to contact if there is concern about symptoms or if there is need for support; sources of support (e.g., support groups, online forums); and how to get support from other services (e.g., social care, housing, financial support). A personalised, multidisciplinary rehabilitation plan that covers physical, psychological, and psychiatric aspects of rehabilitation is an important part of management. 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.
Follow-up: agree with the patient how often follow-up and monitoring are needed (either in person or remotely), and which healthcare professionals should be involved. Take into account the patient’s level of need and the services involved. Tailor monitoring to the patient’s symptoms, and consider supported self-monitoring at home (e.g., heart rate, blood pressure, pulse oximetry). Be alert to symptoms that could require referral or investigation.
In-hospital cardiac arrest is common in critically ill patients with COVID-19, and is associated with poor survival, particularly among older patients. Among 5019 critically ill patients with COVID-19, 14% had an in-hospital cardiac arrest. Risk factors included older age, male sex, presence of comorbidities, and admission to a hospital with a smaller number of intensive care unit beds. Approximately 57% of patients received cardiopulmonary resuscitation. The most common rhythms at the time of resuscitation were pulseless electrical activity (49.8%) and asystole (23.8%). Of those who received resuscitation, 12% survived to hospital discharge with most of these patients being younger than 45 years of age.
Sepsis (diagnosed according to Sepsis-3 or according to the presence of infection-related organ dysfunction necessitating organ support/replacement) has been reported in 78% of intensive care unit patients and 33% of hospitalised patients.
Guidelines for the management of shock in critically ill patients with COVID-19 recommend a conservative fluid strategy (crystalloids preferred over colloids, buffered/balanced crystalloids preferred over unbalanced crystalloids) and a vasoactive agent. Noradrenaline (norepinephrine) is the preferred first-line agent. Vasopressin or adrenaline (epinephrine) can be added to noradrenaline if target mean arterial pressure cannot be achieved with noradrenaline alone. 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. The pooled incidence of DIC is 3%, and it is associated with poor prognosis. The incidence was higher in patients with severe disease and those admitted to the intensive care unit, and in non-survivors compared with 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.
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.
Patients with COVID-19 may have a higher risk of developing ventilator-associated pneumonia compared with patients without COVID-19. Overall, ventilator-associated pneumonia was reported in 48.2% of mechanically ventilated patients and the mortality rate was 51.4%.
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.
However, the pooled mean serum interleukin-6 level was markedly less in patients with severe or critical COVID-19 compared with patients with other disorders associated with elevated cytokines such as cytokine release syndrome, sepsis, and non-COVID-19-related ARDS. These findings question the role of cytokine storm in COVID-19-induced organ dysfunction, and further research is required.
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 SARS-CoV-2 infection. The syndrome appears to be the result of a delayed immune response to SARS-CoV-2 infection with disease peaks following pandemic peaks by 2 to 5 weeks. 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. Mucocutaneous findings may be present, many of which overlap with Kawasaki disease.
Three types of clinical manifestations have been recognised: persistent fever and gastrointestinal symptoms (the most common type); shock with heart dysfunction; and symptoms coincident with the diagnostic criteria for Kawasaki disease.
A systematic review of 27 studies (913 cases) globally found that the median age of patients was 9.3 years of age, and 57% of patients were male. At least one comorbidity was reported in 31% of cases, most commonly obesity, asthma, and chronic lung disease. The most common manifestations were fever (99%), gastrointestinal symptoms (87%), and cardiovascular symptoms such as myocardial dysfunction (55%), coronary artery aneurysms (22%), and shock (66%). The pooled prevalence of respiratory symptoms was 41%, and neurological symptoms was 36%. Other symptoms included conjunctivitis (57%), rash (59%), and oral mucosal changes (42%). Inflammatory and cardiac markers were elevated in the majority of patients, and 38% had abnormal findings on chest x-ray. Approximately 79% of patients required intensive care admission, 63% required inotropic support, 57% required anticoagulation, and 33% required mechanical ventilation. The mortality rate was 1.9%. The majority of patients had good outcomes with no significant medium- or long-term sequelae at 1-year follow-up in a small cohort of patients.
In the UK, 78 cases were reported across 21 paediatric intensive care units in a multicentre observational study. 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.
In the US, 5217 cases have been reported, with 46 deaths (as of 4 October 2021). In a US case series of 1116 patients diagnosed with MIS-C, those with MIS-C were more likely to have the following characteristics compared with patients with severe COVID-19: age 6 to 12 years; non-Hispanic Black ethnicity; cardiorespiratory involvement; cardiovascular without respiratory involvement; mucocutaneous without cardiorespiratory involvement; higher neutrophil-to-lymphocyte ratio; higher C-reactive protein level; and lower platelet count. These patterns may help differentiate between MIS-C and COVID-19. Factors associated with more severe outcomes (e.g., intensive care unit admission, decreased cardiac function, shock, myocarditis) include: age >5 years; non-Hispanic Black ethnicity; symptoms of dyspnoea or abdominal pain; elevated C-reactive protein, troponin, ferritin, D-dimer, brain natriuretic peptide, or interleukin-6; and reduced lymphocyte or platelet counts.
The most common cardiovascular complications include shock, cardiac arrhythmias, pericardial effusion, and coronary artery dilatation. The pooled prevalence of cardiac abnormalities due to MIS-C is as follows: significant left ventricular dysfunction 38%; coronary aneurysm or dilatation 20%; ECG abnormalities or cardiac arrhythmias 28%; raised serum troponin level 33%; and raised proBNP/BNP level 44%.
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. The optimal choice and combination of immunomodulating therapies have not been definitively established, but intravenous immunoglobulin and/or corticosteroids are generally considered first-line treatment, with interleukin-1 antagonists reserved for refractory cases. Initial treatment with intravenous immunoglobulin plus a corticosteroid was associated with a lower risk of new or persistent cardiovascular dysfunction compared with intravenous immunoglobulin alone in one cohort study. However, another cohort study found no evidence of substantial differences in two primary outcomes (inotropic support or mechanical ventilation by day 2 or later or death; and reduction in disease severity on an ordinal scale by day 2) among children who received the three most common treatments for this disorder (i.e., intravenous immunoglobulin alone, intravenous immunoglobulin plus a corticosteroid, and corticosteroids alone). The American College of Rheumatology has published guidelines on the diagnosis and management of MIS-C.
Follow-up of patients at 6 months found that while cardiac, gastrointestinal, renal, haematological, and otolaryngology outcomes largely resolved at 6 months, muscular fatigue and emotional lability were common.
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.
Multisystem inflammatory syndrome has been reported in adults.
vaccine-induced immune thrombocytopenia and thrombosis (VITT)
Also known as thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
Definition: thromboembolic events with thrombocytopenia after vaccination with adenovirus vector-based COVID-19 vaccines (e.g., AstraZeneca, Janssen). The vaccines may trigger the development of an immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. The link between vaccination and the formation of anti-PF4 antibodies is yet to be determined. Anti-PF4 antibodies are transient in most patients, but pathogenic platelet-activating anti-PF4 antibodies may persist for more than 12 weeks in some patients. The blood clots occur in unusual sites and include cerebral venous sinus thrombosis, splanchnic vein thrombosis, and arterial thrombosis, together with thrombocytopenia and sometimes bleeding. Multifocal venous and arterial thromboses have also been reported in serious cases. These events can rapidly progress and may be life-threatening or fatal. A causal relationship is plausible based on current information. Evidence to date does not suggest that these vaccines cause venous thromboembolism without thrombocytopenia. There has been no safety signal following receipt of mRNA vaccines, although a small number of cases have been reported.
Epidemiology: very rare. A study in Denmark and Norway reported 11 excess venous thromboembolic events per 100,000 vaccinations, including 2.5 excess cerebral venous thrombosis events per 100,000 vaccinations with the AstraZeneca vaccine. Data suggest that there is a slightly higher incidence reported in younger adult age groups. Most of the cases reported occurred in women under 60 years of age within 2 to 3 weeks of receiving their first dose. Cases have also been reported after this period, up to 48 days after vaccination. See the Prevention external link opens in a new windowsection for more information.
Diagnosis: advise vaccine recipients who experience any severe symptoms from around 4 to 30 days after vaccination to seek urgent medical attention. Approximately half of patients present with cerebral venous sinus thrombosis. Headache is the most common presenting symptom, and may precede VITT by several days. Signs and symptoms listed by Public Health England include: new-onset headache that is getting worse and does not respond to simple analgesics; an unusual headache that seems worse when lying down or bending over, or may be accompanied by blurred vision, nausea and vomiting, speech difficulty, weakness, drowsiness, or seizures; new unexplained pinprick bruising or bleeding; and shortness of breath, chest pain, leg swelling, or persistent abdominal pain. Ask about vaccination history in people with suspected VITT. Refer people who are acutely unwell to the emergency department immediately. Report all cases to local health authorities and through local vaccine adverse event reporting systems.
Investigations: order a full blood count (with platelets), coagulation screen (including fibrinogen and D-dimer), blood film/peripheral smear, and platelet factor 4 enzyme-linked immunosorbent assay for any patient presenting with acute thrombosis or new-onset thrombocytopenia within 30 days of receiving a COVID-19 vaccination. Typical laboratory features include thrombocytopenia, raised D-dimer levels above the level expected for venous thromboembolism, and low or normal fibrinogen. Antibodies to platelet factor 4 have also been identified. Order same-day imaging studies based on location of symptoms to confirm the site of thrombosis. Repeat imaging may be required in patients whose blood tests suggest probable VITT, but no thrombosis is seen on initial imaging or there is clinical or laboratory suspicion of progression.
Differential: other possible causes of thrombocytopenia with thrombosis include cancer, antiphospholipid syndrome, heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, and paroxysmal nocturnal haemoglobinuria. Consider alternative diagnoses in people whose blood tests indicate it is unlikely they have VITT. A small number of people with VITT do not have thrombocytopenia at presentation. Therefore, repeat a full blood count after 2 to 3 days or if symptoms worsen, if a high clinical suspicion of VITT remains. Discuss the need for further investigations with a haematologist.
Management: promptly treat patients. Consult a haematologist when making decisions about starting or adding treatments. There is limited information about the optimal treatment of this condition; however, management is similar to heparin-induced thrombocytopenia. First-line treatment is urgent administration of intravenous immunoglobulin. A second dose may be considered if there is an inadequate response after 2 to 3 days. Some experts also recommend the use of corticosteroids, especially if intravenous immunoglobulin treatment is insufficient. Anticoagulate with a non-heparin-based therapy such as a direct oral anticoagulant, fondaparinux, danaparoid, or argatroban, depending on the clinical picture, as soon as the benefit outweighs the risk of bleeding. Review response to anticoagulation if the patient’s clinical condition changes, and adjust treatment if needed. Avoid platelet transfusions, heparin (including heparin flushing solution), low molecular weight heparin, and vitamin K antagonists (e.g., warfarin). Consider plasma exchange, fibrinogen replacement, or rituximab in select patients. Some patients may require surgery to treat thrombosis.
Monitoring: after discharge, the patient should be under the care of a haematologist. Assess symptoms and measure D-dimer, fibrinogen, and platelet counts every 2 to 3 days for the first 2 weeks. Repeat enzyme-linked immunosorbent assay (ELISA) for platelet factor 4 antibodies weekly for the first 4 weeks. Repeat tests monthly for the first 6 months and, if no relapses occur, reduce the frequency of testing to every 3 months. When platelet 4 antibodies are no longer detected, review the need for ongoing treatment and monitoring.
Prognosis: mortality due to complications has been reported to be 39%. Fibrinogen levels, age, platelet count, and the presence of intracerebral haemorrhage or cerebral venous thrombosis are significantly associated with an increased risk of mortality.
Management is evolving and there are differences between the guidelines available. Consult the most current local guidelines for more detailed information on the diagnosis and management of this condition. Consult local guidelines for advice on further vaccination after an episode of VITT.
Pregnancy outcome is usually good, although there are little data on exposure during early pregnancy.
The odds of admission to the intensive care unit, invasive ventilation, and need for extracorporeal membrane oxygenation were higher in pregnant and recently pregnant women compared with non-pregnant reproductive-aged women. Pregnant women may also be at an increased risk of maternal death. Risk factors for serious complications include pre-existing comorbidities (e.g., chronic hypertension, diabetes), high maternal age, non-White ethnicity, presence of pregnancy-specific conditions (e.g., gestational diabetes, pre-eclampsia), and high body mass index. Infection during pregnancy is associated with an increased risk of pre-eclampsia.
Preterm birth was more common in pregnant women with COVID-19 compared with pregnant women without the disease. However, the overall rates of spontaneous preterm births in pregnant women with COVID-19 was broadly similar to those observed in the pre-pandemic period, so these preterm births could have been medically indicated.
The overall rates of stillbirths and neonatal deaths do not seem to be higher than the background rates. In England, there is no evidence of an increase in stillbirths regionally or nationally during the pandemic when compared with the same months in the previous year and despite variable community infection rates in different regions.
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. Aspergillosis has been reported in 10.2% of patients admitted to the intensive care unit. The mortality rate was high at 54.9%.
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. Voriconazole levels may need monitoring more frequently in COVID-19 patients due to increased toxicity in these patients. Guidance on the diagnosis and management of COVID-19-associated pulmonary aspergillosis has been published.
Mucormycosis (also known as ‘black fungus’) has been reported rarely. Approximately 275 cases have been reported globally as of 21 June 2021, with 233 of those cases reported from India. The number of cases in India increased significantly during its second wave.
Have a low threshold of suspicion for the diagnosis. It is important not to miss warning signs and symptoms (e.g., nasal congestion; blackish/bloody nasal discharge; sinus or facial pain; toothache or loosening of teeth; vision disturbances; haemoptysis; necrotic eschar on skin, palate, or nasal turbinates). Do not hesitate to order appropriate investigations. The median time to interval between diagnosis of COVID-19 and evidence of mucormycosis was 15 days. Rhino-orbital mucormycosis was most common (42%), followed by rhino-orbito-cerebral mucormycosis (24%), and pulmonary mucormycosis (10%).
Management strategies in the context of COVID-19 include, but are not limited to: controlling hyperglycaemia, diabetes, or diabetic ketoacidosis; reducing corticosteroid dose with the aim to rapidly discontinue; discontinuing immunomodulating drugs; extensive surgical debridement to remove all necrotic material; antifungal therapy (e.g., amphotericin-B) for 4 to 6 weeks; and appropriate supportive care and monitoring.
Patients should be under the care of a multidisciplinary team that includes an infectious disease specialist; an intensivist; a neurologist; a dentist; an ophthalmologist; an ear, nose, and throat specialist; and a surgeon.
Prevention involves controlling hyperglycaemia; monitoring blood glucose level in COVID-19 patients after discharge (whether or not they are diabetic); and judicious use of corticosteroids, antibiotics, and antifungals.
Overall mortality in India (36.5%) was less than that for globally reported cases (61.9%), likely due to the predominance of rhino-orbital mucormycosis in India.
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. Patients had an increased risk of severe pancreatitis and necrotising pancreatitis, and a longer length of hospital stay. 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.
Immune thrombocytopenia has been reported rarely. The majority of cases were in patients >50 years of age, with only 7% of cases reported in children. The majority of cases were in patients with moderate to severe COVID-19; however, 7% of cases were in asymptomatic COVID-19 patients. Onset occurred in 20% of cases 3 weeks after the onset of COVID-19 symptoms, with most cases reported after clinical recovery. Severe life-threatening bleeding was uncommon. Treatment involved the use of corticosteroids, intravenous immunoglobulin, and thrombopoietin-receptor agonists.
Subacute thyroiditis is a thyroid disease of viral or post-viral origin. Emerging evidence suggests that infection with SARS-CoV-2 may trigger subacute thyroiditis. A review of 21 cases found a female predominance, with the mean number of days between the start of COVID-19 illness and the appearance of symptoms of subacute thyroiditis being 25 days. Infection had resolved in the majority of patients before the onset of subacute thyroiditis symptoms. Fever and neck pain were the most common presenting complaints. Symptoms resolved in all patients after treatment; however, 5 patients reported having hypothyroid illness on follow-up.
Critically ill patients may develop gastrointestinal complications; however, it is unclear whether this is a manifestation of critical illness in general, or whether it is specific to COVID-19. One study found that patients with COVID-19 were more likely to develop gastrointestinal complications compared with those without COVID-19, specifically transaminitis, severe ileus, and mesenteric ischaemia.
Macrovascular arterial/venous thrombosis has been identified in almost 50% of patients with bowel ischaemia. Overall mortality in COVID-19 patients with gastrointestinal ischaemia and radiologically evident mesenteric thrombotic occlusion was 38.7% and 40%, retrospectively. Patients with intestinal ischaemia generally present with abdominal pain and vomiting. Management includes gastric decompression, fluids, haemodynamic support, and surgery.
Patients may have an increased risk of gastrointestinal bleeding compared with the general population; however, evidence is limited. The overall gastrointestinal bleeding rate has been reported to be 2%. Risk factors for gastrointestinal haemorrhage in COVID-19 patients include history of gastrointestinal bleeding and anticoagulant use.
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