Complications

Complications table
ComplicationTimeframeLikelihood

post-intensive care syndrome

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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.[371]

thrombosis

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A hypercoagulable state is one of the hallmarks of disease, particularly in critically ill patients, often manifesting as venous and arterial thromboembolism. The coagulopathy in COVID-19 has a prothrombotic character, with increases in D-dimer, fibrin, fibrin degradation products, and fibrinogen.[1082] Antiphospholipid antibodies have been detected 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).[1083]

Epidemiology: 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. The prevalence of arterial thromboembolism appears to be lower at 3.9%; however, evidence is limited.[1084] Thromboembolic events are rare in children.[1085] The risk factors with the most evidence for being predictive of venous thromboembolism are older age and elevated D-dimer levels.[1086] Male sex, obesity, mechanical ventilation, intensive care unit admission, severe parenchymal abnormalities, and elevated white blood cells have also been identified as risk factors.[1087]

Aetiology: the pathogenesis is not completely understood. It has been hypothesised that local thrombi are formed due to a local inflammatory process, rather than the classical emboli coming from elsewhere in the body.[1088][1089] Patients may be predisposed to thromboembolism due to the direct effects of infection, or the indirect effects of infection (e.g., severe inflammatory response, critical illness, traditional risk factors).[1090] Thrombotic events may be due to cytokine storm, hypoxic injury, endothelial dysfunction, hypercoagulability, and/or increased platelet activity.[1091]

Diagnosis: monitor patients for signs or symptoms suggestive of venous or arterial thromboembolism, and proceed according to hospital protocols for diagnosis.[83]

Management: 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. Low molecular weight heparin or unfractionated heparin is preferred over oral anticoagulants. Treat patients who require extracorporeal membrane oxygenation or continuous renal replacement therapy, or who have thrombosis of catheters or extracorporeal filters, with antithrombotic therapy as per the standard institutional protocols for those without COVID-19.[371]

Monitoring: haematological and coagulation parameters are commonly measured in hospitalised patients; however, there is currently insufficient evidence to recommend either for or against using such data to guide management decisions. Patients with very high D-dimer levels have the greatest risk of thrombosis and may benefit from active monitoring.[660][661]

Prognosis: patients with thromboembolic events have 1.93 times the odds of dying compared with patients without venous thromboembolism.[1092]

Also see Disseminated intravascular coagulation below.

cardiovascular complications

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Cardiovascular complications include arrhythmias, myocardial injury, acute coronary syndrome, and heart failure.[1093]

Epidemiology: cardiovascular complications have been reported in 14.1% of patients during hospitalisation.[1093] Higher rates of myocardial injury have been reported in the US (9% to 52%) compared with China (7% to 28%).[1094] A Cochrane review found that the most common cardiovascular complications were arrhythmias, heart failure, and arterial and venous occlusive events.[154] More rarely, cases of fulminant myocarditis, pericarditis, cardiac tamponade, cor pulmonale, and takotsubo syndrome have been reported.[1095][1096][1097][1098][1099] Risk factors include older age, hypertension, underlying cardiovascular disease, and chronic kidney disease.[1094]

Aetiology: COVID-19 is associated with a high inflammatory burden. Inflammation of the myocardium can result in myocarditis, heart failure, arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death.[1100][1101]

Diagnosis: 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.[450]

Management: seek specialist cardiology advice on treatment and follow local treatment protocols.[450] There are limited data to recommend any specific drug treatments for these patients. Involve a multidisciplinary team including intensive care specialists, cardiologists, and infectious disease specialists.[1102]

Monitoring: 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.[450] Laboratory biomarkers may help identify those at greater risk of developing cardiovascular complications. Elevated cardiac biomarkers and emerging arrhythmias are associated with the development of severe disease and need for intensive care admission.[1103]

Prognosis: myocardial injury is associated with poor outcomes and survival. Elevated troponin predicts a poor outcome and higher risk of mortality.[1094] An overall case fatality rate of 9.6% has been reported.[1093] Infection may have longer-term implications for overall cardiovascular health.[1104]

acute kidney injury

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Acute kidney injury is common, particularly in critically ill patients. It can develop at any time before, during, or after hospital admission.[450]

Epidemiology: the pooled incidence of acute kidney injury has been estimated to be 19.45%; however, incidence varies across studies. Patients have a significantly increased risk of in-hospital mortality (54.2%).[1105] Independent risk factors included male sex, older age, smoking history, obesity, hypertension, diabetes, pneumopathy, cardiovascular disease, cancer, chronic kidney disease, mechanical ventilation, and use of vasopressors.[1106]

Aetiology: 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).[450]

Diagnosis: monitor patients for signs or symptoms suggestive of acute kidney injury, and proceed according to hospital protocols for diagnosis.

Management: follow local guidelines for managing acute kidney injury. Supportive measures and fluid management are required.[1105] Potassium binders may be used as options alongside standard care for the emergency management of acute life-threatening hyperkalaemia.[450] 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.[371]

Monitoring: monitor patients with chronic kidney disease for at least 2 years after acute kidney injury.[450]

post-COVID-19 syndrome (long COVID)

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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.[1107] The UK National Institute for Health and Care Excellence defines post-COVID-19 syndrome 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 term long COVID may be used to describe either of these case definitions.[1004] 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.[1108] The syndrome is not thought to be linked to disease severity during the acute phase of illness.[1004] 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.[1109] The neurological symptoms are similar to symptoms of other neurological conditions such as chronic fatigue syndrome and functional neurological disorder.[1110] Evidence from a cross-sectional analysis of a large, population-based cohort suggests that persistent physical symptoms after COVID-19 may be associated more with the belief in having been infected than with having laboratory-confirmed infection. Laboratory-confirmed infection was associated only with anosmia. Findings suggest that persistent physical symptoms after infection should not be automatically ascribed to COVID-19, but further research is required.[1111]

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.[1112][1113][1114] 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.[1115] In a systematic review, 54% of patients reported at least one symptom at 1 month, 55% of patients reported at least one symptom at 2 to 5 months, and 54% of patients reported at least one symptom at 6 months or longer.[1116] 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.[1117][1118] 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.[1119][1120] 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.[1121] Persistent symptoms have been reported in pregnant women and children, but appear to be less common in children compared with adults.[371][1122][1123] The frequency and characteristics of this syndrome are still under investigation in children and adolescents.[23]

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. After ruling out acute or life-threatening complications and alternative diagnoses, consider referring people to an appropriate service, such as an integrated multidisciplinary assessment service, any time from 4 weeks after the start of acute COVID‑19.[1004]

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, but are not limited to, 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, nasal congestion, impaired mobility, peripheral neuropathy, dizziness, tremors, memory loss, mood changes, skin rashes, hair loss, gastrointestinal symptoms, neurocognitive difficulties, sleep disturbances, delirium (older people), and mental health conditions (e.g., anxiety, depression, post-traumatic stress disorder). Children and older people may not have the most commonly reported symptoms. The following symptoms and signs are less commonly reported in children and younger people: dyspnoea; persistent cough; pain on breathing; palpitations; heart rate variations; chest pain.[371][1004][1124][1125] The most common symptoms at 1-year follow-up were fatigue, sweating, chest tightness, anxiety, and myalgia.[1126] 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.[1127]

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, B-type natriuretic peptide, glycosylated haemoglobin [HbA1c], thyroid function), oxygen saturation, blood pressure and heart rate measurements, exercise tolerance test, chest imaging, electrocardiogram, and psychiatric assessment.[371][1004][1124] Approximately 50% of patients had residual abnormalities on chest CT and pulmonary function tests at 3 months.[1128] 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.[1129]

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). There is a lack of evidence for pharmacological interventions to treat the condition. 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.[1004][1124] Consensus guidelines on the specific management of fatigue, breathing discomfort, and cognitive symptoms are also available from the American Academy of Physical Medicine and Rehabilitation.[1130]

Follow-up: recovery time differs but symptoms resolve by 12 weeks in most people. 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.[1004]

BMJ: long covid - mechanisms, risk factors, and management

Long covid" in primary care[Figure caption and citation for the preceding image starts]: Long covid" in primary careBMJ. 2020;370:m3026 [Citation ends].

acute liver injury

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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.[1131] 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.[1132]

Risk factors associated with severe liver injury include older age, pre-existing liver disease, and severe disease.[1133] Medications used in the treatment of COVID-19 (e.g., remdesivir, tocilizumab) may have a detrimental effect on liver injury.[1134] Guidelines on the management of liver derangement in patients with COVID-19 have been published.[1135]

neurological complications

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Neurological complications include acute cerebrovascular disease, impairment of consciousness, ataxia, seizures, status epilepticus, encephalopathy, encephalitis and meningoencephalitis, acute disseminated encephalomyelitis, corticospinal tract signs, demyelinating lesions, peripheral neuropathies, cerebral venous sinus thrombosis, myopathy, Guillain-Barre syndrome, dementia, and abnormal findings on brain magnetic resonance imaging.[1136]

Patients commonly have central or peripheral neurological complications, possibly due to viral invasion of the central nervous system, inflammatory response, or immune dysregulation.[1137] Neurological complications occur across the lifespan in the context of infection, with and without known comorbidities, and with all disease severities (including asymptomatic patients).[1138] Patients may present with these manifestations, or they may develop them during the course of the disease (usually 1 to 2 weeks after the onset of respiratory disease).[1139] Patients with pre-existing neurological disorders may develop an exacerbation of their neurological symptoms.[1140] Long-term sequelae may be possible.[1141]

Epidemiology: reported in 22% to 35% of patients. Central nervous system manifestations were more common than peripheral nervous system manifestations.[1136] Neurological involvement is common in children and adolescents (22% in patients aged <21 years).[1142]

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%).[1137] Patients with severe disease are at an increased risk of ischaemic stroke compared with patients with non-severe disease.[1143] Stroke is relatively frequent among hospitalised 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.[1144][1145] Stroke presents later in severe disease, and earlier in mild to moderate disease.[1146] 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.[1147] 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.[1148] Guidelines for the management of acute ischaemic stroke in patients with COVID-19 infection have been published.[1149]

Guillain-Barre syndrome: both post-infectious and pre-infectious patterns have been reported.[1137] The pooled prevalence among hospitalised and non-hospitalised patients was 0.15%.[1150] 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.[1151] 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).[1150]

Encephalitis: has been reported in <1% of patients overall, 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.[1152]

cardiac arrest

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In-hospital cardiac arrest is common in critically ill patients, 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.[1153]

Cardiac arrest with COVID-19[Figure caption and citation for the preceding image starts]: Cardiac arrest with COVID-19BMJ. 2020;371:m3513 [Citation ends].

pregnancy-related complications

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Pregnancy outcome is usually good, although there are little data on exposure during early pregnancy.[33] The risk for complications was higher in pregnant women who were symptomatic.[1154]

Maternal outcomes: 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.[31][32] A statistically significant higher risk of gestational diabetes, gestational hypertension, poor fetal growth, and pre-eclampsia was reported in pregnant women during the pandemic period compared with the pre-pandemic period.[1155]

Preterm birth: 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.[31][32]

Stillbirth and neonatal death: the overall rates of stillbirths and neonatal deaths do not seem to be higher than the background rates.[31][32][1156] 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.[1157] However, in the US, women with COVID-19 were at an increased risk for stillbirth compared with women without COVID-19 during the period of March 2020 to September 2021, with the magnitude of association being higher during the Delta variant predominance.[1158]

Neonatal infection: 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.[31][32][1159]

sepsis/septic shock

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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.[1160]

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.[371][720] Ultimately, patients who require fluid resuscitation or haemodynamic management of shock should be treated and managed identically to patients with septic shock.[371]

disseminated intravascular coagulation

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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.[1161] 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.[1162] COVID-19-associated coagulopathy appears to be distinct from DIC, although DIC has been reported in severely affected patients. The coagulation changes in COVID-19 patients mimic, but are not identical to, DIC, and the vast majority of patients do not meet the criteria for usual forms of DIC.[1163]

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.[1164]

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.[1165] In patients with heparin-induced thrombocytopenia (or a history of it), argatroban or bivalirudin are recommended.[1161]

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.[1164][783]

acute respiratory failure

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The leading cause of death is respiratory failure from acute respiratory distress syndrome.[1005] Children can quickly progress to respiratory failure.[1166] 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%.[1167]

cytokine release syndrome

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Some patients with severe disease have laboratory evidence of an unregulated inflammatory response similar to cytokine release syndrome, characterised by plasma leakage, increased vascular permeability, diffuse intravascular coagulation, and immunodeficiency. These patients have a poor prognosis. High serum levels of proinflammatory cytokines, particularly interleukin-6, have been identified in these patients. Features of secondary haemophagocytic lymphohistiocytosis may be present. Treatment options include interleukin-6 inhibitors (e.g., tocilizumab), Janus kinase inhibitors (e.g., baricitinib), and anakinra.[1168]

Also see Paediatric inflammatory multisystem syndrome, a cytokine release syndrome-like illness in children, below.

paediatric inflammatory multisystem syndrome (PIMS)

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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.

Definition: a rare but serious delayed complication that may develop in children and adolescents approximately 3 to 4 weeks (or longer) after the onset of acute infection, likely due to a post-infectious inflammatory process. The syndrome resembles, but is distinct from, Kawasaki disease, and also shares common features with toxic shock syndrome. It has a strong temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.[1169] The case definition generally includes the presence of fever, elevated inflammatory markers, multi-organ dysfunction, a history of a positive SARS-CoV-2 test (or close contact with a confirmed case), and no plausible alternative diagnosis. However, case definitions vary.[480][1170][1171]

Epidemiology: a systematic review 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.[1172] Factors associated with more severe outcomes included 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.[1173] Cases have been reported in neonates (temporally associated with antenatal exposure).[1174][1175]

Diagnosis: patients often have predominant cardiac dysfunction and gastrointestinal symptoms. The most common manifestations were fever (99%), gastrointestinal symptoms (87%), shock (66%), rash (59%), conjunctivitis (57%), cardiovascular manifestations (55%), oral mucosal changes (42%), respiratory symptoms (41%), neurological symptoms (36%), and coronary artery aneurysms (22%).[1172] The pooled prevalence of significant left ventricular dysfunction was 38%, coronary aneurysm or dilatation was 20%, and ECG abnormalities/cardiac arrhythmias was 28%.[1176] 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.[1177]

Investigations: inflammatory and cardiac markers were elevated in the majority of patients, and 38% had abnormal findings on chest x-ray.[1172] Raised serum troponin level was reported in 33% of patients, and raised pro B-type natriuretic peptide (proBNP)/BNP level was reported in 44% of patients.[1176]

Management: management is mainly supportive and involves a multidisciplinary team. Approximately 79% of patients required intensive care admission, 63% required inotropic support, 57% required anticoagulation, and 33% required mechanical ventilation.[1172] The optimal choice and combination of immunomodulating therapies have not been definitively established. The World Health Organization recommends corticosteroids in addition to supportive care (rather than either intravenous immunoglobulin plus supportive care, or supportive care alone) in hospitalised children aged 0 to 18 years who meet the standard case definition. It also recommends corticosteroids in addition to supportive care in those who meet both a standard case definition for MIS-C and diagnostic criteria for Kawasaki disease.[83] In the US, the National Institutes of Health guidelines panel recommends intravenous immunoglobulin and/or corticosteroids as first-line therapy, with interleukin-1 antagonists reserved for refractory cases.[371] Consult your local guidelines for further information.

Prognosis: the majority of patients had good outcomes with no significant medium- or long-term sequelae at 1-year follow-up.[1178] Follow-up 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.[1179] The mortality rate was 1.9%.[1172]

vaccine-induced immune thrombocytopenia and thrombosis (VITT)

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Also known as thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). Evidence on this syndrome is limited.

Definition: prothrombotic disorder of thrombosis with concurrent thrombocytopenia and development of antiplatelet factor 4 (anti-PF4) antibodies occurring after vaccination with an adenovirus vector-based COVID-19 vaccine (e.g., AstraZeneca, Janssen). Thrombosis occurs in uncommon sites (e.g., cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial thrombosis) and may be multifocal. The syndrome clinically resembles heparin-induced thrombocytopenia. The exact pathophysiology remains unknown, but there are several hypotheses. Can be rapidly progressive and fatal.[1180][1181] Cases have also been reported with mRNA vaccines, albeit more rarely.[386]

Epidemiology: observational data from the UK suggest the risk for a thrombotic event was highest in people aged <40 years, at 16.1 and 36.3 per million doses, respectively, for cerebral venous thrombosis or another thrombosis event, with the greatest elevated risk within 4 to 13 days after vaccination.[1182] Cases have been reported up to 48 days after vaccination.[1183]

Diagnosis: advise vaccine recipients who experience any severe symptoms from around 4 to 30 days after vaccination to seek urgent medical attention.[1184][1185] Approximately half of patients present with cerebral venous sinus thrombosis.[1186] Headache is the most common presenting symptom, and may precede VITT by several days.[1187][1188] Signs and symptoms 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.[1185] 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.[1185][1189][1190][1191][1192][1193]

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.[1185]

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.[1185][1189][1190][1191][1192][1193]

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.[1185]

Prognosis: mortality due to complications has been reported to be 39%.[1187] Fibrinogen levels, age, platelet count, and the presence of intracerebral haemorrhage or cerebral venous thrombosis are significantly associated with an increased risk of mortality.[1194]

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.

Examples of learned societies with treatment recommendations

aspergillosis

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COVID-19-associated aspergillosis (CAPA) may occur in people who are critically ill. It is a recognised cause of a patient’s clinical condition not improving despite treatment.[450]

Epidemiology: reported in 10.2% of patients admitted to the intensive care unit in one study.[1195] Risk factors include older age, chronic lung disease, intubation for more than 7 days, immunosuppression, and use of high-dose corticosteroids.[450][1196]

Diagnosis: consider diagnosis in patients who deteriorate despite optimal supportive care or who have other suspicious radiological or clinical features.[450][1196] There are no specific signs or symptoms. Base your decisions on individual risk factors and the person's clinical condition, and involve a multidisciplinary team (including an infectious disease specialist).[450] Refer to your local protocols on the diagnosis of CAPA.

Investigations: use a range of tests to increase the likelihood of a confident diagnosis; include bronchoalveolar lavage, if possible. Test for antifungal resistance if an Aspergillus isolate is cultured. Do not order tests if there is a low clinical suspicion.[450]

Management: antifungal therapy is recommended. Only use antifungal therapy if investigations support a diagnosis of CAPA, or CAPA is suspected but the results of investigations are not available yet. There is not enough evidence to recommend specific antifungals. Discuss treatment options with a multidisciplinary team (including an infectious disease specialist). Stop treatment if the results of investigations do not support the diagnosis.[450] Refer to your local protocols on the management of CAPA.

Prognosis: a mortality rate of 54.9% was reported in one study.[1195]

mucormycosis

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Mucormycosis (also known as 'black fungus') has been reported rarely, particularly in countries such as India.

Epidemiology: as of June 2021, 275 cases were reported globally, with 85% of cases reported in India. Cases in India increased significantly during its second wave in early 2021.[1197] Cases have been reported in other countries, including the US.[1198] Risk factors include male sex, uncontrolled diabetes, and immunosuppression (e.g., due to corticosteroid therapy).[1199][1200]

Diagnosis: have a low threshold of suspicion for 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.[1201] 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%).[1199] Cases of atypical-site mucormycosis have been reported, as well as cases in COVID-19 recovered patients.[1202][1203] Do not hesitate to aggressively order investigations as appropriate for detecting fungal aetiology.[1201]

Management: management strategies include: 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.[1201]

Prevention: 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.[1201]

Complications: rare cases of pulmonary artery pseudoaneurysm have been reported with COVID-19-associated pulmonary mucormycosis.[1204]

Prognosis: 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.[1197]

candidaemia

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The overall incidence of candidaemia ranges from 0.7% to 23.5%, with most cases occurring in the intensive care unit in mechanically ventilated patients.[1205] Cases of candidaemia due to Candida auris, an emerging multidrug-resistant pathogen, have been reported.[1206] Reasons for the increased incidence in this population are poorly understood; however, patients are exposed to multiple risk factors for candidaemia including corticosteroid therapy, immunosuppressive therapy, antibiotics, and long stays in the intensive care unit. A high mortality rate has been reported.[1207]

pancreatic injury

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Mild pancreatic injury (defined as elevated serum amylase or lipase levels) has been reported in 17% of patients in one case series.[1208] 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.[1209] Patients with acute pancreatitis had a high pooled mortality (18.5%) and significantly worse clinical outcomes.[1210] Prior history of pancreatitis does not appear to be a risk factor for pancreatic inflammation in patients with COVID-19.[1211]

immune thrombocytopenia

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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.[1212]

subacute thyroiditis

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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.[1213]

gastrointestinal complications

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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.[1214] In patients with acute mesenteric ischaemia, small-bowel ischaemia was the most prevalent finding on abdominal computed tomography, followed by ischaemic colitis. Non-occlusive mesenteric ischaemia was the most common pattern of bowel involvement.[1215]

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.[1216] Patients with intestinal ischaemia generally present with abdominal pain and vomiting. Management includes gastric decompression, fluids, haemodynamic support, and surgery.[1217]

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%.[1218] Risk factors for gastrointestinal haemorrhage in COVID-19 patients include history of gastrointestinal bleeding and anticoagulant use.[1219]

acute hair loss

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Acute telogen effluvium, a type of diffuse hair loss, has been reported in patients recovering from infection. The median age of patients was 44 years, and most patients were female. The mean duration from COVID-19 symptom onset to the appearance of telogen effluvium was 74 days. Most patients recovered; however, a minority of patients had persistent hair fall. Stress may be a contributing factor.[1220]

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