Coronavirus disease 2019 (COVID-19)
Complications
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. The risk can be minimised with medication management, physical rehabilitation, family support, and follow-up clinics. Physical, mental, or cognitive symptoms were reported frequently in patients who survived 1 year following intensive care unit.[946]
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.[947] 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).[948]
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.[949] Thromboembolic events are rare in children.[950] The risk factors with the most evidence for being predictive of venous thromboembolism are older age and elevated D-dimer levels.[951] Male sex, obesity, mechanical ventilation, intensive care unit admission, severe parenchymal abnormalities, and elevated white blood cells have also been identified as risk factors.[952] The cumulative incidence of acute pulmonary embolism and deep vein thrombosis among recovered patients after hospital discharge was 1.2% and 2.3%, respectively, much lower compared with the in-hospital incidence.[953] Non-hospitalised patients may also be at increased risk of thromboembolic events.[954]
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.[955][956] 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).[957] Thrombotic events may be due to cytokine storm, hypoxic injury, endothelial dysfunction, hypercoagulability, and/or increased platelet activity.[958]
Diagnosis: monitor patients for signs or symptoms suggestive of venous or arterial thromboembolism, and proceed according to hospital protocols for diagnosis.[85] Admission D-dimer level has been associated with venous thromboembolism diagnosis during hospitalisation; however, there are no optimal thresholds to guide prophylaxis measures.[959] Evaluate hospitalised patients who experience rapid deterioration of pulmonary, cardiac, or neurological function, or sudden localised loss of peripheral perfusion for thromboembolic disease.
Management: treat patients with a thromboembolic event (or who are highly suspected to have thromboembolic disease if imaging is not possible) with therapeutic anticoagulation. Follow your local institutional protocols.
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.[619][620]
Prognosis: patients with thromboembolic events have 1.93 times the odds of dying compared with patients without venous thromboembolism.[960]
Also see Disseminated intravascular coagulation below.
Cardiovascular complications include arrhythmias, myocardial injury, acute coronary syndrome, and heart failure.[961] While acute infection was associated with a six-fold increase in cardiovascular diagnoses overall, the risk began to decline 5 weeks after infection and returned to baseline levels or below from 12 weeks to 1 year.[962]
Epidemiology: cardiovascular complications have been reported in 14.1% of patients during hospitalisation.[961] The overall pooled incidence of acute myocardial infarction, heart failure, arrhythmias, cardiac arrest, and acute coronary syndrome were 21%, 14%, 16%, 3.45%, and 1.3%, respectively.[963] Higher rates of myocardial injury have been reported in the US (9% to 52%) compared with China (7% to 28%).[964] A Cochrane review found that the most common cardiovascular complications were arrhythmias, heart failure, and arterial and venous occlusive events.[175] More rarely, cases of fulminant myocarditis, pericarditis, cardiac tamponade, cor pulmonale, and takotsubo syndrome have been reported.[965] Risk factors include older age, hypertension, underlying cardiovascular disease, and chronic kidney disease.[964]
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.[966][967]
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.[401]
Management: seek specialist cardiology advice on treatment and follow local treatment protocols.[401] Management of arrhythmias should be based on current guidelines for the respective arrhythmia.[968] 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.[969]
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.[401] 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.[970]
Prognosis: myocardial injury is associated with poor outcomes and survival. Elevated troponin predicts a poor outcome and higher risk of mortality.[964] An overall case fatality rate of 9.6% has been reported.[961] Infection may have longer-term implications for overall cardiovascular health.[971] Cardiovascular problems have been reported up to 1 year after infection, including in those who were not hospitalised for the acute infection.[972]
Acute kidney injury is common, particularly in critically ill patients. It can develop at any time before, during, or after hospital admission.[401] The risk in critically ill patients with COVID-19 appears to be lower compared with patients with influenza.[973]
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%).[974] 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.[975]
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).[401]
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.[974] Potassium binders may be used as options alongside standard care for the emergency management of acute life-threatening hyperkalaemia.[401] Renal replacement therapy may be required.
Monitoring: monitor patients with chronic kidney disease for at least 2 years after acute kidney injury.[401]
Protracted symptoms are common after many viral and bacterial infections, including SARS-CoV-2 infection.[976] Case definitions vary, but the World Health Organization defines long COVID as a condition that occurs in adults 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.[977]
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 may include persistent cough, low-grade fever, breathlessness, fatigue, chest pain/tightness, palpitations, myalgia, arthralgia, headaches, vision changes, hearing loss, tinnitus, sore throat, loss of taste/smell, peripheral neuropathy, dizziness, tremors, mood changes, skin rashes, hair loss, sexual dysfunction, gastrointestinal symptoms, neurocognitive difficulties, sleep disturbances, delirium (older people), and mental health conditions.[978][979][980] The most common symptoms at 1-year follow-up were fatigue, sweating, chest tightness, anxiety, and myalgia.[981] Tailor investigations to the clinical presentation, and to rule out any acute or life-threatening complications and alternative diagnoses.
There is a lack of evidence for pharmacological interventions. A personalised, multidisciplinary rehabilitation plan that covers physical, psychological, and psychiatric aspects of rehabilitation is an important part of management. Give advice and information on self-management including ways to self-manage symptoms. Referral to a specialist may be required in patients where there is clinical concern.[979] The World Health Organization makes several recommendations for the rehabilitation of adults with post-COVID-19 syndrome.[85] Patients should be monitored closely during treatment. Recovery time differs, but symptoms typically resolve by 12 weeks in most people.
Myocarditis or pericarditis may occur following vaccination with mRNA vaccines.[982] It has been postulated that mRNA vaccines may increase inflammation on the endothelium and T-cell infiltration of cardiac muscle, but further research is required as various mechanisms have been hypothesised.[983][984] There is a high likelihood of a causal link, based on autopsy studies.[985] Cases have also been reported with adenovirus vector vaccines and protein subunit vaccines, albeit more rarely.[986][987]
Epidemiology: the incidence of myocarditis may be as high as 140 cases per million doses depending on age and sex. Male adolescents and young adults are at the highest risk; the incidence is highest in males aged 12 to 29 years. Myocarditis is more likely with the Moderna vaccine compared with the Pfizer/BioNTech vaccine, and is more likely after the second dose (data for incidence rates after a third dose are limited, although the manufacturer states that the risk profile is similar after the second and third doses). On average, symptom onset was 2 to 4 days after the vaccine dose, although intervals of up to 20 days (or longer) have been reported. Incidence after the second dose may be lower when administered ≥31 days after the first dose compared with ≤30 days among younger age groups. For pericarditis, data were limited but more variation than myocarditis has been reported in patient age, sex, onset timing, and rate of admission to hospital.[984] Preliminary real-world data has not picked up an increased risk of myocarditis in children ages 5-11 years as yet.[988][989] Reported rates in immunocompromised people were similar to the general population.[990] Vaccinated individuals were twice as likely to develop myocarditis/pericarditis in the absence of SARS-CoV-2 infection compared with unvaccinated individuals within a 30-day follow-up period.[991]
Diagnosis: consider the diagnosis in children, adolescents, or adults with new-onset and unexplained significant chest pain, tachycardia or tachypnoea, dyspnoea, palpitations, dizziness or syncope, or general clinical concern, within 10 days of vaccination (note: patients may also present >10 days after vaccination).[992] The most common presenting symptom was chest pain (34.5%).[993]
Investigations: order a 12-lead ECG, inflammatory blood markers, full blood count, and troponin. If ECG or troponin are abnormal, discuss the management plan with the cardiology team. Further investigations (e.g., cardiac imaging and rhythm monitoring) and follow-up should be led by the cardiology team.[992] The most common findings were ST-related changes on an electrocardiogram (58.7%) and hypokinesia on cardiac magnetic resonance imaging or echocardiography (50.7%). Laboratory findings included elevated troponin I levels (81.7%) and elevated C-reactive protein (71.5%).[993]
Management: strenuous physical activity should be avoided until symptoms improve.[992] Patients should be referred to a cardiologist as management depends on the clinical presentation.
Prognosis: up to 93% of adolescents and young adults required hospital admission, with intensive care unit admission required in up to 25% of patients. Median interval from onset to approval for all physical activity was 98 days. Approximately 81% of patients who completed a follow-up healthcare provider survey were considered recovered at follow-up at least 90 days since onset. However, approximately half of patients continued to self-report symptoms (e.g., chest pain), and 25% were prescribed daily cardiac medications.[994] Severe and potentially fatal myocarditis was reported in 19.8% of all vaccine-related myocarditis cases in one Korean nationwide study, with some patients requiring intensive care unit admission, extracorporeal membrane oxygenation therapy, and heart transplant.[995]
Consult your local public health authority for guidance on administering further doses of a COVID-19 vaccine. Some countries have implemented age-related prescribing restrictions for mRNA vaccines due to the risk of myocarditis/pericarditis. Modifying mRNA vaccine programmes to incorporate age-based product considerations and longer interdose intervals may reduce the risk of myocarditis/pericarditis.[996]
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.[997] Abnormal liver function tests are associated with significantly higher mortality, intensive care unit admission, and mechanical ventilation requirements.[998] 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.[999]
Risk factors associated with severe liver injury include older age, pre-existing liver disease, and severe disease.[1000] Medications used in the treatment of COVID-19 (e.g., remdesivir, tocilizumab) may have a detrimental effect on liver injury.[1001] Guidelines on the management of liver derangement in patients with COVID-19 have been published.[1002]
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, parkinsonism, cerebral venous sinus thrombosis, myopathy, Guillain-Barre syndrome, dementia, and abnormal findings on brain magnetic resonance imaging.[1003][1004] Burning mouth syndrome and burning eye syndrome have been reported.[1005]
Patients commonly have central or peripheral neurological complications, possibly due to viral invasion of the central nervous system, inflammatory response, or immune dysregulation.[1006] Neurological complications occur across the lifespan in the context of infection, with and without known comorbidities, and with all disease severities (including asymptomatic patients).[1007] 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).[1008] Patients with pre-existing neurological disorders may develop an exacerbation of their neurological symptoms.[1009] Long-term sequelae may be possible.[1010][1011]
Epidemiology: reported in 22% to 35% of patients. Central nervous system manifestations were more common than peripheral nervous system manifestations.[1003] Neurological involvement is common in children and adolescents (22% in patients aged <21 years).[1012]
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%).[1006] However, the overall absolute incidence of stroke in inpatients has been reported as 0.175%, lower than that reported in previous observational studies.[1013] Patients with severe disease are at an increased risk of ischaemic stroke compared with patients with non-severe disease.[1014] 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.[1015][1016] Stroke presents later in severe disease, and earlier in mild to moderate disease.[1017] 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.[1018] 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.[1019] Guidelines for the management of acute ischaemic stroke in patients with COVID-19 infection have been published.[1020]
Guillain-Barre syndrome: both post-infectious and pre-infectious patterns have been reported.[1006] The pooled prevalence among hospitalised and non-hospitalised patients was 0.15%.[1021] 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.[1022] Patients had an increased odds for demyelinating subtypes. Clinical outcomes were comparable to those for contemporary or historical controls not infected with SARS-CoV-2.[1021] Guillain-Barre syndrome has also been associated with the administration of COVID-19 vaccines.[1023]
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.[1024] Rare cases of autoimmune encephalitis have been reported.[1025]
The key to the management of neurological complications is a detailed history and examination, together with the appropriate interpretation of laboratory and radiological data. In most cases, management of these conditions should follow pre-COVID-19 guidance.[1026]
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.[1027]
[Figure caption and citation for the preceding image starts]: Cardiac arrest with COVID-19BMJ. 2020;371:m3513 [Citation ends].
Pregnancy outcome is usually good, although there are little data on exposure during early pregnancy.[221] The risk for complications was higher in pregnant women who were symptomatic.[1028] The risk of maternal and neonatal complications appeared to be substantially less during the Omicron-dominant period compared with the pre-Omicron period.[1029] Lower-income countries have reported higher rates of maternal intensive care unit admission and mortality, and stillbirths, compared with higher-income countries.[1030]
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.[219][220][1031] 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.[1032]
Miscarriage: there is no evidence that infection in the first or second trimesters increases the risk of miscarriage. However, further research is required.[1033]
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.[219][220][1031]
Stillbirth and neonatal death: the overall rates of stillbirths and neonatal deaths do not appear to be higher than the background rates.[219][220][1034][1035] However, data are conflicting. In England, there was 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.[1036] 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.[1037] A Scandinavian registry study also found an increased risk of stillbirth after 22 weeks’ gestation, particularly in women infected with the Delta variant.[1038] An individual participant data meta-analysis found no link between infection during pregnancy with an increased risk of stillbirth at or beyond 28 weeks’ gestation or with intrauterine growth restriction.[1039] Another meta-analysis found an increased risk of stillbirth.[1040]
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.[219][220][1031][1041][1042]
Neonatal outcomes: there is limited and conflicting evidence of an increased risk of short- or long-term neonatal morbidity (e.g., respiratory disease), and further research is required.[1035] There is some evidence that maternal infection and perinatal transmission has the potential to affect the auditory system of the newborn, especially during the second and third trimester of pregnancy. However, data are limited and inconsistent and further research is required.[1043] A Nordic registry-based study found infection during the first trimester was not associated with a risk of major congenital anomalies among infants.[1044]
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.[1045]
Guidelines for the management of shock in critically ill patients with COVID-19 recommend a conservative fluid strategy and a vasoactive agent. Noradrenaline (norepinephrine) is the preferred first-line agent in adults (adrenaline [epinephrine] or noradrenaline may be used in children). Vasopressin or adrenaline (epinephrine) can be added to noradrenaline in adults if target mean arterial pressure cannot be achieved with noradrenaline alone.[696] Consult your local guidelines for more information.
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.[1046] 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.[1047] 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.[1048]
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.[1049]
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.[1050] In patients with heparin-induced thrombocytopenia (or a history of it), argatroban or bivalirudin are recommended.[1046]
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.[1049][1051]
The leading cause of death is respiratory failure from acute respiratory distress syndrome.[865] The overall pooled prevalence of COVID-19-induced acute respiratory distress syndrome was 32% globally.[1052] Children can quickly progress to respiratory failure.[1053] 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%.[1054]
Air leak (pneumothorax, pneumomediastinum, and subcutaneous emphysema) is associated with higher mortality and longer hospital stay, especially in older people, and can occur even without positive pressure ventilation. It is mainly due to disease progression resulting in inflammatory insult to lung parenchyma and ventilatory stress-induced alveolar damage. The incidence varies widely across studies and increases with disease severity. The mean age of patients was 58 years and 75% were male. Hypertension was the most common comorbidity, followed by diabetes. Isolated pneumothorax was the most common type of air leak (48.5%), with 17% of patients developing a spontaneous pneumothorax. Mortality was 40%. Further research is required.[1055]
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.[1056]
Also see Paediatric inflammatory multisystem syndrome, a cytokine release syndrome-like illness in children, below.
Also known as paediatric inflammatory multisystem syndrome (PIMS), paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), as well as other variations. Multisystem inflammatory syndrome in adults (MIS-A) has also been reported, albeit more rarely.[1057]
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 SARS-CoV-2 infection.[1058] 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.[432][1059] Can occur rarely after COVID-19 vaccination.[1060][1061]
Epidemiology: the risk of MIS-C within 2 months of confirmed infection was 0.05% in one Danish cohort study.[1062] The risk decreased in the second year of the pandemic and decreased with evolution of the SARS-CoV-2 variant.[1063] MIS-C continued to occur in 2023, but at low rates compared with early in the pandemic.[1064] A systematic review found that the median age of patients was 7.8 years of age, and 60% of patients were male. Obesity was the most common comorbidity, followed by respiratory diseases, prematurity, and asthma.[1065] Risk factors for developing MIS-C include male sex, age 5 to 11 years, foreign-born parents, asthma, obesity, and life-limiting conditions.[1066] 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.[1067] Cases have been reported rarely in neonates (temporally associated with antenatal exposure), and there may be a higher risk of mortality in neonates compared with older children.[1068] There appears to be a lower risk of MIS-C with the Omicron variant.[1069]
Diagnosis: patients often have predominant cardiac dysfunction and gastrointestinal symptoms. The most common manifestations were fever (99%), gastrointestinal symptoms (77%), and dermatological symptoms (63%).[1065] The pooled prevalence of significant left ventricular dysfunction was 38%, coronary aneurysm or dilatation was 20%, and ECG abnormalities/cardiac arrhythmias was 28%.[1070] Neonates commonly present with cardiorespiratory compromise.[1068] Approximately 20% of children develop acute kidney injury.[1071] 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.[1072] Patients with MIS-C presented more frequently with respiratory and gastrointestinal symptoms and shock compared with patients with Kawasaki disease; however, they had a lower incidence of conjunctivitis.[1073] Disease may be less severe after infection with the Omicron variant compared with the Alpha and Delta variants.[1074]
Investigations: inflammatory, coagulation, and cardiac markers were elevated in the majority of patients.[1065] 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.[1070]
Management: management is mainly supportive and involves a multidisciplinary team. Approximately 53% of patients required intensive care admission.[1065] 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.[85] In the US, the Infectious Diseases Society of America recommends initial therapy with intravenous immunoglobulin and/or a corticosteroid. Anakinra, tocilizumab, or infliximab may be used in refractory cases.[398] Guidance has also been published by the American College of Rheumatology.[1075] 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.[1076] 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.[1077] The mortality rate was 3.9%.[1065]
Future COVID-19 vaccination: there are limited data on the safety of COVID-19 vaccines in people who have had MIS-C or MIS-A and who have not yet received a vaccine. A history of MIS-C or MIS-A may be a precaution for vaccination. Consult your local guidelines for more information.
VITT is also known as thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). Adenovirus-vector vaccines, the cause of VITT, are no longer available in most countries.
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. 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.[1078][1079] Cases have also been reported with mRNA vaccines, albeit more rarely.[1080][1081][1082]
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.[1083] In the US, the overall risk with the Janssen vaccine was estimated to be 3.83 cases per million people who received the vaccine, with the reporting rate highest among women aged 30 to 39 years (10.6 cases per million doses) and 40 to 49 years (9.02 cases per million doses), and a case fatality rate of 15%.[1084] Cases have been reported up to 48 days after vaccination.[1085]
Diagnosis: advise adenovirus-vector vaccine recipients who experience any severe symptoms from around 4 to 20 days (or longer) after vaccination to seek urgent medical attention.[1086] Approximately half of patients present with cerebral venous sinus thrombosis.[1087] Headache is the most common presenting symptom, and may precede VITT by several days.[1088][1089] Patients may rarely present with ischaemic stroke.[1090][1091] 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 42 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 signs and 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.[1092][1093][1094][1095]
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.
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 (other than emergency situations), heparin (including heparin flushing solution), low molecular weight heparin, and vitamin K antagonists (e.g., warfarin). Heparin may be used if non-heparin-based anticoagulants are not available. Consider plasma exchange, fibrinogen replacement, or rituximab in select patients. Some patients may require surgery to treat thrombosis.[1092][1093][1094][1095][1096]
Prognosis: mortality due to complications has been reported to be 39%.[1088] Fibrinogen levels, age, platelet count, and the presence of intracerebral haemorrhage or cerebral venous thrombosis are significantly associated with an increased risk of mortality.[1097] Consult local guidelines for advice on further vaccination after an episode of VITT.
Thromboembolic events that are distinct from VITT may occur after vaccination with any COVID-19 vaccine, but most commonly occur after vaccination with adenovirus-vector vaccines. Venous thrombosis was more common than arterial thrombosis. Cerebral venous thrombosis was the most common manifestation in patients with venous thrombosis, followed by deep vein thrombosis. Myocardial infarction was common in patients with arterial thrombosis, followed by ischaemic stroke.[1098] Adenovirus-vector vaccines may be associated with an increased incidence of pulmonary embolism and myocardial infarction in the second week after vaccination.[1099]
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.[401]
Epidemiology: reported in 10.2% of patients admitted to the intensive care unit in one study.[1100] Risk factors include older age, chronic lung disease (including pre-existing COPD), chronic liver disease, haematological malignancies, cerebrovascular disease, renal replacement therapy, mechanical ventilation, immunosuppression, receipt of interleukin-6 inhibitors, and use of high-dose corticosteroids.[401][1101][1102][1103]
Diagnosis: consider diagnosis in patients who deteriorate despite optimal supportive care or who have other suspicious radiological or clinical features.[401][1101] 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).[401] Frequently manifests as COVID-19 pneumonia without the common computed tomography scan abnormalities of pulmonary aspergillosis.[1104] 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.[401]
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.[401] Refer to your local protocols on the management of CAPA.
Prognosis: a mortality rate of approximately 55% has been reported.[1100][1102]
Mucormycosis (also known as 'black fungus') has been reported rarely, particularly in low- and middle-income countries, predominantly India.[1105] COVID-19-associated pulmonary mucormycosis is diagnosed either simultaneously with, or within 3 months of, virologically confirmed COVID-19. Case definitions for proven, probable, or possible pulmonary disease have been published. Co-infection with aspergillosis is possible.[1106]
Epidemiology: approximately 88% of cases were reported from low- or middle-income countries.[1107] Cases in India increased significantly during its second wave in early 2021.[1108] Cases have been reported in other countries, including the US.[1109] Risk factors include male sex, uncontrolled diabetes, and immunosuppression (e.g., due to corticosteroid therapy).[1110][1111]
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.[1112] 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%).[1110] Cases of atypical-site mucormycosis have been reported, as well as cases in COVID-19 recovered patients.[1113][1114] Do not hesitate to aggressively order investigations as appropriate for detecting fungal aetiology.[1112] Flexible bronchoscopy and chest imaging are recommended to enable early diagnosis of pulmonary mucormycosis.[1106]
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 initial therapy, followed by posaconazole or isavuconazole maintenance therapy or salvage therapy) 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.[1106][1112]
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.[1112]
Complications: rare cases of pulmonary artery pseudoaneurysm have been reported with COVID-19-associated pulmonary mucormycosis.[1115]
Prognosis: overall mortality rate has been reported to be 39%.[1107] The 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.[1108] Risk factors for increased mortality includes older age, specific comorbidities, aspergillus co-infection, and use of tocilizumab.[1107] A significant proportion of survivors had life-changing morbidities (e.g., vision loss).[1105] Patients with pulmonary and rhino-orbito-cerebral mucormycosis and those who receive medical treatment only are at increased risk for mortality.[1116]
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.[1117] Cases of candidaemia due to Candida auris, an emerging multidrug-resistant pathogen, have been reported.[1118] 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.[1119]
Mild pancreatic injury (defined as elevated serum amylase or lipase levels) has been reported in 17% of patients in one case series.[1120] 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.[1121] Patients with acute pancreatitis had a high pooled mortality (18.5%) and significantly worse clinical outcomes.[1122] The most common presenting symptom was abdominal pain.[1123] Prior history of pancreatitis does not appear to be a risk factor for pancreatic inflammation in patients with COVID-19.[1124] A causal relationship between SARS-CoV-2 infection and acute pancreatitis has not been established.[1125]
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.[1126]
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, based on case reports and case studies.[1127][1128] 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.[1129]
COVID-19 may also cause autoimmune thyroid disease or exacerbate underlying thyroid disease in remission. Cases of Grave's disease, Hashimoto's thyroiditis, and postnatal thyroiditis have been reported.[1130]
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.[1131] 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.[1132]
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.[1133] Patients with intestinal ischaemia generally present with abdominal pain and vomiting. Management includes gastric decompression, fluids, haemodynamic support, and surgery.[1134]
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%.[1135] Risk factors for gastrointestinal haemorrhage in COVID-19 patients include history of gastrointestinal bleeding and anticoagulant use.[1136]
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.[1137] Cases of new-onset alopecia areata, as well as recurrences or exacerbations, have also been reported after infection.[1138]
There is emerging evidence that patients may rarely have signs, symptoms, and radiological and laboratory features indicative of involvement of the lower urinary tract and male genital system. This may include scrotal discomfort, swelling, or pain (acute orchitis, epididymitis, or epididymo-orchitis); low-flow priapism; impaired spermatogenesis (including decreased sperm count, sperm concentration, sperm motility, and normal sperm morphology; decreased circulating testosterone level); bladder haemorrhage; acute urinary retention; and worsening of existing lower urinary tract symptoms (including exacerbation of benign prostatic hyperplasia). Semen parameters appear to return to normal as patients recover. Further research is required.[1139][1140][1141][1142][1143][1144]
Parosmia (misperception of an odour) is a late-onset symptom that may develop approximately 3 months after infection. It may occur without any preceding apparent smell loss, or it may follow a short recovery period from initial anosmia. There are no effective, evidence-based treatments available; however, the patient should be offered useful tips on living with parosmia until recovery.[576]
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