post-intensive care syndrome
Early reports suggest that COVID-19 patients treated in the intensive care unit can present with post-intensive care syndrome, a spectrum of psychiatric, cognitive, and/or physical disability (e.g., muscle weakness, cognitive dysfunction, insomnia, depression, anxiety, post-traumatic stress disorder, delirium, encephalopathy) that affects survivors of critical illness, and persists after the patient has been discharged from the intensive care unit. Weakness affects 33% of patients who receive mechanical ventilation, 50% of patients with sepsis, and <50% of patients who remain in the intensive care unit for more than 1 week. Cognitive dysfunction affects 30% to 80% of patients. The risk can be minimized with medication management, physical rehabilitation, family support, and follow-up clinics.
The pooled incidence of venous thromboembolism, deep vein thrombosis, and pulmonary embolism among hospitalized patients was 17%, 12%, and 7%, respectively. The incidence was higher in patients admitted to the intensive care unit. The pooled incidence was 10% in nonintensive care settings, and 28% in in intensive care settings. COVID-19 patients with thromboembolic events have 1.93 times the odds of dying compared with patients without venous thromboembolism.
Coagulopathy in COVID-19 has a prothrombotic character, which may explain reports of thromboembolic complications. Patients may be predisposed to venous thromboembolism due to the direct effects of COVID-19, or the indirect effects of infection (e.g., severe inflammatory response, critical illness, traditional risk factors). Thrombotic events may be due to cytokine storm, hypoxic injury, endothelial dysfunction, hypercoagulability, and/or increased platelet activity.
The risk factors with the most evidence for being predictive of venous thromboembolism are older age and elevated D-dimer levels. Patients with very high D-dimer levels have the greatest risk of thrombosis and may benefit from active monitoring.
If venous thromboembolism is suspected, perform a computed tomographic angiography or ultrasound of the venous system of the lower extremities.
Treat patients with a thromboembolic event (or who are highly suspected to have thromboembolic disease if imaging is not possible) with therapeutic doses of anticoagulant therapy as per the standard of care for patients without COVID-19. There are currently insufficient data to recommend either for or against using therapeutic doses of antithrombotic or thrombolytic agents for COVID-19. Patients who require extracorporeal membrane oxygenation or continuous renal replacement therapy, or who have thrombosis of catheters or extracorporeal filters, should be treated with antithrombotic therapy as per the standard institutional protocols for those without COVID-19.
Initial parenteral anticoagulation with a low molecular weight heparin or unfractionated heparin is preferred in acutely ill hospitalized patients; however, direct oral anticoagulants may be used provided there is no potential for drug-drug interactions (lead-in therapy with a parenteral anticoagulant is required for dabigatran and edoxaban). Warfarin can be used after overlap with initial parenteral anticoagulation. Parenteral anticoagulation with a low molecular weight heparin or fondaparinux is preferred over unfractionated heparin in critically ill patients. Direct oral anticoagulants are the preferred option in outpatients provided there is no potential for drug-drug interactions, with warfarin considered a suitable alternative. Anticoagulation therapy is recommended for a minimum of 3 months. Thrombolytic therapy is recommended in select patients with pulmonary embolism.
The American Society of Hematology has published draft guideline recommendations on the use of anticoagulation in patients with COVID-19.
A high incidence (14.7%) of asymptomatic deep vein thrombosis was reported in a cohort of patients with COVID-19 pneumonia. An autopsy study of 12 patients revealed deep vein thrombosis in 58% of patients in whom venous thromboembolism was not suspected before death. These studies highlight the importance of having a high suspicion for venous thromboembolism in patients who have signs of coagulopathy, including elevated D-dimer level.
While these patients are at higher risk of thrombotic events, they may also be at an elevated risk for bleeding. In a small retrospective study, 11% of patients at high risk of venous thromboembolism also had a high risk of bleeding.
Antiphospholipid antibodies and lupus anticoagulant have been detected in a small number of critically ill patients. The presence of these antibodies can rarely lead to thrombotic events in some patients (especially those who are genetically predisposed) that are difficult to differentiate from other causes of multifocal thrombosis. In other patients, antiphospholipid antibodies may be transient and disappear within a few weeks. The significance of this finding is unknown, although it is thought that these antibodies may not be involved in the pathogenesis of venous thromboembolism in patients with severe COVID-19. Anticoagulation should be considered in these patients.
It has been suggested that a new term (e.g., COVID-19-associated pulmonary thrombosis, diffuse pulmonary intravascular coagulopathy, or microvascular COVID-19 lung vessels obstructive thrombo-inflammatory syndrome [MicroCLOTS]) be used rather than the term pulmonary embolism as it has been hypothesized that the pathophysiology is different; local thrombi are formed in the lung vessels due to a local inflammatory process rather than the classical emboli coming from elsewhere in the body. However, this has not become accepted practice.
COVID-19 is associated with a high inflammatory burden that can result in cardiovascular complications with a variety of clinical presentations. Inflammation in the myocardium can result in myocarditis, heart failure, arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. These complications can occur on presentation or develop as the severity of illness worsens. It is uncertain to what extent acute systolic heart failure is mediated by myocarditis, cytokine storm, small vessel thrombotic complications, microvascular dysfunction, or a variant of stress-induced cardiomyopathy.
Myocardial injury has been reported in 20% of hospitalised patients. Factors associated with the development of myocardial injury include older age, male sex, and the presence of comorbidities. Cardiac injury was associated with higher risk of mortality, intensive care unit admission, mechanical ventilation, and developing coagulopathy.
Cardiovascular complications have been reported in 14.1% of patients during hospitalization, with an overall case fatality rate of 9.6%. Patients with preexisting cardiovascular comorbidities or risk factors are at higher risk for cardiovascular complications and mortality. Complications include arrhythmias or palpitations (18.4%), myocardial injury (10.3%), angina (10.2%), acute myocardial infarction (3.5%), and acute heart failure (2%). Cases of fulminant myocarditis, cardiac tamponade, cor pulmonale, takotsubo syndrome, and pericarditis have also been reported.
Elevated cardiac biomarkers and emerging arrhythmia are associated with the development of severe COVID-19 and the need for intensive care admission.
Prevalence of cardiac disease is high among patients who are severely or critically ill, and these patients usually require intensive care and have a poor prognosis and higher rate of in-hospital mortality. These patients are more likely to require noninvasive or invasive ventilation, and have a higher risk of thromboembolic events and septic shock compared with patients without a history of cardiac disease.
Perform an ECG and order high-sensitivity troponin I (hs-cTnI) or T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with symptoms or signs that suggest acute myocardial injury in order to make a diagnosis. Results should be considered in the clinical context.
Monitor blood pressure, heart rate, and fluid balance, and perform continuous ECG monitoring in all patients with suspected or confirmed acute myocardial injury.
There are limited data to recommend any specific drug treatments for these patients. Management should involve a multidisciplinary team including intensive care specialists, cardiologists, and infectious disease specialists. It is important to consider that drugs such as hydroxychloroquine and azithromycin may prolong the QT interval and lead to arrhythmias. Guidelines for the management of COVID-19-related myocarditis are available.
Infection may have longer-term implications for overall cardiovascular health; however, further research is required. A study of 100 patients who had recently recovered from COVID-19 found that cardiovascular magnetic resonance imaging revealed ongoing myocardial inflammation in 60% of patients, independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis.
acute kidney injury
The pooled incidence of acute kidney injury is 10.6%, which is higher than the incidence in hospitalized patients without COVID-19. Patients with acute kidney injury have a significantly increased risk of in-hospital mortality (odds ratio of 11.05). The mortality rate and incidence in patients in China was significantly lower than those in patients outside of China. Risk factors include older age ≥60 years, male sex, and severe infection.
In a small UK cohort, 29% of hospitalized children met the diagnostic criteria for acute kidney injury, with most cases occurring in children admitted to the intensive care unit and in those with pediatric inflammatory multisystem syndrome.
Can develop at any time before or during hospital admission. Causes include hemodynamic changes, hypovolemia, viral infection leading directly to kidney tubular injury, thrombotic vascular processes, glomerular pathology, or rhabdomyolysis. Direct kidney infection has been confirmed in an autopsy study of a single patient.
The European Medicines Agency has started a review of a safety signal to assess reports of acute kidney injury associated with the use of remdesivir in some patients. At this stage, it has not been determined whether there is a causal relationship between remdesivir and acute kidney injury.
Patients should meet criteria for acute kidney injury for diagnosis. NHS England: acute kidney injury (AKI) algorithm external link opens in a new window Perform a urinalysis for blood, protein, and glucose to help identify the underlying cause. Imaging is recommended if urinary tract obstruction is suspected.
Stop any drugs that can cause or worsen acute kidney injury, if possible. Aim to achieve optimal fluid status (euvolemia) in all patients. Consider a loop diuretic for treating fluid overload only. Manage hyperkalemia according to local protocols. See local protocols for guidance on renal replacement therapy.
Specialist input may be required in some cases (e.g., uncertainty about cause, abnormal urinalysis results, complex fluid management needs, indications for renal replacement therapy), and some patients may require critical care admission. Continuous renal replacement therapy (CRRT) is recommended in critically ill patients with acute kidney injury who develop indications for renal replacement therapy; prolonged intermittent renal replacement therapy is recommended over hemodialysis if CRRT is not available or possible.
Monitor fluid status daily, as well as serum blood urea nitrogen, creatinine, and electrolytes at least every 48 hours (or more often if clinically indicated). Monitor patients for the development of, or progression to, chronic kidney disease for at least 2 to 3 years after acute kidney injury.
acute liver injury
The pooled prevalence of hepatic manifestations on admission is: elevated alanine aminotransferase (26.6%); elevated aspartate aminotransferase (37.2%); decreased albumin (45.6%); and elevated total bilirubin (18.2%). The incidence of acute hepatic injury was higher in Chinese populations and groups with a higher prevalence of preexisting chronic liver disease; the incidence was similar in younger and older patients. Hepatic complications such as acute hepatic injury have been associated with an increased risk of severe disease and mortality. The prevalence of elevated aspartate aminotransferase was significantly higher in patients with severe disease (45.5%) compared with nonsevere cases (15%).
Risk factors associated with severe liver injury include older age, preexisting liver disease, and severe COVID-19.
Medications used in the treatment of COVID-19 (e.g., lopinavir/ritonavir) may have a detrimental effect on liver injury.
Guidelines on the management of liver derangement in patients with COVID-19 have been published.
Patients commonly have central or peripheral neurologic complications, possibly due to viral invasion of the central nervous system, inflammatory response, or immune dysregulation.
Neurologic manifestations have been reported in 4% to 57% of patients in large retrospective observational studies. Central nervous system manifestations were more common than peripheral nervous system manifestations. However, most studies included minor symptoms such as headache and dizziness, which are classified as symptoms of COVID-19 in this topic rather than complications. Neurologic complications are rare in children.
Neurologic complications include acute cerebrovascular disease, impairment of consciousness, ataxia, seizures, corticospinal tract signs, meningoencephalitis, encephalopathy, encephalomyelitis, peripheral demyelinating lesions, peripheral neuropathy, intracerebral hemorrhage, cerebral venous sinus thrombosis, myopathy, myasthenia gravis, Guillain-Barre syndrome and other neuropathies, and abnormal findings on brain magnetic resonance imaging.
Patients may present with these manifestations, or they may develop them during the course of the disease. Neurologic complications tend to develop 1 to 2 weeks after the onset of respiratory disease.
Acute cerebrovascular disease (including ischemic stroke, hemorrhagic stroke, cerebral venous thrombosis, and transient ischemic attack) has been reported in 0.5% to 5.9% of patients. The most common type was ischemic stroke (0.4% to 4.9%). Stroke is relatively frequent among hospitalized COVID-19 patients relative to other viral respiratory infections, and has a high risk of in-hospital mortality. Risk factors include older age and male sex. Median time from onset of COVID-19 symptoms to stroke was 8 days. Stroke presents later in severe disease, and earlier in mild to moderate disease. Ischemic stroke appears to be more severe and result in worse outcomes (severe disability) in patients with COVID-19, with the median NIH Stroke Scale score being higher among those with COVID-19 compared with those without. Guidelines for the management of acute ischemic stroke in patients with COVID-19 infection have been published.
Guillain-Barre syndrome has been reported. Both post-infectious and pre-infectious patterns have been reported. The mean age of patients was 55 years with a male predominance. Most patients had respiratory and/or severe symptoms of COVID-19, although it has also been reported in asymptomatic patients. A higher prevalence of the classic sensorimotor form and acute inflammatory demyelinating polyneuropathy have been reported, although rare variants have also been noted.
Patients with preexisting neurologic disorders may develop an exacerbation of their neurologic symptoms and severe COVID-19.
Patients may show cerebral changes on magnetic resonance imaging months after recovery, suggesting that long-term consequences may be possible.
post-COVID-19 syndrome (long COVID)
Definition: 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 syndrome is not thought to be linked to disease severity or specific signs and symptoms during the acute phase of illness. Protracted symptoms are common in many viral and bacterial infections.
Epidemiology: in a study in Italy, nearly 90% of hospitalized patients who recovered from COVID-19 reported persistence of at least one symptom 2 months after discharge. Only 12.6% of patients had no related symptoms, 32% had one or two symptoms, and 55% had three or more symptoms. Another study in the UK found that nearly 75% of patients who are discharged from hospital remain symptomatic at 3 months. A study in China found that at 6 months after acute infection, the most common persistent symptoms were fatigue or muscle weakness (63%), sleep difficulties (26%), and anxiety or depression (23%). Patients who were more severely ill had more severe impaired pulmonary diffusion capacities. Prolonged illness can occur among young adults with no underlying comorbidities. In a survey study of symptomatic adults, 35% had not returned to their usual state of health 2 to 3 weeks after testing. Among those ages 18 to 34 years with no underlying chronic medical conditions, 20% had not returned to their usual state of health. 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 nonhospitalized patients. Persistent symptoms have been reported in pregnant women and children, but appear to be less common in children compared with adults.
Diagnosis: use a holistic, person-centered 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 hypoxemia, signs of severe lung disease, cardiac chest pain, multisystem inflammatory syndrome in children) urgently to the relevant acute services.
Signs and symptoms: symptoms vary widely, may relapse and remit or fluctuate, can change unpredictably, and can occur in those with mild disease only. Common long-term symptoms include persistent cough, low-grade fever, breathlessness, fatigue, pain, chest pain/tightness, palpitations, myalgia, arthralgia, headaches, vision changes, hearing loss, earache, tinnitus, sore throat, loss of taste/smell, impaired mobility, numbness in extremities, dizziness, tremors, memory loss, mood changes, skin rashes, gastrointestinal symptoms, neurocognitive difficulties, sleep disturbances, delirium (older people), and mental health conditions (e.g., anxiety, depression). Some of the symptoms may overlap with post-intensive care syndrome (see above). The inability to return to normal activities, emotional and mental health outcomes, and financial loss are common.
Investigations: tailor investigations to the clinical presentation, and to rule out any acute or life-threatening complications and alternative diagnoses. Investigations may include blood tests (e.g., complete blood count, kidney and liver function tests, C-reactive protein, ferritin, thyroid function), oxygen saturation, blood pressure and heart rate measurements, exercise tolerance test, chest x-ray, electrocardiogram, and psychiatric assessment. Around 9% of patients had deteriorating chest x-ray appearances at follow-up, which may indicate lung fibrosis. Persistently elevated D-dimer and C-reactive protein have also been reported.
Management: give advice and information on self-management including ways to self-manage symptoms (e.g., set realistic goals, antipyretic for fever, breathing techniques for chronic cough, home pulse oximetry for monitoring breathlessness, pulmonary rehabilitation, staged return to exercise); who to contact if there is concern about symptoms or if there is need for support; sources of support (e.g., support groups, online forums); and how to get support from other services (e.g., social care, housing, financial support). A personalized, 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 neurologic symptoms that are new, persistent, or progressive.
Follow-up: agree with the patient how often follow-up and monitoring are needed (either in person or remotely), and which healthcare professionals should be involved. Take into account the patient’s level of need and the services involved. Tailor monitoring to the patient’s symptoms, and consider supported self-monitoring at home (e.g., heart rate, blood pressure, pulse oximetry). Be alert to symptoms that could require referral or investigation.
In-hospital cardiac arrest is common in critically ill patients with COVID-19, and is associated with poor survival, particularly among older patients. Among 5019 critically ill patients with COVID-19, 14% had an in-hospital cardiac arrest. Risk factors included older age, male sex, presence of comorbidities, and admission to a hospital with a smaller number of intensive care unit beds. Approximately 57% of patients received cardiopulmonary resuscitation. The most common rhythms at the time of resuscitation were pulseless electrical activity (49.8%) and asystole (23.8%). Of those who received resuscitation, 12% survived to hospital discharge with most of these patients being younger than 45 years of age.
Guidelines for the management of shock in critically ill patients with COVID-19 recommend a conservative fluid strategy (crystalloids preferred over colloids) and a vasoactive agent. Norepinephrine (noradrenaline) is the preferred first-line agent, with vasopressin or epinephrine (adrenaline) considered suitable alternatives. Vasopressin can be added to norepinephrine if target mean arterial pressure cannot be achieved with norepinephrine alone. Dopamine is only recommended as an alternative vasopressor in certain patients (e.g., those with a low risk of bradycardia or tachyarrhythmias). Dobutamine is recommended in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressors. Low-dose corticosteroid therapy is recommended for refractory shock.
disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is a manifestation of coagulation failure, and an intermediate link in the development of multi-organ failure. Patients may be at high risk of bleeding/hemorrhage or venous thromboembolism. Reported in 71% of nonsurvivors.
Coagulopathy manifests as elevated fibrinogen, elevated D-dimer, and minimal change in prothrombin time, partial thromboplastin time, and platelet count in the early stages of infection. Increasing interleukin-6 levels correlate with increasing fibrinogen levels. Coagulopathy appears to be related to severity of illness and the resultant thromboinflammation. Monitor D-dimer level closely.
Anticoagulant therapy with a low molecular weight heparin or unfractionated heparin has been associated with a better prognosis in patients with severe COVID-19 who have a sepsis-induced coagulopathy (SIC) score of ≥4 or a markedly elevated D-dimer level. In patients with heparin-induced thrombocytopenia (or a history of it), argatroban or bivalirudin are recommended.
Standard guidance for the management of bleeding manifestations associated with DIC or septic coagulopathy should be followed if bleeding occurs; however, bleeding manifestations without other associated factors is rare.
acute respiratory failure
Reported in 8% of patients in case series.
Leading cause of mortality in patients with COVID-19.
Children can quickly progress to respiratory failure.
cytokine release syndrome
Cytokine release syndrome may cause ARDS or multiple-organ dysfunction, which may lead to death. Elevated serum proinflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-2, interleukin-6, interleukin-8, interleukin-10, granulocyte-colony stimulating factor, monocyte chemoattractant protein 1) and inflammatory markers (e.g., C-reactive protein, serum ferritin) have been commonly reported in patients with severe COVID-19. This likely represents a type of virus-induced secondary hemophagocytic lymphohistiocytosis, which may be fatal. Interleukin-6, in particular, has been associated with severe COVID-19 and increased mortality.
One study found that patients who require admission to the intensive care unit have significantly higher levels of interleukin-6, interleukin-10, and tumor necrosis factor alpha, and fewer CD4+ and CD8+ T cells.
However, the pooled mean serum interleukin-6 level was markedly less in patients with severe or critical COVID-19 compared with patients with other disorders associated with elevated cytokines such as cytokine release syndrome, sepsis, and non-COVID-19-related ARDS. These findings question the role of cytokine storm in COVID-19-induced organ dysfunction, and further research is required.
Cytokine release syndrome has been reported in children, although cases appear to be rare. See the section below on pediatric inflammatory multisystem syndrome.
pediatric inflammatory multisystem syndrome
A rare, but severe condition, reported in children and adolescents approximately 2 to 4 weeks after the onset of COVID-19, likely due to a postinfectious inflammatory process. The syndrome has a strong temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Also known as PIMS, multisystem inflammatory syndrome in children (MIS-C), pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), as well as other variations.
The syndrome shares common features with Kawasaki disease and toxic shock syndrome, but case definitions vary. Most patients have fever, as well as features of shock, cardiac involvement (e.g., elevated cardiac markers, congestive heart failure, cardiac dysfunction, myocarditis, coronary artery dilatation or aneurysm, hypotension, pericardial effusion, mitral regurgitation), gastrointestinal symptoms (e.g., abdominal pain, vomiting, diarrhea), and significantly elevated inflammatory markers. Additional clinical and laboratory characteristics including thrombocytopenia, fatigue, headache, myalgia, sore throat, and lymphadenopathy have been suggested to refine the case definition. Mucocutaneous findings may be present, many of which overlap with Kawasaki disease.
Three types of clinical manifestations have been recognized: persistent fever and gastrointestinal symptoms (the most common type); shock with heart dysfunction; and symptoms coincident with the diagnostic criteria for Kawasaki disease.
A systematic review of 35 studies (783 cases) found that the median age of patients was 8.6 years of age, and 55% of patients were male. Comorbidities were reported in 20% of cases, with obesity being the most common. Cardiovascular symptoms (82% of patients were tachycardic and 61% were hypotensive) and gastrointestinal symptoms (71%) were prominent. Rashes were reported in 42% of patients. Respiratory symptoms were infrequent. The proportion of patients with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) or serology test result was 59%, and 41% had chest imaging abnormalities. Inflammatory markers were elevated in 83% of patients. Cardiac markers were also elevated in the majority of patients. Approximately 68% of patients required intensive care admission, 63% required inotropic support, and 28% of patients required respiratory support. The mortality rate was 1.5%.
In a multicenter observational study in the UK, 78 cases were reported across 21 pediatric intensive care units. The median age was 11 years and 67% were male. Children from minority ethnic backgrounds accounted for 78% of cases. Fever, shock, abdominal pain, vomiting, and diarrhea were the common presenting features. Around 36% had evidence of coronary artery abnormalities. In terms of treatment, 46% required invasive ventilation and 83% required vasopressor support.
The most common cardiovascular complications include shock, cardiac arrhythmias, pericardial effusion, and coronary artery dilatation.
Management is mainly supportive and involves a multidisciplinary team (pediatric infectious disease, cardiology, rheumatology, critical care). Patients are commonly managed with intravenous immune globulin, vasopressor support, corticosteroids, immune modulators, anticoagulation, antiplatelet therapy, and respiratory support. A national consensus management pathway from the UK is available. The American College of Rheumatology has published guidelines on the diagnosis and management of MIS-C.
While an association between this syndrome and COVID-19 seems plausible based on current evidence, the association is not definitive and further research is required. It is not clear yet whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or whether this is a different syndrome, although increasing evidence suggests that they are two separate syndromes. The syndrome appears to occur in children who have not manifested the early stages of COVID-19, but appears similar to the later phase of COVID-19 in adults. Immunologically, PIMS appears to be a distinct clinical entity from Kawasaki disease as neutrophilia and raised monocyte counts, features of Kawasaki disease, were not observed in one cohort.
Cases of COVID-19-associated Kawasaki-like multisystem inflammatory disease have been reported in adults.
Pregnancy outcome is usually good, although there are little data on exposure during early pregnancy. Risk factors for severe disease in pregnant women include preexisting comorbidities (e.g., chronic hypertension, diabetes), high maternal age, and high body mass index. Pregnant women are more likely to need intensive care unit admission and invasive ventilation, especially those with a preexisting comorbidity. Preterm birth is more common in pregnant women with COVID-19 compared with pregnant women without the disease. Cesarean delivery occurs in approximately 50% of cases, with the most common indication being severe maternal pneumonia or concern about sudden maternal decompensation. Perinatal deaths are rare, and occur in less than 1% of cases. Maternal morbidity is similar to that of women of reproductive age. Stillbirths have been reported. However, there is no evidence of an increase in stillbirths regionally or nationally during the pandemic in England when compared with the same months in the previous year and despite variable community infection rates in different regions.
Limited low-quality evidence suggests that the risk of infection in neonates is extremely low. Most infections are acquired in the postpartum period, although congenitally acquired infection has been reported. Unlike children who generally have asymptomatic infection, two-thirds of neonatal cases are symptomatic and a significant proportion require intensive care, although the overall prognosis appears to be excellent.
Invasive pulmonary aspergillosis has been reported in critically ill patients with moderate to severe ARDS. A prospective observational study found that one third of mechanically ventilated patients with COVID-19 had putative invasive pulmonary aspergillosis.
Intubation for more than 7 days may be a risk factor. Other potential risk factors include older age, chronic obstructive pulmonary disease, immunosuppression, critical illness, or use of high-dose corticosteroids. Consider aspergillosis in patients who deteriorate despite optimal supportive care or have other suspicious radiologic or clinical features.
Mild pancreatic injury (defined as elevated serum amylase or lipase levels) has been reported in 17% of patients in one case series. It is unknown whether this is a direct viral effect or due to the harmful immune response that occurs in some patients. Clinical acute pancreatitis has not been reported. Prior history of pancreatitis does not appear to be a risk factor for pancreatic inflammation in patients with COVID-19.
autoimmune hemolytic anemia
Warm or cold autoimmune hemolytic anemia (first episode) has been reported in 7 patients after the onset of COVID-19 symptoms and within the timeframe compatible with cytokine release syndrome. Four patients had indolent B lymphoid malignancy. It is unknown whether the hemolytic anemia is related to COVID-19 infection.
Immune thrombocytopenia has been reported rarely. The majority of cases were in patients >50 years of age, with only 7% of cases reported in children. The majority of cases were in patients with moderate to severe COVID-19; however, 7% of cases were in asymptomatic COVID-19 patients. Onset occurred in 20% of cases 3 weeks after the onset of COVID-19 symptoms, with most cases reported after clinical recovery. Severe life-threatening bleeding was uncommon. Treatment involved the use of corticosteroids, intravenous immune globulin, and thrombopoietin-receptor agonists.
Cases of subacute thyroiditis have been reported in patients with COVID-19 who require intensive care. The first known case of subacute thyroiditis was reported in an 18-year-old woman. Subacute thyroiditis is a thyroid disease of viral or post-viral origin.
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 ischemia. Macrovascular arterial/venous thrombosis has been identified in almost 50% of patients with bowel ischemia. Overall mortality in COVID-19 patients with gastrointestinal ischemia and radiologically evident mesenteric thrombotic occlusion was 38.7% and 40%, retrospectively.
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