Systemic and organ-specific immune-related manifestations of COVID-19

Abstract

Immune-related manifestations are increasingly recognized conditions in patients with COVID-19, with around 3,000 cases reported worldwide comprising more than 70 different systemic and organ-specific disorders. Although the inflammation caused by SARS-CoV-2 infection is predominantly centred on the respiratory system, some patients can develop an abnormal inflammatory reaction involving extrapulmonary tissues. The signs and symptoms associated with this excessive immune response are very diverse and can resemble some autoimmune or inflammatory diseases, with the clinical phenotype that is seemingly influenced by epidemiological factors such as age, sex or ethnicity. The severity of the manifestations is also very varied, ranging from benign and self-limiting features to life-threatening systemic syndromes. Little is known about the pathogenesis of these manifestations, and some tend to emerge within the first 2 weeks of SARS-CoV-2 infection, whereas others tend to appear in a late post-infectious stage or even in asymptomatic patients. As the body of evidence comprises predominantly case series and uncontrolled studies, diagnostic and therapeutic decision-making is unsurprisingly often based on the scarcely reported experience and expert opinion. Additional studies are required to learn about the mechanisms involved in the development of these manifestations and apply that knowledge to achieve early diagnosis and the most suitable therapy.

Fig. 1. Guiding signs and symptoms of suspected systemic immune-related disease in patients with COVID-19.

The two main systemic inflammatory syndromes associated with COVID-19, multisystem inflammatory syndrome in children (MIS-C) and haemophagocytic lymphohistiocytosis (HLH, including macrophage activation syndrome, MAS) are detailed at the top of the figure. The first sign prompting suspicion of these syndromes is persistent fever without a clear clinical source, together with multisystem organ involvement. The MIS-C phenotype includes Kawasaki disease-like features (conjunctivitis, red cracked lips, swollen hands and feet, and rash), coronary artery enlargement and/or aneurysms, gastrointestinal symptoms (abdominal pain, nausea, vomiting or diarrhoea) and neurological manifestations (headaches and meningitis). With respect to HLH and MAS, the cardinal features are enlarged lymphohaematopoietic organs (lymph nodes, spleen and/or liver) and severely abnormal values for multiple laboratory parameters suggesting involvement of multiple organs (such as severe cytopenia and liver and renal dysfunction). The main signs and symptoms of suspected systemic autoimmune and rheumatic diseases associated with COVID-19 are detailed at the bottom of the figure. Petechial and/or purpuric cutaneous lesions are the main signs prompting suspicion of vasculitis, and the addition of extracutaneous symptoms such as severe abdominal pain, haemoptysis or neurological features could indicate systemic vasculitis. In patients with thrombosis who have antiphospholipid (aPL) antibodies, fulfilment of the classification criteria for antiphospholipid syndrome (APS) should be ruled out. Severe myalgia in association with creatine kinase (CK) levels >10,000 U/l (concurrent with renal failure in some patients) are suggestive of myositis and/or rhabdomyolysis, whereas inflammation of several joints can follow different patterns including symmetric polyarthritis (resembling rheumatoid arthritis), oligoarticular arthritis with cutaneous lesions (resembling psoriatic arthritis) or axial involvement with enthesitis (resembling spondyloarthritis).

Fig. 2. Guiding signs and symptoms of suspected organ-specific immune-related diseases in patients with COVID-19.

The list of clinical symptoms is long, including important features such as dyspnoea (suggestive of interstitial lung disease (ILD) or organizing pneumonia), chest pain (myocarditis, pleuritis and pericarditis), severe acute upper abdominal pain with nausea and vomiting (acute pancreatitis) and neurological features such as confusion, seizures (encephalitis) or weakness with bladder dysfunction (myelitis and Guillain–Barré syndrome (GBS)). Examination is crucial when organ-specific immune-related disease is suspected in patients with COVID-19, paying special attention to eye redness (conjunctivitis and uveitis), jaundice (haemolytic anaemia), cutaneous lesions such as petechiae (immune thrombocytopenia (ITP)) or painful red inflammation on the hands or feet (chilblains), and glandular enlargement in the neck (thyroiditis). Simple laboratory tests such as haemography, biochemical analyses (measuring troponin, pancreatic enzymes, parameters of haemolysis, creatine kinase, haematuria and proteinuria) and determination of thyroid hormone levels could have an important role in diagnosis.

Fig. 3. Immune-related manifestations predominantly diagnosed during the first 2 weeks of COVID-19 (early features).

This figure illustrates the distribution of reported cases of immune-related manifestations predominantly diagnosed within 2 weeks of the onset of symptoms of acute COVID-19, as summarized in Table 3. The thickness of each segment corresponds to the proportion of cases reported in each time period (within the first 7 days of onset, between 8 and 14 days after, and 15 or more days after; the last period includes cases diagnosed in patients with asymptomatic infection). The bottom of the figure illustrates the representative positivity rate of the main microbiological tests from the first day of symptomatic infection; the intensity of colour corresponds to a higher rate of positive test results.

Fig. 4. Immune-related manifestations predominantly diagnosed after the first 2 weeks of COVID-19 (late features).

The top part of the figure illustrates the distribution of reported cases of immune-related manifestations predominantly diagnosed more than 2 weeks after the onset of symptoms of acute COVID-19, as summarized in Table 3. The thickness of each segment corresponds to the proportion of cases reported within each time period (the first 7 days, between 8 and 14 days after onset, and 15 or more days after onset; the last period includes cases reported in patients with asymptomatic SARS-CoV-2 infection). The bottom part of the figure illustrates the representative positivity rate of the main microbiological tests from the first day of symptomatic infection; the intensity of colour corresponds to a higher rate of positive test results. MIS-C, multisystem inflammatory syndrome in children.

Fig. 5. Time-dependent clinical scenarios in patients with symptomatic SARS-CoV-2 infection.

a | Acute infection. The mean duration of symptoms in patients with symptomatic SARS-CoV-2 infection has been reported as ~11 days^,, and as long as 13–28 days in patients with COVID-19 requiring hospitalization^,,–. Complete recovery is reported in >85% of patients 4 weeks after the onset of symptoms. b | Immune-related manifestations of COVID-19. Most immune-related COVID-19 manifestations are diagnosed during the first 4–6 weeks after symptom onset. Some immune-related manifestations tend to appear during the first 2 weeks of infection (early immune-related features of COVID-19), whereas others tend to emerge in a late post-infectious stage or even in asymptomatic patients (late immune-related features of COVID-19). c | Post-COVID-19 sequelae. Symptoms related to organ-specific sequelae caused by the viral infection — affecting internal organs such as the lungs (interstitial lung disease in patients with severe pneumonia), the heart (chronic heart failure in patients with myocarditis) or the kidneys (chronic renal failure in patients with glomerulonephritis) — can emerge after resolution of the acute infection. d | Long COVID. One or more of the symptoms related to the acute viral infection, such as fatigue, pain, chills, anosmia, dysgeusia or headaches (as the most frequently reported), can persist for more than 12 weeks, a situation often referred to as ‘long COVID’. These symptoms can affect any bodily system, are not explained by an alternative diagnosis and, in some patients, may follow a relapsing–remitting pattern, possibly fluctuating and changing over time.