Recently, the Diagnostic and Statistical Manual of Mental Disorders by the American Psychiatric Association marked a break in the consensus that previously seemed to apply to the concept of hysteria and approach to the clinical manifestations. The clinical manifestations of hysteria are numerous and multifaceted, comprising 3 main classifications: paroxysms, attacks, and acute manifestations; long-lasting functional syndromes, and visceral events.
Each main classification can be subdivided into several subgroups. The first main group of paroxysms, attacks, and acute manifestations includes major hysterical attacks, such as prodrome, trance and epileptic states, minor hysterical attacks such as syncope and tetany, twilight states, paroxysmal amnesia, and cataleptic attacks. In contrast to the above-mentioned systemic presentations that can involve multiple organs, some patients with COVID present with immune-related manifestations involving a single organ, which can mimic a wide range of organ-specific autoimmune diseases Table 2 , Fig.
Examination is crucial when organ-specific immune-related disease is suspected in patients with COVID, 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. Symptoms of cutaneous involvement can affect 0. For maculopapular and urticarial lesions, a predominant drug-induced aetiology is suggested 85 , whereas immune-related mechanisms could be postulated for other cutaneous lesions.
The term chilblains also referred to as pernio describes a rare inflammatory condition affecting the extremities after exposure to cold, which can cause painful or itchy erythematous or violaceous lesions An association between chilblains and COVID was initially supported because most reported cases of chilblains in southern Europe occurred during the first peak of the pandemic, and because in one of the largest case series cutaneous lesions appeared after infection onset in two-thirds of patients with symptoms of COVID ref.
The patient profile derived from more than 1, cases of chilblains included in selected studies indicates a clear predominance of young people, with half of the studies reporting only children under the age of 18 years, and the other half including patients with a mean age ranging from 22 to 32 years. Reports of the presence of viral particles in biopsy-obtained skin from children with chilblains and negative results of PCR testing for SARS-CoV-2 might support the need for histopathological studies to confirm a causal relationship between SARS-CoV-2 and these skin lesions Erythema multiforme is an inflammatory dermatological condition that has been overwhelmingly linked to infectious agents and, less frequently, to drugs Reports of cases of erythema multiforme in patients with COVID reveal a clearly differentiated age-dependent pattern.
Cytopenia is overwhelmingly asymptomatic, and symptomatic autoimmune cases such as thrombocytopenic purpura or haemolytic anaemia have been infrequently reported in patients with COVID Supplementary Table In two of the three patients with COVID presenting with thrombotic thrombocytopenic purpura, infection was confirmed by positive IgG serology, suggesting a delayed immune-related response.
Encephalitis is inflammation of the brain parenchyma, clinical evidence of which includes cerebrospinal fluid pleocytosis, neuroimaging results or focal abnormalities on electroencephalogram Reported cases of encephalitis in patients with COVID reveal a similar extent of involvement among women and men, with a mean age at diagnosis of 55 years including cases in patients ranging from 11 to 84 years old Supplementary Table The pathogenesis of COVIDassociated encephalitis is unknown, although one study has suggested that patients with COVID can develop neurological manifestations that share notable similarities with those of CAR-T cell-related encephalopathy, involving different pathophysiological mechanisms including CRS, endothelial activation, blood—brain barrier dysfunction and immune-related damage GBS is a typical post-infectious disorder, with more than two-thirds of patients reporting symptoms of respiratory or digestive tract infections within the 6 weeks prior to GBS onset The clinical presentation and severity of GBS in these cases was similar to that in non-COVID GBS; the electrodiagnostic pattern was classified as demyelinating in most cases although other phenotypic variants, such as Miller Fisher syndrome and acute motor and sensory axonal neuropathy, have also been reported , serum anti-ganglioside antibodies were absent in most patients tested and cerebrospinal fluid, when assessed, was negative for SARS-CoV-2 refs , Supplementary Table Some studies have reported individual cases of patients who developed severe, bilateral pulmonary fibrosis after COVID refs , , Owing to the large number of patients affected by severe COVID pneumonia, long-term respiratory complications can be expected and could cause substantial population morbidity Although several post-mortem studies have suggested diffuse alveolar damage as the predominant pathological lung damage caused by SARS-Cov-2, other studies suggest a more heterogeneous pathological scenario, including a predominant pattern suggestive of organizing pneumonia in some patients 47 , In patients with COVID, development of myocardial damage is indicated by abnormal laboratory parameters, cardiac imaging studies, and in vivo and post-mortem histopathological data.
Acute myocarditis is often categorized into the histologically defined entities of lymphocytic, eosinophilic and giant cell myocarditis and sarcoid heart disease To date, acute myocarditis related to COVID has been overwhelmingly described as lymphocytic and rarely as eosinophilic, in contrast to SARS-CoVassociated myocarditis, which did not exhibit lymphocytic infiltration , Reports of cases of acute myocarditis in patients with COVID show that a wide range of ages are involved from 17 to 79 years , more frequently affecting men than women, with the main symptoms thoracic pain and dyspnoea being presented mainly during the first 2 weeks of COVID, although several cases have been described some weeks after the infection is resolved.
The clinical relevance of these findings remains unclear, although the findings demonstrating chronic inflammation and left ventricular dysfunction a couple of months after the clinical onset of COVID could represent an increased risk of developing new-onset heart failure and other cardiovascular complications COVID has been associated with both tubular and glomerular renal damage.
Proximal tubule dysfunction has been reported in a subset of patients with COVID presenting with low-molecular-weight proteinuria, neutral aminoaciduria and defective handling of uric acid Most renal pathology in patients with COVID falls within the spectrum of podocytopathies with most classified as collapsing glomerulonephritis, and some as focal segmental glomerulosclerosis or minimal change disease , primarily affecting men of African ancestry carrying high-risk APOL1 genotypes.
The next most frequently reported type of glomerulonephritis after podocytopathies in patients with COVID is pauci-immune crescentic glomerulonephritis associated with autoantibodies, which in all cases but one affected women.
Other types of glomerulonephritis have been also reported, including membranous and IgA glomerulonephritis. In some patients, acute renal disease appeared more than 2 weeks after onset of COVID symptoms, showing negative PCR results and positive serological tests. Patients with COVID presenting with glomerulonephritis have a poor prognosis, and more than half of the reported cases required dialysis most even after being discharged from the hospital Supplementary Table To date, all reported cases of COVIDassociated thyroid dysfunction are overwhelmingly consistent with overt hyperthyroidism defined as low levels of thyroid-stimulating hormone plus high levels of free T4 , often presenting with clinical symptoms of thyrotoxicosis and enlarged painful thyroid gland in physical and ultrasonography examinations; cases presenting with subclinical hypothyroidism are rare.
From a pathogenic point of view, some findings seem to suggest that thyroid dysfunction could be a transient phenomenon related to the hyperinflammatory biological scenario correlating with increased concentrations of IL-6 and infection severity, with abnormal values reverting after infection recovery.
Most patients who were tested for anti-thyroid antibodies had negative results. Adrenal involvement can include acute adrenal infarction as an incidental CT finding in one quarter of patients , adrenal haemorrhages and micro-infarctions and, rarely, adrenal insufficiency 47 , , Supplementary Table Several patients with COVID presenting with abdominal pain and elevated concentrations of pancreatic enzymes have been diagnosed with acute pancreatitis, most frequently women Supplementary Table The clinical and epidemiological scenario is wide, and includes involvement of children and older people, patients presenting without clinical symptoms, post-mortem studies, family cases, or patients with underlying predisposing factors.
Compared with patients without COVID, patients with COVID presenting with acute pancreatitis showed a similar epidemiological profile but a worse bedside index for severity in acute pancreatitis BISAP score, a higher frequency of persistent organ failure and a worse survival rate Supplementary Table Some inflammatory ocular diseases have been diagnosed in patients with COVID, including one reported case of bilateral anterior uveitis and conjunctivitis, which has been reported in more than 50 adult patients, mostly from Asian countries An increasing number of studies are reporting about collateral manifestations related to an excessive response of the immune system against SARS-CoV-2, breaking the natural self-tolerance maintained by the immune system, as has been previously described in other acute and chronic viral infections , , , or that has been related to the administration of biologic drugs , Immune-related manifestations related to COVID were initially described in hospitalized patients, especially in those with severe disease, but have also been described in patients with an already resolved infection or even in asymptomatic patients.
The clinical phenotype seems to be modified by epidemiological factors such as age manifestations clearly differentiated between children and adults , sex myositis, arthritis, GBS, myelitis and glomerulonephritis are reported mainly in men, whereas thyroiditis and pancreatitis occur more frequently in women or ethnicity although the role of socioeconomic factors must always be assessed , Tables 1 and 2 , and some pathogenic mechanisms could be specifically involved in certain epidemiological subsets of patients.
For instance, in comparison with adults, children with COVID predominantly generate IgG antibodies specific for the SARS-CoV-2 spike protein, targeting mainly the S2 subunit, but not for the nucleocapsid protein, a virus-related pathogenic mechanism that could help to explain the differentiated phenotype reported in children and adults , The severity of the manifestations of COVID is also very wide, ranging from completely benign and self-limiting manifestations for example, perniosis to systemic syndromes such as MIS-C or HLH that can lead to the need for intensive care and potentially to death.
Multidisciplinary management of patients with COVID is mandatory, including experts in the corresponding systemic and organ-specific autoimmune diseases, and should always follow a holistic diagnostic approach owing to the large variety of multisystem symptoms that patients with COVID might present Figs 2 and 3.
In the absence of specific data about the therapeutic management of immune-related COVID manifestations, following an approach similar to that used in the corresponding non-COVID diseases could be a reasonable option, as has been suggested for neuroinflammatory COVID with the use of corticosteroids, intravenous immunoglobulin and plasma exchange , 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, 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. Little is known about the pathogenesis of these manifestations , although involvement of specific responses by the acquired immune system seems to be of little consequence if we consider that serum autoantibodies one of the main pathogenic hypotheses of autoimmune diseases are absent in most patients tested for them.
Studies centred on investigating the role of interferon-related pathways in COVID, an important mechanism also involved in the pathogenesis of several autoimmune diseases , have reported the presence of autoantibodies against type I interferon or inborn errors of type I interferon immunity , in patients with severe COVID In the literature we reviewed, there seems to be a certain pattern of occurrence of many immune-related manifestations in relation to the onset of SARS-CoV-2 infection: some features tend to appear in the first 2 weeks of infection Fig.
This differentiated temporal distribution along the different stages of SARS-CoV-2 infection could suggest the involvement of different aetiopathogenic mechanisms triggered by a common aetiological agent , , with some features being predominantly linked to early viral immune responses and other features with subsequent inflammatory responses emerging once the virus has been eliminated.
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, 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. Immune-related manifestations of COVID should be distinguished from other clinical scenarios with a different pathogenic basis Fig.
In patients with severe COVID, some vital internal organs can be severely damaged by the inflammatory process. Several cases of pulmonary fibrosis have also been reported , , , suggesting that long-term respiratory complications could cause substantial morbidity in the population , Other studies have reported chronic cardiac inflammation and left ventricular dysfunction a couple of months after the clinical onset of COVID, findings that could increase the risk of developing new-onset heart failure and other cardiovascular complications To date, no study has demonstrated that immune-related mechanisms could be involved in the pathogenesis of these symptoms Most immune-related COVID 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 , whereas others tend to emerge in a late post-infectious stage or even in asymptomatic patients late immune-related features of COVID 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.
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 The novelty of these manifestations and the large number of different specialties involved make it very difficult at present to have consensus on a diagnostic definition for most of them, and two different approaches have been followed to date.
The first has been to propose a new syndrome, as has been done with the MIS-C in children, to separate it from other known diseases with which this syndrome has notable similarities in the case of MIS-C, Kawasaki disease.
The second has been to include SARS-CoV-2 within the multi-aetiological spectrum often reported in patients affected by the classical syndrome or disease, considering that patients with COVID might have a different clinical phenotype but under the umbrella of the same syndrome such as HLH, vasculitis, autoimmune cytopenia, GBS or glomerulonephritis.
Immune-related manifestations are increasingly recognized in patients with COVID, with a protean clinical presentation affecting a wide range of organ systems in both children and adults. Unsurprisingly, therefore, diagnostic and therapeutic decision-making are often based on scarce clinical experience and expert opinion.
Without being able to offer solid conclusions and plausible aetiopathogenic explanations, the main objective of this Review is to awaken the interest of the scientific community in this emerging group of manifestations and thus facilitate the development of studies specifically devoted to investigating the pathogenic mechanisms that could help enable the early detection and adequate management of immune-related manifestations of COVID Connors, J.
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