This RNA virus belongs to a family of coronaviruses that includes Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) .
Upon SARS-CoV-2 infection, typical symptoms include dry cough, fever, and loss of smell and/or taste. However, the presentation of infection can range from asymptomatic to critical illness which has led to categorisation of disease based on severity of symptoms. One definition of severe COVID-19 is the need for admission to an intensive care unit and need for a ventilator/supplementary oxygen which is less likely in mild to moderate COVID-19.
The need for hospitalisation is mainly due to infection of the lower respiratory tract and therefore inflammation of lung alveoli, also known as pneumonia. This can lead to acute respiratory distress syndrome (ARDS), sepsis and multi-organ failure which are some of the main causes of mortality in COVID patients .
Aside from classifying severity of disease based on symptoms, histopathological differences can also be used for classification purposes. For example, it has been suggested that the formation of hyaline membranes, due to lack of surfactant leading to alveolar collapse, are characteristic of pneumonia and therefore of severe COVID-19 .
The development of severe COVID is attributed to a dysregulated immune response characterised by a cytokine storm, a severe and sustained activation of the inflammatory pathway mediated by overexpression of cytokines . Cytokines usually act as a signal for innate immune cells, such as neutrophils and macrophages, to move to the site of infection.
However, when this is inappropriately sustained, the increased vascular permeability can lead to pulmonary consolidation and other lung tissue injury. In addition to accumulation of pulmonary exudates, the signalling cascade can result in apoptosis of lung epithelial cells which can lead to the complication of ARDS since oxygen transfer is severely impaired.
Studies have reported a correlation of higher levels of pro-inflammatory cytokines (e.g. IL-6) and inflammatory markers (e.g. C-reactive protein (CRP)) with more severe clinical presentations .
There is also evidence that type 1 interferon, an antiviral defence, is suppressed during the initial phase of the disease, which promotes the over-activity of the inflammatory pathway underlying disease severity . The combination of low interferon levels and high pro-inflammatory cytokines is what indicates the dysregulated innate immune response to COVID-19.
Following genome-wide association studies (GWAS) of susceptibility to severe COVID-19 infection, Mendelian Randomisation (MR) can then be used for causal inference of the role of a specific variant or risk factor. The outputs of such analyses could serve as guide in clinical trials aiming to repurpose existing medications for effective COVID-19 management.
Baricitinib is an example of an anti-inflammatory rheumatoid arthritis drug that has been repurposed to help buffer the cytokine storm that leads to lung injury . Furthermore, evidence of under expression of IFNAR2, which encodes the receptor of interferon, amongst severe COVID-19 patients has led to clinical trials of interferons to reduce mortality rate .
In addition, genomic analyses could reveal new therapeutic targets for drug development. 3CLpro, PLpro and RdRp, the main enzymes responsible for SARS-COV-2 replication using host machinery, emerged as potential therapeutic targets aids such as therapy with monoclonal antibodies [7, 8].
GWAS have identified several loci associated with increased susceptibility to COVID-19 infection and severe disease . The underlying genes of these association signals can be broadly divided into underactive genes that enable viral replication and overactive genes that result in pulmonary inflammation and the symptoms of severe COVID-19.
The most prominent findings include reduced activity of IFNAR2, increased activity of TYK2 and mutation of OAS1 which means poor activation of an enzyme involved in stopping viral replication .
An additional finding is a gene cluster on chromosome 3 that is associated with severe COVID-19 outcomes.
COVID-19 individuals with gene variants at this locus had 1.6 odds of requiring hospitalisation . The same study found that the susceptibility haplotype was most strongly associated with people of Bangladeshi origin which may in part explain the higher COVID-19 related mortality amongst Bangladeshi men compared to White males [12, 13].
It is theorised that historically, gene flow from Neanderthals in this part of the world may have provided protection against certain pathogens through selection pressure amongst people who live in or come from what is now known as Bangladesh, but in the case of COVID-19 it confers a greater risk of severe infection . The COVID-19 susceptibility haplotype showed similarity to Neanderthal Vindija haplotypes .
The risk of infection and severity of COVID-19 is modulated by various risk factors. The most frequently reported finding in the literature is that older patients or those with existing respiratory or cardiovascular disease are more susceptible to severe infection.
A study found that a 60–74-year-old individual has a 5-times higher risk of hospitalisation and 90 times higher risk of death from COVID-19 compared to an 18–29-year-old . Additional studies suggest that individuals with chronic inflammatory diseases and vascular disease are also at higher risk of adverse COVID-19 outcomes .
The other most significant risk factor is body mass index (BMI) , which has a biological basis since obesity is associated with other conditions such as heart disease and diabetes, both of which are independent risk factors. Genetic susceptibility to obesity was found in MR studies to be associated with increased risk of infection .
The authors suggest that obesity could be causally linked to infection because of impaired lung function, increased baseline adipokines and cytokines which increase risk to developing ARDs. Additional studies support the causal relationship between obesity as a risk factor, although some findings suggest that this relationship might be mediated by type 2 diabetes .
Cardiovascular disease is also a predictor of poor COVID-19 outcomes. The combination of the hyperinflammatory environment due to a SARS-CoV-2 infection also puts the patient into a hypercoagulable state which leads to complications such as multi-organ failure, observed complication of severe COVID-19 .
Furthermore, hypertension could be a causal risk factor due to the viral spike protein binding to ACE2 receptors, thereby enhancing the activity of the renin-angiotensin-aldosterone system which leads to inflammation and fibrosis . Similarly, smoking is a risk factor that has been found to increase expression of the ACE2 receptor in the lung which provides some explanation for why smokers are more likely to require hospital admission .
*-*-*-*- reference link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256988
Some patients with COVID-19 can develop a severe, acute virus-induced lung injury under the umbrella of acute respiratory distress syndrome (ARDS), a clinical syndrome characterized by acute lung inflammation and increased-permeability pulmonary oedema due to injury to the alveolar capillary barrier6.
The hyperinflammatory phenotype of ARDS is characterized by elevated concentrations of pro-inflammatory cytokines, an increased incidence of shock and adverse clinical outcomes7,8. Although the mechanisms of COVID-19-induced ARDS are still being elucidated9, the term ‘cytokine storm’ has become synonymous with its pathophysiology, although some authors have suggested use of this term is misleading in the context of severe COVID-19 (ref.10).
Even the term cytokine storm has been frequently interchanged with the term ‘cytokine release syndrome’ (CRS)10, which describes an immune-related dysregulation associated with the release of large amounts of cytokines that trigger systemic inflammation with multi-organ failure and high mortality rates.
CRS is one of the most frequent serious adverse effects of chimeric antigen receptor T (CAR-T) cell therapies11 and is characterized by fever, tachycardia, tachypnoea and hypotension, the key symptoms that define systemic inflammatory response syndrome10.
IL-6, a pro-inflammatory cytokine, is an important mediator of the acute inflammatory response in ARDS and CRS, and seems to also factor in severe COVID-19, contributing to elevated C-reactive protein concentrations, hypercoagulation and hyperferritinaemia12,13. However, serum IL-6 concentrations reported in patients with COVID-19 are substantially lower than those reported in patients with CRS, ARDS or sepsis10,14, or even influenza15.
Why some patients with severe COVID-19 rapidly enter a state of multi-organ failure is unknown, but the pathophysiology of COVID-19-associated ARDS seems to be more complex than a simple overproduction of cytokines9.
The systemic phenotype related to the inflammatory reaction triggered by SARS-CoV-2 infection is very broad and can be reminiscent of that of some autoimmune or inflammatory diseases. In children, systemic involvement has a substantial overlap with Kawasaki disease, whereas in adults it seems to be closer to haemophagocytic lymphohistiocytosis (HLH), antiphospholipid syndrome (APS) or systemic vasculitis (Table 1, Fig. 1).
Fig. 1: Guiding signs and symptoms of suspected systemic immune-related disease in patients with COVID-19.
Immune-related organ-specific manifestations
In contrast to the above-mentioned systemic presentations that can involve multiple organs, some patients with COVID-19 present with immune-related manifestations involving a single organ, which can mimic a wide range of organ-specific autoimmune diseases (Table 2, Fig. 2).
Fig. 2: Guiding signs and symptoms of suspected organ-specific immune-related diseases in patients with COVID-19.
Symptoms of cutaneous involvement can affect 0.2% to 5% of patients with COVID-19 (ref.83), including maculopapular eruptions, urticarial lesions, chilblains and livedoid/necrotic lesions84. For maculopapular and urticarial lesions, a predominant drug-induced aetiology is suggested85, 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 lesions86. An association between chilblains and COVID-19 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-19 (ref.87).
The patient profile derived from more than 1,300 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. However, only 6% of these reported cases had confirmed COVID-19 (although it should be noted that testing for the virus was not performed in nearly half of the cases), supporting a weak link between chilblains and COVID-19 (Supplementary Table 9).
Potentially, lifestyle changes related to lockdown lead to more inactivity for long periods and this inactivity could contribute to triggering chilblains, especially in predisposed patients (that is, those with a previous history of perniosis, Raynaud syndrome or β-blocker treatment)88. 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 lesions89.
Erythema multiforme is an inflammatory dermatological condition that has been overwhelmingly linked to infectious agents and, less frequently, to drugs90. Reports of cases of erythema multiforme in patients with COVID-19 reveal a clearly differentiated age-dependent pattern. Most cases reported in children were associated with chilblain lesions or Kawasaki disease91,92 and had negative PCR results for SARS-CoV-2, whereas the use of drugs was noted in all reported cases in adults (hydroxychloroquine in all, in most in combination with azithromycin, antivirals and/or antibiotics) (Supplementary Table 10).
Other immune-related skin manifestations have been reported in patients with COVID-19, including livedoid and/or acrocyanotic lesions84,93,94,95,96, retiform purpura97,98,99, oral ulcers84,100, erythema nodosum101,102, periorbital erythema103, generalized pustular figurate erythema (in all reported cases, appearing in patients who were being treated with hydroxychloroquine)94,104,105, drug reaction with eosinophilia and systemic symptoms94,106 and Sweet syndrome107.
Lymphopenia is a prominent feature of COVID-19, not only because of its high frequency (around half of COVID-19 cases) but also because of its relevance to prognosis (it has been linked with the development of ARDS, a need for intensive care and poor survival)108,109,110, whereas thrombocytopenia and anaemia have been reported in 24% and 59% of COVID-19 cases, respectively (Supplementary Table 5). Cytopenia is overwhelmingly asymptomatic, and symptomatic autoimmune cases (such as thrombocytopenic purpura or haemolytic anaemia) have been infrequently reported in patients with COVID-19 (Supplementary Table 11).
Patients with COVID‐19 can present with symptomatic thrombocytopenia, including immune thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura. COVID-19-related ITP predominantly affects people older than 50 years (~75%) presenting with a platelet count below 10,000 per mm3 (~80%), with the ITP symptoms (purpura and mucosal bleeding) appearing at least 2 weeks after onset of COVID-19 symptoms in nearly half the cases.
In two of the three patients with COVID-19 presenting with thrombotic thrombocytopenic purpura, infection was confirmed by positive IgG serology, suggesting a delayed immune-related response. Autoimmune haemolytic anaemia (AIHA; presenting as either warm or cold haemolysis) is also diagnosed predominantly in people older than 50 years (~70%) presenting with a haemoglobin lower than 8 g/l (74%), with the AIHA symptoms (mainly asthenia and jaundice) appearing during the first/second week of COVID-19 (Supplementary Table 11).
The neurological manifestations caused by SARS-CoV-2 are diverse and have been related to neuroinvasion or neurotropic damage (including encephalopathy, encephalitis and cerebrovascular pathologies) or to neuroinflammatory damage (Guillain–Barré syndrome (GBS) or acute myelitis)111,112.
Encephalitis is inflammation of the brain parenchyma, clinical evidence of which includes cerebrospinal fluid pleocytosis, neuroimaging results or focal abnormalities on electroencephalogram112. Reported cases of encephalitis in patients with COVID-19 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 12).
In one-third of cases, neurological symptoms started at least 2 weeks after COVID-19 onset. Although several cases were classified as non-specific viral encephalitis or meningoencephalitis, some specific clinical entities were identified in other patients, including autoimmune encephalitis associated with anti-NMDA receptor autoantibodies, acute disseminated encephalomyelitis, acute necrotizing encephalopathy and mild encephalitis/encephalopathy with a reversible splenial lesion (Supplementary Table 12).
The pathogenesis of COVID-19-associated encephalitis is unknown, although one study has suggested that patients with COVID-19 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 damage113.
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 onset114. Therefore, that SARS-CoV-2 could be a potential new viral trigger of GBS is not unexpected, but the frequency of COVID-19-related GBS is unknown, with only one large study estimating a frequency of GBS of ~0.1% among hospitalized patients with COVID-19 (ref.73).
So far, almost all cases of GBS related to SARS-CoV-2 have been reported as isolated cases and in one small series; these cases mainly affected men aged >50 years (90% of cases) and were diagnosed at least 2 weeks after the onset of COVID-19 respiratory symptoms in two-thirds of reviewed cases.
The clinical presentation and severity of GBS in these cases was similar to that in non-COVID-19 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 (refs115,116) (Supplementary Table 13).
Several cases of myelitis have been reported in patients with COVID-19, mainly in men and with two discrete age peaks, one at ~30 years old and the other at ~60–70 years old (Supplementary Table 14); additional reports of other immune-related neurological manifestations include cranial neuropathies and optic neuritis73,117,118,119,120, plexopathy121 or myasthenia gravis122.
Among studies of COVID-19 pneumonia to date, few have evaluated the long-term natural history of pulmonary damage, and they often have a short follow-up period (~1 month after starting COVID-19 symptoms). These studies have reported that a substantial percentage of patients have abnormal pulmonary findings, including abnormal pulmonary function test (PFT) results in 54% of patients and abnormal CT imaging studies in 40–94%123,124,125,126.
One small study has reported that PFT results remain abnormal in ~25% of patients evaluated 3 months after diagnosis of COVID-19 (ref.127), suggesting the development of a post-pneumonia interstitial lung disease. Some studies have reported individual cases of patients who developed severe, bilateral pulmonary fibrosis after COVID-19 (refs128,129,130). Owing to the large number of patients affected by severe COVID-19 pneumonia, long-term respiratory complications can be expected and could cause substantial population morbidity131.
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 patients47,132. A late development of new respiratory symptoms and opacities (>2 weeks after the first symptoms of COVID-19), especially if these features were not detected in previous CT studies, could suggest the late development of organizing pneumonia, as has been reported in influenza infection133.
Pleural involvement has also been linked to COVID-19, with an estimated frequency of 27% for pleural thickening and 5–6% for pleural effusion80,81. Some patients can have symptoms of pleurisy as the initial manifestation of COVID-19 (ref.134) and others might develop pleural effusion even though it was absent in the initial examination135.
In patients with COVID-19, development of myocardial damage is indicated by abnormal laboratory parameters, cardiac imaging studies, and in vivo and post-mortem histopathological data. Around 40–80% of patients with COVID-19 can have raised troponin-I levels136,137, cardiac MRI identified cardiac involvement in 78%137, and several studies have reported myocardial interstitial infiltration by mononuclear cells and lymphocytic infiltration138 with evidence of active viral replication139,140; a myocyte-specific upregulation of ACE2 has been suggested as a putative pathogenic mechanism for SARS-CoV-2-associated viral myocarditis141.
Acute myocarditis is often categorized into the histologically defined entities of lymphocytic, eosinophilic and giant cell myocarditis and sarcoid heart disease142. To date, acute myocarditis related to COVID-19 has been overwhelmingly described as lymphocytic and rarely as eosinophilic, in contrast to SARS-CoV-2-associated myocarditis, which did not exhibit lymphocytic infiltration143,144.
Reports of cases of acute myocarditis in patients with COVID-19 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-19, although several cases have been described some weeks after the infection is resolved. Only around half cases had a confirmatory MRI study (the remaining underwent only cardiac ultrasonography) and most required ICU admission, with a mortality rate of ~30% (Supplementary Table 15).
A study137 in 100 patients evaluated a mean of 2 months after confirmed COVID-19 diagnosis showed that raised levels of high-sensitivity troponin were detected in 76% and that cardiac MRI showed cardiac involvement in 78%, including evidence of active myocardial inflammation in 60%. In comparison with healthy volunteers, the patients who had recovered from COVID-19 had lower left ventricular ejection fractions and higher left ventricular volumes; moreover, 32% manifested myocardial late gadolinium enhancement and 22% had pericardial involvement.
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-19 could represent an increased risk of developing new-onset heart failure and other cardiovascular complications145.
Pericardial effusion has been reported in ~5% of patients with COVID-19 (ref.81), and it seems that patients with suspected myocarditis could have a higher rate of pericardial effusion (22–75%)137,146. Cardiac tamponade was reported in 11 (1%) of 1,216 patients with available echocardiographic findings147, and several additional cases have been reported, mainly diagnosed in the first 7–10 days of COVID-19 illness (Supplementary Table 16).
COVID-19 has been associated with both tubular and glomerular renal damage. Proximal tubule dysfunction has been reported in a subset of patients with COVID-19 presenting with low-molecular-weight proteinuria, neutral aminoaciduria and defective handling of uric acid148. With respect to glomerular disease, several studies have reported patients with biopsy-proven glomerulonephritis presenting with acute renal failure (in some cases accompanied by haematuria and/or nephrotic syndrome), with a clear differentiation in profile between podocytopathies and other types of glomerulonephritis (Supplementary Table 17).
Most renal pathology in patients with COVID-19 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-19 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-19 symptoms, showing negative PCR results and positive serological tests. Patients with COVID-19 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 17).
Studies have reported abnormal thyroid function potentially related to SARS-CoV-2 infection. A retrospective study in patients hospitalized with COVID-19 found thyrotoxicosis in 20% and hypothyroidism in 5%149, whereas another study found low concentrations of thyroid-stimulating hormone in 56% of patients150.
To date, all reported cases of COVID-19-associated 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 insufficiency47,151,152 (Supplementary Table 18).
Several patients with COVID-19 presenting with abdominal pain and elevated concentrations of pancreatic enzymes have been diagnosed with acute pancreatitis, most frequently women (Supplementary Table 19). 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-19, patients with COVID-19 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 rate153 (Supplementary Table 19). Several pathogenic mechanisms have been suggested to explain the putative association between acute pancreatitis and COVID-19, including direct viral damage to pancreatic cells, endothelial damage and ischaemic and/or thrombotic mechanisms154.
Some inflammatory ocular diseases have been diagnosed in patients with COVID-19, including one reported case of bilateral anterior uveitis155 and conjunctivitis, which has been reported in more than 50 adult patients, mostly from Asian countries156.
reference link : https://www.nature.com/articles/s41584-021-00608-z