PIMS-TS: A rare child syndrome during the COVID-19 pandemic

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Researchers have uncovered how the immune system is altered in a rare COVID-19 related illness in children referred to as paediatric inflammatory multisystem syndrome (PIMS-TS).

PIMS-TS is a rare syndrome which has emerged in a small number of children during the COVID-19 pandemic.

The condition causes severe inflammation in blood vessels and can lead to heart damage.

The team from Evelina London Children’s Hospital and King’s College London analysed blood samples from 25 children who had PIMS-TS and compared these to healthy children.

The study, supported by the NIHR Guy’s and St Thomas’ BRC and published in Nature Medicine, showed that in the acute stage of PIMS-TS, children have raised levels of molecules called cytokines, and reduced levels of white blood cells called lymphocytes.

They saw that by the time the children had recovered, the immune system changes had gradually returned to normal.

Although the number of children in the study was small, this is the first evidence about the role of the immune system in the disease.

It provides vital evidence for future research and will indicate what treatments may help patients with the condition.

The first cases of PIMS-TS were treated at Evelina London in mid-April 2020. Initial reports suggested the condition may be similar to existing conditions such as Kawasaki disease. However, the new research confirms that PIMS-TS affects the body in a different way to other known conditions and has been identified as a new syndrome.

The research, led by Dr. Shankar-Hari within the King’s College London School of Immunology and Microbial Sciences, worked to understand the immune system changes underlying this new condition.

Blood samples were analysed from 25 children who had tested positive for the SARS-COV-2 virus, had symptoms of COVID-19, had been in close contact with someone who had tested positive, or whose parent was a healthcare worker.

Blood samples were tested from children these children at different stages of the disease, from the acute phase when they first came onto hospital, through to their outpatient appointments. The researchers compared these results to those of seven healthy age-matched children.

Dr. Manu Shankar-Hari is a consultant in intensive care medicine at Guy’s and St Thomas’ and NIHR Clinician Scientist and Reader and Consultant in Intensive Care Medicine at King’s College London.

He said: “PIMS-TS is a new syndrome. Our research has allowed us to provide the first description of the profound immune system changes in severely ill children with this new illness.

“These immune changes are complex. The innate, otherwise known as the rapidly responding, immune cells are activated.

The lymphocytes, a particular type of white cell involved in specific protective immunity, are depleted, but appear to be actively fighting infection.

“Clinically, these children respond to treatments that calm the immune system such as corticosteroid and immunoglobulins. Although there are similarities to existing conditions such as Kawasaki Disease, these clinical and immunological changes that we observe imply that PIMS-TS is a distinct illness associated with SARS-Co-V-2 infections.”

Dr. Shane Tibby, paediatric ICU consultant at Evelina London said: “When we first saw the immunophenotyping results in this paper, it confirmed our clinical impression: that this was neither Toxic Shock nor Kawasaki Disease, but rather a new entity that likely requires both organ support and careful, targeted immunotherapy.”

Dr. Michael Carter is a Paediatric NIHR Academic Clinical Lecturer and sub-speciality registrar in paediatric intensive care at Evelina London.

He said: “The support of children and young people with PIMS-TS was crucial in this study. Their help enabled us to monitor changes in the immune system during their illness and recovery and may contribute towards developing targeted immune therapy for children with PIMS-TS in the future.”


Case definitions and clinical spectrum
Different terminology and case definitions for this COVID-19-associated multisystem inflammatory phenotype in children are used depending on the country and region.

An internationally accepted case definition for MIS-C is still evolving. The UK has used PIMS-TS as their preliminary case definition for this disease, with criteria that include clinical manifestations (eg, persistent inflammation), organ dysfunction, SARS-CoV-2 PCR testing, which might be positive or negative, and exclusion of any other microbial cause.9, 39

The US CDC case definition is based on clinical presentation, evidence of severe illness and multisystem (two or more) organ involvement, no plausible alternative diagnoses, and a positive test for current or recent SARS-CoV-2 infection or COVID-19 exposure within 4 weeks before the onset of symptoms.37

WHO has developed a similar preliminary case definition and a case report form for multisystem inflammatory disorder in children and adolescents.

This case definition for MIS-C includes clinical presentation, elevated markers of inflammation, evidence of infection or contact with patients who have COVID-19, and exclusion of other obvious microbial causes of inflammation (table 1).6

Table 1Preliminary case definitions for MIS-C

MIS-C associated with COVID-19PIMS-TSMIS-C associated with COVID-19Complete Kawasaki diseaseIncomplete Kawasaki diseaseKawasaki disease shock syndrome
Organisation or publicationWHO6Royal College of Pediatrics and Child Health39US Centers for Disease Control and Prevention37American Heart Association40American Heart Association40Kanegaye et al,41
Age0–19 yearsChild (age not specified)<21 yearsChild (age not specified)Child (age not specified)Child (age not specified)
InflammationFever and elevated inflammatory markers for 3 days or moreFever and elevated inflammatory markersFever and elevated inflammatory markersFever lasting 5 days or more*Fever lasting 5 days or more*Fever
Main featuresTwo of the following: (A) rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands, or feet); (B) hypotension or shock; (C) features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiogram findings or elevated troponin or N-terminal pro B-type natriuretic peptide); (D) evidence of coagulopathy (elevated prothrombin time, partial thromboplastin time, and elevated D-dimers); and (E) acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain)Single or multiple organ dysfunction (shock or respiratory, renal, gastrointestinal, or neurological disorder; additional features appendix 6 pp 3–4Clinically severe illness requiring hospitalisation; and multisystem (two or more) organ involvement (cardiac, renal, respiratory, haematological, gastrointestinal, dermatological, or neurological)Four or more principal clinical features: (A) erythema and cracking of lips, strawberry tongue or oral and pharyngeal mucosa; (B) bilateral bulbar conjunctival injection without exudate; (C) rash; (D) erythema and oedema of the hands and feet in acute phase and periungual desquamation in subacute phase; and (E) cervical lymphadenopathyTwo or three principal clinical features or a positive echocardiogramKawasaki disease-like clinical features and any of the following causing initiation of volume expansion, vasoactive agents, or transfer to the intensive care unit: systolic hypotension based on age, or a decrease in systolic blood pressure from baseline by 20% or more, or clinical signs of poor perfusion
ExclusionOther microbial cause of inflammationAny other microbial causeOther plausible alternative diagnoses....Other microbial cause
SARS-CoV-2 statusPositive RT-PCR, antigen test, or serology; or any contact with patients with COVID-19RT-PCR positive or negativePositive RT-PCR, serology, or antigen test; or COVID-19 exposure within the past 4 weeks before symptom onset......

MIS-C=multisystem inflammatory syndrome in children. PIMS-TS=paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.* In the presence of four or more principal clinical features, particularly when redness and swelling of the hands and feet are present, the diagnosis of Kawasaki disease can be made with only 4 days of fever.

Cases reported in the past 3 months, which met the current diagnostic criteria, most likely represent a small proportion of MIS-C cases, and those individuals were severely affected by the illness.

A broader UK definition of MIS-C describes this illness as a spectrum ranging from persistent fever and inflammation, to characteristic features of Kawasaki disease in children, and to children who are severely ill with shock and multiple organ failure.39, 40

In the study by Dufort and colleagues,21 a third of the reported cases did not meet the US CDC case definition for MIS-C but presented with similar clinical and laboratory features to those seen in confirmed cases.

Despite overlap in clinical presentation, the initially speculated relationship between MIS-C and toxic shock syndrome seems implausible because most MIS-C cases had negative blood cultures (appendix 6 pp 3–4); thus, there is no evidence that staphylococcal or streptococcal toxins are involved in the cause of MIS-C.

However, studies to exclude infection with superantigen-producing organisms are scarce. Overlap has also been observed between the diagnostic criteria of Kawasaki disease, Kawasaki disease shock syndrome, and the newly emerged MIS-C.

According to criteria developed by the American Heart Association,42 the diagnosis of complete Kawasaki disease includes the presence of a high fever for 5 days or more and at least four of the five principle clinical features, whereas incomplete Kawasaki disease is diagnosed when children present with unexplained fever for 5 days or more and two to three of the principle clinical features supported by laboratory findings or cardiac lesions (table 1).

Kawasaki disease shock syndrome is a severe form of Kawasaki disease,41 defined as complete or incomplete Kawasaki disease complicated by haemodynamic instability, resulting in the patient requiring intensive care, without evidence of another bacterial infection such as group A streptococcus or staphylococcus.

The cause and factors contributing to the development of Kawasaki disease shock syndrome are still unclear, but a contributory role for underlying inflammation and more intense vasculitis has been suggested on the basis of laboratory results, progression, and the disease outcome.43, 44, 45, 46, 47

Researchers have suggested several possible explanations for Kawasaki disease shock syndrome including a superantigen-mediated response,48 overexpression of proinflammatory cytokines,49 and gut bacteria involvement.50 A large number of MIS-C cases present with Kawasaki-like clinical symptoms, and cardiac impairment and shock similar to Kawasaki disease shock syndrome.

Gastrointestinal symptoms, hyponatremia, hypoalbuminemia, and intravenous immunoglobulin resistance are also common in Kawasaki disease shock syndrome and MIS-C (appendix 6 pp 3–4).
Although features of MIS-C overlap with those of Kawasaki disease, a study from Whittaker and colleagues18 found a wider spectrum of MIS-C symptoms.

Despite differences in severity, coronary aneurysms have occurred in all three groups of patients, including those with shock, those who meet the criteria for Kawasaki disease, and those with fever and inflammation but who do not have shock or meet the criteria for Kawasaki disease.

In addition to a wider clinical spectrum, there are several other distinct features of MIS-C compared with Kawasaki disease, including the age and ethnic groups affected. Patients with MIS-C are typically older than 7 years, of African or Hispanic origin, and show greater elevation of inflammatory markers.10, 13, 15, 18 Over 80% of patients with MIS-C also present with an unusual cardiac injury shown by high concentrations of troponin and brain natriuretic peptide, whereas others develop arrhythmia, left ventricle dysfunction, and unusual coronary dilatation or aneurysms (appendix 6 pp 3–4).10, 12, 13, 15, 16, 17, 18, 19

Blondiaux and colleagues28 examined cardiac MRI findings in four patients who had MIS-C with cardiovascular involvement, and found a diffuse myocardial oedema on T2-weighted short-tau inversion recovery sequences and native T1 mapping, with no evidence of late gadolinium enhancement suggestive of replacement fibrosis or focal necrosis.

These findings favour the hypothesis of an immune response to an antigen rather than a direct complication secondary to SARS-CoV-2 infection.

COVID-19 pathophysiology and link with MIS-C

Coronaviruses are a large family of positive-sense single-stranded RNA viruses. There are four described genera of coronaviruses (α, β, δ, and γ).69

Six species of human coronaviruses are known, with one species subdivided into two different strains.

The β coronavirus genus includes SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome. SARS-CoV-2, similarly to other coronaviruses, is transmitted between humans primarily through close contact with the infected individual or through contaminated surfaces—eg, dispersing droplets when coughing or sneezing.

The virus enters a cell mainly by binding to the angiotensin-converting enzyme 2, which is highly expressed in lung cells, alveolar cells, cardiac myocytes, the vascular endothelium, and a small subset of immune cells.70, 71, 72, 73, 74

The pathogenesis of COVID-19 is still being studied. Evidence has shown that a dysregulated innate immune response and a subsequent cytokine storm,70, 74, 75, 76, 77, 78, 79, 80 and endothelial damage,81, 82 might play a role in the clinical manifestation of severe COVID-19 cases, leading to acute lung injury, acute respiratory distress syndrome, and multiple organ failure.

Neutrophils play a major role in the innate immune response. One of their functional mechanisms is the formation of neutrophil extracellular traps (NETs).83 NETs are a lattice-like web of cell-free DNA, histones, and neutrophil granule content including microbicidal proteins and enzymes.

NETs have been involved in the pathophysiology of a wide range of inflammatory and prothrombotic states such as sepsis, thrombosis, and respiratory failure.

The generation of NETs by neutrophils, called NETosis, can be stimulated by many viruses. Although their major function is to trap the virus, virus-induced NETs can trigger inflammatory and immunological reactions in an uncontrolled manner, leading to an exaggerated systemic inflammatory response,84 similar to hyperinflammation seen in MIS-C.

Zuo and colleagues85 have shown that NETs are increased in the plasma of patients infected with SARS-CoV-2, and higher concentrations of NETs are seen in those with respiratory failure.

Thrombotic complications have been reported in severe COVID-19 cases. Abnormal coagulopathy (eg, elevated D-dimer or fibrinogen) has also been observed in many cases of MIS-C. NETosis plays a crucial part in promoting thrombosis;86, 87, 88 therefore, the role of NETs in MIS-C is highly plausible.

Although NETosis might be an important mechanism linking neutrophil activation, cytokine release, and thrombosis in COVID-19, they have not yet been reported to be involved in MIS-C.

Children form only a small portion of confirmed COVID-19 cases.

Most children have had minor symptoms or an asymptomatic SARS-CoV-2 infection.4, 55, 56 Unlike in adults, severe respiratory illness such as acute respiratory distress syndrome is rare in children.

The newly emerging MIS-C might lead to severe clinical manifestations; however, its distinct characteristics are different from other severe complications seen in paediatric COVID-19 cases.

First, MIS-C cases start appearing around 1 month after a COVID-19 peak in the population. According to data from Public Health England, the number of MIS-C cases increased drastically around April 16, 2020, approximately 4 weeks after the substantial increase in COVID-19 cases in the UK (figure 1).89

Epidemiological studies from the USA22 and France68 revealed similar trends. Second, children often show previous rather than a current infection with SARS-CoV-2. Only a third of reported MIS-C cases are positive by RT-PCR for SARS-CoV-2, whereas most cases are positive with an antibody test, indicating past infection.

The delay in presentation of this condition relative to the pandemic curve, a low proportion of cases who were SARS-CoV-2 positive by RT-PCR, and a high proportion who were antibody positive suggest that this inflammatory syndrome is not mediated by direct viral invasion but coincides with the development of acquired immune responses to SARS-CoV-2.

Figure thumbnail gr1
Figure 1Time course of MIS-C in PCR-positive COVID-19 cases
Figure thumbnail gr2
Figure 2Possible mechanisms of inflammatory processes for MIS-C – Antibodies might enhance disease by increasing viral entry into cells. Alternative mechanisms include antibody or T-cell-mediated cell damage or activation of inflammation. Antibodies or T cells attack cells expressing viral antigens or attack host antigens which cross-react or mimic viral antigens. The low rate of virus detection in MIS-C would favour this second mechanism rather than the classic antibody-dependent enhancement. ACE2=angiotensin-converting enzyme 2. DAG=diacylglycerol. FcγR=Fc-gamma receptor. IL=interleukin. MCP=monocyte chemoattractant protein. MIS-C=multisystem inflammatory syndrome in children. MIP=macrophage inflammatory protein. PIK3=phosphoinositide 3 kinase. PKC=protein kinase C. PLCγ=phospholipase C gamma. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. SYK=tyrosine protein kinase SYK. TMPRSS2=transmembrane serine protease 2. TNF=tumour necrosis factor.

Selva and colleagues90 compared the antibodies produced by children and adults against coronavirus proteins and found marked differences between the antibody responses in patients with COVID-19.

The varying responses were linked to different Fcγ receptor binding properties and antibody subgroup concentrations. Although studies in patients with MIS-C are needed, these research findings suggest that differences in antibody response might contribute to the hyperinflammatory response seen in adults with COVID-19.

Considering the similarities between the adult hyperinflammatory response and MIS-C, antibodies might play a role in both conditions. In a preprint study, Gruber and colleagues91 have reported that patients with MIS-C had neutralising antibodies against SARS-CoV-2, which are associated with interleukin-18 (IL-18) and IL-16 activation, myeloid chemotaxis, and activation of lymphocytes, monocytes, and natural killer cells.

Upregulation of the intercellular adhesion molecule 1 and Fc-γ receptor 1 on neutrophils and macrophages suggests enhanced antigen presentation and Fc-mediated responses. Gruber and colleagues91 also reported the presence of autoantibodies against endothelial, gastrointestinal, and immune cells in patients with MIS-C.

Antibodies to SARS-CoV might accentuate disease through antibody-dependent enhancement of viral entry and amplification of viral replication, as observed in dengue,92, 93, 94 or by triggering a host inflammatory response through the formation of immune complexes or direct anti-tissue antibody activation or cellular activation, or both.

Similar mechanisms might be involved in the inflammatory disorder associated with SARS-CoV-2. SARS-CoV-2 is not usually detected in patients with MIS-C; thus the antibody-dependent enhancement of inflammation is more likely to occur through an acquired immune response rather than increased viral replication.

Anti-spike antibodies against SARS-CoV have been shown to accentuate inflammation in primates and in human macrophages;95 therefore, the anti-spike antibodies against SARS-CoV-2 might also be able to trigger inflammation through a similar mechanism (figure 2).

Hoepel and colleagues96 have reported, in a preprint study, that immune complexes generated by linking patient anti-spike antibodies with spike protein cause macrophage activation, which supports the proposed mechanism for SARS-CoV-2.

The inflammatory disorders triggered by SARS-CoV-2 have features similar to Kawasaki disease and can also result in coronary aneurysms. This finding suggests that the virus might be acting as the immune trigger and causing a similar immune-mediated injury to the heart and coronary arteries as the one seen in Kawasaki disease.

Immune complexes have been well documented in Kawasaki disease,97, 98, 99, 100 and might mediate vascular injury by activation of inflammatory responses through the Fc-γ receptor or complement activation.

This theory is supported by the fact that genetic variants associated with Kawasaki disease include FCGR2A, B-lymphoid tyrosine kinase, and the CD40 ligand gene,101, 102, 103 which are genes involved in antibody production or clearance of immune complexes.

The development of T-cell responses to SARS-CoV-2 might also play a role in organ damage and inflammatory processes since increased T-cell responses were seen in Kawasaki disease. Genetic variants in the inositol 1,4,5-triphosphate 3-kinase C (ITPKC) gene, regulating T-cell activation,104 are associated with increased susceptibility to Kawasaki disease, and treatment with cyclosporin, which works by lowering T-cell activity, might have beneficial effects in the treatment of Kawasaki disease.105

The possible mechanisms for an acquired immune response to accentuate SARS-CoV-2 include:

(1) antibody or T-cell recognition of self-antigens (viral mimicry of the host) resulting in autoantibodies;

(2) antibody or T-cell recognition of viral antigens expressed on infected cells;

(3) formation of immune complexes which activate inflammation; and

(4) viral superantigen sequences which activate host immune cells.106

reference link : https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30651-4/fulltext


More information: Michael J. Carter et al, Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection, Nature Medicine (2020). DOI: 10.1038/s41591-020-1054-6

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