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REVIEW ARTICLE Table of Contents  
Ahead of print publication
Multisystem inflammatory syndrome in adults - In COVID-19


 Department of Medicine, MVJMC and RH, Bengaluru, Karnataka, India

Click here for correspondence address and email

Date of Submission23-Sep-2021
Date of Decision18-Oct-2021
Date of Acceptance18-Oct-2021
Date of Web Publication23-Feb-2022
 

  Abstract 


The spectrum of COVID-19 continues to evolve, uncovering several manifestations with every passing day. One of the complications is multisystem inflammatory syndrome (MIS) that occurs both in children and adults. MIS in children (MIS-C) has become a recognized syndrome, whereas a parallel syndrome in adults (MIS in adults [MIS-A]) has not been yet well defined. Due to the overlap between COVID 19 and MIS-A, we tend to miss cases of MIS-A. In this review, we have focused on MIS-A, its diagnostic criteria, pathogenesis, treatment, its relationship with vaccination, and differentiation from COVID 19.

Keywords: Anakinra, Kawasaki disease, multisystem inflammatory syndrome-adults, multisystem inflammatory syndrome-children


How to cite this URL:
Kamath V, Nivea B, Sheeba R. Multisystem inflammatory syndrome in adults - In COVID-19. APIK J Int Med [Epub ahead of print] [cited 2022 Sep 25]. Available from: https://www.ajim.in/preprintarticle.asp?id=338145





  Introduction Top


Coronavirus 2019 (COVID 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic which has strained health resources resulting in global healthcare crisis. As per WHO reports of 7th September 2021, there have been 221,134,742 confirmed cases of COVID-19. Among them, 97.9% have recovered accounting for 2.06% of deaths. Mortality was the most common in old adults, particularly with noncommunicable diseases.[1],[2],[3],[4] With 97.9% of survivors, it is now important for us to focus on the prolonged effects of the COVID 19 pandemic. Like postviral syndromes occurring in many viral diseases, COVID 19 is also characterized by persistent or prolonged effects affecting multiple organs with various manifestations. Although its more than a year of research with various studies on post COVID complications, still there are several complications hidden, which needs further research. One such complication is multisystem inflammatory syndrome (MIS), mostly noticed in children/pediatric age group. However, MIS-C-like illness has manifested in quite a few cases of adults too. Hence, our attempt has been made to discuss MIS in adults.


  Multisystem Inflammatory Syndrome Top


MIS is a parainfectious or postinfectious extrapulmonary complications of COVID-19, manifesting as febrile syndrome 2–6 weeks after SARS-CoV-2 with elevated inflammatory markers.[5],[6],[7],[8] Although it occurs rarely, it is a serious condition. It causes inflammation of different organs of the body including the heart, lungs, brain, kidney, skin, eyes, or gastrointestinal system.[9]

The multisystem inflammatory disease affects both children (MIS-C) and adults (MIS-A). MIS-C case definition includes people who are younger than 21 years old, and MIS-A case definition includes people who are 21 years and older.[9]


  Multisystem Inflammatory Syndrome-Children Top


When the COVID-19 pandemic began in China in late December 2019, case reports of COVID-19 were available for adults, with the pediatric illness being relatively rare. Evidence suggest that children are as likely as adults to become infected with COVID-19 but with mild clinical course not requiring hospitalization and with lower case fatality rates.[10] Hyper inflammatory syndrome in pediatric cases resembling Kawasaki disease and toxic shock syndrome was first reported in April 2020 in Europe.[11],[12] However, later several cases were reported from the United Kingdom, Italy, the United States, and elsewhere.[13],[14] Initially, it was called pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS).[15] Later US Centers for Disease Control and Prevention established the initial case definition and the name MIS in children (MIS-C) was coined.[15] These patients present with fever associated with any of the following symptoms like abdominal pain, red eyes, chest pain, diarrhea, easy fatigability, headache, neck pain, rash, vomiting, or hypotension. They mostly follow COVID-19 infection which is confirmed by positive COVID-19 serology in the majority of patients. Children with respiratory illness like asthma, those with cardiovascular complications, and immunosuppression are at increased risk. Children have been treated with anti-inflammatory treatment, including parenteral immunoglobulin and steroids. Although MIS-C is a serious complication requiring ICU admission, many children had a good prognosis with proper medical care.[9],[14]


  Multisystem Inflammatory Syndrome-Adults Top


Anecdotal reports of MIS-C-like illness have been reported in adults, raising concern that this rare presentation of COVID-19 may also have some penetrance into adult age groups called MIS-A. MIS-A came to attention when CDC reported the first case series in June 2020. It is still a topic of research, with very few cases reported globally till date.[7]

The patient should not have a more likely alternative diagnosis for the illness (e.g., bacterial sepsis, exacerbation of a chronic medical condition).

  1. Clinical Criteria
  2. Laboratory Evidence.



  Clinical Criteria Top


  1. Subjective fever or documented fever (≥38°C) for equal to or more than 24 h before hospitalization or within the first 3 days of hospitalization. And
  2. Minimum three of the following clinical criteria occurring before hospitalization or within the first 3 days of hospitalization. At least one must be a primary clinical criterion.[9]


Case definition for multisystem inflammatory syndrome in adults

A patient aged more than or equal to 21 years hospitalized for more than or equal to 24 h, or with an illness resulting in death, who meets the following clinical and laboratory criteria. The patient should not have a more likely alternative diagnosis for the illness (e.g., bacterial sepsis, exacerbation of a chronic medical condition).

  1. Clinical Criteria
  2. Laboratory Evidence.


    1. Subjective fever or documented fever (≥38°C) for equal to or more than 24 h before hospitalization or within the first 3 days of hospitalization. And
    2. Minimum three of the following clinical criteria occurring before hospitalization or within the first 3 days of hospitalization. At least one must be a primary clinical criterion.[9]


Primary clinical criteria

  • Severe cardiac illness includes myocarditis, pericarditis, coronary artery dilatation/aneurysm, or new-onset right or left ventricular dysfunction (LVEF <50%), 2nd/3rd degree A-V block, or ventricular tachycardia (Note: Cardiac arrest alone does not meet this criterion).
  • Rash and nonpurulent conjunctivitis.


Secondary clinical criteria

  • New-onset neurologic signs and symptoms include encephalopathy in a patient without prior cognitive impairment, seizures, meningeal signs, or peripheral neuropathy (including Guillain-Barré syndrome)
  • Shock or hypotension not attributable to medical therapy (e.g., sedation, renal replacement therapy)
  • Abdominal pain, vomiting, or diarrhea
  • Thrombocytopenia (platelet count <150,000/cumm).


These criteria must be met by the end of hospital day 3, where the date of hospital admission is hospital day 0.[9]


  Laboratory Evidence Top


The presence of laboratory evidence of inflammation and SARS-CoV-2 infection:

Elevated levels of at least two of the following:

  1. C-reactive protein, ferritin, IL-6, erythrocyte sedimentation rate, procalcitonin.
  2. A positive SARS-CoV-2 test during the current illness by RT-PCR, serology, or antigen detection.[9]



  Pathophysiology Top


The proposed COVID-19 infectious process includes three progressive clinical phases:[16],[17]

  • Stage I: Early infection phase, with clinical manifestations driven by actively replicating the virus
  • Stage II: Pulmonary phase, with an overlap of viral replication effects and host inflammatory response
  • Stage III: Hyperinflammation phase, with the pathophysiological process driven by the host inflammatory response.


The pathophysiology of MIS in both children and adults is currently unknown. It can be antibody-mediated process or dysregulated immune system uncommon complication of SARS COV 2 or due to diversity of phenotypes of MIS. With the high proportion of cases with positive antibodies, there is a possibility that antibodies can play a role in the pathophysiology of MIS-A. Antibodies can augment the inflammatory response by triggering the host immune response with the antibody-dependent enhancement of viral entry and amplification of viral replication as is similarly seen in dengue. It has also been suggested that the syndrome results from an abnormal immune response to the virus or an antibody-mediated process, with some clinical similarities to Kawasaki disease, toxic shock syndrome, and cytokine release syndrome. Thirty per cent of adults in a CDC report had negative PCR while testing positive for the SARS-CoV-2 antibody, suggesting MIS-A might represent a postinfectious process driven by dysregulated immune complex activation, causing direct endothelial damage and associated thrombo-inflammation and dysregulation of renin-angiotensin system. There is diversity in phenotype in not only among different persons but also among different age groups, younger children mostly presenting with mucocutaneous manifestations while myocarditis and gastrointestinal complications are more common in young adults.[15],[18]


  Treatment Top


Management of MIS-A is still a topic of research with the need for more studies to elaborate on the treatment modalities and clinical predictors. In the postinfectious phase of COVID-19, the initial recommendation for hyperimmune response particularly with MIS was published by the American College of Rheumatology on the role of immunoregulatory therapies, i.e., intravenous immunoglobulin and anakinra.[19]

IVIG influences the number and function of regulatory T-cells which help control inflammation based on its mechanism of action, IVIG is considered first-line therapy, and steroids can be used as adjunctive therapy in cases of distributive shock. The proposed starting dose of IVIG is 2 g/kg.[20],[21] Anakinra, a recombinant IL-1 receptor antagonist, is a well-known drug due to its role in the management of various autoimmune conditions. It has been shown to have a quick onset of action, short half-life (4 h), and a large therapeutic window. Moreover, anakinra is rather preferred over tocilizumab, because of its safety profile and lesser myelosuppressive and hepatotoxic effects.[22] In its recommendations regarding MIS-A, the American College of Rheumatology has mentioned that anakinra can be considered as an additional therapy in patients refractory to IVIG and glucocorticoids. The proposed starting dose of anakinra is over 4 mg/kg/day SC, with an eventual plan to taper the dose based on clinical recovery and resolution of the markers of inflammation.[16],[17],[23]


  Studies with Multisystem Inflammatory Syndrome-Adult Top


Since June 2020, significant number of cases of multisystem inflammatory syndrome adult has been reported

  • The first reported case series of CDC Morbidity and Mortality Weekly Reports by Morris et al. included 11 MIS-A patients based on data collected from March to August 2020, seven of whom presented with cardiogenic shock[6]
  • In October 2020, the CDC published an initial review of 27 cases with a clinical course consistent with MIS-A. These cases had heterogeneous involvement of cardiac, gastrointestinal, dermatological, and neurological symptoms without severe respiratory system involvement at presentation[17],[24],[25],[26]
  • Feldstein et al. in their study illustrated that as compared with severe COVID-19, patients with MIS are more likely to demonstrate cardiorespiratory involvement (56.0% vs. 8.8%) and cardiovascular without respiratory involvement (10.6% vs. 2.9%) on presentation[27]
  • Bastug et al. in a recent review of 51 cases with MIS-A highlighted that cardiovascular involvement has been the most frequently reported finding (82.4%), followed by gastrointestinal manifestations (72.5%)[17],[28]
  • Morris et al. and Bastug et al. have reported that in MIS initial COVID-19 may be asymptomatic[6],[28]
  • Feldstein et al. also demonstrated that more than 75% of patients have elevated CRP, ESR, Neutrophil count, and fibrinogen[29]
  • Morris et al. have also demonstrated the dysregulation of immune complex activation leading to endothelial damage and thrombo inflammation[6]
  • Bastug et al. and Heikimian et al. have demonstrated that though serology consistent with prior COVID 19 is necessary to fulfill the case definition of MISA it has poor prognostic and diagnostic role[28],[30]
  • Henderson et al. have demonstrated the role of immunoregulatory therapies in MIS-A.[19]


Multisystem inflammatory syndrome-children and multisystem inflammatory syndrome-adult

MIS-C and MIS-A are similar in several ways however MIS-C is more common than MIS-A with severe outcomes in adults due to differences in the immune system and underlying conditions. Unlike adult cases of acute COVID-19, most pediatric patients experience asymptomatic infection or mild COVID-19 symptoms, thus allowing a contrast between the diagnoses of acute COVID-19 and MIS-C but posing a challenge in adults.[9]


  COVID-19 and Multisystem Inflammatory Syndrome-Adult Top


The symptoms of acute COVID-19 and MIS-A are similar, posing difficulty to a clinician in differentiating them. It is likely that among those diagnosed with severe or critical acute COVID-19, a proportion are cases of MIS-A. Underscoring this challenge, the authors found that 60.0% of the patients with MIS-A had overlapping acute COVID-19 symptoms. Importantly, in MIS-A, initial COVID-19 infection can be asymptomatic too which has been further illustrated in a case-based review of 51 MIS-A cases, in which only 14 patients had previous symptomatic COVID-19 illness, while in the remaining cases the initial COVID-19 infection was asymptomatic. Although hyperinflammation and extrapulmonary organ dysfunction have been described in hospitalized adults with severe COVID-19, they are generally accompanied by respiratory failure. In contrast, patients of MIS-A have minimal respiratory symptoms, hypoxemia, or radiographic abnormalities in accordance with the working case definition, which was meant to distinguish MIS-A from severe COVID-19.[6],[17]


  Postvaccination and Multisystem Inflammatory Syndrome-Adult Top


Case reports of MIS-A following COVID 19 vaccination have been reported.[31],[32],[33],[34] The timeline could be similar to MIS happening postinfection (i. e.) 4–6 weeks postvaccination in children and 12 weeks in adults. Clinical features and management are the same, the Vaccine Adverse Event Reporting System co-managed by CDC and the US Food and Drug Administration used for monitoring adverse reactions following COVID 19 vaccine have added MIS C/A as an adverse event postvaccination.[35]


  Conclusion Top


Our understanding of the myriad of COVID-19 symptoms and sequelae is rapidly evolving. We recommend the physicians to remain vigilant for inflammatory syndromes that mimic Kawasaki disease/Toxic shock syndrome which may warrant prompt treatment with IVIG and steroids. Further research is needed to understand the pathogenesis and long-term effects of this condition. Ultimately, the recognition of MIS-A reinforces the need for preventive efforts to limit the spread of SARS-CoV-2.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Vasantha Kamath,
Department of Medicine, MVJMC and RH, Hoskote, Bengaluru - 562 114, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_100_21





 

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Abstract
Introduction
Multisystem Infl...
Multisystem Infl...
Multisystem Infl...
Clinical Criteria
Laboratory Evidence
Pathophysiology
Treatment
Studies with Mul...
COVID-19 and Mul...
Postvaccination ...
Conclusion
References

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