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Multisystem inflammatory syndrome post-SARS-CoV-2 infection: A case series

      To the Editor
      Multisystem inflammatory syndrome (MIS) is a hyperinflammatory condition that can happen weeks after a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection hallmarked by a hyperinflammatory state, cardiac injury, and/or shock. As cases of SARS-CoV-2 continue to persist it is imperative for clinicians to be aware of short- and long-term sequelae of these infections. MIS was first identified in children (MIS-C) in Spring of 2020 and adults (MIS-A) in early 2021. After this, the Centers for Disease Control (CDC) published a case series along with a way to report cases of MIS directly.
      • Morris SB
      • Schwartz NG
      • Patel P
      • et al.
      Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020.
      Our cases were not submitted to the CDC and thus have not been included in the current literature. Very little is known about the pathologic mechanism of this condition and literature regarding MIS-A remains sparse despite numerous studies on MIS-C. MIS-A shares many of the same characteristics as MIS-C, and if not recognized and treated promptly, it can lead to severe complications.
      We identified four patients who were treated for MIS between December 2020 and March 2021 at two academic tertiary care hospitals. Three patients met the CDC Case Definition for MIS-A, and one met criterion for MIS-C.
      Centers for Disease Control and Prevention
      Multisystem inflammatory syndrome in adults (mis-A) case definition information for healthcare providers.
      ,
      • Henderson LA
      • Canna SW
      • Friedman KG
      • Gorelik M
      • Lapidus SK
      • Bassiri H
      • et al.
      American College of Rheumatology Clinical Guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19. Version 1.
      Analysis of each patient's hospitalization was conducted examining laboratory results, diagnostics, and clinical indicators of disease severity including vasopressor requirement and length of ICU stay.
      The demographics, comorbidities, and clinical outcomes are described in Table 1. All patients were Black, aged between 20 – 42 years, three were male and two were obese. All patients presented with constitutional symptoms of fever, chills, and myalgias, three had gastrointestinal symptoms (abdominal pain, nausea, vomiting, or diarrhea) and two had cardiopulmonary manifestations (chest pain, shortness of breath, or cough). All patients met systemic inflammatory response syndrome (SIRS) criteria and required the intensive care unit (ICU) during their hospitalization. All had a negative SARS-CoV-2 RT-PCR but positive serology (IgG and IgM positive: n=2; IgG positive: n=3; IgM positive n=3). Of note, skin manifestations were not seen in our patients, which is one primary clinical criterion for MIS-A. However, all our patients exhibited severe cardiac dysfunction based on transthoracic echocardiogram (TTE), which would satisfy the primary clinical criterion based on the case definition for MIS-A.
      Centers for Disease Control and Prevention
      Multisystem inflammatory syndrome in adults (mis-A) case definition information for healthcare providers.
      TTE revealed reduced left ventricular ejection fraction (LVEF) in all patients. Two had left heart catheterization (LHC), and both demonstrated normal coronary arteries. Laboratory findings showed marked elevation of C-reactive protein (CRP), procalcitonin, ferritin, d-dimer, troponin, and B-type natriuretic peptide (BNP). All patients were hypotensive but only two patients required vasopressors.
      TABLE 1Demographics, presentation, clinical findings, treatment, and outcomes of patients with MIS treated in adult hospitals.
      Average:Patient 1Patient 2Patient 3Patient 4
      Demographics
      Age (y), Sex30.5 (+/- 11.62)21, Male20, Male39, Female42, Male
      RaceBlackBlackBlackBlack
      BMI28.85 (+/- 5.61)21.527.532.633.8
      Medical HistoryNo reported PMHGunshot wound w/ nephrectomy + small bowel resection.PreeclampsiaHTN
      Clinical Presentation
      Presenting symptomsHeadache, fever, anorexia due to nausea/vomiting, diarrhea, neck/back painFever, abdominal pain, nausea/vomiting, diarrhea, muscle achesHeadache, fever, chills, abdominal pain, nausea/vomiting, body aches, sore throat, chest painFever, chills, shortness of breath, cough, muscle aches, chest pain
      Admission VitalsT 39.4C, BP 140/81 mmHg, HR 123 bpm, 100% on RAT 39.2C, BP 132/81 mmHg, HR 103 bpm, 99% on RAT 39.5C, BP 97/60 mmHg, HR 139 bpm, 100% on RAT 39.3, BP 131/75 mmHg, HR 110 bpm, 99% on RA
      Peak Temperature (C)39.55 (+/- 0.1)39.539.739.539.5
      Lowest BP (mmHg)77.25/5083/4772/4666/4888/59
      Laboratory Results
      Peak Creatinine (mg/dL)1.76 (+/- 0.78)1.1

      Reference Range:

      0.5-1.2 mg/dL
      2.8

      Reference Range:

      0.5-1.2 mg/dL
      1.23

      Reference Range: 0.52-1.21 mg/dL
      1.9

      Reference Range:

      0.52-1.21 mg/dL
      Peak CRP333.5 (+/- 84.59)263

      Reference Range:

      0.00-0.50 mg/dL
      379

      Reference Range:

      0.00-0.50 mg/dL
      430

      Reference Range: <3.00 mg/L
      262

      Reference Range: <3.00 mg/L
      Peak Procalcitonin (ng/ml)42.77 (+/- 44.53)9.46

      Reference Range:

      0.00-0.50 ng/mL
      47.91

      Reference Range:

      0.00-0.50 ng/mL
      9.85

      Reference Range:

      0.5-2.0 ng/mL
      103.84

      Reference Range:

      0.5-2.0 ng/mL
      Peak Ferritin (ng/mL)(1548.35 (+/- 914.60)1853.1

      Reference Range:

      11.0-306.8 ng/mL
      2103.1

      Reference Range:

      11.0-306.8 ng/mL
      186

      Reference Range:

      8.0-252 ng/mL
      2051.2

      Reference Range:

      8.0-252 ng/mL
      Peak D-Dimer8.09 (+/- 3.32)11.87

      Reference Range:

      0.00-0.50 mcg/mL
      9.24

      Reference Range:

      0.00-0.50 mcg/mL
      4

      Reference Range:

      0.00-0.44 FEU/mL
      7.25

      Reference Range:

      0.00-0.44 FEU/mL
      Peak Troponin (ng/mL)0.23 (+/- 0.16)0.11

      Reference Range:

      0.00-0.034 ng/mL
      0.19

      Reference Range:

      0.00-0.034 ng/mL
      0.465

      Reference Range:

      0.00-0.045 ng/mL
      0.173

      Reference Range:

      0.00-0.045 ng/mL
      Peak BNP (pg/mL)1463 (+/- 44.53)1808

      Reference Range:

      0.0-100 pg/mL
      940

      Reference Range:

      0.0-100 pg/mL
      3600

      Reference Range:

      <125 pg/mL
      1641

      Reference Range:

      <125 pg/mL
      Microbiology Results
      SARS-CoV-2 PCRNegativeNegativeNegativeNegative
      SARS-CoV-2 IgMPositivePositiveNot testedPositive
      SARS-CoV-2 IgGPositiveNot testedPositivePositive
      Blood CulturesNo growth, 2 setsNo growth, 2 setsNo growth, 2 setsNo growth, 4 sets
      Imaging Results
      Initial CXRNormalScattered granulomatous changes; no acute CP findingsNormalNormal
      Initial CTNo PE and no abnormal lung findings.Bilateral small pleural effusions with bilateral consolidations with adjacent GGOs.Bibasilar atelectasis.Medial left lung base opacity.
      Initial TTELVEF 20-25% with stage II diastolic dysfunction; global hypokinesis; RVSP 35-40mmHg; mild tricuspid regurgSevere global LV systolic dysfunction w/ LVEF 10-15%; unable to eval diastolic function; RVSP 30-35mmHgLVEF 25-30% with global hypokinesisLVEF 25-30% with global hypokinesis
      Follow up TTENoneNormal LV systolic function with LVEF 55-60%LVEF 50-55% with normal regional wall motionNone
      LHCNoneNoneNormal coronary arteries, nonischemic cardiomyopathyNormal coronary arteries, LVEF 35-40%, global hypokinesis
      Treatment
      IV SteroidMethylprednisoloneMethylprednisoloneMethylprednisoloneMethylprednisolone
      IVIGYesYesYesYes
      Pressor requirement?NoneNorepinephrineNorepinephrineNone
      Length of time on Pressors (days)1.75 (+/- 2.06)0340
      Respiratory SupportNIPPVHFNCNCNC
      Length of stay in ICU (days)3.75 (+/- 0.96)3453
      OutcomeDischarged homeDischarged homeDischarged home with home healthDischarged against medical advice
      Length of stay in hospital (days)11.25 (+/- 1.71)9111213
      All patients were treated with intravenous (IV) methylprednisolone and IV immunoglobulins (IVIG). All patients required respiratory support; nasal cannula (NC) (n = 2), high flow nasal cannula (HFNC) (n = 1), non-invasive positive pressure ventilation (NIPPV) (n = 1). Two patients had a repeat TTE after treatment, and both demonstrated normalization of LVEF. Ultimately, all patients were discharged home.
      This case series describes a hyperinflammatory state previously identified in recently published cases as MIS.
      • Morris SB
      • Schwartz NG
      • Patel P
      • et al.
      Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020.
      ,
      • Chau VQ
      • Giustino G
      • Mahmood K
      • et al.
      Cardiogenic shock and hyperinflammatory syndrome in young males with COVID-19.
      ,
      • Hékimian G
      • Kerneis M
      • Zeitouni M
      • et al.
      Coronavirus Disease 2019 acute myocarditis and multisystem inflammatory syndrome in adult intensive and cardiac care units.
      ,
      • Patel P
      • DeCuir J
      • Abrams J
      • Campbell AP
      • Godfred-Cato S
      • Belay ED.
      Clinical characteristics of multisystem inflammatory syndrome in adults: a systematic review.
      It remains unclear if there is a genetic or social predisposition to developing MIS. All patients in our case series were black. While this could represent local demographics of our area hospitals, where the black population represents 64.1% of Memphis and 54.3% of Shelby County, it should be noted that a disproportionate amount of ethnic minority groups develops MIS
      • Morris SB
      • Schwartz NG
      • Patel P
      • et al.
      Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020.
      ,
      • Patel P
      • DeCuir J
      • Abrams J
      • Campbell AP
      • Godfred-Cato S
      • Belay ED.
      Clinical characteristics of multisystem inflammatory syndrome in adults: a systematic review.
      , which was again demonstrated in our case series. This concept could be explored further as more cases develop to adequately assess any genetic or social predispositions.
      MIS is a unique condition, and more studies need to be done to further link or differentiate MIS-A and MIS-C. Fortunately, MIS appears to respond well to anti-inflammatory treatments and immune modulation resulting in a relatively low mortality rate highlighting the possibility of immune mediated injury as an underlying mechanism for MIS-A.
      • Henderson LA
      • Canna SW
      • Friedman KG
      • Gorelik M
      • Lapidus SK
      • Bassiri H
      • et al.
      American College of Rheumatology Clinical Guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19. Version 1.
      The American College of Rheumatology have published guidelines on the treatment of MIS-C, however no guidelines on the treatment of MIS-A have been established. Treatment focuses on immune modulation which includes IVIG, steroids, and anakinra.
      • Henderson LA
      • Canna SW
      • Friedman KG
      • Gorelik M
      • Lapidus SK
      • Bassiri H
      • et al.
      American College of Rheumatology Clinical Guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19. Version 1.
      All of our patients received medical therapy consistent with MIS-C treatment guidelines including steroids and intravenous immunoglobulins at the time of their illness and improved.
      Additionally, all our patients exhibited cardiac dysfunction which has occurred in an estimated 60% of patients with MIS-A according to a recent systematic review.
      • Patel P
      • DeCuir J
      • Abrams J
      • Campbell AP
      • Godfred-Cato S
      • Belay ED.
      Clinical characteristics of multisystem inflammatory syndrome in adults: a systematic review.
      This suggests that MIS-A may have a component of myocarditis and myocardial injury.
      • Chau VQ
      • Giustino G
      • Mahmood K
      • et al.
      Cardiogenic shock and hyperinflammatory syndrome in young males with COVID-19.
      ,
      • Hékimian G
      • Kerneis M
      • Zeitouni M
      • et al.
      Coronavirus Disease 2019 acute myocarditis and multisystem inflammatory syndrome in adult intensive and cardiac care units.
      Furthermore, the CDC recently established a case definition for MIS-A where severe cardiac illness is listed as a primary clinical criterion which includes myocarditis, pericarditis, coronary artery dilatation/aneurysm, new onset right or left ventricular dysfunction, 2nd/3rd degree heart block, and ventricular tachycardia.
      Centers for Disease Control and Prevention
      Multisystem inflammatory syndrome in adults (mis-A) case definition information for healthcare providers.
      It is also important to note that MIS-A can be difficult to differentiate from primary SARS-CoV-2 as evidenced by the fact that both conditions usually produce a hyperinflammatory state. However, MIS-A typically involves extrapulmonary symptoms and is heralded by a past SARS-CoV-2 infection with MIS-A symptoms starting around four weeks after the initial infection.
      • Patel P
      • DeCuir J
      • Abrams J
      • Campbell AP
      • Godfred-Cato S
      • Belay ED.
      Clinical characteristics of multisystem inflammatory syndrome in adults: a systematic review.
      We also recognize that the number of cases of MIS that we observed were disproportionately high considering the rarity of the condition. This could be attributed to the high number of SARS-CoV-2 cases we saw in our region and the subsequent surge in cases during that time. Our hospital also has a high proportion of physicians who concurrently care for hospitalized children, so familiarity with MIS-C may have contributed to earlier recognition. In response to this, we did develop hospital guidelines for recognition, diagnosis, and treatment in April 2021 which were approved by hospital administration and disseminated to the medical staff.
      These cases emphasize the need for recognition and diagnosis of MIS-A, especially in the absence of alternative diagnoses. All patients had negative blood cultures, no source for their severe sepsis, and progressive clinical deterioration. This study demonstrates that more work needs to be done to further examine MIS-A/C, develop treatment algorithms for adult hospitals, and explore its short- and long-term effects in all patient outcomes.

      Funding

      We have no financial disclosures.

      Disclosure

      Institutional Review Board approval was obtained prior to our study.

      Conflicts of Interest

      We declare no competing interests.

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        • Friedman KG
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        • Lapidus SK
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