Article ID: CJ-23-0914
Background: Multisystem inflammatory syndrome (MIS) is a hyperinflammatory shock associated with cardiac dysfunction and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there are no reports on using MIS criteria, such as multisystemic inflammation (MSI) in fulminant myocarditis, without SARS-CoV-2 infection. This study investigated the differences in clinical characteristics and course between patients with fulminant lymphocytic myocarditis (FLM) plus MSI and those without MSI.
Methods and Results: This multicenter retrospective cohort study included 273 patients with FLM registered in the JROAD-DPC database between April 2014 and March 2017. We evaluated the presence of MSI using criteria modified from previously reported MIS criteria and compared the characteristics and risk of mortality or heart transplantation between FLM patients with MSI and without MSI. Of the 273 patients with FLM, 107 (39%) were diagnosed with MSI. The MSI group was younger (44 vs. 57 years; P<0.0001) and had more females (50% vs. 36%; P=0.0236), a higher incidence of pericardial effusion (58% vs. 40%; P=0.0073), and a lower 90-day mortality rate (19% vs. 33%; P=0.0185) than the non-MSI group. The risk of mortality at 90 days was lower in FLM patients aged <50 years with MSI aged <50 years than in those without MSI (P=0.0463).
Conclusions: These results suggest that MSI may influence the prognosis of FLM, especially in patients aged <50 years.
Myocarditis is an inflammatory myocardial disease often resulting from viral infections or autoimmune disorders.1 Fulminant myocarditis (FM) is a rare, serious condition that requires treatment with intravenous inotropes or mechanical circulatory support.2 However, the mechanisms underlying myocardial inflammation in FM remain unclear. Predicting the prognosis of patients with FM is challenging because of a lack of evidence.
Some children develop a life-threatening hyperinflammatory state 1–6 weeks after primary COVID-19 infection, termed multisystem inflammatory syndrome in children (MIS-C).3 A similar condition is known as a rare complication of COVID-19 in adults (MIS-A),4 and often leads to cardiac dysfunction, including myocarditis.4 Reportedly, adult patients with fulminant COVID-19-related myocarditis have different prognoses based on the presence of multisystem inflammatory syndrome (MIS).5
Approximately 90% of cases of myocarditis are lymphocytic,6 mostly caused by viruses that may directly damage tissues in humans, act as triggers for autoimmunity-mediated damage, or both.7 However, it is unclear whether the criteria for MIS can differentiate between the characteristics and clinical course of FM associated with viruses other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The aim of this study was to evaluate the clinical usefulness of multisystemic inflammation (MSI) defined using the criteria for MIS in fulminant lymphocytic myocarditis (FLM) unrelated to SARS-CoV-2 infection and to compare differences in the characteristics and clinical course between patients with and without MSI. We also aimed to compare 2 groups classified by age 50 years based on previous studies on cardiovascular diseases.8–12
Based on The Japanese Registry of Fulminant Myocarditis, this study is a multicenter retrospective cohort study performed in collaboration with 235 facilities across Japan (Supplementary Appendix).13 First, patients with myocarditis (International Classification of Diseases 10th Revision codes I40, I41, or I423) in the Japanese Registry of All Cardiac and Vascular Diseases – Diagnosis Procedure Combination (JROAD-DPC) discharge database between April 2012 and March 2017 were identified. Subsequently, patients with FM were grouped into those requiring treatment with mechanical circulatory support, or intravenous inotropes.2
Furthermore, we selected patients with FLM, which was defined histologically based on previous studies14 in addition to the clinical diagnostic criteria of the European Society of Cardiology15 or the Japanese Circulation Society16 and the histologic definitions of the World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) criteria.17
Individual patient data (retrospective anonymous data) and treatment details during hospitalization were collected from each facility. The data were uploaded to Research Electronic Data Capture (REDCap; Vanderbilt University).
This study complied with the Declaration of Helsinki, and the study protocol was approved by locally appointed ethics committees at Nagasaki University and the Japanese Circulation Society (Registration no. 20081719-4 and 10, respectively).
OutcomesThe primary outcome was all-cause mortality at 90 days. Secondary outcomes were ventricular tachycardia (VT), ventricular fibrillation (VF), and advanced atrioventricular block. Because MIS occurred in younger people, we compared 2 groups classified by age 50 years based on previous studies of cardiovascular diseases.8–12
VariablesWe defined MSI based on the MIS criteria reported by Vogel et al,18 except for mucocutaneous clinical features, erythrocyte sedimentation rate, ferritin, procalcitonin, neutrophilia, lymphopenia, and thrombocytopenia, because they were not included in this study. We also added respiratory symptoms. Thus, the definition of MSI was as follows:
the presence of fever
the presence of ≥2 of the following clinical features: (1) gastrointestinal symptoms (abdominal pain, vomiting, diarrhea); (2) shock/hypotension; (3) neurologic features (altered mental status, headache, weakness, paresthesia, lethargy); and (4) respiratory symptoms (sputum, cough, rhinorrhea).
Characteristics and events were compared between the MSI(−) and MSI(+) groups. Information on demographic characteristics, prodromal symptoms, medical history, clinical, laboratory, electrocardiogram, and echocardiographic findings on admission, histologic findings of the biopsied myocardium, medications administered during hospitalization, temporary mechanical circulatory support, and events was collected.
The severity of myocarditis was categorized as mild or severe using the following semiquantitative scale: (1) mild, damaged cardiomyocytes account for less than half of all cardiomyocytes; (2) severe, damaged cardiomyocytes account for more than half of all cardiomyocytes.
Statistical AnalysesBaseline characteristics were summarized as median and interquartile range (IQR) for continuous variables or as counts with percentages for categorical variables. Characteristics between age groups were compared using the Wilcoxon rank-sum test or Fisher’s exact test, as appropriate.
We used the Kaplan-Meier method and log-rank tests to evaluate the association between MSI and mortality in patients with FLM. In addition, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using the Cox proportional hazards model to assess the contribution of baseline characteristics to the primary outcome by age group. All hypothesis tests were 2-sided, and statistical significance was set at P<0.05. Given the absence of corrections for multiple comparisons, the findings were interpreted as exploratory. All analyses were performed using JMP statistical software (JMP 17Pro; SAS Institute, Cary, NC, USA).
Of the 1,327 patients identified as having FM presentations from the 2,511 patients with suspected myocarditis in the JROAD-DPC database, 819 were hospitalized in 235 facilities with permission that they were eligible for inclusion in this study. Among these patients, 736 patients were identified with clinically suspected FM. The 329 who did not undergo histological diagnosis, the 23 who did not have histological findings, and the 40 who did not meet the WHO/ISFC criteria were excluded from the study. From the 344 patients with histologically diagnosed with FM, 51 with eosinophilic myocarditis and 20 with giant cell myocarditis were excluded, leaving 273 patients with FLM who were included in the study. Figure 1 shows a flowchart of patient inclusion/exclusion.
Study flow chart of the Japanese Registry of Fulminant Myocarditis. ESC, European Society of Cardiology; ICD-10, International Classification of Disease 10th revision; ISFC, International Society and Federation of Cardiology; JCS, Japanese Circulation Society; JROAD-DPC, Japanese Registry of All Cardiac and Vascular Diseases – Diagnostic Procedure Combination; WHO, World Health Organization.
Characteristics of the study population are summarized in Table 1. The median age was 54 years (IQR 39–64 years), and 114 (42%) patients were women. Of the 273 patients in the study, 107 (39%) met the criteria for MSI (the frequency of each item of the MSI criteria is provided in the Supplementary Table), and 223 (85%) had New York Heart Association functional class III and IV. MSI was more common in younger patients (Figure 2). On admission, the median white blood cell count was 9,180/mm3 (IQR 6,800–12,550/mm3) and C-reactive protein (CRP) was 4.7 mg/dL (IQR 1.75–10.15 mg/dL). Cardiac troponin levels were elevated in 92% of patients. The median left ventricular ejection fraction (LVEF) was 30.5% (IQR 20–45%). Intravenous steroids and immunoglobulins were used in 137 (50%) and 101 (37%) patients, respectively. Furthermore, 218 (79%), 144 (52%), and 37 (14%) patients were treated with an intra-aortic balloon pump, venoarterial extracorporeal membrane oxygenation (VA-ECMO), and a left ventricular assist device, respectively.
Clinical Characteristics in All Patients (n=273) and in Patients With and Without Multisystemic Inflammation Separately
| Characteristics | No. patients with available data |
All patients | MSI(−) (n=166) |
MSI(+) (n=107) |
P value |
|---|---|---|---|---|---|
| Age (years) | 273 | 54 [39–64] | 57 [41–67] | 44 [34–58] | <0.0001 |
| Female sex | 273 | 114 (42) | 60 (36) | 54 (50) | 0.0236 |
| Prodromal symptoms | |||||
| Fever | 273 | 200 (73) | 93 (56) | 107 (100) | <0.0001 |
| Headache | 273 | 22 (8.0) | 1 (0.6) | 21 (19) | <0.0001 |
| Respiratory syndrome | 273 | 81 (29) | 23 (13) | 58 (54) | <0.0001 |
| Gastrointestinal symptoms | 273 | 72 (26) | 23 (13) | 49 (45) | <0.0001 |
| MSI | 273 | 107 (39) | 0 (0) | 107 (100) | – |
| Medical history | |||||
| Hypertension | 273 | 55 (20) | 41 (24) | 14 (13) | 0.0208 |
| Diabetes | 273 | 20 (7.3) | 17 (10) | 3 (2.8) | 0.0300 |
| Chronic kidney disease | 273 | 7 (2.6) | 3 (1.8) | 4 (3.7) | 0.4380 |
| Clinical findings on admission | |||||
| BMI (kg/m2) | 261 | 22 [20–25] | 22 [20–25] | 23 [20–24.5] | 0.9717 |
| SBP (mmHg) | 267 | 97 [83–114] | 100 [86–115] | 93 [80–111] | 0.1271 |
| Body temperature (℃) | 249 | 37 [36–38] | 37 [36–37] | 37 [36–38] | 0.1026 |
| NYHA Class III or IV | 261 | 223 (85) | 137 (85) | 86 (85) | 1.0000 |
| CPA on admission | 270 | 3 (1.1) | 2 (1.2) | 1 (1.1) | 1.0000 |
| Laboratory data on admission | |||||
| WBC (/μL) | 273 | 9,180 [6,800–12,550] |
9,060 [6,490–12,575] |
9,400 [7,000–12,600] |
0.3895 |
| eGFR (mL/min/1.73 m2) | 273 | 55 [36–76] | 49 [33–72] | 62 [42–80] | 0.0154 |
| CRP (mg/dL) | 269 | 4.7 [1.75–10.15] | 4.75 [1.5–10.2] | 4.7 [2.1–9.8] | 0.7300 |
| Elevated CRPA | 269 | 258 (95) | 151 (93) | 107 (100) | 0.0038 |
| BNP (pg/mL) | 219 | 525 [318–1,023] | 518 [313–1,065] | 549 [338–886] | 0.8339 |
| NT-proBNP (pg/mL) | 58 | 7,940 [2,693–20,635] |
8,740 [2,512–24,449] |
7,936 [4,525–15,113] |
0.9208 |
| Elevated troponinB | 244 | 224 (92) | 134 (91) | 90 (91) | 1.0000 |
| Creatinine kinase (IU/L) | 272 | 742 [417–1,349] | 685 [383–1,385] | 757.5 [471–1,290] | 0.2936 |
| ECG findings on admission | |||||
| Sinus rhythm | 272 | 190 (69) | 117 (70) | 73 (68) | 0.7878 |
| QRS duration (ms) | 249 | 120 [94–143] | 121 [97–143] | 120 [90–142] | 0.3520 |
| ST elevation | 272 | 176 (64) | 107 (64) | 69 (65) | 1.0000 |
| VT/VF | 270 | 62 (22) | 36 (21) | 26 (24) | 0.6581 |
| Echocardiography | |||||
| LVDd (mm) | 217 | 46 [42–50] | 47 [42–50] | 46 [42–50] | 0.5650 |
| LVEF (%) | 262 | 30.5 [20–45] | 30 [20–45] | 31 [19–42] | 0.1332 |
| Pericardial effusion | 253 | 122 (48) | 61 (40) | 61 (58) | 0.0072 |
| Histologic findings (severity of myocarditis) | |||||
| Severe type | 162 | 67 (41) | 39 (40) | 28 (44) | 0.6284 |
| Medication during hospitalization | |||||
| β-blocker | 273 | 152 (55) | 85 (51) | 67 (62) | 0.0805 |
| ACEi/ARB | 273 | 159 (58) | 96 (57) | 63 (58) | 0.9004 |
| Intravenous steroids | 273 | 137 (50) | 76 (45) | 61 (57) | 0.0828 |
| IVIG | 272 | 101 (37) | 57 (34) | 44 (41) | 0.1665 |
| Inotropes | 273 | 265 (97) | 160 (96) | 105 (98) | 0.4875 |
| Temporary MCS devices | |||||
| IABP | 273 | 218 (79) | 130 (78) | 88 (82) | 0.4451 |
| VA-ECMO | 273 | 144 (52) | 85 (51) | 59 (55) | 0.5373 |
| Ventricular assist device | 273 | 37 (14) | 19 (11) | 18 (16) | 0.2107 |
| Event | |||||
| 90-day mortality | 273 | 76 (27) | 55 (33) | 21 (19) | 0.0185 |
| Death and TX | 273 | 84 (30) | 63 (37) | 21 (19) | 0.0013 |
| VT | 273 | 90 (33) | 55 (33) | 35 (32) | 1.0000 |
| VF | 273 | 45 (16) | 24 (14) | 21 (19) | 0.3163 |
| Advanced AV block | 273 | 91 (34) | 56 (33) | 35 (32) | 0.8959 |
Unless indicated otherwise, values are presented as n (%) or as the median [interquartile range]. AElevated C-reactive protein (CRP) was defined as CRP >0.3 mg/dL. BElevated troponin was defined as troponin >0.02 ng/mL or qualitative test positive. ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; AV block, atrioventricular block; BMI, body mass index; BNP, B-type natriuretic peptide; CPA, cardiopulmonary arrest; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; IABP, intra-aortic balloon pumping; IVIG, intravenous immunoglobulin; LVDd, left ventricular diastolic dimension; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; MSI, multisystemic inflammation; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; TX, cardiac transplantation; VA-ECMO, veno-arterial extracorporeal membrane oxygenation; VF, ventricular fibrillation; VT, ventricular tachycardia; WBC, white blood cell count.
Distribution of multisystemic inflammation by age. The number of patients with multiple systemic inflammation increased significantly from the lowest to the highest age quartile (P=0.0005). Q1, 16–38 years; Q2, 39–53 years; Q3, 54–63 years; Q4, 64–91 years.
Patients in the MSI(+) group were younger (median 44 years; IQR 33–58 years) than those in the MSI(−) group (median 57 years; IQR 42–67 years; P<0.0001; Table 1). In addition, the MSI(+) group had a greater proportion of women (54 [50%] vs. 60 [36%]; P=0.0236) and patients with elevated CRP (107 [100%] vs. 151 [93%]; P=0.0038) and pericardial effusion (61 [58%] vs. 61 [41%]; P=0.0072) that the MSI(−) group (Table 1). There was no significant difference in the severity of myocarditis between the MSI(−) and MSI(+) groups (severe myocarditis 40% vs. 44%, respectively; P=0.6284; Table 1).
Comparing patients aged ≥50 and <50 years (Table 2), the group aged <50 years (median age 36 years) had more MSI (64 [52%] vs. 43 [28%]; P<0.0001), lower systolic blood pressure (91 [IQR 80–107] vs. 100 [IQR 86–117] mmHg; P=0.0134), lower LVEF (30% [IQR 20–40%] vs. 35% [IQR 20–46%]; P=0.0208), lower 90-day mortality (20 [16%] vs. 56 [36%]; P=0.0002), and fewer events of death and cardiac transplantation (21 [17%] vs. 63 [41%], P<0.0001) than the group aged ≥50 years (median 63 years).
Clinical Characteristics of Younger (Age <50 Years) and Older (Age ≥50 Years) Patients (Total n=273)
| Characteristics | No. patients with available data |
Age <50 years (n=121) |
Age ≥50 years (n=152) |
P value |
|---|---|---|---|---|
| Demographic findings | ||||
| Age (years) | 273 | 36 [27–42] | 63 [57–69] | <0.0001 |
| Female sex | 273 | 57 (47) | 57 (37) | 0.1381 |
| Prodromal symptoms | ||||
| Fever | 273 | 103 (85) | 97 (63) | <0.0001 |
| Headache | 273 | 11 (9) | 11 (8) | 0.6566 |
| Respiratory syndrome | 273 | 40 (33) | 41 (26) | 0.2886 |
| Gastrointestinal symptoms | 273 | 38 (31) | 34 (22) | 0.0989 |
| MSI | 273 | 64 (52) | 43 (28) | <0.0001 |
| Medical history | ||||
| Hypertension | 273 | 2 (1) | 53 (34) | <0.0001 |
| Diabetes | 273 | 3 (2) | 17 (11) | 0.0086 |
| Chronic kidney disease | 273 | 3 (2) | 4 (2) | 1.0000 |
| Clinical findings on admission | ||||
| BMI (kg/m2) | 261 | 21 [20–24] | 23 [21–25] | 0.0030 |
| SBP (mmHg) | 267 | 91 [80–107] | 100 [86–117] | 0.0134 |
| Body temperature (℃) | 249 | 37 [36–38] | 37 [36–37] | 0.0041 |
| NYHA Class III or IV | 261 | 100 (85) | 123 (85) | 1.0000 |
| CPA on admission | 271 | 1 (0.8) | 2 (1.3) | 1.0000 |
| Laboratory data on admission | ||||
| WBC (/μL) | 273 | 9,700 [7,000–13,850] | 8,700 [6,640–11,515] | 0.0543 |
| eGFR (mL/min/1.73 m2) | 273 | 70 [43–86] | 46 [30–65] | <0.0001 |
| CRP (mg/dL) | 269 | 3.8 [1.5–8.6] | 5.6 [2.1–10.8] | 0.0755 |
| Elevated CRPA | 269 | 115 (95) | 143 (96) | 0.5502 |
| BNP (pg/mL) | 219 | 477 [298–817] | 596 [337–1,141] | 0.0533 |
| NT-proBNP (pg/mL) | 58 | 7,192 [2,144–14,824] | 10,931 [3,529–28,076] | 0.0556 |
| Elevated troponinB | 245 | 95 (88) | 129 (94) | 0.1597 |
| Creatinine kinase (IU/L) | 273 | 665 [300–1,319] | 763 [457–1,360] | 0.1518 |
| ECG findings on admission | ||||
| Sinus rhythm | 272 | 87 (71) | 103 (68) | 0.5951 |
| QRS duration (ms) | 249 | 119 [89–140] | 124 [99–144] | 0.1403 |
| ST elevation | 272 | 80 (66) | 96 (63) | 0.7027 |
| VT/VF on admission | 273 | 35 (29) | 27 (18) | 0.0410 |
| Echocardiography | ||||
| LVDd (mm) | 218 | 47 [42–51] | 46 [41–50] | 0.4584 |
| LVEF (%) | 262 | 30 [20–40] | 35 [20–46] | 0.0208 |
| Pericardial effusion | 253 | 60 (51) | 62 (45) | 0.3154 |
| Medication during hospitalization | ||||
| β-blocker | 273 | 70 (57) | 82 (53) | 0.5416 |
| ACEi/ARB | 273 | 80 (66) | 79 (51) | 0.0195 |
| Intravenous steroids | 273 | 58 (49) | 79 (51) | 0.5434 |
| IVIG | 272 | 50 (41) | 51 (33) | 0.2063 |
| Inotropes | 273 | 117 (96) | 148 (97) | 0.7359 |
| Temporary MCS devices | ||||
| IABP | 273 | 94 (77) | 124 (81) | 0.4504 |
| VA-ECMO | 273 | 69 (57) | 75 (49) | 0.2238 |
| Ventricular assist device | 273 | 16 (13) | 21 (13) | 1.0000 |
| Event | ||||
| 90-day mortality | 268 | 20 (16) | 56 (36) | 0.0002 |
| Death and TX | 273 | 21 (17) | 63 (41) | <0.0001 |
| VT | 273 | 36 (29) | 54 (35) | 0.3646 |
| VF | 273 | 21 (17) | 24 (15) | 0.7451 |
| Advanced AV block | 273 | 36 (29) | 55 (36) | 0.3017 |
Unless indicated otherwise, values are presented as n (%) or as the median [interquartile range]. AElevated CRP was defined as CRP >0.3 mg/dL. BElevated troponin was defined as troponin >0.02 ng/mL or qualitative test positive. Abbreviations as in Table 1.
The clinical characteristics of 4 groups according to MSI status (MSI(+)/MSI(−)) and aged (<50 and ≥50 years) are presented in Table 3. Younger patients (age <50 years) in both the MSI(+) and MSI(−) groups had a lower prevalence of hypertension and a higher estimated glomerular filtration rate (eGFR).
Clinical Characteristics of Patients According to the Presence of Multisystemic Inflammation and Age (Total n=273)
| Characteristics | No. patients with available data |
MSI(+) | MSI(−) | ||||
|---|---|---|---|---|---|---|---|
| Age <50 years (n=64) |
Age ≥50 years (n=43) |
P value | Age <50 years (n=57) |
Age ≥50 years (n=109) |
P value | ||
| Age (years) | 273 | 36 [26–43] | 62 [56–64] | <0.0001 | 37 [29–42] | 64 [58–71] | <0.0001 |
| Female sex | 273 | 33 (52) | 21 (49) | 0.7822 | 24 (42) | 36 (33) | 0.3075 |
| Prodromal symptoms | |||||||
| Fever | 273 | 64 (100) | 43 (100) | – | 39 (68) | 54 (50) | 0.0220 |
| Headache | 273 | 11 (17) | 10 (23) | 0.4384 | 0 (0) | 1 (0.9) | 1.0000 |
| Respiratory syndrome | 273 | 35 (55) | 23 (53) | 0.9029 | 5 (9) | 18 (17) | 0.2373 |
| GI symptoms | 273 | 30 (48) | 19 (44) | 0.7843 | 8 (14) | 15 (13) | 1.0000 |
| MSI | 273 | 64 (100) | 43 (100) | – | 0 (0) | 0 (0) | – |
| Medical history | |||||||
| Hypertension | 273 | 2 (3.1) | 12 (28) | 0.0002 | 0 (0) | 41 (38) | <0.0001 |
| Diabetes | 273 | 0 (0) | 3 (7) | 0.0321 | 3 (5.3) | 14 (13) | 0.1785 |
| Chronic kidney disease | 273 | 2 (3.1) | 2 (4.7) | 0.6833 | 1 (1.8) | 2 (1.8) | 1.0000 |
| Clinical findings on admission | |||||||
| BMI (kg/m2) | 261 | 21 [19.5–24] | 23 [20–25] | 0.0301 | 21 [20–24] | 23 [20–25] | 0.0276 |
| SBP (mmHg) | 267 | 90 [80–104] | 98 [80–125] | 0.0703 | 94 [80–111] | 101.5 [86.5–117] | 0.2481 |
| Body temperature (℃) | 249 | 37 [37–38] | 37 [36–37] | 0.0116 | 37 [36–38] | 37 [36–37] | 0.2304 |
| NYHA Class III or IV | 261 | 53 (85) | 33 (85) | 1.0000 | 47 (85) | 90 (86) | 1.0000 |
| CPA on admission | 270 | 1 (1.6) | 0 (0.0) | 0.4065 | 0 (0.0) | 2 (1.8) | 0.5515 |
| Laboratory data on admission | |||||||
| WBC (/μL) | 273 | 9,650 [7,000–13,350] |
8,700 [7,000–11,690] |
0.2929 | 10,000 [6,685–13,945] |
8,700 [6,460–11,490] |
0.1679 |
| eGFR (mL/min/1.73 m2) | 273 | 68 [47.5–88.5] | 52 [35–71] | 0.0108 | 72 [41–83.5] | 44 [29.5–61.5] | <0.0001 |
| CRP (mg/dL) | 269 | 4.35 [1.95–8.73] | 5.2 [2.1–11.2] | 0.4610 | 2.8 [1.25–9.15] | 5.7 [2.05–10.6] | 0.0783 |
| Elevated CRPA | 269 | 64 (100) | 43 (100) | – | 51 (89) | 100 (95) | 0.1967 |
| BNP (pg/mL) | 219 | 466 [338–819] | 601 [327–1,207] | 0.2497 | 479 [212–800] | 586 [338–1,125] | 0.1039 |
| NT-proBNP (pg/mL) | 58 | 7,936 [4,525–15,113] |
8,685 [3,089–27,110] |
1.0000 | 5,088 [1,023–12,708] |
11,333 [3,530–28,077] |
0.0319 |
| Elevated troponinB | 244 | 53 (90) | 37 (95) | 0.3723 | 42 (88) | 92 (94) | 0.2093 |
| Creatinine kinase (IU/L) | 272 | 746 [378–1,648] | 770 [559–1,146] | 0.8743 | 522 [245–1,149] | 763 [434–1,469] | 0.0320 |
| ECG findings on admission | |||||||
| Sinus rhythm | 272 | 44 (69) | 29 (69) | 0.9742 | 43 (75) | 74 (68) | 0.3719 |
| QRS duration (ms) | 249 | 120 [89–142] | 114 [93–143] | 0.7564 | 109 [90–140] | 124 [102–147] | 0.0545 |
| ST elevation | 272 | 42 (66) | 27 (64) | 0.8875 | 38 (67) | 69 (64) | 0.7341 |
| VT/VF | 270 | 18 (28) | 8 (19) | 0.2880 | 17 (30) | 19 (18) | 0.0742 |
| Echocardiography | |||||||
| LVDd (mm) | 217 | 47 [42–50] | 46 [41–50] | 0.8760 | 46 [42–52] | 46 [42–50] | 0.8744 |
| LVEF (%) | 262 | 30 [20–39] | 38 [18–46] | 0.2153 | 30 [20–40] | 35 [23–48] | 0.0939 |
| Pericardial effusion | 253 | 39 (62) | 22 (54) | 0.4040 | 21 (40) | 40 (42) | 0.8629 |
| Medication during hospitalization | |||||||
| β-blocker | 273 | 42 (66) | 25 (58) | 0.4327 | 28 (48) | 57 (52) | 0.7451 |
| ACEi/ARB | 273 | 42 (66) | 21 (49) | 0.0836 | 38 (67) | 58 (53) | 0.1015 |
| Intravenous steroids | 273 | 36 (56) | 25 (58) | 0.8465 | 22 (39) | 54 (50) | 0.1932 |
| IVIG | 272 | 31 (48) | 13 (30) | 0.0730 | 19 (34) | 38 (35) | 1.0000 |
| Inotropes | 273 | 62 (97) | 43 (100) | 0.2419 | 55 (96) | 105 (96) | 1.0000 |
| Temporary MCS devices | |||||||
| IABP | 273 | 52 (81) | 36 (84) | 0.7430 | 42 (74) | 88 (81) | 0.3246 |
| VA-ECMO | 273 | 39 (61) | 20 (47) | 0.1413 | 30 (53) | 55 (50) | 0.8705 |
| Ventricular assist device | 273 | 11 (18) | 7 (16) | 0.9020 | 5 (9) | 14 (13) | 0.6087 |
| Event | |||||||
| 90-day mortality | 273 | 7 (11) | 14 (32) | 0.0117 | 13 (23) | 42 (38) | 0.0556 |
| Death and TX | 273 | 7 (11) | 14 (33) | 0.0117 | 14 (25) | 49 (45) | 0.0116 |
| VT | 273 | 19 (30) | 16 (35) | 0.4162 | 17 (30) | 38 (35) | 0.6032 |
| VF | 273 | 10 (16) | 11 (26) | 0.2036 | 11 (19) | 13 (12) | 0.2459 |
| Advanced AV block | 273 | 20 (31) | 15 (35) | 0.6945 | 16 (28) | 40 (37) | 0.3023 |
Unless indicated otherwise, values are presented as n (%) or as the median [interquartile range]. AElevated CRP was defined as CRP >0.3 mg/dL. BElevated troponin was defined as troponin >0.02 ng/mL or qualitative test positive. Abbreviations as in Table 1.
Clinical Outcomes
The median follow-up was 650 days (IQR 35–1,691 days). Of the 273 patients included in the study, 76 died within 90 days and 7 died and 1 underwent cardiac transplantation after 90 days. The cumulative risks of death and cardiac transplantation at 90 days and after 90 days were 27% and 30%, respectively.
In all patients with FLM, those in the MSI(+) group had significantly lower long-term mortality, including cardiac transplantation (HR 0.47; 95% CI 0.29–0.76; P=0.0033), and lower 90-day mortality (log-rank, P=0.0062; HR 0.49; 95% CI 0.29–0.83; P=0.0062) than those in the MSI(−) group (Figure 3A,B).
Incidence of (A) long-term mortality or heart transplantation in all patients with fulminant lymphocytic myocarditis (FLM) and (B–D) 90-day mortality or heart transplantation in all FLM patients (B), FLM patients aged <50 years (C), and FLM patients aged ≥50 years (D). CI, confidence interval; MSI, multisystemic inflammation.
Cox regression analysis also showed that age, serum creatinine kinase (CK) concentrations, non-sinus rhythm (SR), and VT or VF on the first day were associated with worse 90-day prognosis (Table 4).
Factors Associated With 90-Day Mortality in Younger (<50 Years) and Older (≥50 Years) Patients
| Characteristic | Age <50 years (n=121) | Age ≥50 years (n=152) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Death (n) | HR (95% CI) | P value | Death (n) | HR (95% CI) | P value | ||||
| No | Yes | No | Yes | ||||||
| Age | 101 | 20 | 1.04 (0.98–1.10) |
0.1433 | 96 | 56 | 1.05 (1.02–1.09) |
0.0002 | |
| Female sex | No | 54 | 11 | 1.05 (0.42–2.58) |
0.9137 | 62 | 33 | 1.17 (0.68–2.02) |
0.5513 |
| Yes | 47 | 9 | 34 | 23 | |||||
| MSI | No | 44 | 13 | 0.37 (0.14–0.98) |
0.0463 | 67 | 42 | 0.77 (0.41–1.43) |
0.4128 |
| Yes | 57 | 7 | 29 | 14 | |||||
| Diabetes | No | 98 | 20 | – | – | 86 | 49 | 1.03 (0.44–2.42) |
0.9337 |
| Yes | 3 | 0 | 10 | 7 | |||||
| Clinical findings on admission | |||||||||
| NYHA Class III or IV | No | 15 | 3 | 0.95 (0.27–3.29) |
0.9390 | 14 | 7 | 1.24 (0.53–2.92) |
0.6104 |
| Yes | 83 | 16 | 76 | 47 | |||||
| CRP | 1.008 (0.94–1.06) |
0.7648 | 1.02 (0.98–1.06) |
0.2522 | |||||
| Elevated troponinA | No | 9 | 3 | 0.48 (0.13–1.69) |
0.2565 | 8 | 0 | – | – |
| Yes | 82 | 14 | 82 | 47 | |||||
| Creatinine kinase per 100-IU/L increase |
1.006 (0.99–1.01) |
0.1204 | 1.017 (1.00–1.02) |
0.0001 | |||||
| ECG findings on admission | |||||||||
| Non-sinus rhythm | No | 25 | 9 | 2.34 (0.95–5.77) |
0.0634 | 24 | 24 | 1.93 (1.13–3.32) |
0.0159 |
| Yes | 76 | 11 | 71 | 32 | |||||
| VT/VF | No | 77 | 9 | 3.67 (1.47–9.14) |
0.0051 | 83 | 41 | 2.06 (1.13–3.74) |
0.0172 |
| Yes | 24 | 11 | 11 | 16 | |||||
| Echocardiography | |||||||||
| LVEF | 0.98 (0.95–1.01) |
0.4427 | 0.98 (0.96–0.99) |
0.0255 | |||||
| Therapy | |||||||||
| MCS initiated on the first day |
No | 33 | 6 | 1.40 (0.50–3.89) |
0.5159 | 53 | 22 | 1.59 (0.92–2.74) |
0.0928 |
| Yes | 68 | 14 | 41 | 34 | |||||
Among patients aged <50 years, NYHA Class III or IV data were available for 117, elevated troponin data were available for 108, and LVEF data were available for 118. Among patients aged ≥50 years, NYHA Class III or IV data were available for 144, elevated troponin data were available for 137, VT/VF data were available for 150, and LVEF data were available for 150. AElevated troponin was defined as >0.02 ng/mL or qualitative test positive. CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.
Among younger patients (age <50 years) with FLM, 90-day mortality was significantly lower in the MSI(+) than MSI(−) group (log-rank, P=0.0378; HR 0.47; 95% CI 0.14–0.98; P=0.0463; Figure 3C). In multivariable analyses including MSI, age, sex, eGFR, and the presence of hypertension and diabetes, 90-day mortality was lower in patients with MSI and age <50 years (HR 0.36; 95% CI 0.12–1.02).
Cox regression analysis showed that MSI was associated with a better 90-day prognosis, and VT or VF on the first day was associated with a worse prognosis (Table 4). However, there was no significant difference in 90-day mortality between the MSI(+) and MSI(−) groups among older patients (age ≥50 years) with FLM (Figure 3D). Cox regression analysis revealed that older age; CK concentration, non-SR, VT, or VF on the first day; and lower LVEF were associated with a worse 90-day prognosis in older (age ≥50 years) patients with FLM (Table 4).
In this study, we demonstrated in that: (1) 9% of patients with FM fulfilled the criteria for MIS without SARS-CoV-2 infection (defined as MSI); (2) MSI in patients with FM was associated with younger age, a greater likelihood of elevated CRP, and a higher rate of pericardial effusion; and (3) mortality within 90 days was lower for all patients with MSI, especially the younger (<50 years) group (median age 36 years), than for the MSI(−) group. However, in older (≥50 years) patients (median age 63 years), older age, high CK concentrations, and low LVEF were associated with worse mortality at 90 days, but MSI was not.
There have been 3 clinical studies on prognostic factors in patients with FM.13,19,20 These studies reported that older age, non-SR, lower LVEF, VT/VF on admission, VA-ECMO use, and high CRP concentrations were associated with 90-day survival in patients with FM, including giant cell myocarditis and eosinophilic myocarditis.13,19 High CK-MB levels and VT/VF/asystole in FM patients supported by VA-ECMO were associated with poor heart recovery.20 Consistent with these studies, in the present study we also demonstrated that older age, high CK concentrations, non-SR, and VT/VF were associated with poor prognosis in FLM.
There have been no reports on MSI defined by the criteria for MIS in FLM. We demonstrated that MSI was associated with a better 90-day prognosis. However, there was no significant difference in the severity of myocarditis between patients with and without MSI.
Recently, Patel et al21 reported that patients with MIS-C myocarditis (median age 10.9 years) had better prognoses, including rapid cardiac function recovery, than those with classic myocarditis. The authors explained that cardiac dysfunction was related to a systemic inflammatory state in MIS-C patients, whereas in patients with classic myocarditis the cardiac dysfunction was due primarily to direct myocyte injury.21 Recently, it has been reported that the prognosis of patients with fulminant COVID-19-related myocarditis (median age 27.5 years) was better for those with MIS than without MIS, and that patients with MIS had higher cytokine (e.g., interleukin ([IL]-22, IL-17, and tumor necrosis factor-α) concentrations than those without MIS.5 These findings are consistent with our findings of MSI in FLM.
The mechanisms underlying the cardiac dysfunction in patients with MIS-C/A and MSI remain unclear. However, it has been reported that cardiac dysfunction associated with MIS-C/A seems more likely to be transient (“stunning”), with a return to normal function rather than myocardial damage in most cases because of rapid resolution of cardiac dysfunction, mild to moderate troponin elevation, and a cytokine storm suggested by inflammatory markers.22
Conversely, the secretion of cytokines from various immune cells, such as neutrophils, monocytes, and lymphocytes, is dysregulated in the early phase of FM.23 Cytokines may cause myocardial stunning and decrease cardiac function without cell death due to a negative inotropic effect and a direct decrease in myocardial contraction.24–27 They can also directly inhibit mitochondrial function and change the metabolic status of the heart to reduce myocardial contraction.28–30 These factors may play a role in the pathogenesis of acute myocardial pump failure in FM.31
The systemic inflammatory response is a coordinated set of physiological actions that fight infections, heal wounds, and promote recovery from external stressors. Thus, under most circumstances, an intact systemic inflammatory response increases the likelihood of a successful outcome following acute injury or infection.32 However, Barhoum et al5 showed that a high frequency of RNA polymerase III autoantibodies, usually associated with severe systemic sclerosis, is associated with high MIS(−), although it was absent in MIS(+) patients. These findings suggest that an abnormal autoimmune response may be associated with a worse prognosis in FLM without MSI.
This study has some limitations. The criteria for MIS require certain clinical features (mucocutaneous, gastrointestinal, and neurological symptoms) and laboratory markers of inflammation, such as ferritin, procalcitonin, and D-dimer. However, we could not obtain all these data. Therefore, the incidence of MSI may have been underestimated. In the future, specific criteria for MSI in patients with FLM are needed to determine the prognosis.
In conclusion, MSI may be associated with prognosis in patients with FLM.
The authors thank Saori Usui, a secretary of Department of Cardiovascular Medicine, Nagasaki University Hospital for her help with data presentation.
This study did not receive any specific funding.
K.M. is a member of Circulation Journal’s Editorial Team. The remaining authors declare that there are no conflicts of interest.
This study was approved by the ethics committees at Nagasaki University Hospital and the Japanese Circulation Society (Registration no. 20081719-4 and 10, respectively).
The deidentified participant data will not be shared.
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-23-0914
