key: cord-1049775-lrn53pan authors: Henrina, Joshua; Putra, Iwan Cahyo Santosa; Lawrensia, Sherly; Marta, Della Sabrina; Wijaya, Ellen; Saboe, Aninka; Cool, Charlotte Johanna; Suciadi, Leonardo Paskah title: Cardiac Manifestations, Treatment Characteristics, and Outcomes of Paediatric Inflammatory Multisystem Syndrome Temporally Associated with Severe Acute Respiratory Syndrome Coronavirus-2: systematic review of case reports and case series date: 2021-02-09 journal: Prog Pediatr Cardiol DOI: 10.1016/j.ppedcard.2021.101365 sha: f9afcbe5c006b9f6b78895163b27c3ba5365f00c doc_id: 1049775 cord_uid: lrn53pan Objective To investigate cardiac manifestations, treatment characteristics, and outcomes of paediatric inflammatory multisystem syndrome (PIMS) temporally associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (PIMS-TS) Method We performed a comprehensive literature search of several databases and qualitatively synthesized findings from studies. Results Twenty-six studies were included with 1228 pooled subjects, with a mean age of 8.6 years, which were dominated by male gender (53%), and African ethnicity (31%). 732 (38%) patients were reactive on a serological test, and 457 patients (45%) were positive on SARS-CoV-2 RT-PCR. ST-segment abnormalities were the most common ECG findings (16%, n/N: 34/212). Various markers of troponin and the pooled mean of BNP and NT-pro-BNP levels were elevated. Cardiomegaly and pericardial effusion (21.8%, n/N: 164/751) was the most common chest X-ray findings. In echocardiography, the majority of patients’ left ventricular ejection fraction was reduced (59.0%, n/N: 180/305), with pericardial effusion/ pericarditis seen the most (17.44%, n/N: 221/1267), and Z score ≥ 2 in 28% (n/N: 42/139). Cardiac MRI findings were consistent with acute myocarditis. Intravenous immunoglobulin, corticosteroids, and vasoactive drugs were frequently utilized. The mean length of stay was 6 days, with most patients (71%, n/N: 834/1163) were admitted to the ICU. However, the overall prognosis was favourable, with 98% alive (n/N: 1235/1260), and more than 50% of patients experienced recovery of left ventricular systolic functions at discharge (116 out of 206 patients). Conclusion PIMS-TS is a rare clinical syndrome associated with a multiorgan system dysfunction, especially acute cardiac injury, and mandates a higher level of care. Nevertheless, when appropriate treatments are available, the cardiac function rapidly reverted to normal in most cases, and it was associated with a favourable outcome in general. Of concern, medium and long-term prognosis remains to be elucidated. Coronavirus disease of 2019 (COVID-19) is a highly contagious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although mostly asymptomatic, this disease can present with life-threatening clinical presentation. [1, 2] COVID-19 is also known to disproportionately affect the elderly and patients with cardiovascular comorbidities. [3] [4] [5] On the contrary, the majority clinical presentation of COVID-19 in the paediatric population tends to be mild. [6, 7] However, an emerging report from the United Kingdom (UK) of hyperinflammatory syndrome mimicking Kawasaki disease (KD) and toxic shock syndrome alerted paediatricians worldwide. [8] Later, this novel entity was designated as a paediatric inflammatory multisystem syndrome (PIMS) temporally associated (TS) with SARS-CoV-2 (PIMS-TS). [9] [10] [11] PIMS-TS was associated with multiple organ involvement, with variable presentations. Of interest, the heart was also affected by this syndrome, and multiple studies had reported the cardiac consequences of PIMS-Echocardiography OR Cardiac Magnetic Resonance Imaging). Also, we searched google scholar and relevant articles from the reference of included studies. We finalised the search on 1 October 2020. The inclusion criteria for studies were case reports/ case series that reported cardiac manifestations of patients with PIMS-TS in terms of one of the following: signs and symptoms of cardiac involvement, cardiac biomarkers (brain natriuretic peptide [BNP], n-terminal brain natriuretic peptide [NT-pro-BNP], creatine kinase-myocardial band [CK-MB] , troponin [I/ T/ non-specific], electrocardiography findings, chest radiography (CXR), echocardiography, and cardiac magnetic resonance imaging (CMR). We excluded non-English articles, articles without full-text availability, articles that did not describe cardiac manifestations of PIMS-TS, case reports and case series with less than 10 patients, and letters that did not report PIMS-TS cases. Exceptions will be made for case series <10 patients with important findings, such as CMR/ Echocardiographic studies. Data extracted from these studies will be only the CMR/Echocardiographic findings. J o u r n a l P r e -p r o o f Two independent reviewers (JH and ICSP) screened the titles and abstracts for full-text eligibility and applied protocol inclusion and exclusion criteria to the full-text publication. Any discrepancies between the two reviewers were discussed with third and fourth reviewers (SL and DSM). Figure 1 . depicts the study selection flowchart. We collected the data regarding the first author name, date of patient recruitment, country, study type, demographic characteristics (age, sex, ethnicity), SARS-CoV-2 PCR and serological status, and cardiac manifestations (sign and symptoms of cardiac involvement, brain natriuretic peptide [BNP], n-terminal brain natriuretic peptide [NT-proBNP], creatine kinase [CK], troponin [I/ T/ non-specific], electrocardiography findings, chest radiography (CXR), echocardiography, cardiac magnetic resonance imaging (CMR), treatment characteristics, and outcomes. Outcomes consist of death/alive, ICU admission, length of stays, and left ventricular ejection fraction (LVEF) improvement at discharge. Data other than the mean (SD) is transformed using a J o u r n a l P r e -p r o o f calculator if available using a calculator available online (http://www.math.hkbu.edu.hk/~tongt/papers/median2mean.html), then we combine all of the mean (SD)s into a single mean (SD) value. In total, we identified 1288 patients from 26 articles that reported cardiac manifestations of PIMS-TS. ( Figure. 1) [13, 14, Further detail on population characteristics and SARS-CoV-2 results are provided in Table 1 . Of 1288 patients with PIMS-TS, 689 (53.49%) were male. The mean age of patients with PIMS-TS was 8.6 (5.5) years. Of thirteen studies that reported data on ethnicity (n=1063), 331 (31.14%) were Black, 235 (22.11%) were Hispanic, 173 (16.27%) were Of 1288 patients pooled across 24 studies, signs of shock were seen in 652 patients (50.62%). However, it is important to note that other than cardiogenic shock, vasoplegic shock was also common. Respiratory distress was found in 270 patients (20.96%) . [13, Data on brain natriuretic peptide (BNP) was available in 4 studies, whereas NT-proBNP was available in 10 studies. The pooled mean (SD) of the BNP level from 84 patients Among various troponin markers used as an indicator of cardiac injury (high-sensitivity [HS] troponin I, troponin I, troponin T, and unexplained specifically troponin), data J o u r n a l P r e -p r o o f showed 50 out of 67 patients (74.6%) had elevated troponin I levels [18, 23, 27, 33] , 61 out of 68 patients (89.71%) had elevated high sensitivity troponin I [25, 28, 31] , and 335 out of 778 patients (46.6%) had elevated unspecified troponin. [20, 24, 29, 32, 34, 35, 40] . In addition, the pooled mean (SD) of the troponin I, troponin T, and high sensitivity troponin I were 869 (1229) [18, 23, 33] , 75.8 (132) [36] [37] [38] , 1183 (3307) [25, 28, 31] , respectively. Based on 9 studies of patients that underwent chest radiography (n= 751), 164 patients experienced cardiomegaly or pericardial effusion (21.83%), 105 patients with pleural effusion (13.98%), and 169 patients with focal or bilateral opacity (22.5%), 16 patients with lung oedema (2.13%). [17] [18] [19] 21, 22, 28, 30, 33, 37] Based on 212 patients with data available on electrocardiography, pooled from 7 studies, most abnormality found was ST segment abnormalities (n=34) 16.04%. In J o u r n a l P r e -p r o o f addition, other notable findings were abnormal T waves (n= 21) 9.91%, AV block (n= 5) 2.36%, and ventricular arrhythmia (n=4) 1.89%. [13, 17, 28, [33] [34] [35] 38] Five studies comprising 139 subjects reported the coronary artery size based on the Z score. [27, 30, 33, 35, 36] The total of abnormal coronary arteries, defined as dilatation with a Z score of 2 -< 2.5, was 9 patients and an aneurysm with a Z score of > 2.5 was 18 patients. Moreover, data on ejection fraction (EF) was available in 13 studies with a total of 305 patients, with more than 59.02% of them (n= 180) had EF less than 55%. In Only one case series [14] consists of 4 patients providing detailed descriptions of cardiac findings of PIMS-TS on MRI. There were elevations in T1 mapping values and J o u r n a l P r e -p r o o f Journal Pre-proof T2-Short Tau Inversion Recovery (STIR) ratio, which suggest myocardial hyperemia and oedema without evidence of fibrosis replacement at LGE at the acute disease phase. Moreover, pericardial effusions were present in 3 out of 4 patients. Nonetheless, the patient with negative pericardial effusion underwent CMR after being discharged from the hospital. A full description of treatment characteristics is available in Table 3 . Among all patients, 845 received intravenous immunoglobulin (IVIG), 663 received corticosteroid, and 480 received aspirin. [13, [16] [17] [18] [19] [20] [23] [24] [25] [26] [27] [28] [29] [30] [31] [33] [34] [35] [36] [37] [38] In addition, cytokine inhibitors; TNF-α antagonist/ Infliximab, IL-1 antagonist/ Anakinra, and IL-6 antagonist/ Tocilizumab were sparingly used in 16 [20, 35, 36] , 30, and 43, respectively. [13, 20, [26] [27] [28] 31, [35] [36] [37] [38] J o u r n a l P r e -p r o o f Of 1010 patients, 477 received vasoactive agents [13, [17] [18] [19] 23, 24, [26] [27] [28] [29] [30] [33] [34] [35] 37] , including dobutamine, norepinephrine, epinephrine, vasopressin, milrinone, and dopamine. In addition, volume expander/fluid resuscitation, indicated for refractory shock/ hypotension, was used in 21 patients. [30, 33] Of note, patients might receive more than one vasoactive agent. Of 193 patients, 176 received empirical antibiotics, such as vancomycin, meropenem, ceftriaxone, cefepime, metronidazole, linezolid, and cefazolin. [20, 23, 28, 30, 33, 37] Out of 845 patients, 92 patients were therapeutically anticoagulated , 62 patients were prophylactically anticoagulated, and 241 patients received nonspecific anticoagulants. [13, 19, 20, 23, 24, 27, 28, 37, 38] J o u r n a l P r e -p r o o f Of 252 patients, 21 patients received extracorporeal membrane oxygenation (ECMO). [13, 26, 28, 29, 35, 37] Intra-aortic balloon pump (IABP) was utilized in one patient. [18] Moreover, 144 and 77 patients were invasive [13, 17, 21, 23, 24, 26, [28] [29] [30] [31] [32] [33] [34] [35] 37] and non-invasively ventilated. [13, 17, 24, 28, 29, 31, 32, 34, 37, 37] Renal replacement therapy (RRT), was also utilized in three patients. [19, 32] Diuretics were also utilized in 21 patients. [37] Furthermore, two putative antiviral drugs, namely remdesivir and hydroxychloroquine, were used in thirteen patients [20, 27, 28, 37 ] and 3 patients [28, 31] , respectively. Of 1163 patients, 834 were admitted to ICU/ PICU. [13, 16, 17, [19] [20] [21] [22] [23] [29] [30] [31] [33] [34] [35] [36] [37] [38] On the contrary, of 1260 patients hospitalized, only 25 patients (1.98%) died. [13, [16] [17] [18] [19] [20] [21] [22] [23] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] The mean length of stay (n= 5 studies) was 6.02 (2.93 SD) days. [20, 29, 30, 36, 37] Of 153 patients that experienced EF reduction during J o u r n a l P r e -p r o o f hospitalization, 116 were normalized after discharge. A detailed description of the outcome is provided in Table 4 . The life-threatening syndrome associated with delayed COVID-19 disease and mimicking incomplete Kawasaki disease (KD) and toxic shock syndrome has been identified as PIMS-TS or a multisystem inflammatory syndrome in children (MIS-C) [8] [9] [10] [11] . Although rare, this syndrome remains an important source of morbidity and mortality of paediatric COVID-19 patients. In addition, the heart is one of the major organs affected by this syndrome. In our review, the mean age (SD) was 8.6 (5.5) years old (n= 1188). In addition, African descent makes up more than 30% of all ethnicities. Contrastingly, the incidence of typical KD exclusively occurred in East Asian ethnicity, with the peak age at 2.5 years old. [41] Older children that were affected by PIMS-TS in comparison to KD might imply more developed immunity as underlying pathophysiology. [42] Indeed, one case series found that along with ferritinemia, age >5 years were a remarkable prognosticator of a severe course. [31] J o u r n a l P r e -p r o o f Several mechanistic underpinnings may explain the occurrence of PIMS -TS. First, SARS-CoV-2 can block type I and III interferon responses, which subsequently cause delayed cytokine storms in patients with high virus load of SARS-CoV-2 or uncontrolled viral replication. [43, 44] Alternative hypothesis is proposed antibodydependent enhancement as the mechanistic underpinnings of COVID-19. [42, 45] However, this hypothesis has several shortcomings that could not explain, such as why there is no report of an apparent clinical problem in COVID-19 patients who received convalescent plasma as a part of their treatment. [42] The third one is autoantibodies In contrast, shock or vascular compromise affects less than 10% of patients with Kawasaki's disease. [49] Strikingly, more cardiovascular involvement is observed based on a multimodality cardiac evaluation of PIMS-TS patients, which consists of left ventricular dysfunction, myocardial ooedema, and coronary artery changes even after defervescence. [39] Moreover, coronary artery involvement incidence is higher (60%) compared to their Kawasaki counterparts (23 -50%). [50, 51] The pattern of coronary involvement is also different from Kawasaki disease, reinforcing PIMS-TS as an entity of its own and not part of the Kawasaki disease spectrum. [39] In acute COVID-19 infection, incidences of acute cardiac injury have been well documented. [4] Regardless, a shared underlying pathomechanism of cardiac dysfunction between PIMS-TS and during acute COVID-19 infection is unlikely due to the temporal differences. This is reinforced by the cardiac MRI findings of PIMS-TS patients which showed diffuse myocardial oedema without replacement fibrosis or focal necrosis. [14] Therefore, it is a distinct clinical entity and should be distinguished from the acute COVID-19 infection. Our review also provided detailed descriptions of the treatment characteristics of PIMS-TS patients. The majority of patients received immunosuppressant, which mostly constitutes IVIG. In Kawasaki disease, treatment with IVIG is effective for the majority of cases. [44, 45] Indeed, the treatment with immunoglobulin was associated with improved left ventricular systolic function in PIMS-TS. [13] Corticosteroid, which was the second most commonly used immunosuppressant, was used in 156 patients. Two studies highlighted that this immunomodulator was considered in high-risk patients with symptoms similar to an incomplete form of Kawasaki disease [13] and the presence of cytokine storm with Kobayashi score of 5. [18] Acetylsalicylic acid was used in 90 patients. Varying doses of aspirin were also used, with 30 -80 mg/Kg used for anti-inflammatory and lower dose for antiaggregative. [31] Cytokine inhibitors which constitute TNF-α antagonist, IL-1 antagonist, and IL-6 antagonist were also sparingly used in 16 [20, 35, 36] , 30, and 43, respectively. [13, 20, [26] [27] [28] 31, [35] [36] [37] [38] Mainly due to persistent inflammatory state, respiratory distress, and extremely elevated CRP. [13, 31, 35] Nevertheless, high survival rates of PIMS-TS patients in the paucity of highquality evidence should be carefully attributed to these biological agents as cytokine J o u r n a l P r e -p r o o f storm in COVID-19 is not as severe as the cytokine storm in other infectious processes. This can explain the futility of Tocilizumab (anti-IL-6 antibody) in randomized controlled trials for hospitalized COVID-19 patients. [52] [53] [54] Other cytokine profiles (IL1, TNF alpha, IL8) were much lower in severe-critical COVID-19 than sepsis, ARDS, or cytokine release syndrome related to Chimeric Antigen Receptor T Cell (CAR-T) cell therapy. [55] Indeed, system-level analyses of blood immune cells, cytokines, and autoantibodies of PIMS-TS patients confirmed this. [46] Nonetheless, the role of aberrant adaptive immune response activation in PIMS-TS patients is evident, as treatment with intravenous immunoglobulin (IVIG) results in the resolution of the disease. [47] The need for vasopressors and fluid resuscitation was not uncommon, whereas only 21 patients needed veno-arterial/ veno-venous ECMO, and one patient needed an intra-aortic balloon pump as mechanical circulatory supports. Of note, patients might receive more than one type of vasopressors, and comparable amounts of norepinephrine and epinephrine were used, signifying the incidence of cardiogenic and vasoplegic shock is not uncommon J o u r n a l P r e -p r o o f More than 90% of the total patients received empirical antibiotics. Indeed, an initial broad-spectrum antibiotic was endorsed because symptoms overlap between PIMS-TS and severe bacterial infection. [46] Therefore, empirical broad-spectrum antibiotics seem rational with the uncertainty of diagnosis. We also noted that almost half (44.2%) of patients were anticoagulated, prophylactically or therapeutically, with the majority receiving enoxaparin. Recently, the American College of Rheumatology has published a treatment guideline for MIS-C patients, specifically antiplatelet and anticoagulation therapy. With limited evidence, this guideline can provide interim guidance for clinicians. [56] Finally, we have defined the outcome of PIMS-TS patients. The mean length of stay was 6 days, and although patients' ejection fraction was decreased (n= 153), the majority (n= 116) reverted to normal at discharge. Out of 1163 patients, 834 patients were admitted to the intensive care unit, which underscore this syndrome's critical nature. Nevertheless, this syndrome has an excellent prognosis, with 25 out of 1260 patients die. Of interest, all studies were reported in developed countries, implicating that the wide range of pharmacologic and non-pharmacologic armamentarium in J o u r n a l P r e -p r o o f treating this complex syndrome is readily available, which might not be the case in developing countries. Several limitations of this review exist due to the nature of case series. First, we could not rule out the possibility of selection bias, i.e., whether all cases or only a few selected individuals are described. Second, we could not confirm whether all caseseries are self-reported or through clinical records, billing, or administrative codes, in which the latter three are more reliable than the first. Therefore, ascertainment bias could not be ruled out. Third, reliable conclusions could not be drawn, and more prospective observational cohort studies are needed. Nevertheless, our systematic review compiles 26 studies, which will help with the rapid dissemination of these important findings. In conclusion, PIMS-TS is a severe but rare clinical syndrome associated with a multiorgan system dysfunction. It mandates a higher level of care, which often needs advanced circulatory and respiratory supports. Nevertheless, when prompt recognition and appropriate treatments are available, the prognosis is generally favourable, and the cardiac function rapidly reverted to normal. 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