Multisystem inflammatory syndrome in children (MIS-C) is a new inflammatory disease that emerged worldwide between April and May 2020.1-5 It is characterized by fever and a wide range of signs and symptoms and frequently presents with shock, and a major morbidity associated with MIS-C is cardiac injury with cardiac dysfunction and occasionally aneurysms.6,7
MIS-C has been temporally linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and appears to be related to a dysregulated immune response to this infection that occurs primarily in children.8
Critical questions and challenges have arisen since the first descriptive reports of MIS-C.
1. First, it is not known if this is the “tip of the iceberg” 9 and if the cases admitted to date represent a small, but serious, fraction of a similar phenotype that was observed in the outpatient setting.
2. Second, we face the difficulty of discriminating MIS-C patients requiring referral for cardiac evaluation from the large number of children presenting for medical care in primary care and other outpatient settings due to fever.
Further amplifying the challenge, patients with MIS-C have presented with and without shock, and with and without features that overlap with Kawasaki disease (KD) and toxic shock syndrome. Neither the presence of features of shock nor KD have been useful in predicting cardiac complications, including aneurysms, cardiac inflammation, and mechanical dysfunction.5,7,9
Additionally, with the expansion of telemedicine, the limited hours and capacity of pediatricians’ offices, and the reluctance of families to seek in-person visits in offices and emergency departments (EDs), pediatricians often evaluate patients remotely with fractured care from other urgent care services or telemedicine.
In recognition of these challenges, the authors analyzed outpatient records to determine whether the clinical presentations of patients admitted and treated for MIS-C were similar to or distinguishable from other febrile patients in the outpatient service.
Given the broad nature of some diagnostic guidelines for MIS-C, the authors’ intent was to look for “red flags” to indicate the need to require referral and further evaluation.
| Methods |
They retrospectively reviewed the medical records of patients with MIS-C who presented to a tertiary care hospital during the peak of MIS-C cases and all sick visit encounters in febrile patients at a subset of affiliated primary care pediatric clinics. during the same period. Study staff reviewed each encounter of patients who met inclusion criteria related to the febrile episode of interest.
To construct the MIS-C cohort, they reviewed records of patients reported by the authors’ institution as possible MIS-C to the New York City Department of Health from April 16 to June 10, 2020.1
Patients with MIS-C were then defined as patients who were treated with corticosteroids and immunoglobulin, after consultation with rheumatologists and infectious disease physicians, who determined that the cases were compatible with MIS-C.
They identified patients with KD who were evaluated by the same consulting services at the institution, who determined based on the 2017 American Heart Association guidelines10 and by clinical criteria, that they had symptoms compatible only with KD; these cases were excluded from most analyses.
The analysis focuses on symptoms reported at presentation for patients with MIS-C, and although outpatient records were not available for MIS-C cases, relevant information from ED documentation was reviewed and used.
The febrile outpatient cohort was constructed using a complete list of all acute outpatient visits to primary care clinics affiliated with the participating hospital during the same time period. Patients were included if they were brought for evaluation of a febrile illness.
Because there were no infants with MIS-C, patients younger than 12 months of age were excluded. A subset of febrile outpatients was also evaluated after the clinic visit in the ED for the same febrile condition. These encounters were included as part of the larger febrile outpatient group and as a separate subset (“DE group”) for some analyses.
Three children in the febrile outpatient group had more than 1 febrile episode during the study period, with documented periods of well-being in between; To facilitate interpretation, only the final febrile episode was included in the main analysis.
All encounters reviewed included demographic data, reported symptomatology during the course of their illness up to the time of presentation, findings on examination, results of basic laboratory tests, suspected or confirmed exposure to SARS-CoV-2, and the final documented diagnosis.
Historical clinical variables that were not documented as present by providers were presumed negative. For the purposes of analysis, each patient’s febrile episode was represented as a clinical encounter. For patients with multiple encounters for the same illness, each visit was reviewed and all information from the last encounter was included in the patient’s symptomatology.
Objective data, including vital signs and laboratory test results, were captured as repeated measurements if there were multiple outpatient or ED encounters/tests.
Fever was defined as a temperature ≥38 C. The maximum temperature reported was based on parent report. If a patient’s medical record documented a reported fever but did not document a measured temperature, or the only measured temperature was <38 C, the patient was considered febrile by data analysis, but their maximum fever record was recorded as “subjective.”
> Statistical analysis
Clinical and demographic variables were described using summary statistics and compared using univariate analyzes between febrile outpatients, febrile outpatients referred to the ED, and patients with MIS-C. For temperature grade and duration comparisons, Student’s t test with false discovery analysis was performed using the 2-stage linear step-up procedure of Benjamini, Krieger and Yekutieli, with Q = 1%. Each row was analyzed individually.
For comparisons of temperature for duration and degree, second-order polynomial curves were fitted to the data points of all outpatients and patients referred to the ED, and 95% CI bands were plotted for all MIS-C patients. . For patient characteristics associated with MIS-C, significance levels ≤ 0.1 were tested in logistic regression using a stepwise procedure.
Patient characteristics with significance levels <0.05 in multivariable analyzes were retained in the final models. Models were tested for confounders and effect modification. In the sensitivity analyses, we repeated the analyses, including the 3 patients with more than 1 febrile episode, and pooled the DSs for repeat patients.
For collinear variables, adjusted R2 was used to determine variable inclusion. For the ORs, a stepless non-parsimonious logistic regression model was performed using all variables. Statistical analysis was performed using STATA, version 16 (StataCorp LLC) and additional figures/statistics using PRISM 8.3 (GraphPad Software).
This study was approved by the institutional review board of Columbia University Irving Medical Center. A waiver of informed consent was provided.
| Results |
They identified 59 patients who met New York City Department of Health reportable criteria for possible MIS-C11 who were admitted to the authors’ institution during the time frame of the study.
Of these, 44 patients were diagnosed and treated for MIS-C; 7 met the criteria for KD only and were excluded. In total, 181 control patients with 184 separate febrile episodes were identified. Of the patients initially seen in the outpatient clinic, 23 patients also had visits to the ED.
Patients with MIS-C were generally older than patients with other febrile illnesses and KD, with a median age of 8.2 years (IQR 5.3-13 years) vs 3.5 years (IQR 1.4-6 .9 years) vs 2.4 years (1.3-3.9 years, p <0.001), consistent with previous reports.1-5,7,11
There were no significant differences between MIS-C and febrile outpatient groups with respect to sex, race, or ethnicity. More than 50% of patients in both groups were identified as Hispanic, consistent with the population served at the institution.
> Clinical and symptom complex of patients with MIS-C versus febrile controls
Patients admitted and treated for MIS-C had higher levels of the SARS-CoV-2 association (reported contact and laboratory confirmed), significantly higher reported maximum temperatures (400 C vs 38.90 C, P < 0.001), and a longer duration total fever reported at the time of medical consultation (5 days vs. 2 days, P < 0.001) than other febrile outpatients. Additionally, 42 febrile outpatient controls, and one who was referred to the ED, had fever that had resolved before receiving medical care.
None of the patients in the MIS-C group had fever that resolved before treatment, including one patient who was only recognized as MIS-C 15 days after his hospitalization and had persistent fever throughout this period.
Patients requiring hospitalization and treatment for MIS-C had a higher temperature at all time points compared to febrile outpatients. When matching for age and site of presentation (ED and MIS-C patients only), the finding that MIS-C patients had significantly higher temperatures compared to other febrile children persisted.
A symptomatological correlation of all variables and a multivariable regression were performed to see significant correlations and symptoms. Resolution of both fever and the presence of respiratory congestion demonstrated the trend of a modest negative correlation with the absence of MIS-C requiring treatment due to evidence of possible cardiac injury. The presence of abdominal pain, vomiting, mucosal irritation, neck pain or stiffness, and rash were associated with a significant correlation (P < 0.05) with MIS-C requiring treatment.
> Comparisons of laboratory and echocardiographic characteristics
Of 181 febrile outpatients, most were seen as telehealth visits, which did not include laboratory testing; only patients referred to the ED and, in rare cases, patients seen in person at an outpatient clinic had blood or urine tests performed. Therefore, they only compared the laboratory test results for the ED group for MIS-C.
At presentation, the MIS-C cohort compared with febrile patients in the ED demonstrated profound lymphopenia (absolute lymphocyte counts of 900 cells/ml, 490-1700 vs 2860, 1900-5400, respectively; P < 0.001 ) and higher percentage of neutrophils (80.5%, 71.6-85.7 vs 40.1%, 19 - 60, respectively; P <0.001).
Patients with MIS-C requiring admission and treatment also tended to have lower platelet counts (179,000/ml, 130,000 - 243,000 vs. 224,000/ml, 195,000-308,000; P < 0.05 ) than other febrile patients.
Finally, patients with MIS-C demonstrated markedly higher serum concentrations of C-reactive protein (164 mg/L, 52-250) and N-terminal brain natriuretic peptide (ntBNP) levels (6700 pg/mL, 2509-25 550). ). These were statistically greater than those observed in febrile outpatients (4 mg/L, IQR < 1-14.8 and 98, IQR 65-194; P < 0.001 for both); however, these tests were performed in only 14 and 9 outpatients, respectively.
Patients with KD had higher absolute value of lymphocyte counts and lower ntBNPs than patients with MIS-C but composed of a very small number of patients.
Most patients treated for MIS-C showed some evidence of end-organ dysfunction in the form of shock and/or echocardiographic evidence of cardiac involvement or dysfunction.
| Discussion |
The authors found a clear difference in the presentation of symptomatology and basic laboratory test findings in patients diagnosed and treated for MIS-C compared to febrile outpatients who received other diagnoses.
The consequences of a missed diagnosis of MIS-C are not yet known, but in several series of patients (with the total number of patients described to date <1000), the incidence of cardiac damage in the form of an aneurysm is small but present ( approximately 8% - 10%), and few patients have died.2,3,5,7,11
At the same time, there is a risk of overdiagnosing and overtreating suspected MIS-C patients. Unpublished communications suggest that patients with other serious conditions, including malignancies, have been treated with corticosteroids and intravenous immunoglobulin for suspected MIS-C before a correct diagnosis.
Although patients presenting in shock are clearly different from those presenting with low-grade fever, MIS-C had to be ruled out in the majority of children presenting for care with fever.
The question of when to refer patients for laboratory and cardiac evaluation arose among outpatient providers. The study demonstrates some useful "red flags." For example, an older patient with prolonged high fever, rash, severe abdominal pain, and neck pain or stiffness, with a history of suspected exposure to SARS-CoV-2, should be referred. A younger patient with a low-grade fever and upper respiratory congestion should have follow-up, but not further evaluation.
The difficulty in clearly identifying MIS-C in a clinical setting extends to the difficulty in studying and understanding the disease in a research setting. This issue was raised by Rowley, who noted that the "very broad case definition for MIS-C is concerning because the inclusion of children who have other conditions will bias the results and obscure precise conclusions." 12
Therefore, they defined the MIS-C cohort for the study as patients who received treatment not only after meeting the suggested criteria for MIS-C, but also having evidence of possible cardiac compromise due to cardiac dysfunction on echocardiogram, coronary abnormalities, or ntBNP. sustained, progressive or markedly elevated.
Elevated ntBNP has been reported to be associated with cardiac dysfunction or cardiogenic shock in the setting of MIS-C.13,14 However, it should be noted in this cohort that all 44 patients in the MIS-C cohort who were treated had ntBNP abnormal and only 56% had abnormal function on echocardiogram and 5% had coronary abnormalities. This emphasizes the nonspecific nature of ntBNP as a marker of cardiac dysfunction, but suggests that it may have a role in prompting cardiac evaluation for suspected MIS-C.
The authors’ study has important limitations. Perhaps important to note, MIS-C cases were initially seen in the ED, while most controls were seen in outpatient telehealth visits.
Although this presents some challenges for interpretation, 2 points are of particular importance:
1. First, both groups’ records were from the initial encounter with the health system and therefore had a complete history potentially providing effectively the same information for both groups.
2. Second, in light of the limitations introduced by the pandemic, outpatient telehealth visits replaced in-person urgent care visits. MIS-C patients and febrile outpatients had similar sex, race, and ethnicity distributions, were drawn from the hospital referral area, and during the same time period.
3. Third, laboratory data in febrile outpatients are limited.
4. Fourth, data on current illness history and exposures are limited to a retrospective review.
These data were likely strongest in those hospitalized for MIS-C. Fifth, there was no formal follow-up of febrile children. However, none of the control patients were subsequently admitted to the system with a diagnosis of MIS-C.
Symptoms at a given time may not be reported in retrospective studies. However, abdominal pain associated with MIS-C is typically severe and suggestive of peritoneal irritation, with guarding almost always present.
The rash in these patients, on the other hand, is generally polymorphic, sometimes evanescent, often diffuse with predominance of the trunk, with erythematous and whitening macular lesions. Similarly, some laboratory features observed at initial presentation of MIS-C are not static. Although platelet counts are reduced during initial presentation, they tend to increase dramatically (2 to 3 times above the normal range) in patients at later time points.
Although KD and MIS-C may have overlapping features, 9,15,16 for the study, they excluded patients with recognizable KD without widespread features as seen in MIS-C from formal comparisons. Findings in KD patients were included to give readers a complete view of the data.
The authors’ data suggest that children who will require intervention for MIS-C are clinically distinguishable from other febrile children and that red flags can be looked for and patients who will require further evaluation can be identified. Further long-term studies of children exposed to SARS-COV-2 are needed to clarify whether there is a spectrum of MIS-C phenotypes that could also be associated with cardiac injury or long-term cardiac sequelae.
