MIS-C, Can Latency Interval Help in Diagnosis?

To the Editors:

We read with interest an Multisystem Inflammatory Syndrome in Children (MIS-C) case of a 15-year-old female 16 weeks after a confirmed infection by reverse transcription-polymerase chain reaction (RT-PCR) SARS-CoV-2 (COVID-19) that has been published recently.¹

The Multisystem Inflammatory Syndrome in Children (MIS-C) has been observed in temporal association with COVID-19, typically several weeks after illness or exposure.² However, to date, there is scarce data regarding the interval of time following acute SARS-CoV-2 infection and diagnosis of MIS-C.

We attended in our institution (Hospital 12 de Octubre, Madrid, Spain) 11 cases of MIS-C between October 2020 and January 2021; in 10 of them, initial SARS-CoV-2 infection could be microbiologically dated.

In this series, the median time between the first SARS-CoV-2 positive RT-PCR or antigen test and the onset of symptoms compatible with MIS-C was 34 days (range: 19–40) (Table 1). In the mentioned paper, it was stated that to their knowledge, the longest period between initial exposure and MIS-C diagnosis was 5 weeks (35 days); however, in our series, 5/10 (50%) patients presented with symptoms of MIS-C at least 5 weeks after the infection. Similar ranges are commented in other studies,^2,3 but information about time intervals is scarce.³ The shortest period observed in our series was 19 days, longer than the 6 days reported by others.³ Although it is expected that new interval periods will be published, we should be cautious in cases with symptoms before 2 weeks or beyond 8 weeks after the infection.

TABLE 1. - Features of Patients With MIS-C

Age*		Sex†	Latency‡	Symptomatic Acute Infection	Rash	Conjunctival Injection	Acute Gastrointestinal Symptoms§	Coagulopathy¶	Hypotension‖	Ventricular Failure**
1	3	M	30	Yes	Yes	Yes	Yes	Yes	Yes	No
2	12	M	36	No	No	No	Yes	Yes	Yes	No
3	13	M	19	Yes	No	No	Yes	Yes	Yes	No
4	8	F	24	Yes	Yes	Yes	Yes	Yes	Yes	Yes
5	8	F	40	No	No	Yes	Yes	Yes	No	No
6	12	M	38	No	Yes	Yes	Yes	Yes	Yes	Yes
7	12	F	40	Yes	Yes	Yes	Yes	Yes	Yes	No
8	8	M	No data	No	Yes	Yes	Yes	Yes	Yes	Yes
9	8	M	23	No	Yes	Yes	Yes	Yes	Yes	Yes
10	11	M	38	No	No	Yes	Yes	Yes	Yes	Yes
11	16	M	33	Yes	No	Yes	Yes	Yes	Yes	Yes

*Age in years.

†M: male, F: female.

‡Latency between the first RT-PCR or antigen positive and the onset of MIS-C in days.

§Diarrhea, vomiting or abdominal pain.

¶Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).

‖Hypotension or shock.

**All patients presented World Health Organization cardiac involvement (features of myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP). Those with ventricular failure were shown in the table.

Among, 55% (6/11) of patients in our series presented only mild symptoms during the acute infection by SARS-CoV-2. Nevertheless, 45% (5/11) were asymptomatic and were tested only for being a close contact of a known COVID-19 case. Upon admission due to suspected MIS-C, 36% (4/11) still had RT-PCR positive. All patients had positive IgG against SARS-CoV-2 detected by enzyme-linked immunosorbent assay. It is currently unknown if there is any trigger that could cause MIS-C after SARS-CoV-2 infection and if it could have played a role in the latency time. In our patients, as in the presented case, other infectious tests were unrevealing (blood cultures, Epstein Barr Virus, Cytomegalovirus and HIV serologies, throat cultures, and respiratory virus RT-PCR panel were negatives).

On the other hand, it was published that a disproportionate number of cases of MIS-C have been reported in Black and South American children. Even if 4/11 (36%) of our cases were from these origins, this proportion is similar in healthy children in this area and we speculate that this finding is related to sociodemographic factors.⁴

To conclude, broader access to diagnostic techniques for SARS-CoV-2 infection during the second and subsequent waves, either for symptomatic COVID-19 or asymptomatic close contacts, has allowed better characterization of the latency time between acute infection and the development of MIS-C.