Rebound multi-system inflammatory syndrome in children (MIS-C): A case report of an extremely rare phenomenon

doi:10.21203/rs.3.rs-2732946/v1

Download PDF

Case Report

Rebound multi-system inflammatory syndrome in children (MIS-C): A case report of an extremely rare phenomenon

https://doi.org/10.21203/rs.3.rs-2732946/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Multi-system inflammatory syndrome in children (MIS-C) is a newly defined clinical syndrome characterized by systemic inflammation, fever, and multi-organ dysfunction related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While MIS-C is familiar to most physicians, recurrent and rebound cases of MIS-C are extremely rare, with only two such cases reported to date.

Case presentation: Here, we report the case of a five-month-old boy diagnosed with rebound MIS-C (19 days apart), with the second episode being more severe and featuring a right coronary artery aneurysm. The immunodeficiency workup returned normal. Standard MIS-C treatment protocols were followed in both episodes, eventually yielding an excellent outcome. The patient remained well within 12 months of follow-up.

Conclusions: We conclude that longer and closer follow-ups of MIS-C patients may be needed, perhaps with a more aggressive treatment protocol to prevent a rebound or recurrence of the disease, though further studies are required to guide clinical decision-making.

Multi-system inflammatory syndrome in children

SARS-CoV-2

Rebound MIS-C

Multi-system inflammatory syndrome in children (MIS-C) is a newly defined clinical syndrome characterized by systemic inflammation, fever, and multi-organ dysfunction related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (1). The clinical characteristics of MIS-C are somewhat similar to those of Kawasaki disease, toxic shock syndrome, sepsis, and macrophage activation syndrome (2). Hence, intravenous immunoglobulin (IVIG) is the treatment of choice (3).

A disease rebound is the reappearance of a disease within 4–6 weeks of ending treatment or while tapering drugs. While MIS-C is familiar to most physicians, recurrent and rebound cases of MIS-C are extremely rare, with only two such cases reported to date (4, 5). Here, we describe the case of a five-month-old boy with rebound MIS-C, with a 19-day interval between the complete resolution of the initial episode and the start of the second episode.

A five-month-old boy was referred to the emergency department with a prolonged fever associated with erythematous skin rashes, diarrhea, and vomiting. He was a term baby with a history of two episodes of non-complicated pneumonia about two and four months earlier and coronavirus disease 2019 (COVID-19) one month earlier, confirmed by polymerase chain reaction (PCR) testing.

The boy's mother reported that the fever had started five days before hospitalization. The boy had diarrhea, nausea, vomiting, bloating, a generalized rash with periorbital erythema, and a strawberry tongue. Upon admission, his temperature was 38.1°C. The physical examination revealed tachypnea (respiratory rate = 60/min), tachycardia (pulse rate = 168/min), and abdominal tenderness. Wheeze and rales were heard bilaterally over the lungs, along with a murmur over the heart. The venous blood gas (VBG) analysis showed respiratory alkalosis and borderline O2 saturation (94% in room air). The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were raised, along with other inflammatory markers (Table 1). Also, the COVID-19 serology (IgG and IgM antibody) tests returned positive.

Table 1

Laboratory results of the patient before and after treatment during each episode
Test	First admission	First discharge	Second admission	Second discharge
Hemoglobin, g/dl	9.0	11.5	9.1	10.0
Hematocrit, %	26.7	34.4	29.1	31.9
White blood cells/µl	14,600	11,900	9,600	9,400
Neutrophil, %	86.7	65		15
Lymphocyte, %	11.8	29		85
Platelets/µl	361,000	679,000	908,000
CRP (< 6 mg/l)	> 150	10	58
ESR, mm/h		57	101	66
LDH (225–450 U/l)	564
CPK, µg/l	468
D-dimer, µg/ml			1,500
Fibrinogen level, mg/dl	452		500
Blood culture	No growth	No growth	No growth	No growth
Urine culture	No growth	No growth	No growth	No growth
Troponin I rapid test	Negative	Positive
Sodium, mEq/l	135	134	139
Potassium, mmol/l	3.1	4.4	5.4
Calcium, mEq/l	8.6		9.9
Creatinine, mg/dl	0.35	0.46	0.33
BUN, mg/dl	11	9	4
Alkaline phosphatase, IU/l	395	318	684	739
AST, U/l	23	134	111	73
ALT, U/l	38	40	62	88
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; CPK, creatine phosphokinase, BUN, blood urea nitrogen; AST, aspartate transaminase; ALT, alanine transaminase

An electrocardiogram (ECG) was taken but showed no significant abnormalities. Echocardiography showed a mildly dilated left ventricle and normal coronary arteries (right coronary artery diameter: 0.97 mm; left coronary artery diameter: 1.19 mm) (Fig. 1); however, a previously undiagnosed patent foramen ovale was seen.

High-dose methylprednisolone (30 mg/kg, three times), IVIG (2 g/kg IV infusion over 10–12 hours), aspirin, and ceftriaxone were started with the diagnosis of MIS-C. Although symptoms like the rash improved, the respiratory rate increased, so the patient was transferred to the pediatric intensive care unit (PICU). A pulse of methylprednisolone was continued for him.

All signs and symptoms resolved four days later except for the lung sounds. The boy was transferred back to the immunology ward, where vancomycin and meropenem were commenced instead of ceftriaxone in consideration of pneumonia (due to the patient’s history). Oral prednisolone was also started (2 mg/kg/day every 12 hours for the first five days, 1 mg/kg/day every 12 hours for the second 5 days). Six days after starting oral prednisolone, the patient was discharged with a stable condition, where all MIS-C manifestations had completely resolved. Prednisolone was continued at home at 0.5 mg/kg/day daily for another nine days.

Ten days after prednisolone was stopped (i.e., 19 days after discharge), he developed a fever, tachypnea, lethargy, and weakness and was brought back to the emergency department. Considering the recurrent episodes of pneumonia and the rebounding of MIS-C symptoms, an immunodeficiency workup was requested. The flow cytometry results returned normal (CD3: 48%, CD4: 28%, CD8: 17%, CD16: 22%, CD19: 30%, CD45: 97%, CD56: 22%, CD4/CD8: 1.2, CD20: 30%, CD11b: normal, CD14: 3%, DHR: 582, 99% of neutrophils expressed the CD11b marker and 87% of leukocytes expressed the INF-g receptor). Echocardiography showed an aneurysm in the right coronary artery (diameter = 5.1 mm, z-score = 12) (Fig. 1). A chest X-ray revealed pleural effusion. Blood investigations again showed a hyperinflammatory state (Table 1). A high dose of methylprednisolone (30 mg/kg IV daily) was started for him, along with IVIG (2 mg/kg IV infusion over 10–12 hours), aspirin, and ceftriaxone. After three days, the methylprednisolone pulse was changed to oral prednisolone (same dosing schedule as initial admission). Eight days later, the boy was discharged again in stable condition. No further episodes or complications were noted within 12 months of follow-up, with echocardiography parameters being normal on two follow-up echocardiograms.

We report a child diagnosed with rebound MIS-C, with a 19-day interval between the complete resolution of the initial episode and the start of the second episode. The second episode was more severe and featured a right coronary artery aneurysm. No immunodeficiencies were detected, and both episodes were successfully treated using standard treatment protocols.

Since April 2020, MIS-C has been reported as a severe clinical condition in many countries (6). This condition occurs in less than 1% of children with confirmed SARS-CoV-2 infection, though its incidence is uncertain (7). Due to the novelty of this syndrome, different diagnostic guidelines have been proposed. The common aspects of all guidelines include prolonged fever, multi-organ dysfunction, laboratory evidence of hyperinflammation, and presumed or confirmed infection by SARS-CoV-2. Still, they substantially differ in other criteria (8).

During both admissions, our patient had the criteria specified by the World Health Organization (WHO) regarding MIS-C (9). Although the second admission featured a less typical presentation than the first, treatment was commenced sooner. MIS-C most commonly affects the gastrointestinal (82–87%), cutaneous (69–73%), and cardiovascular systems (71–100%) (8), with all three being involved in our case. We considered an alternative diagnosis of Kawasaki disease, which was rejected due to the positive COVID-19 history, gastrointestinal symptoms, hyperinflammatory state, and cardiac involvement during the second admission (10).

Based on clinical guidance for MIS-C patients with a hyperinflammatory state released by the American College of Rheumatology (3), initial treatment involves both IVIG (2 g/kg) and high-dose methylprednisolone (1–2 mg/kg/day); we acted accordingly in both admissions. Due to suspicion of pneumonia, antibiotics were also given. As we did not have active COVID-19, remdesivir was not indicated (11). We note interleukin-1 antagonists as an alternative treatment option, especially for the second (more severe) episode (12).

The prognosis of MIS-C overall looks positive, as most children achieve a complete clinical recovery. The mortality rate due to MIS-C is about 1.7% (13). Most patients with cardiac involvement show recovery of ventricular function, regression of coronary artery aneurysms, and resolution of arrhythmias (14), though coronary artery aneurysms can persist in up to 20% of patients (15). In our case, the aneurysm did not persist.

A previous study by Pawar et al. reported rebound MIS-C in a 17-year-old boy with Down syndrome (4). The symptoms recurred eight days after oral steroids were stopped, similar to the ten days seen in our case. Pawar et al. discussed whether such cases should be classified as a rebound, recurrence, or relapse—three similar and somewhat confusing terms. Recurrence can be described as a reappearance of the disease after the complete resolution of the previous episode, while a relapse is the worsening of a condition while under treatment. Finally, a disease rebound is the reappearance of a disease within 4–6 weeks of ending treatment or while tapering drugs (16). Similar to the case of Pawar et al., our case fits the definition of a disease rebound since the patient was symptom-free for 19 days between the two episodes (4).

In our case, the disease repeated after a total resolution, and the patient returned with more severe complications. This is while in Kawasaki disease, the recurrence is usually milder or incomplete, occurring in about 0.98% of patients (17). Further studies on rebound/recurrence patterns of MIS-C are needed.

In summary, an unusual case of rebound MIS-C was successfully treated and will be monitored closely. According to our experience, we recommend a longer and closer follow-up of MIS-C patients and perhaps a more aggressive or extended treatment period to prevent a rebound of the disease or its complications, which may become more severe in the second episode. It might also be necessary to consider moving biologic agents reserved for refractory cases to the first line of treatment (18), though further case reports and larger studies are essential in guiding clinical decision-making

Ethics approval and consent to participate:

The Ethics Committee of Shiraz University of Medical Sciences approved this study (IR.SUMS.MED.REC.1401.491).

Consent for publication:

The authors confirm that the necessary consent forms were completed. The patient’s guardians consented to the publication of this case report, including clinical data and figures.

Availability of data and materials:

All information required by the patient is given in the text, other supplementary information can be obtained upon email from the corresponding author.

Competing interests

Funding

Authors' contributions

SA and LJ saw the case for the first time and realized its specialness and completed its information with the cooperation of RN. RM and LJ did the work of writing and reviewing the literature and collecting information, also SA and NM managed all the steps as the professor and supervisor of team. All authors read and approved the final manuscript.

Acknowledgements:

This manuscript's language, grammar, and writing quality were reviewed by a native English-speaking language editor, Dr. Seyed Ali Hosseini (Native Editor Co., Iran).

Pavlyshyn H, Slyva V, Dyvonyak O, Horishna I. Multisystem inflammatory syndrome in children (MIS-C) temporally associated with SARS-CoV-2: the first clinical case in Ternopil, Ukraine. Germs. 2021;11(1):120–7.
Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management.Children (Basel). 2020;7(7).
Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3. Arthritis Rheumatol. 2022;74(4):e1–e20.
Pawar RS, Tarkasband VA, Patil RK, Naik AV. Second Episode of Multisystem Inflammatory Syndrome in Children: Relapse, Rebound, or Recurrence? Pediatr Infect Dis J. 2021;40(11):e452.
Hancock WC, Green AM, Creel C, Moyen S, Collins KP, Pishko SD et al. Two Distinct Illnesses Consistent With MIS-C in a Pediatric Patient.Pediatrics. 2022;149(5).
Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771–8.
Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. 2020;383(4):347–58.
Esposito S, Principi N. Multisystem Inflammatory Syndrome in Children Related to SARS-CoV-2. Paediatr Drugs. 2021;23(2):119–29.
(WHO) WHO. Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19: WHO 2020 [Available from: https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19.
Wessels PA, Bingler MA. A comparison of Kawasaki Disease and multisystem inflammatory syndrome in children. Prog Pediatr Cardiol. 2022;65:101516.
Hennon TR, Penque MD, Abdul-Aziz R, Alibrahim OS, McGreevy MB, Prout AJ et al. COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach.Prog Pediatr Cardiol. 2020:101232.
Bassiri H, Canna SW. IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2. Lancet Rheumatol. 2022;4(5):e305–e7.
Kaushik A, Gupta S, Sood M, Sharma S, Verma S. A Systematic Review of Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 Infection. Pediatr Infect Dis J. 2020;39(11):e340–e6.
Feldstein LR, Tenforde MW, Friedman KG, Newhams M, Rose EB, Dapul H, et al. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA. 2021;325(11):1074–87.
Aziz OA, Sadiq M, Qureshi AU, Hyder N, Kazmi U, Batool A et al. Short to midterm follow-up of multi-system inflammatory syndrome in children with special reference to cardiac involvement.Cardiol Young. 2022:1–9.
Saxena A, Kumar RK, Gera R, Radhakrishnan S, Mishra S, Ahmed Z. Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease. Indian Pediatr. 2008;45(7):565–73.
Guleria S, Pilania RK, Jindal AK, Bhattarai D, Suri D, Singh S. Recurrent Kawasaki disease at a tertiary care center in Chandigarh, North West India: 24 years of clinical experience. Int J Rheum Dis. 2019;22(7):1183–7.
Yamaguchi Y, Takasawa K, Irabu H, Hiratoko K, Ichigi Y, Hirata K, et al. Infliximab treatment for refractory COVID-19-associated multisystem inflammatory syndrome in a Japanese child. J Infect Chemother. 2022;28(6):814–8.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Rebound multi-system inflammatory syndrome in children (MIS-C): A case report of an extremely rare phenomenon

Status:

Version 1

Abstract

Figures

1. Introduction

2. Case Presentation

3. Discussion

4. Conclusions

Declarations

References

Additional Declarations

Status:

Version 1