Ten-month follow-up of patients with covid-19 temporally related multi-system inflammatory syndrome in children: the experience of the children hospital of Palermo

Symptoms started 1–8 days before the hospitalization. The following diagnostic criteria were detected in the patients included in the study:

-fever (was present in 100% of the cases)

- cheilitis and/or pharyngeal hyperaemia (86%)

- latero-cervical lymphadenitis (82%)

- skin rash (73%)

- conjunctivitis (64%)

- abdominal pain and/or vomiting and/or diarrhoea (64%)

- hands and feet oedema (18%) (Table 1).

Table 1 Clinical signs and symptoms of the patients

Nasopharyngeal swab for SARS-CoV-2 was positive in 15/22 patients, who showed positive serological IgG, negative or grey zone IgM-type antibodies. 5 patients with negative swab had a history of recent infection and positive IgG-type antibodies; 2 patients had parents with positive swab, with no positive serological test, however fulfilling the CDC and WHO case definitions of multisystem inflammatory syndrome in children [1].

Infections other than SARS-CoV-2 were excluded in all the patients, by haemoculture and sept fast.

At the admission, a significant increase of C-reactive protein (CRP) and hyponatraemia was found in 100% of cases. AST, ALT, gamma-GT were above the range in 59% of the children. Increased pancreatic amylase and lipase levels were found in 14%, a lymphocyte count ≤ 1000 was documented in 36% of the patients enrolled.

Pro-BNP levels were increased (> 320 pg/ml) in 50% and troponin levels were increased (> 14 ng/ml) in 18% of cases.

D-Dimer was increased in all the patients, with a range of 0.56–13.36 mg/L (n.v. < 0.5); ferritin was increased (with levels > 365 ng/ml) in 11/22 (50%) of the patients.

IL-6 levels were evaluated in 14/22 patients and 13/14 showed a significant increase of IL-6 levels (30.2–285 pg/ml).

Furthermore, a mild kidney involvement was documented in 36% of the patients, with low-grade proteinuria in 8 and microhaematuria in 3 (Table 2).

Table 2 Laboratory parameters of the patients

Patients were divided in two groups: group A (with cardiac involvement: pericarditis, valvular damage, CAL) and group B (without cardiac involvement) (Table 3).

Table 3 M ± DS and significant p-value (in red) of haematochemical parameters, dividing the patients in two groups: group A (with cardiac involvement: pericarditis, valvular damage, CAL) and group B (without cardiac involvement)

Proteinuria and microhaematuria were more frequent in patients of group A (7/13) than in of group B (1/9) (p-value: 0.0019). Furthermore, in group A lymphocyte count was lower (p-value: 0.027) and creatinine was higher (p-value: 0.0113).

Patients of group A had higher CRP levels (16.09 ± 11.61) than in group B (7.1 ± 10.9) and procalcitonin concentrations (5.14 ± 4.99) than group B (2.37 ± 3.81), even not reaching the statistical significance.

The cardiac involvement was documented by echocardiogram in 59% of children (pericardial effusion in 5; Mitral or Tricuspid insufficiency in 8; Mitral and Aortic insufficiency in 2; Mitral and Tricuspid insufficiency in 1; 4 with coronary artery lesions (CAL)). The Z score value was 3 in 1 patient; 3 patients showed a Z score < 3, with persistent brightness of the coronary wall. 4/5 (80%) of patients with pericarditis showed Mitral valve insufficiency as well. All the patients showed normal left ventricular ejection fraction. The ejection fraction of patients with cardiac involvement was > 60%. The 2 patients with shock did not show reduced cardiac contractility.

De-novo arrhythmia was documented in 8/22 children (36%): among those, tachycardia followed by persistent bradycardia was documented in 5 (23%), lasting for 8–10 days after the resolution of the acute phase of MIS-C. It was not correlated with increased levels of troponin and pro-BNP. Among those children who developed bradycardia, 2 showed alterations of the repolarization phase. Further 3 children showed alterations of the repolarization terminal phase or of the QRS, not known before. One patient showed a pre-existing Brugada pattern, revealed by fever with arrythmia.

Pleural effusion, ascitic effusion and mesenteric adenitis were found in 18%, 27% and 36% of the patients, respectively.

18% of patients dramatically and rapidly evolved in a MAS-like form, fulfilling the classification criteria for the diagnosis of MAS (ACR/EULAR 2016). High doses of steroids were promptly started and associated with IVIG, obtaining a significant improvement of the clinical course.

In all the patients, treatment was started within 72 h after the admission, with IVIG (2 g/Kg/dose), methylprednisolone (2 mg/Kg/day in 73% of patients; 30 mg/Kg/day for 3 days, followed by 2 mg/Kg/day in 27% of patients for the severe and acute progression of the MIS-C), acetylsalicylic acid (ASA) (3–5 mg/Kg/day). Two patients were treated with enoxaparin. Two patients with shock, were additionally treated with vasoactive drugs, albumin, diuretics. All the patients were treated with methylprednisolone at 1–2 mg/Kg/day until the normalization of inflammatory markers (CRP, ferritin, IL-6), troponin, D-Dimer, AST, ALT, gamma-GT, pancreatic amylase, lipase, lymphocyte count.

Hence, a gradual and slow tapering of methylprednisolone was performed, with the end of the therapy in 2–3 weeks. Treatment with low dose of ASA was maintained for 6–8 weeks, in patients with the resolution of CAL. The child with persistent CAL is still treated with ASA.

In this case series, no patients needed treatment with anakinra, indicated in patients who are refractory to IVIG and steroids, due to its efficacy in treating systemic inflammatory diseases.

All the patients were included in a follow-up, to investigate on clinical outcome and resolution of organ involvement. The follow-up was performed for a median time of 10 months and included medical examination, blood samples, ECG and echocardiogram, abdominal US.

Haematological parameters normalized in all the patients. The patients with increased pancreatic amylase showed the restore of pancreatic enzymes in 2 weeks. Proteinuria and/or haematuria resolved in 5 ± 2 days after the start of IVIG and steroids. Nobody showed a relapse of signs of kidney damage during the follow-up.

IL-6 levels showed a prompt normalization after steroids and IVIG treatment. At the contrary, the increase of pro-BNP levels persisted for 7–10 days after IVG and steroids treatment.

In all the patients, during the follow-up, we did not observe an inflammation rebound, with maintained normal levels of CRP, ESR, IL-6, ferritin, LDH, fibrinogen, D-Dimer. Troponin and pro-BNP levels, after the normalization, persisted in the normal range for all the period of the follow-up, as the other biochemical markers, also in patients with persistent valvular insufficiency or CAL.

Cardiac damage evolved into the complete resolution of lesions in most of the patients. The resolution was observed and documented by echocardiogram after 7–14 days since IVIG and steroids treatment was started. The time occurred between the diagnosis and the resolution of cardiac involvement was not correlated with biochemical parameters. One patient with pre-existing Mitral valve insufficiency had a persisting defect; in 1 patient, Mitral and Tricuspid insufficiency persisted over all the time of follow-up; 1 patient with pre-existing aortic insufficiency, worsened during the acute phase of MIS-C, showed the reduction of aortic insufficiency during the follow-up, while Mitral insufficiency reached the complete resolution. In 3 patients the Mitral insufficiency reduced but did not resolve during the follow-up.

In conclusion, 18% of patients with acquired valvular insufficiency persisted with the valvular impairment during the follow-up.

CAL resolved in 2 patients, within 2 weeks since IVIG and methylprednisolone treatment was started, persisted in 1, which is still treated with ASA at 5 mg/Kg/day.

The treatment strategy, the timing and the dosage of methylprednisolone did not differ between patients with and those without resolution of valvular or coronary lesions.

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