Kawasaki disease complicated by macrophage activation syndrome and parvovirus b19 infection: Which relationship?

ABSTRACT

Introduction: Macrophage activation syndrome (MAS) is characterized by massive production of cytokines leading to macrophage activation and haemophagocytosis presenting with prolonged fever, rash, hepatosplenomegaly, pancytopenia, liver dysfunction, hypertriglyceridemia, hyperferritinemia and coagulopathy that can complicate rheumatic conditions such as Systemic Juvenile Idiopathic Arthritis (sJIA) and Systemic Lupus Erythematosus (SLE). Incidence of MAS in Kawasaki Disease (KD) has been estimated in about 1.1% patients but subclinical MAS may be detected in 30-40% of KD. Objectives: Case description Methods: A previously healthy 10 years-old girl presented high grade fever for 4 days, pharyngitis and vomiting. After 24 hours, she developed diffuse maculo-papular rash and oedema on extremities. She presented progressive worsening of general conditions and bilateral bulbar conjunctivitis, mucositis with strawberry-like tongue and left cervical lymph nodes enlargement. On admission remarkable laboratory tests were increased C reactive protein (CRP), neutrophilic leucocytosis, low sodium and albumin, increased gGT and gallbladder hydrops on abdominal ultrasound. Suspecting Kawasaki disease 2 gr/kg IVIG were administered with salicylic acid (50 mg/kg/day). Nevertheless, she presented persistent remitting fever, low consciousness, diffuse vasculitic rash, worsening of mucositis and pericardial and pleural effusion. Lab tests showed low haemoglobin, platelets and fibrinogen (9,3 g/L, 65.000/ml and 1.05 g/L, respectively), ferritin 16.492 g/L, SGOT 487 U/L, SGT 351 U/L, triglycerides 345 mg/dl, Ddimers 10.353 microgr/L and soluble interleukin-2 receptor (sIL-2R), 6464 kU/L. Active haemophagocytosis was retrieved in bone marrow and cerebrospinal fluid (CSF) so MAS was diagnosed. Three consecutive iv methylprednisolone pulses (30 mg/kg) were administered followed by dexamethasone 10 mg/m2/day and cyclosporin A 2 mg/kg/day as well as plasma infusions and oxygen supplementation (6 l/min) for 48 hours. Parvovirus B19 (HPVB19) DNA was found in peripheral blood, bone marrow and CSF, while other microbiological analysis (EBV, CMV, HHV6, VZV, Influenza A-B, Measles, Adenovirus, HSV) were negative. The patient progressively improved with reduction of fever, oedema of extremities and skin rash and after 6 days presented extensive desquamation on hands, feet and limbs. Lab tests slowly improved and normal values were achieved on day 23. Echocardiogram did not show any coronary aneurism or dilatation, cerebral MRI was normal and neurological impairment gradually disappeared. Primary HLH mutations for UNC13D, STXBP2, STX11, RAB27a, SH2D1A, XIAP were not found. Corticosteroids and Ciclosporin were gradually tapered and discontinued after 7 and 12 months respectively, whilst acetylsalicylic acid was stopped after 2 months. Results: MAS is a relatively infrequent complication in KD and may be associated with severe course and poor outcome. Several potential infectious agents have been suggested as trigger factors of both MAS and KD, such as Epstein Barr virus, Influenza virus etc. and, more recently, the SARS-COV-2 epidemic has been associated with severe forms of systemic inflammatory syndrome resembling KD and MAS. Conclusion: To the best of our knowledge, this is the first case in which demonstration of HPVB19 DNA in peripheral blood, bone marrow and CSF during acute phase strongly suggests a direct role of the virus in triggering both KD and MAS rather than an antibody or immune-complex mediated mechanism.