Kawasaki Disease with Peripheral and Facial Gangrene: A Case report and review of literature

Introduction

SARS-CoV-2 pandemic and Kawasaki Disease (KD) have many similar atypical manifestations. ¹ As the pandemic progressed the potential for the virus to cause a hyper- inflammatory syndrome has come to light and was given different names: Kawasaki-like syndrome (KLS), atypical Kawasaki disease, incomplete Kawasaki disease, SARS-CoV-2-induced Kawasaki-like hyper-inflammatory syndrome (SCiKH Syndrome) and Kawa-COVID-19. A syndrome of fever with gastrointestinal and skin manifestations with features of cardiorespiratory instability, raised serum inflammatory markers and evidence of SARS-CoV2 infection was described where no other plausible explanation for the symptoms was found. There was an obvious overlap with KD.

KD is a clinical diagnosis with no available biochemical markers. There is a difference of opinion amongst paediatricians regarding the principal clinical features of Kawasaki disease, especially in tropical countries where infections such as dengue, Rickettsiosis, leptospirosis, measles and staphylococcal infections are common and often give an overlapping clinical picture. These children often have incomplete or atypical presentations with severe dermatological, musculoskeletal, gastrointestinal and ophthalmological manifestations, thus leading to missed or delayed diagnosis. ² Children may also present with predominant dermatological symptoms and signs accompanied by minimal systemic signs.

Complications of peripheral gangrene have been previously reported in the literature, especially during infancy. The pathogenesis of gangrene in KD includes possible coagulopathy and vasculopathy owing to a hyper-inflammatory state that disrupts the endothelial lining. ³ Although inflammation of the coronary arteries and resultant aneurysms are the most frequent complication of KD, it is characterized by systemic inflammation involving all medium-sized arteries of the body. This process results in other atypical presentations including hepatitis, interstitial pneumonitis, gastrointestinal complaints with gallbladder hydrops, aseptic meningitis, myocarditis, pericarditis, valvulitis, pyuria, pancreatitis, and lymphadenopathy. ⁴ Prompt recognition and treatment with IVIG and steroids as well as other immunomodulators can lead to rapid resolution.

Case report

A 3 years 6-month old male child, resident of Nepal, presented with remittent fever for 5 days along with violaceous discoloration and gangrene of both hands and feet and face (Figure 1). There was no history of cough, coryza, loose stools, vomiting, photosensitivity, irritability, photophobia, drug intake, oral ulceration or joint swelling.

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Figure 1.

Clinical images of gangrene of all 4 limbs.

On examination the child was haemodynamically stable. All peripheral pulses were palpable and blood pressure was normal in all four limbs. He was febrile and had oedema of all four extremities. Anthropometric parameters were normal. There was bilateral non-exudative conjunctival injection. There was violaceous rash over all four limbs and face along with evolving gangrene of the extremities. There was no mucosal or corneal involvement. There was mild hepatomegaly and rest of the systemic examination was normal. Initial laboratory investigations revealed a hemoglobin of 105 g/L and total leucocyte count of 18 × 10⁹/L with 84% neutrophils and 15% lymphocytes. Initial platelet count was 2.63 × 10⁹/L followed by gradual increase to 13.9 × 10⁹/L during the clinical course. Inflammatory markers were raised with CRP of 128 mg/dl and ESR of 54 mm/h but procalcitonin was <0.5 ng/ml thus making bacterial sepsis unlikely. Serum albumin was 2.8 gm/dl. Liver function tests were mildly elevated with SGOT and SGPT of 0.95µkat/L and 0.88 µkat/L respectively. Renal function tests and urinalysis was normal. Cultures showed no growth. The coagulation profile was normal but D-dimer levels were raised five times the upper limit of normal. The fibrinogen and ferritin were elevated to 3.46 g/L and 185 ng/ml (0.415 nmol/L) respectively. The triglycerides, troponin T, creatinine phosphokinase (CPK-MB) and lactate dehydrogenase were normal. There was no evidence of macrophage activation syndrome (MAS) or myocarditis. Anti-nuclear antibody (ANA) and anti-neutrophil cytoplasmic antibody was (C-ANCA) were negative, thus ruling out systemic lupus erythematosus (SLE) or childhood polyarteritis nodosa (PAN). The COVID RT-PCR and serology were negative.

A Doppler study of all four limbs was unremarkable. Skin biopsy showed epidermis lined by stratified squamous keratinized epithelium showing basket weave orthokeratosis, crusting of epithelium and parakeratosis with congested vessels in papillary dermis, suggestive of early stage of purpura fulminans. Echocardiography showed SD score of 0.12 in LMCA (Left main coronary artery), 1.98 in LAD (Left anterior descending artery) and 1.05 in RCA (Right coronary artery). There was no evidence of left ventricular dysfunction nor pericardial effusion.

A diagnosis of incomplete KD, based on clinical and laboratory criteria of the AHA 2017 guidelines was made. ⁵ In view of the emergent gangrene, broad spectrum antibiotics, IVIG (2g/kg), unfractionated heparin and pulse doses of methylprednisolone were started. Low molecular weight heparin (LMWH) was introduced after 72h with aspirin. As fever persisted after 36 h of IVIG, a second dose was administered. Despite this, the fever and gangrene persisted along with progressively rising platelet counts. Hence, infliximab infusion at 5mg/kg was administered following the second dose of IVIG. With, this a progressive improvement was seen. (Figure 2 a, b, c, d).

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Figure 2.

Extensive purpura fulminans with facial gangrene showing gradual resolution. (a) Pre IVIG (b) Post 1st dose of IVIG (c) Post 2nd dose of IVIG (d) Post Infliximab infusion.

On follow up, the echocardiography on follow-up showed delta change of more than 1 in SD score of LAD, thus confirming the diagnosis of incomplete KD with coronary artery dilatation of LAD. Skin changes recovered without facial scarring. Subsequent laboratory tests showed normal protein C, S and anti-phospholipid antibody.

Discussion

Severe cutaneous manifestations are rarely reported in Kawasaki disease. In addition to classic polymorphous exanthema, skin involvement in Kawasaki disease can be variable in type and extension,^6,7 with acute or sub-acute changes of nonspecific exanthems, desquamation, erythema, urticarial or angioedematous rash. Severe purpura fulminans seems rare. Even with initial normal coronary artery SD scores, biochemical markers are needed to diagnose incomplete KD. According to AHA 2017 guidelines, delta change of more than 1 SD score on follow may indicate coronary artery dilatation in retrospect, as in our patient. Despite severe phenotype of the disease, there was no evidence of MAS, myocarditis or KD shock syndrome.

With rise in KD cases during the SARS-CoV2 pandemic, the ability of the virus to cause hyperinflammatory syndrome has been noted. A possible mechanism is the presence of autoantibodies due to T-cell recognition of self- or viral antigens expressed on infected cells, resulting in a hyper-immune response state and cytokine storm with dysregulated immune responses. ⁸ In our case, both COVID RTPCR and serology were negative, hence no such correlation was found.

Ischemia or gangrene of peripheral limbs is a rare and serious complication of Kawasaki disease. It is usually seen in young infants usually after 2–3 weeks. However, it may also be an initial presenting feature. It has a poor prognosis and often leads to limb loss if not treated in a timely fashion. ⁹

Our patient also had worsening thrombocytosis during the course of his illness despite therapy. Thrombocytosis in children with KD increases the risk for thrombosis due to hyper-aggregability of platelets in the coronary arteries. Platelet activation may be a major determinant of various complications in KD. ¹⁰ An aggressive therapy for control of inflammation in the face of rising platelet counts is therefore justified.

Conclusion

Though peripheral gangrene is reported in infants, Kawasaki disease must be thought of as a differential diagnosis even in older children who present with extensive gangrene. Intravenous immunoglobulin and steroids must be started as soon as possible to prevent long term morbidities. Echocardiography and biochemical parameters must be evaluated to detect incomplete KD. Initial normal echocardiography does not rule out KD.