Peripheral Gangerene, an Unusual Presentation of Infantile Kawasaki: A Case Report and Literature Review

Introduction Diagnosing infantile Kawasaki disease with atypical symptoms is difficult, and it also has higher risk of coronary abnormalities which is one of the most common complications of KD. Other complications such as pericardial effusion, mitral insufficiency, congestive heart failure, myocardial systolic dysfunction, and systemic vasculitis were also reported. Peripheral gangrene and necrosis are among the rare complications of this systemic vasculitis. Case Presentation. We report an 8-month-old girl with prolonged fever, generalized petechial rash, cracked erythematous lips, edema, and coronary ectasia who received two doses of IVIG in another center, but short after her discharge, she started to develop a necrotic plaque on her knee. She was admitted in our hospital, and the repeat echocardiography showed sustained coronary ectasia. She received 3 doses of methylprednisolone pulse therapy and was discharged with aspirin and prednisolone. In the follow-up visits, the coronary ectasia was resolved and the necrotic ulcer was healing with a scar. Conclusions The diagnosis of Kawasaki disease and echocardiographic evaluation of the coronary arteries should be considered in young infants with prolonged fever of unknown origin. Peripheral gangrene is a rare but important complication of infantile Kawasaki disease, although the exact mechanism in not fully understood.


Introduction
Kawasaki disease (KD) is an acute, self-limited febrile disease of unknown origin that affects children. It is now the most common cause of acquired heart disease in children in developed countries and the second most common vasculitis of childhood after Henoch-Schonlein Purpura [1]. 80% of the affected patients are younger than 4 years [2], and the peak age of incidence is between 9 and 11 months [3,4].
Diagnosing infantile Kawasaki disease with atypical symptoms is very difficult, and it has higher risk of coronary abnormalities [5]. e algorithm recently published by the American Heart Association increases the sensitivity of KD diagnosis in infancy while maintaining specificity [6].
Coronary artery lesions are the most significant complication of KD [7], but other complications such as pericardial effusion, mitral insufficiency, congestive heart failure, myocardial systolic dysfunction, and systemic vasculitis were also reported. Peripheral gangrene and necrosis are among the rare complications of this systemic vasculitis [1,2,7,8]. Early diagnosis and treatment improves the prognosis significantly and lowers the risk of coronary artery involvement and other complications [4,6].
Here, we report a case of an 8-month-old girl with necrotic ulcer on her knee along with KD presentations.

Case Presentation
e patient is an 8-month-old girl without any significant past medical history with fever, bilateral conjunctivitis, and generalized nonpalpable petechial rash from 7 days prior to her first admission. She was treated with broad-spectrum antibiotics with the impression of meningococcemia. But, all the obtained cultures were reported negative, the fever persisted, and the patient started to develop red cracked lips and edematous extremities. e echocardiography showed coronary ectasia, and she received 2 doses of IVIG (2 gr/kg each) with the impression of Kawasaki disease, which stopped the fever, and she was discharged after 3 weeks of hospitalization in good health.
e chest X-ray and abdominopelvic ultrasound were normal. Doppler ultrasound showed normal flow and no sign of thrombosis, and the repeated echocardiography in our center showed sustained left coronary ectasia with a LMCA diameter of 2.9 mm and LAD diameter of 1.6 mm. e patient received 3 doses of methylprednisolone pulse therapy (30 mg/kg) and was discharged with aspirin and prednisolone.
In the 1-month follow-up of the patient, the coronary ectasia was resolved and the necrotic ulcers were healed with a scar. e 6-month and 1-year follow-up was also normal. Due to continuation of local edema in the scar location, a bone scan was performed after 6 months, which was normal.
Although gangrene is a rare complication of Kawasaki disease, it carries significant morbidity for patients and requires more attention by clinicians. While we do not know the exact pathogenesis of vascular changes in KD that result in gangrene, the suggested etiologies are arteritis, arteriospasm, thrombosis of inflamed vessels, peripheral perfusion decrement [1], and, most likely, a combination of some or all of these factors.
We have found 19 similar case reports of Kawasaki patients with gangrene and a total of 24 patients in previously published Medline-indexed literatures (Table 1) (unavailable data are presented with question marks in the table content). e average age of the reported patients was 5 months, although a 4-year-old and a 22-year-old with Kawasaki and gangrene were reported as well [10,11]. e young age of these patients could be due to delayed diagnosis of KD in this age or a possible genetic predisposition which is suggested in many studied [28].
ere have been reports of ADA2 deficiency similarities and PAN in recent papers [29], and considering the close nature of KD and PAN, maybe this could branch in as well. It could explain the reported positive clinical response with anti-TNF drugs seen in patients with KD and gangrene [1,12]. Although ADA2 deficiency is associated with endothelial damage, the exact function of this protein in endothelial integrity is still not fully understood [30].
Most of the patients were male (2 : 1), 15 patients had incomplete KD (60%), and the necrosis started from day 15-31 of the beginning of the fever. It can be assumed that since incomplete KDs are usually diagnosed later than complete KD due to the nature of their atypical symptoms and requirement for laboratory and echocardiographic evaluation for the diagnosis, the course of the disease is much more aggressive and we see more cases of peripheral necrosis in incomplete KD. e most common gangrene site was the distal part of extremities, but our patient's ulcer was on her knee. 19 patients (79%) had coronary involvement which shows the strong association between peripheral gangrene and coronary artery aneurisms. Our patient also had coronary ectasia which improved after treatment. Half of the patients had received IVIG before the 10 th day of the disease. Early treatment with IVIG has been shown to reduce the incidence of coronary aneurism [6,7]; thus, it is safe to speculate that early treatment might also reduce peripheral ischemia and gangrene [13].
ere has been one report of infantile KD and gangrene in a patient with factor V Leiden heterozygous mutation which could be due to the susceptibility of thrombosis formation in this patient which possibly was triggered by KD [14]; this supports the hypothesis that thrombosis plays a key role in this complication.
Different treatment approaches were suggested for these cases: methylprednisolone pulse, heparin, propranolol, warfarin, urokinase, PGE1 and prostacyclin, dipyridamole, nitroprusside, tissue plasminogen activator, topical TNG, and even caudal block [15]. Treatment with PGE1 and prostacyclin seems to have positive effects on reperfusion. However, treatment is only effective if started early in therapy [11,13,[15][16][17]. von Planta et al. mentioned that their patient developed myocardial infarction after prostaglandin infusion and raise the concern that this might steal perfusion and cause ischemia in compromised coronary arteries of KD  Case Reports in Rheumatology   Case Reports in Rheumatology patients [18]. No proven treatment or prophylaxis approach is available in the literature. In the review of the 25 cases, only 6 experienced no significant sequel, especially amputation. It seems that once the necrosis has developed, it is really difficult to manage and control. In our patient, considering the tissue necrosis and coronary involvement along with abnormal liver function tests, high IL6, and the previous treatment with IVIG, we gave her methylprednisolone pulse therapy which showed excellent results.
We reported a case of peripheral gangrene in an infantile Kawasaki disease to raise concern about the importance of early diagnosis, especially in atypical cases. Because this complication of KD is less mentioned, we have to report more cases to understand the epidemiology and to find the best treatment option for these patients to reduce morbidity and even mortality in such cases.

Conflicts of Interest
e authors did not have any conflicts of interest relevant to this article.