Leptospirosis Associated Kawasaki Disease. Differential Diagnosis or Disease Association? Case Report and Review of The Literature.

Background: Kawasaki disease (KD) is a systemic vasculitis which affects medium-sized arteries. Although diagnostic and classication criteria exist, differentiation from other diseases can be dicult. Case Presentation: We present a 3-year old patient with a diagnosis of complete KD with positivity for urine-PCR on leptospirosis. In our patient conjunctivitis, rash, fever, cervical lymphadenopathy, palmar swelling, exanthema were seen, indicating all criteria for complete KD. After 2 weeks periungual desquamation developed. Besides this patient two further cases were retrieved form the literature with similar clinical courses indicating leptospirosis associated KD. Conclusion: These cases indicate that leptospirosis may not only mimic but also be associated with KD shown by specic ndings like desquamation of ngers, toes and oropharyngeal mucous membrane changes. To distinguish between KD, leptospirosis and leptospirosis associated KD a proper history taking including travel history and contact to animals is fundamental as well as thorough clinical and cardiac examinations in the course of the disease. While diagnostic procedures and observation might take time, treatment of acute KD should not be delayed.


Introduction
Kawasaki disease (KD) is a systemic vasculitis which affects medium-sized arteries. The exact pathophysiology is not known. 1 Besides genetic predisposition, immunologic and infectious associations are reported. 2,3,4 Moreover, in the recent pandemic multiple cases of pediatric patients diagnosed with KD or hyperin ammation associated with positive COVID-19 (pediatric in ammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS)) were reported, indicating infectious triggers. 5,6,7,8 KD should be considered mainly in pre-school children, who present with fever, conjunctivitis, lymphadenitis, oropharyngeal mucous membranes, palmoplantar swelling and generalized skin rash. 2,9 The patients can develop desquamation of the ngers and the toes in the second week of the disease, which is a hallmark of KD. 10 The correct diagnosis can be challenging as no con rmatory test exists.
In this article we present a case of a 3-year old patient diagnosed as complete KD including desquamation of the ngers. This girl also tested positive for Leptospirosis. A comprehensive literature review in PubMed was done revealing only two other cases of leptospirosis associated KD patients.
As the patient ful lled all criteria for complete KD IVIG and Aspirin were started. Since the patient was clinically severely ill, had high in ammation parameters as well as high NT-Pro BNP, prednisolone was additively commenced. In less than 24 hours, the fever subsided, and the patient improved clinically. Echocardiography showed no signs of cardiac involvement. In ammations parameters decreased subsequently showing normal CRP on day 7 of the disease course.
Due to the mother´s report on mouse contact and the described symptoms in combination with proteinuria leptospirosis examinations were ordered. As urine PCR for leptospirosis was positive penicillin was started over a course of 14 days. Speci c leptospirosis antibodies in the serum were negative. In the second week of the disease the patient developed marked desquamation of the ngers ( Fig. 1). At follow up at 6 weeks the patient remained asymptomatic and showed no heart abnormality through echocardiography or other KD complications like hearing impairment.

Literature Review
A comprehensive literature review revealed two further cases KS and positivity for Leptospirosis blood values. Humphry et al reported a 2-year-old girl with a 3 day history of fever, pharyngitis, conjunctivitis, abdominal pain and vomiting. She had also, erythematous, macular rash involving the trunk. She had close contact with several dogs one of whom died about three weeks prior to the onset of this illness. On examination, she had lymphadenopathy, swollen lips, and a "strawberry tongue". Laboratory values showed high CRP, ESR and high liver function test. Over the course of the disease she developed acral swelling and arthralgia progressing to arthritis. Initial viral cultures and antibody titers were negative, including leptospirosisa antibody titers. A diagnosis of KD was made.
Interestingly control of leptospira antibody titer drawn on the twelfth hospital day was highly positive. In the third week of her illness the patient developed desquamation of the skin of her hands and feet indicating leptospirosis associated KD. 17 In 2017 Yao Foo et al described another case of a 7-year old girl with fever for 4 days associated with a papular rash over her chest and limbs, lymphadenitis, conjunctivitis, diarrhea, and headaches. Her family gave a history of travelling to South India a month before presentation. On physical examination, her lips were red and she had a "strawberry tongue". Initial laboratory investigations showed high CRP and ESR. The child was unsuccessfully treated with Amoxicillin. On day 7 of the illness a diagnosis of KD was made and the girl was treated with IVIG and Aspirin leading to deferescence. Post discharge leptospira serology was traced and turned out to be positive for IgM. At day 14 of the illness -when performing an unremarkable echocardiography skin peeling distally over her ngers was noted. 18

Discussion
Leptospirosis is a zoonosis caused by a spirochetal bacteria that can be shed in the urine of different animals such as dogs, livestock and rodents. Transmission occurs mostly via contact with contaminated urine. 11 Rapid dissemination of the pathogen leads to the clinical presentation with a septicaemic stage of 3-7 days with fever, headache, myalgia in 40-97% of the cases, nausea, conjunctival suffusion in 28-99%, accompanied or followed by an immune mediated phase (0 days -1 month with meningitis, uveitis, rash and fever. 11,12,13 Leptospira can affect any tissue, and primarily cause proteinurea and hemorrhagic vasculitis, as well as hepatocellular dysfunction. Although more than one million human infections are estimated to occur worldwide annually, in Germany less than 20 pediatric cases are reported each year. 16 Antibiotic treatment is recommended, to prevent long-term sequelae such as uveitis. As many signs and symptoms between leptospirosis and KS are identical it can not only mimic but also be associated with KD (Fig. 2), although desquamation, oropharyngeal mucous membrane changes and coronary aneurysms are speci c for KD. 2,11 In our case the patient presented with a clinical picture of complete KD bearing in mind that nonclassi cation criteria like nephritis is seen regularly in leptospirosis but is also a -rare-manifestation in KD. 11,12 Besides the clinical symptoms with fever, conjunctivitis, headache, myalgia, exanthema, meningism, proteinurea, the history of contact to mice and the DNA positivity in the urine proves the infection with leptospira. The latter being the most sensitive test for Leptospirosis. 11 Negative serologic results -despite con rmed diagnosis-are reported in the literature. 11,13 In the literature review, another two cases (Foo et al and Humphry et al) had been found, which also ful ll the criteria of KD and showed a positive serology for Leptospirosis. 17,18 In all three cases the patient developed desquamation of the ngers that are a hallmark of KD. All the three patients showed a positive history of contact with animals, animals' product or travel history to an endemic area indicating the importance of a speci c history taking. A summary of the cases is shown in Table 1.

Conclusion
There is a broad clinical overlap between KD and Leptospirosis which might represent distinct diagnosis but also leptospirosis associated KD.
According to the rarity of leptospirosis in developed countries we would like to remind this differential diagnosis and emphasize the importance of timely treatment of KD. A proper history including travel history and contact to animals is fundamental to reach the right diagnosis. Informed consent was obtained in written and for publishing the case report and the pictures.

Availability of data and materials
Not applicable Competing interests: The authors declare that they have no competing interests.

Funding:
This study was not funded. Authors'contribution: MN interpreted the patient data in rheumatological view, FR interpreted the patient data in infectious view, FB collected the data from pubmed research, AH collected the data from pubmed research, CS wrote the introduction, FN critical reviewed he article, KT interpreted the nephrological data.TH write the discussion and reviewed the article critically. All authors read an ap-proved the nal manuscript and agreed both to be personally accountable for the contribution.