key: cord-0892096-9r7tdrpc
authors: Baerlocher, Severin; Helfenstein, Seth; Mahr, Alfred; Crippa, Selina; Garcia Boy, Regine; Kahlert, Christian R; Yurttas, Timur; Hatz, Christoph; Kohler, Philipp
title: Leptospirosis Followed by Kawasaki-Like Disease: Case Report From an Adult Swiss Patient and Review of the Literature
date: 2021-02-24
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab088
sha: 6d18be582a3936fdd4133d96f3cc95c9b34c3b7e
doc_id: 892096
cord_uid: 9r7tdrpc

Kawasaki disease (KD) is a vasculitis that mostly occurs in children, but rare cases in adults have been reported. We describe the case of a 43-year-old Swiss male who developed symptoms compatible with KD 7 weeks after leptospirosis, which was presumably acquired after swimming in a creek in the Swiss Alps. We performed a literature review and identified 10 other cases (all in children), in which Kawasaki-like disease was diagnosed in the context of leptospirosis. Outcome was favourable in most cases, including our patient. This exceptional case demonstrates both the possibility of autochthonous cases of leptospirosis in Switzerland as well as a possible association of leptospirosis with Kawasaki-like disease.

A 43-year-old, otherwise healthy male presented to an external hospital with fever and cough in the beginning of November 2019 (episode 1, hospital A) ( Figure 1 ). The patient also had acute kidney injury and thrombocytopenia. He recovered after treatment with amoxicillin-clavulanic acid and clarithromycin for suspected pneumonia. For the next 5 weeks, he remained completely free of symptoms. On December 30, 2019, he had an acute onset of fever up to 39.3°C, a mild cough, dry eyes, arthralgia, and a generalized rash. He sought medical care as an outpatient and was again started on amoxicillin/clavulanic acid and clarithromycin for suspected relapse of pneumonia. The fever continued and the patient developed yellow discoloration of his eyes, redness and swelling of the genital region, chapped lips, and extensive scaling of his skin, whereupon he presented to our tertiary hospital (episode 2, hospital B) on January 2, 2020 ( Figure 1 ).

The patient reported frequent outdoor activities before the onset of episode 1, including hunting, skinning of animals, and swimming in mountain lakes and creeks near the Swiss-Austrian border. He denied any other animal contacts. He was in a stable relationship with a woman for approximately 1 year and did not report any other sexual contacts. He also denied any illicit drug use. Upon admission to hospital B, the patient's blood pressure was 125/80mmHg, pulse was 88/minute, oxygen saturation on room air was 98%, and tympanal temperature was 39.3°C. Clinical examination revealed generalized jaundice, a swollen nuchal lymph node, and tenderness in the upper right abdomen. The rash had disappeared, but his skin appeared dry and showed extensive desquamation, mainly involving the lips, palms, and soles. There was diffuse swelling of the genital region ( Figure 2 ). The papillae of the tongue were enlarged. The right knee was slightly swollen. The C-reactive protein was increased at 209 mg/L. Liver enzymes were slightly and bilirubin (119 μmol/L) was markedly increased (Table 1) . Abdominal ultrasound showed no liver pathology; intrahepatic bile ducts were not dilated. The spleen (13.5 cm) was slightly enlarged. Chest x-ray was inconspicuous.

Upon hospital admission, the patient was started on ceftriaxone for 7 days to cover possible bacterial disease. Results of the extensive laboratory diagnostic work-up, which included search for infectious (eg, sexually transmitted and zoonotic diseases) and immune-mediated causes, are shown in Table 1 . In the course of the hospitalization in hospital B, serology for Leptospirosis interrogans immunoglobulin (Ig)M was positive, but it was repeatedly negative for IgG. Urine polymerase chain reaction (PCR) for L interrogans was also negative. Therefore, we performed a microscopic agglutination test (MAT) that identified Igs against L interrogans spp Bratislava (titer 1:1280). Because of the suggestive clinical presentation in hospital A, we retrospectively performed PCR on the patients' serum from episode 1 (hospitals A and B are being served by the same microbiology laboratory), which was indeed positive for L interrogans, confirming the suspected diagnosis of leptospirosis ( Figure 1 ). However, the symptoms and laboratory findings of episode 2 were not consistent with a diagnosis of leptospirosis. With the persisting fever, the peripheral extremity changes, the irritation of the enoral mucosa and the eyes, the extensive scaling of his skin, and the nuchal lymphadenopathy, the diagnosis of adult Kawasaki disease (KD) was made [1] . Transthoracic echocardiography did not reveal any signs for a coronary aneurysm or other pathological findings. On day 6 of the hospital admission (ie, 10 days after symptom onset), the fever started to subside. Therefore, we refrained from a therapy with intravenous Igs (IVIG) [2] . Although the patient was afebrile, we initiated a 1-week course of doxycycline on January 9, 2020 because of a positive urine PCR for Mycoplasma hominis. By January 13, 2020 (ie, day 12 after hospital admission), C-reactive protein and bilirubin had almost returned to normal range values and the patient was discharged.

We obtained written informed consent from the patient.

We performed a systematic literature review searching for records reporting cases of Kawasaki-like disease associated with leptospirosis. A professional librarian ran a literature search in Leptospira interrogans PCR urine Jan 9th neg.

L interrogans PCR blood Nov 9th pos.

Salmonella spp neg.

Campylobacter jejuni/Campylobacter coli neg.

Shigella spp/enteroinvasive Escherichia coli neg.

Ureaplasma urealyticum neg.

Neisseria gonorrhoea neg.

Mycoplasma gentialium neg.

Ureaplasma parvum neg.

Treponema pallidum neg.

Herpes simplex I/II neg. Table 2 ). The 10 cases (2 cases are from the same report) were published between 1977 and 2018 [3] [4] [5] [6] [7] [8] [9] [10] [11] . All were pediatric patients, with an age range between 2 and 14 years and a male to female ratio of 1.5:1. All patients had fever, 9 had conjunctivitis, 9 had a skin Leucocytes + = 10-25 cells/μl; Leucocytes +++ = approx. 500 cells/μl; Hemoglobin ++ = approx. 25 erythrocytes/μl; Bilirubin + = low concentration in urine (semiquantitative on a scale from negativ to +++); Bilirubin +++ = high concentration in urine (see above).

Abbreviations: HIV, human immunodeficiency virus; Ig, immunoglobulin; Jan, January; NA, not applicable; neg., negative; Nov, November; PCR, polymerase chain reaction; pos., positive. [1] : fever lasting at least 5 days PLUS 4 of the following: conjunctival injection; oral mucous membrane changes; peripheral extremity changes; rash; cervical lymphadenopathy. rash (6 of these with desquamation), and 8 had gastrointestinal symptoms (predominantly nausea, diarrhoea, and abdominal pain). Leptospirosis was mostly diagnosed by serology or MAT; the leptospiral serovar was reported in 3 cases: 1 L interrogans spp Hepdomandis and Canicola [3] , 1 L interrogans serovar Copenhageni [11] , and 2 L interrogans serovar Grippothyposa [10] . Diagnostic criteria for KD were fully met in 7 of the 10 cases (ie, complete KD), whereas 3 had incomplete KD. Latency between leptospirosis and Kawasaki-like disease was not reported in most cases because both diagnoses were made at the same time. In 1 case, latency was 25 days [9] . Treatment consisted of IVIG in 6 cases, acetylsalicylic acid (ASS) in 3, and steroids in 1 case. Outcome was favorable in 9 cases, except for one 2.5-year-old child where amputation had to be performed due to extensive acral desquamation and necrosis [8] .

We present the unusual case of an adult patient developing Kawasaki-like disease after infection with Leptospira interrogans spp Bratislava. The thorough literature review identified 10 similar cases, all of which were reported in children.

Kawasaki disease, also termed mucocutaneous lymph node syndrome, is a medium-sized vessel vasculitis that was first described in 1967 [12] . Hallmarks of KD, which usually occurs in children, include persistent fever, desquamating skin rash, strawberry tongue, and cervical lymph nodes [1, 13] . Adult onset KD is still rare to date and might thus often be missed by clinicians [13] . Compared with children, adult KD more often manifests with hepatitis, arthralgia, and cervical adenopathy [14] , which were all present in our patient. A potentially fatal complication-which can be found in up to 23% of children with KD-is the involvement of the coronary arteries, which can lead to the development and subsequent rupture of aneurysms [14, 15] . A single dose of IVIG 2 g/kg in combination with ASS is usually given to treat the disease. The etiology of KD remains unclear. One hypothesis is that a variety of bacterial and viral infections can trigger the disease [1, [16] [17] [18] . This includes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is being suspected of causing a KD-like syndrome called multisystem inflammatory syndrome in children and adolescents (MIS-C) [19] .

In 1977, the first report suggesting leptospirosis as cause of KD was published [5] . Leptospirosis is one of the most common zoonotic infections globally [20] . Approximately two thirds of patients with leptospirosis diagnosed in Switzerland between 1970 and 2015 were autochthonous cases, most of them with exposure to natural waters, as in our case [21] . Other published cases include a fisherman from the lake of Geneva as well as a cluster of cases among river surfers from Central Switzerland [22, 23] . Incidentally, our patient is the first published case from North-Eastern Switzerland. The annual incidence in the country was estimated at 0.08 cases/100 000 population before 1998, which is comparable to data from Germany [21, 24] . However, more recent data from Austria, another country neighboring Switzerland, showed a much higher incidence of 1.26/100 000 population [25] ; in addition, a seroprevalence study from Southern Germany (bordering Switzerland) reported that leptospiral antibodies can be detected in 4.2% of the general population. Although some of the study participants with detectable antibodies reported having had symptoms compatible with leptospirosis in the past, none of them was ever diagnosed with the disease [26] . These data suggest that leptospirosis is vastly underreported in the region, which is most probably also the case for Switzerland.

In symptomatic patients, leptospirosis presents in a biphasic course. The first phase features flu-like symptoms including fever, headache, and myalgia [27] . A second immunological phase begins within days after resolution of the first phase and may present itself with pulmonary symptoms, kidney failure, electrolyte disorders, jaundice, or pancytopenia [28] . Leptospirosis is usually diagnosed through PCR from blood (first phase) or urine (late phase). After resolution of the first phase (ie, after 5 to 7 days of illness), specific antibodies can usually be detected; approximately 10% of cases do not show any seroconversion to IgG in the further course [29] .

There is a certain overlap in the clinical presentation of leptospirosis and KD. Symptoms that have been described in both diseases-and in almost all cases in our review-include fever, conjunctivitis, gastrointestinal symptoms, and rash. These symptoms might be attributable to the vasculitic changes observed in KD but also to the late phase of leptospirosis. From a pathophysiological perspective, the overproduction of interleukin (IL)-6 has been associated with more severe disease manifestation in both KD and leptospirosis (together with IL-10 overproduction) [30, 31] . Symptoms that are more specific for KD include peripheral extremity changes, skin desquamation, a strawberry tongue, dry or cracked lips, and cervical lymph nodes [1] . It is noteworthy that in several cases identified in our review, the diagnosis of leptospirosis and Kawasaki-like disease were made concurrently. However, leptospirosis was mostly diagnosed by serology, which suggests that many patients may have had a previous asymptomatic or only mildly symptomatic episode of leptospirosis, which is perfectly in line with our current understanding of the clinical presentation of leptospirosis [28] . In general, data on the time lag between onset of KD and the potential previous triggering infection are scarce. However, in a French MIS-C cohort, the median duration between symptoms of SARS-CoV-2 infection and onset of KD was 45 days, which is very similar to our patient [32] .

In our case, it seems unlikely that the symptoms observed during the second hospital admission were in fact directly related to leptospirosis. First, the latency between the early phase of leptospirosis and the occurrence of Kawasaki-like disease was 7 weeks, a time span far too long to be coherently attributed to the immunological phase of acute leptospirosis.

Second, a leptospiral PCR in the urine was negative at that time, which is usually not the case during the second phase of leptospiral infection. Third, the patient showed typical features of KD, meeting the diagnostic criteria suggested by Newburger et al [1] . It is interesting to note that, as seen in our patient, thrombocyte counts tend to be decreased in leptospirosis, whereas they are mostly normal or increased in KD [13] . The relevance of M hominis, which can be found in up to 10% of urethral samples of asymptomatic men [33] , remains unclear. However, we did not find any cases of M hominis related with KD in the literature. In addition, the patient showed defervescence before we started treatment with doxycycline.

Our case is remarkable for several reasons. First, leptospirosis is very uncommon in Switzerland. Because of the protean manifestation of leptospirosis and a nonnegligible seroprevalence in the general population from neighboring countries, we hypothesize that leptospirosis is underreported in Switzerland. Second, the patient did not show seroconversion in the course despite PCR-confirmed leptospirosis, an unusual finding that has been reported to occur in approximately 10% of cases. Third, this case highlights the possible association of leptospirosis and subsequent Kawasaki-like disease, which has previously not been described in adults. The potentially unfavorable outcome associated with KD requires not only pediatricians, but also physicians involved in care of adult patients to be aware of this disease entity.

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young

Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association

A case of Kawasaki disease with concomitant leptospirosis

Leptospirosis mimicking MLNS

Leptospirosis mimicking collagen vascular disease in a thirteen-year-old Iranian girl. researchgate.net

Leptospirosis: report of one case

Leptospirosis: a childhood disease

Leptospirosis in a child with acute respiratory distress syndrome. researchgate.net

Leptospirosis_in_a_child_with_acute_respiratory_distress_syndrome/ links/5b45fd1fa6fdcc6619181df8/Leptospirosis-in-a-child-with-acute-respiratorydistress-syndrome

Kawasaki syndrome as complication of leptospirosis in children

A case of leptospirosis encountered in a non-endemic region (Hokkaido Prefecture)

Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children

Kawasaki disease in adults: observations in France and literature review

Adult Kawasaki disease: report of two cases and literature review

The treatment of Kawasaki syndrome with intravenous gamma globulin

Infections and Kawasaki disease: implications for coronary artery outcome

Kawasaki-like disease in a young adult: association with primary Epstein-Barr virus infection

Mucocutaneous lymph node syndrome: a case masquerading as Rocky Mountain spotted fever

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review

Leptospirosis: a neglected tropical zoonotic infection of public health importance-an updated review

Leptospirosis in Switzerland: an emerging disease or emerging awareness? Available at

Severe leptospirosis with multiple organ failure successfully treated by plasma exchange and high-volume hemofiltration

Cluster of leptospirosis acquired through river surfing in Switzerland

Autochthonous leptospirosis in South-East Austria

Risk factors for human Leptospira seropositivity in South Germany

Assessment of the clinical presentation and treatment of 353 cases of laboratoryconfirmed leptospirosis in Hawaii

Behaviour of specific IgM, IgG and IgA class antibodies in human leptospirosis during the acute phase of the disease and during convalescence

Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm

Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study

Ureaplasma urealyticum, Ureaplasma parvum, Mycoplasma hominis and Mycoplasma genitalium infections and semen quality of infertile men