Adult-onset Kawasaki disease: A great masquerader

Abstract

Kawasaki disease is a necrotising small-to-medium vessel vasculitis affecting children between age groups of 6 months and 5 years. Following the first description in Japanese infants, it has been recognised as the single most common cause of non-infectious vasculitis in children worldwide. Presentation in adult age groups, although described, is rare. Herein, we report a case about a 19-year-old female Indian patient diagnosed with Kawasaki disease and managed with antiplatelets and intravenous immunoglobulin, without further sequalae. We aim to highlight the importance of recognising this entity in adult age groups in day-to-day clinical practice.

Background

First described as mucocutaneous lymph node syndrome by Dr Tomisaku Kawasaki in 1967 in Japan, Kawasaki disease (KD) has now surpassed rheumatic heart disease as the leading cause of acquired paediatric heart disease in the developed world.¹ Predominantly, a disease of children in the age groups of 6 months to 5 years, presentation in adult age groups is rare, with 101 cases of adult onset KD reported worldwide, till 2018.² As of 2007, incidence among 10 000 children aged less than 15 years was 4.54, as per a hospital-based study in Eastern part of India.³ Due to its rarity in ages above 5 years, it is often overlooked as a possible differential in adult cases with unexplained fever and mucocutaneous eruption. That KD is a clinical diagnosis, is another factor contributing to its possible underestimation in clinical practice. Diagnosis is based on at least 5 days of fever and 4 out of 5 of the following features: bilateral conjunctival injection, polymorphous rash, non-purulent cervical lymphadenopathy, mucocutaneous changes of lips and oral cavity, and indurative oedema of extremities and membranous desquamation from fingertips⁴ (Box 1). These diagnostic criteria were laid down for children and have not been validated in adult population. Coronary artery disease is the most dreaded complication of the disease, being expressed as either aneurysms, calcification or stenosis of coronary vessels.^{5 6}

Box 1. Diagnostic criteria for Kawasaki disease (KD).

Fever of 5 days or more without other explanation and at least 4 of the 5 following criteria*⁴

1. Polymorphic exanthema.

2. Changes in peripheral extremities:

a. Acute phase: erythema and/or indurative oedema of the palms and soles.

b. Convalescent phase: desquamation from fingertips.

3. Bilateral non-exudative conjunctival injection.

4. Changes in oropharynx: injected or fissured lips, strawberry tongue and injected pharynx.

5. Acute non-suppurative cervical lymphadenopathy (>1.5 cm).

*Patients with fewer than our of these signs can be diagnosed as atypical KD if coronary artery abnormalities are present.

Case presentation

In September 2017, a 19-year-old girl, of Asian Indian ancestry, without any significant medical history, presented with high grade fever of 10 days duration, accompanied by malaise, anorexia and arthralgia. On third day of fever, she developed a reddish, pruritic rash over abdomen, back, forearm, palms and tips of fingers and front of thighs. Her mother also noted swelling on both sides of throat with reddening and watering of eyes without complaints of photophobia. The patient noted difficulty in swallowing both solids and liquids with pain in throat. After 5 days of onset of rash, she noted that it began to fade and that the skin ‘peeled off’. There was no history of headache, altered sensorium, rhinorrhoea, cough, pain abdomen, dysuria, yellowish discolouration of eyes or urine or bleeding manifestations.

On examination, higher mental functions were intact and there were no meningeal signs. She was febrile with a high pulse rate (110 beats/min, regular) and normotensive. Respiratory rate was increased (24 breaths/min) and pallor was noted on general survey. Ocular examination was significant for the presence of bilateral conjunctival injection. There was periungual peeling of skin, with desquamated macular rash over front of torso and back, forearms and thighs (figure 1). Her tongue was fissured and erythematous with the presence of reddish-white spots over its dorsum (figure 2). No definite nail changes were noted. Palpation around neck revealed non-tender cervical lymphadenopathy of size 2 cm. Abdominal examination did not reveal any organomegaly. Breath sounds were equally heard on both sides of chest and cardiac examination was uneventful except for the presence of a loud first heart sound (S1).

Figure 1.

Desquamation of skin over forearm (right) and tip of fingers (left).

Figure 2.

Desquamative macular rash over abdomen (left) and fissuring along lips with erythematous tongue and the presence of reddish-white spots over dorsum of tongue (right).

Investigations

Routine blood investigations revealed a normocytic, normochromic type of anaemia (haemoglobin:83 g/L), neutrophilic leucocytosis (30 x 10⁹/L with 84% neutrophils) and normal platelet counts. Erythrocyte sedimentation rate and C reactive protein levels were markedly elevated. Liver and renal function tests were unremarkable (table 1). Urine and blood culture examinations were unyielding. Serum ferritin was elevated (662 μg/L). Antinuclear antibody and antiphospholipid antibody profiles were negative. Serum complement levels were within normal limits. Serum immunoassays for scrub typhus, leptospirosis, HIV and hepatotropic viruses were negative. A pharyngeal throat swab was unremarkable and antistreptolysin O titres were within normal limits. Skin biopsy was non-specific, revealing epidermal hyperplasia with patchy inflammatory infiltrates (lymphocytes) in dermal layer.

Table 1.

Values of laboratory parameters of patient at time of admission

Laboratory parameters	Values (reference)
Haemoglobin	83 g/ L(≥120 g/L)
Total leucocyte count	30 x 109/L(4.5-11.0 x 109 / L)
Platelets	192 x 109/LL (150-400 x 109 /L)
Albumin	6.8 g/dL (3.2–5.0 g/dL)
ALT	36 IU/L (5–35 IU/L)
AST	55 IU/L (5–35 IU/L)
Total bilirubin	0.8 g/dL (0.1–1.0 g/dL)
CRP	16 mg/L (<6 mg/L)
ESR	96 mm/hr (0–29)
Ferritin	662 μg/L (16–305 μg/L)
ANA	Negative
HIV-1 and HIV-2 antibodies	Negative
Leptospira IgM	Negative
Scrub typhus IgM	Negative
Hepatitis A (IgM), hepatitis B (HBsAg, anti-HBc), hepatitis C (IgG), hepatitis D (IgM) and hepatitis E (IgM)	Negative
ASO titre	Negative
Malarial dual antigen	Negative
Dengue NS1 antigen and IgM antibody	Negative
Serum complement levels	Normal

ALT, alanine transaminase; ANA, antinuclear antibody; anti-HBc, Hepatitis B core antibody; ASO, antistreptolysin O; AST, aspartate transaminase; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; HBsAg, Hepatitis B surface antigen; Ig, immunoglobulin; NS1, Non-structural protein 1.

Echocardiography did not reveal any abnormality and was normal on subsequent follow-ups as well. Echocardiogram was suggestive of sinus tachycardia. Ultrasonography of abdomen was unremarkable.

Differential diagnosis

Fever with generalised maculopapular rash gave rise to initial suspicions of an infectious processes such as Staphylococci-induced and Streptococci-induced sepsis. Stevens-Johnson syndrome, erythema multiforme and drug-induced hypersensitivity reactions were excluded owing to lack of preceding drug history. Viral infections such as rubella, measles, herpesvirus, adenoviral and parvoviral infections were strong possibilities but eventually ruled out by serological assays. The presence of cervical lymphadenopathy gave rise to suspicions of infectious mononucleosis. Adult-onset Still’s disease was a distinct possibility as well. Other non-infective inflammatory aetiologies such as lupus and rheumatic fever were also considered.

Treatment

After ruling out all possible differentials, including infections, a provisional diagnosis of KD was made as per the clinical diagnostic criteria (Box 1). She was treated conservatively with intravenous crystalloids and paracetamol infusions. Antibiotic coverage was ensued to prevent superimposed bacterial infections. Following assessment of baseline immunoglobulin A (IgA) levels, definitive therapy was administered with intravenous Ig (IVIg) infusion (2 gm/kg single dose over 12 hours) and tablet aspirin (650 mg four times per day). This dose of aspirin was continued for 72 hours following remission of fever. Liquid paraffin wax and anaesthetic gel was applied topically for symptomatic relief of denuded skin lesions.

Outcome and follow-up

Low-dose aspirin was continued for 6 weeks. Subsequent blood counts and inflammatory markers improved over next 2 weeks. Echocardiography was repeated twice in course of admission, both times within normal limits. The patient became afebrile and discharged after 3 weeks of hospital stay. She was followed-up in outpatient department for next 2 years and she remained stable and asymptomatic. Echocardiography was repeated quarterly. She did not have any relapse of her symptoms until.

Discussion

KD is a clinical diagnosis without specific laboratory tests for confirmation. Adult-onset KD is much rarer than the classical childhood variant and hence lacks established standards of management. Adults also have different patterns of clinical presentation than children⁷ (table 2).

Table 2.

Comparison* of clinical features and laboratory parameters among adult and paediatric patients with Kawasaki disease^37–40

Clinical parameters	Adults (percentage)	Children (percentage)
Adenopathy	93	15
Arthralgia	61	24–38
Abnormal LFTs	65	10
Coronary artery aneurysms	5	20
Meningitis	10	34
Thrombocytosis	55	100

*Reprinted (adapted) from Sève P, Stankovic K, Smail A, et al. Adult Kawasaki Disease: report of two cases and literature review. Semin Arthritis Rheum. 2005;34:785–92, with permission from Elsevier.⁷

LFTs, Liver function tests.

Previous reports of adult-onset KD by Kontopoulou et al⁸ and Wolff et al,⁹ in young adult males demonstrated uneventful recovery without any cardiac or systemic sequalae. In contrast, Zazoulina et al¹⁰ reported on an adultonset patient with ‘incomplete KD’ presenting with heart failure, shock and coronary artery aneurysm. In contrast, recovery in our patient with adult KD was uneventful and serial monitoring for 2 years failed to establish any coronary artery pathology. This may have been attributed to early initiation of antiplatelet and immunomodulatory therapy; however, larger studies are needed to validate this presumption. In a series of 10 patients of adult-onset KD by Gomard-Mennesson et al,¹¹ coronary involvement was a feature of six patients.

Although KD is a diagnosis of exclusion, with infectious diseases forming a major chunk of the differentials, it has been previously reported in context of HIV^12–19 and more recently, SARS-CoV-2.²⁰ KD was the initial presentation, which led to diagnosis of HIV in two cases.^{12 17} In a recent series by Verdoni et al,²¹ 10 paediatric cases of a severe Kawasaki-like disease were described from Bergamo, Italy, between February 2020 and April 2020. In view of several anecdotal reports across Europe describing similar multisystem inflammatory disease, the terms paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 or multi-system inflammatory syndrome in children were coined by experts.^{22 23}

The pathogenesis of KD is unknown, although seasonal outbreaks, particularly in summer and winter, might suggest a possible infectious trigger. In the acute phase (<10 days), perivascular inflammation is the hallmark of this disease, which ultimately progresses to pan vasculitis and causes vascular occlusion, thrombosis or aneurysm.²⁴ Initiated within this acute phase, IVIg may arrest progression of vasculitis.⁸ Due to the atypical nature of presentation and lack of general awareness among physicians, only 28% of patients with adult KD are treated with immunomodulation within 10 days of presentation.²⁴

Skin biopsy is not mandatory for diagnosis and shows non-specific findings such as oedema and effacement of dermal layer with mononuclear infiltrates.²⁵ Previous reports by Drago et al²⁶ and Guzmán Montealegre et al²⁷ have demonstrated perivascular mononuclear cell infiltrates in patients with adult KD (table 3).

Table 3.

Comparison of skin biopsy findings among previous and current reports of patients with adult Kawasaki disease

	Drago et al26	Guzmán Montealegre et al27	Present report
Age	21 years	36 years	19 years
Sex	Male	Male	Female
Ethnicity	Caucasian	Latin American	Indian
Skin biopsy	Mild epidermal hyperplasia with dermal lymphocytic perivascular infiltrates	Perivascular lymphocytic infiltrate	Epidermal hyperplasia with patchy lymphocytic infiltrates in dermal layer

Previously, Harada²⁸ and Beiser et al²⁹ have attempted to develop risk stratification models for children with KD to predict long-term coronary complications. However, owing to the imprecise performance of these scoring systems, all patients diagnosed with KD should be treated with IVIg at the earliest. This holds true for all patients with KD, since, given its rarity, it is impossible to formulate separate guidelines for adult KD cases.

The recommended treatment regime of KD is a single 2 g/kg infusion of IVIg, which may be repeated if the fever is persistent or recurs after 36 hours, a condition known as resistant KD.^{30 31} A study by Furusho et al demonstrated marked superiority of a single dose IVIg infusion over a 4-day regimen, with respect to preventing coronary artery aneurysms.³² Usual infusion rates are over 10–12 hours³³ as faster infusions carry chances of aseptic meningitis.³⁴ It is highly desirable to rule out serum IgA deficiency before initiating IVIg as deficiency of the former predisposes to anaphylactic reactions.³⁵ Pulse methylprednisolone may be considered in cases of resistant KD, where two IVIg infusions have not managed to alleviate fever.³³

High-dose aspirin is recommended during the febrile stage as it theoretically reduces vascular inflammation and thrombosis.³⁰ Forty-eight hours to 72 hours after fever resolution, dose of aspirin may be reduced to 3–5 mg/kg/day and continued for 4–6 weeks in the absence of detectable coronary aneurysms, as per recent American Heart Association guidelines. In cases of uncomplicated KD, echocardiography may be performed within 1–2 weeks and 4–6 weeks of completion of therapy. On detection of coronary artery abnormalities in acute stage, monitoring should be done at least twice weekly till halting of progression. Cardiac follow-up should continue till 1 year or beyond depending on degree of coronary artery perturbations.³⁶

Patient’s perspective.

My daughter was in such terrible pain that I thought she won’t make it’, said the mother of the patient. ‘By God’s grace, we came across these wonderful team of doctors who worked tirelessly to ensure my child’s well-being. I shall be forever grateful to them for their kindness and dedication towards us.

Learning points.

• It is prudent to consider Kawasaki disease (KD) as a possibility in adults with unexplained fever, mucocutaneous changes and evidence of high-grade systemic inflammation.

• Early treatment with immunomodulation and high-dose aspirin may prevent long-term cardiac sequalae in patients.

• It is imperative to recognise and publish data on patients with adult-onset KD to formulate evidence-based guidelines for diagnosis and treatment in adult subset of patients.

• Once a diagnosis of KD is made, cardiac work-up is mandatory irrespective of age of presentation.