Non-Langerhans cell histiocytosis in a child with Kawasaki disease

Abstract

Polymorphous skin rashes are one of the major presentations in children with Kawasaki disease. This report describes an unusual presentation of a skin rash (non-Langerhans cell histiocytosis) in a 4-month-old baby with resistance to intravenous immunoglobulin (IVIG) treatment and coronary artery dilatation. Though refractory to repeat dosages of IVIG treatment, the patient had a favourable response to methylprednisolone pulse therapy.

BACKGROUND

Kawasaki disease (KD) is an acute febrile systemic vasculitis that was first described by Kawasaki et al, but the aetiology of the disease remains unknown. It occurs worldwide and mainly affects children less than 5 years old. The clinical characteristics of patients with KD include prolonged fever for more than 5 days, polymorphous skin rashes, diffuse mucosal inflammation, bilateral non-purulent conjunctivitis, indurative angioedema over the hands and feet, and cervical lymphadenopathy. In addition to the manifestations of the major diagnostic criteria, a broad range of non-specific clinical features can be found in patients with KD; these features include irritability, uveitis, aseptic meningitis, cough, vomiting, diarrhoea, abdominal pain, gallbladder hydrops, urethritis, arthralgia, arthritis, hypoalbuminaemia and liver function impairment. The most serious complication of KD is the occurrence of coronary artery lesions (CALs), including myocarditis, myocardial infarction, pericardial effusion, coronary artery dilatation or coronary artery aneurysm.^1,2 In developed countries, KD has been the leading cause of acquired heart diseases in children. Refractory or recurrent fever occurs in 7.8–38.3% (14.1% in our hospital) of patients with KD, despite treatment with intravenous immunoglobulin (IVIG), and is associated with a higher risk of CAL.¹ More than 90% of children with KD present with polymorphous skin rash during the acute phase.² A polymorphous exanthema usually appears within 5 days after the onset of fever. The rash may present as various forms on the trunk and extremities, including an urticarial exanthema, a maculopapular morbilliform eruption, a scarlatiniform erythroderma, an erythema multiforme-like rash and, rarely, a fine micropustular eruption. Here we report an unusual presentation of a skin rash (non-Langerhans cell histiocytosis (non-LCH)) associated with KD in a 4-month-old baby with CAL who was resistant to treatment with IVIG. After remaining refractory to three doses of IVIG treatment, the patient had a favourable response to methylprednisolone pulse therapy.

CASE PRESENTATION

A previously healthy 4-month-old female infant was admitted to a medical centre due to fever for 7 days. Bilateral conjunctivitis and a diffuse vesiculopapular skin rash over the trunk and extremities were noted. None of the following were noted at that time: strawberry tongue, fissured lips, induration over the BCG vaccination scar, indurative angioedema over the hands and feet, or cervical lymphadenopathy. Two-dimensional echocardiography disclosed an enlarged right coronary artery of 2.3 mm internal lumen diameter. Under the impression of atypical KD, a high dose of IVIG (2 g/kg) and aspirin (100 mg/kg/day) was prescribed. The fever resolved within 48 h, and she was discharged the following day on low-dose aspirin. The skin rash improved after the IVIG. Two days after she had been discharged, a fever flared up without obvious infectious focus, and subsided 2 days later under supportive treatment. However, an intermittent spiking fever was noted 2 days later associated with a mild cough. The patient’s birth, travel and infectious contact history were unremarkable.

The patient was admitted to our hospital due to recurrent fever, tachycardia (152 beats/min), and mild hypertension (112/74 mm Hg). There was no desquamation of the fingers or toes, but some scattered imprinted scar (the same as the previous skin rash) was noted over the trunk and extremities. A physical examination revealed that the abdomen was soft and flat without hepatosplenomegaly. No other abnormal findings were noted. Initial laboratory data revealed a leucocyte count of 10.9×10⁹/l (40% neutrophils, 47% lymphocytes, 11% monocytes, 1% basophils, 1% eosinophils), platelet count of 716×10⁹/l and haemoglobin level of 88 g/l. The plasma levels of C-reactive protein (CRP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 53 mg/l, 59 U/l and 34 U/l, respectively. A clean-catch urinalysis showed no pyuria. Cultures of blood, throat swabs and urine that were collected at the time of admission were negative. Epstein–Barr virus capsid antigen immunoglobulin M (IgM) was negative, though early antigen antibody (1:20), nuclear antigen (1:320) and capsid antigen IgG (1:320) were positive. Cytomegalovirus IgM and Widal tests were negative. Chest radiography and abdominal sonography were unremarkable. A second dose of IVIG (2 g/kg) was given under the impression of recurrent KD with right coronary artery dilatation (2.96 mm in diameter). However, the patient failed to respond to the second dose of IVIG, and laboratory findings revealed: leucocyte count of 13.3×10⁹/l (20% neutrophils, 74% lymphocytes, 5% monocytes, 1% atypical lymphocytes); platelets 656×10⁹/l, haemoglobin 88 g/l, and elevated levels of CRP 46.2 mg/l, AST 108 U/l, ALT 59 U/l and erythrocyte sedimentation rate (102 mm/h), and a lower albumin level of 32 g/l. Empiric antibiotics were shifted to teicoplanin plus meropenem from ampicillin plus cefotaxime due to persistent fever. Four days after the second dosage of IVIG, the patient continued to exhibit a spiking fever and then received a third dose of IVIG (2 g/kg); however the fever persisted (fig 1) Methylprednisolone pulse therapy (30 mg/kg/day) was given for three successive days, and the fever resolved within 24 h without recurrence thereafter. Two-dimensional echocardiography showed regression of the CAL (right (2.58 mm) and left (2.49 mm) coronary arteries) before the patient was discharged.

Figure 1.

Dynamic changes of body temperature showed significant decrease in body temperature after methylprednisolone pulse therapy. IVIG, intravenous immunoglobulin (2 g/kg); MP, methylprednisolone pulse therapy (30 mg/kg/day).

A generalised vesiculopapular skin rash with slight desquamation was noted over the trunk, extremities and face 2 weeks later (fig 2A, B). A consultation with a dermatologist was made, and a skin biopsy disclosed an unusual presentation with non-LCH showing multinucleated giant cells, positivity for CD68, and negativity for CD1a and S100 in immunohistochemical studies, with pale cytoplasm histiocytes in the dermis (fig 3A–D). Supportive treatment with low-dose aspirin was continued and there were no further relapses.

Figure 2.

(A) Gross picture of the patient showed generalised vesiculopapular skin rash with slight desquamation over the trunk, extremities and face. (B) Close-up view of the skin rash.

Figure 3.

(A) The dermis revealed infiltration of histiocytes and multinucleate giant cells mixed with some lymphocytes (H&E, ×100). Touton giant cells were also present (upper right corner, ×400). On immunohistochemical study, the histiocytes were diffusely positive for CD68 (B), but negative for S100 (C) and CD1a (D).

INVESTIGATIONS

Skin biopsy and pathology findings.

DIFFERENTIAL DIAGNOSIS

Langerhans cell histiocytosis, Kawasaki disease, severe bacterial infection, viral skin rash.

TREATMENT

Intravenous immunoglobulin, methylprednisolone pulse therapy, antibiotics, aspirin.

OUTCOME AND FOLLOW-UP

Supportive treatment with low-dose aspirin was continued and there were no further relapses.

DISCUSSION

Langerhans cell histiocytosis (LCH) is a disorder with unclear aetiology and pathogenesis, and it is characterised by abnormal clonal proliferation and accumulation of Langerhans cells various tissue and organs. Non-LCH may also be called “class II histiocytosis”, “non-X histiocytosis” and “histiocytosis of mononuclear phagocytes other than Langerhans cells”. Non-LCH is a group of disorders defined by the accumulation of histiocytes that do not meet the phenotypic criteria for the diagnosis of Langerhans cells. Non-LCH consists of a long list of diverse disorders that have been difficult to categorise. Although some may have a haemophagocytic component, the definition excludes primary and secondary forms of haemophagocytic lymphohistiocytosis (HLH). HLH has been reported to be associated with KD.³ To the best of our knowledge, there are no published articles regarding non-LCH in patients with KD. The skin rash associated with KD is usually a diffuse non-specific maculopapular eruption involving predominantly the chest, abdomen and extremities.² Urticariform, scarlatiniform, psoriasiform, hyperkeratotic, pustular rash, pustule-vesicular or other rare skin manifestations occur less commonly. Vesiculopapular skin rashes are frequently found in patients with histiocytosis X and other virus infection associated diseases. Pustulo-vesicular skin rashes have been reported in KD with and without CAL formation,⁴ and these could be associated with failure of initial IVIG therapy and the development of CAL.

There are many regimens and clinical trials for patients with KD who have a poor response to initial IVIG treatment; these regimens include repeated administration of IVIG or infliximab, or steroid pulse therapy. In this case we prescribed three doses of IVIG followed by methylprednisolone pulse therapy. The patient’s plasma IgG levels were 28.6 g/l within 3 days after the third dosage of IVIG, and 18 g/l 2 weeks later. The plasma IgG levels were not significantly different from patients who received only one dose of IVIG.⁵

Of interest, this patient requiring three doses of IVIG and methylprednisolone pulse therapy is similar to patients with atypical skin manifestations in previous reports. In patients with atypical KD skin manifestations, it may reflect a severe vasculitis or skin-specific disease. This might make accurate diagnosis difficult, and lead to a higher resistance to initial IVIG therapy and higher cardiac abnormalities. Here we present an uncommon type of skin rash in a patient with KD to remind clinicians to recognise that a diffuse vesiculopapular skin rash, showing non-LCH, can be associated with KD.

LEARNING POINTS

• Clinicians should be aware that a diffuse vesiculopapular skin rash, showing non-Langerhans cell histiocytosis, can be associated with Kawasaki disease.

• Intravenous immunoglobulin treatment failure should consider other regimens.

• Atypical presentation of Kawasaki disease especially in a young infant.