Kawasaki disease, <i>Mycoplasma pneumoniae</i> infection and anaplastic large cell lymphoma: An uncommon association

doi:10.4236/ojped.2012.23039

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Open Journal of Pediatrics, 2012, 2, 250-252 OJPed

http://dx.doi.org/10.4236/ojped.2012.23039 Published Online September 2012 (http://www.SciRP.org/journal/ojped/)

Kawasaki disease, Mycoplasma pneumoniae infection and

anaplastic large cell lymphoma: An uncommon association

Jalel Chemli1, Saida Hassayoun1, Soumaya Ketata2, Ajmi Houda1, Moncef Mokni3, Noura Zouari1,

Saoussen Abroug1, Abdelaziz Harbi1

1Department of Paediatrics, Sahloul Hospital, Sousse, Tunisia

2Laboratory of Bacteriology-Virology, Sahloul Hospital, Sousse, Tunisia

3Department of Cytopathology, Farhat Hached Hospital, Sousse, Tunisia

Email: [email protected]

Received 20 October 2011; revised 13 February 2012; accepted 19 July 2012

ABSTRACT

Kawasaki disease (KD) is an acute febrile systemic

vasculitis occurring predominantly in young children

less than 5 years of age. Although imperfectly known,

the aetiopathogenesis of KD would be secondary to

immunological abnormalities that could constitute a

favourable terrain for neoplasms. We report on a

case in a 2-year-old girl who presented clinical mani-

festations compatible with Kawasaki disease compli-

cated by coronary aneurysm. Aetiopathological in-

vestigations revealed M. pneumoniae infection as spe-

cific IgM were present in the serum (Elisa). The pa-

tient was initially treated by intravenous immu-

noglobulins (IVIG) and aspirin to anti-inflammatory

dose. Following a few days of desquamation, resolu-

tion of the symptomatology occurred. Four weeks

later she developed disseminated tumorous syndrome.

Lymph node biopsy revealed massive infiltration by

large cells lymphomatous proliferation. Histologic

and immunophenotypic findings were characteristic

of ALK-1+ anaplastic large cell lymphoma. Four

weeks later, the patient died from a severe nosocomial

infection complicated by septic shock. Our observa-

tion is the first cases describing the association be-

tween anaplastic large cell lymphoma, KD and M.

pneumoniae. Immunologic disorder due to KD and M.

pneumoniae infection may play probably a central

role for malignancy .

Keywords: Kawasaki Disease; Mycoplasma

pneumonia e; Anaplastic Large Cell Lymphoma;

Immunological Abnormality

1. INTRODUCTION

Kawasaki disease (KD) is a systemic vasculitis that oc-

curs predominantly in infants and young children, first

described in Japan in l967 by Tomisaku Kawasaki [1].

The etiology and pathogenesis of KD still remain un-

known. However, immunological abnormalities in the

acute phase of KD are well documented and may be

pathogenic in the known cardiac and noncardiac compli-

cations of the disease. Despite the well-known associa-

tion between acquired immunodeficiency states and neo-

plasia, there are only a few reports of malignant neo-

plasms accompanying or following the onset of this dis-

ease [2-4]. We report here an exceptional case of KD

associated with Mycoplasma pneumoniae infection and

complicated by anaplastic large cell lymphoma in a

young girl.

2. CASE REPORT

A 2-year-old Tunisian girl was diagnosed with Kawasaki

disease after presenting with a 10-day history of fever,

bilateral nonexudative conjunctivitis, erythema of the

lips and oral mucosa, swelling and erythema of the palms

and soles, rash, and cervical lymphadenopathy. Labora-

tory investigation revealed an haemoglobin concentration

of 6 g/dL, white blood cell count of 15,700/mm3 (with

72% neutrophils, 24% lymphocytes and 3% monocytes)

and platelet count of 750 × 103 cells/L. C-reactive protein

was elevated to 102 mg/L and erythrocyte sedimentation

rate to 65mm in the first hour. Visceral laboratory invest-

tigations (renal and hepatic function, muscular enzyme)

revealed no abnormalities. Chest X-ray revealed bron-

chial syndrome associated with diffuse alveolar opacities.

Echocardiogram showed coronary artery ectasia (left

main coronary artery 5 mm, left anterior descending ar-

tery 3.4 mm and right coronary artery 3.2 mm). Aetio-

logical investigations revealed M. pneumoniae infection

as specific IgM were present in the serum (Elisa, DRG

Diagnostic, Allemagne). Serologic tests for Epstein-Barr

virus (EBV), rubella and cytomegalovirus (CMV) were

negative. The patient was treated with intravenous im-

munoglobulin (IV-IG) 2 g/Kg single infusion and started

on aspirin 100 mg/Kg/day and erythromycin (50 mg/

OPEN ACCESS

J. Chemli et al. / Open Journal of Pediatrics 2 (2012) 250-252 251

Kg/day). Following a few days of desquamation, com-

plete resolution of the symptomatology occurred. Four

weeks later, she developed tumorous syndrome with

moderate hepatosplenomegaly and palpable left cervical

and profound lymph adenopathies detected by the ultra-

sonography of the abdomen and the chest computed to-

mography. Examination of the bone marrow revealed

only granulous hyperplasia without tumorous infiltration.

Lymph node biopsy revealed massive infiltration by

large cells lymphomatous proliferation. The neoplastic

elements were immunoreactive for leukocyte common

antigen, CD30, ALK-1 and ep ithelial membrane antigen.

These histologic and immunophenotypic findings were

characteristic of ALK-1+ anaplastic large cell lymphoma.

A combination chemotherapy with methotrexate, idaru-

bicin, cytarabine and thiotepa was started.

Two weeks later, the patient died from a severe noso-

comial infection complicated by septic shock.

3. DISCUSSION

Although coronary artery involvement is the feature re-

sponsible for most of the morbidity in KD, other com-

plications can also occur.

Our observation is particular by the associatio n of KD

with M. pneumoniae infection and anaplastic large cell

lymphoma never described at to day. However, if linking

M. pneumoniae to KD is actually considered that is a

possible trigger [5-9], relationship between KD and ma-

lignancies remains unclear and controversial. The hy-

pothesis that there may be an unrecognized peri-malig-

nant syndrome of signs and symptoms is discussed by

Murray et al. [2]. Clinicians must rely on the presence of

specific clinical criteria and laboratory data, excluding

other illnesses that can mimic the disease [10]. In this

situation the strict diagnostic criteria of Kawasaki disease

are required. However, some patients do not fulfil all

major clinical criteria of the disease and are diagnosed

based on echocardiogram findings. Because of the pro-

longed history of unexplained fever, bilateral nonexuda-

tive conjunctivitis, erythema of th e lips and oral mucosa,

swelling and erythema of the palms and soles, rash, and

cervical lymphadenopathy, KD was considered in our

patient and confirmed sonographically with coronary ar-

te ry ectasia.

Inaba et al. [11] reported one case of anaplastic large

cell lymphoma associated with Sjogren’s syndrome sug-

gesting that the association of vasculitis with malignancy

remains possible.

The aetiology of KD is unclear. The hypothesis that

Kawasaki disease is related to a bacterial superantigenic

toxin has been suggested because of the reported selec-

tive expansion of V



2 and V



8 T-cell receptor families,

but this theory remains controversial. Mycoplasma ar-

thritis has been shown to produce superantigen, and it is

therefore possible that other Mycoplasma organisms may

do likewise. However, the relationship between KD and

malignancies remains unclear. There are only a few re-

ports of malignant neoplasms associated with KD [2-4].

This association sugg ests that there may be a relationship

between immunological disorder in KD and the devel-

opment of malignancy. In the Japanese literature eight

patients (6 males and 2 females) with history of KD de-

veloped neoplasm [4]. The interval between KD and de-

velopment of neoplasm is variable: 4 weeks to 14 years.

Four of them died. The nature of the neoplasm is also

variable: 3 cases of acute lymphocytic leukemia, 1 case

of Hodgkin’s disease, 1 case of schwannoma, 1 cases of

giant cell tumor of th e tendon sheath, 1 case of osteosar-

coma and 1 case of malignant reticuloma. Seven of the

eight KD patients who developed neoplasms, were treated

with high-dose intravenous immunoglobulin (IVIG). It is

noteworthy that lymphoid malignancies developed in

five cases very shortly after the onset of KD. This sug-

gests that lymphoid malignancies might have developed

in the bone marrow and/or lymphoid tissues at the onset

of KD [4]. Physiopathology of development malignancy

after KD remains unclear. However, it actually admitted

that immunological disorder may play probably a central

role.

Striking immune perturbations occur in acute KD, in-

cluding marked cytokine cascade stimulation and endo-

thelial cell activation. Both HLA-DR+ CD3 + (activated T

cells) and DR+ CD4+ cells (activated helper T cells) were

significantly increased in the lamina propria of patients

with acute Kawasaki disease as compared with controls.

In contrast, CD8+ cells (suppressor/cytotoxic T cells)

were significantly reduced in both the epitheliu m and the

lamina propria of individuals with Kawasaki disease as

compared with controls [12].

Polyclonal activation of T cells in KD as manifested

by increased interleukins, tumor necrosis factor-



(TNF-



) and increased level HLA-DR+ CD3+ (activated T cells)

and DR+ CD4+ cells (activated helper T cells) is well

documented [13]. Moreover, many growth factors such

as G-CSF (granulocyte colony-stimulating factor), M-CSF

(macrophage colony-stimulating factor) [14], VEGF

(Vascular endothelial growth factor) [15] in the acute

phase of KD, might accelerate the development of lym-

phoid malignancies [16]. This immunological disorder

present in the acute phase of KD may persist for a long

period.

The role of infectious factor is not excluded. However,

patients with conditions causing aberration of lympho-

cyte function such as EBV infection, human immunode-

ficiency virus infection (HIV) and post morrow trans-

plantation appear to be a favourable terrain for theses

neoplasms. Our patient presented M. pneumoniae infec-

tion. Extrapulmonary manifestations in M. pneumoniae

J. Chemli et al. / Open Journal of Pediatrics 2 (2012) 250-252

252

[8] Wang, J.N., Wang, S.M., Liu, C.C. and Wu, J.M. (2001)

Mycoplasma pneumoniae infection associated with Ka-

wasaki disease. Acta Paediatrica, 90, 594-595.

doi:10.1111/j.1651-2227.2001.tb00810.x

infection may occur through immune dysregulation [17].

But relationship between this type of infection and ma-

lignancy remains unclear and not well documented yet.

Our observation is the first case describing the associa-

tion between anaplastic large cell lymphoma, KD and M.

pneumonia e. Immunologic disorder due to KD and M.

pneumonia e infection may play probably a central role

for malignancy and especially for anaplastic large cell

lymphoma.

[9] Lee, M.N., Cha, J.H., Ahn, H.M., Yoo, J.H., Kim, H.S.,

Sohn, S. and Hong, Y.M. (2011) Mycoplasma pneumo-

niae infection in patients with Kawasaki disease. Korean

Journal of Pediatrics, 54, 123-127.

[10] Newburger, J.W., Takahashi, M., Gerber, M.A., Gewitz,

M.H., Tani, L.Y., Burns, J.C., et al. (2004) Diagnosis,

treatment, and long-term management of Kawasaki dis-

ease: A statement 158 for health professionals from the

Committee on Rheumatic Fever, Endocarditis and Ka-

wasaki Disease, council on cardiovascular disease in the

young, American Heart Association. Circulation, 110,

2747-2771. doi:10.1161/01.CIR.0000145143.19711.78

Further, more detailed epidemiolog ical studies may be

required to clarify the relationship between malignancy,

KD and M. pneumoniae infection.

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