intrODuCtiOn

Macrophage activating syndrome (MAS) is a potentiallylife-threatening condition caused by dysregulation inmacrophage-lymphocyte interaction, and it manifests as ahigh-grade fever, disturbed liver function, pancytopenia,and central nervous manifestations. MAS has been asso-ciated with several conditions such as drugs, infections,Kawasaki and rheumatic diseases, specifically systemiconset juvenile idiopathic arthritis (SoJiA). Kawasaki dis-ease (KD), previously known as mucocutaneous lymphnode syndrome, is the most common vasculitis and majorcause of acquired heart disease in infants that presentsacutely with an unknown etiology and self-limited course[1]. Another type known as atypical KD is characterizedwith an unusual presentation not fulfilling the diagnostic

criteria of KD and is more common in infants [2]. themain conflict that arises is that the initial presentation ofatypical KD is similar to that of SoJiA, and both entitiesshare common laboratory findings from an elevated Crpand eSr, thrombocytosis, anemia, leukocytosis leadingto a confusion with respect to diagnosis [3]. herein, wereport a case of a 12-month-old male child with undiag-nosed SoJiA presenting with MAS and initially treatedfor atypical KD refractory to intravenous immunoglobu-lin (iViG) treatment, along with a literature review.

CASe repOrt

A previously healthy 12-month-old male child with up-to-date vaccinations presented to our hospital for a three-dayhistory of high-grade fever (up to 40°C), non-productivecough, somnolence, vomiting, oliguria, and decreased ap-petite. there was no history of a similar episode and fam-ily history was significant for Crohn’s disease as well asjuvenile and rheumatoid arthritis on the maternal side.however, the child had developed an urticarial rash fivemonths ago localized to the extremities which lasted for

Lebanese Medical Journal 2018 • Volume 66 (1) 49

CAS CLINIQUE / CASE REPORTMACRoPHAGE ACTivATion SynDRoME in A PATiEnT WiTH SySTEMiC-onSET juvEniLEiDioPATHiC ARTHRiTiS iniTiALLy TREATED FoR ATyPiCAL KAWASAKi DiSEASEA Case-Based Reviewhttp://www.lebanesemedicaljournal.org/articles/66-1/case2.pdf

essa hAriri1, rawan DeMAChKieh2, Ahmad nAJA1, Ahmad hACheM3, Gerard wAKiM2

hariri e, Demachkieh r, naja A, hachem A, wakim G.Macrophage activation syndrome in a patient with systemic-onset juvenile idiopathic arthritis initially treated for atypicalKawasaki disease: a case-based review. J Med liban 2018 ; 66(1) : 49-53.

hariri e, Demachkieh r, naja A, hachem A, wakim G. Syn-drome d’activation macrophagique chez un enfant atteintd’arthrite rhumatoïde juvénile traité initialement pour une pré-sentation aypique de Kawasaki. Cas clinique. J Med liban2018 ; 66 (1) : 49-53.

ABSTRACT • Systemic-onset juvenile idiopathic arthritis(SoJIA) is the most common rheumatic disorder in childrenand its presentation can mimic atypical Kawasaki disease.The diagnosis of SoJIA is often challenging and childrenare often diagnosed and treated for Kawasaki disease ini-tially, especially after an unremitting fever lasting for sev-eral days. This fact can delay the treatment of SoJIA as in-correct treatment with intravenous immunoglobulins (IVIG)is being given and this may probably lead to a worse out-come in those individuals. This is a case of a 12-month-oldinfant who was initially treated for atypical Kawasaki in-stead of a SoJIA presenting with a macrophage activatingsyndrome (MAS). We also present a review of the litera-ture that supports the diagnosis of SoJIA presenting withMAS.

Keywords : systemic onset-juvenile idiopathic arthritis;atypical Kawasaki; macrophage activating syndrome; coro-nary artery dilatation; corticosteroids

RÉSUMÉ • L’arthrite juvénile idiopathique systémique (AJIS)est la pathologies rhumatologique la plus fréquente chez l’enfantavec une présentation pouvant souvent imiter une manifestationatypique de la maladie de Kawasaki. Établir un diagnostic peuts’avérer compliqué. Les enfants affectés sont le plus souventdiagnostiqués porteurs d’une maladie de Kawasaki et traitésinitialement par des immunoglobulines intraveineuses (IGIVs).Avec pour conséquence directe de retarder, parfois de plusieursjours, l’initiation d’un traitement efficace avant qu’un diagnosticcorrect soit établi. à noter également que des IGIVs administréesà un patient atteint d’AJIS peuvent aggraver ses symptômes etprécipiter une détérioration de son état clinique. Nous rappor-tons le cas d’un enfant âgé de 12 mois traité initialement pourune présentation atypique de Kawasaki et qui s’est avéré atteintd’AJIS avec un syndrome d’activation macrophagique. La revuede littérature qui suit le cas que nous rapportons confirme lacomplexité d'un tel diagnostic.

Mots-clés : arthrite juvénile idiopathique systémique; atypiquemaladie de Kawasaki; syndrome d’activation macrophagique;dilatation des artères coronaires; corticoïdes

1 School of Medicine, lebanese American university (lAu),Byblos, lebanon.

2Department of pediatrics, lAu Medical Center – rizk hospital,Beirut, lebanon.

3Department of pediatrics, American university of Beirut Medi-cal Center, Beirut, lebanon.

*Corresponding author : Gerard Wakim, MD.e-mail: gerard.wakim@umcrh.com

one week without any treatment. upon arrival his vital signswere: heart rate: 152 beats/min, respiratory rate: 30 breaths/min and a temperature of 38.7°C. physical examinationshowed erythematous and bulging tympanic membraneswith a slightly distended abdomen and mild tenderness.furthermore, no skin rashes, lymphadenopathy or red-ness and inflammation of joints were reported. initiallaboratory workup revealed anemia, thrombocytopenia,and hyponatremia with evidence of systemic inflamma-tion and infection (table i).

the child was managed for pyrexia of unknown origin,and differential diagnoses of meningitis, pneumonia, eBVand CMV were considered. Blood and urine cultures werenegative for any organism. A lumbar puncture was contra-indicated due to the low platelet count, and the infant wasadmitted and treated with iV ceftriaxone (100 mg/kg/day)for the presumptive diagnosis of meningitis. An abdominalultrasound was performed and revealed hepatosplenomeg-aly with multiple mesenteric lymph nodes.

On the 8th day of admission, bilateral conjunctivitis wasobserved and diagnosed as anterior uveitis. the infant alsocontinued to experience daily intermittent fever during thefirst 8 days (fig. 1), remained lethargic with a decreasedappetite, and spent most of the day sleeping. he had epi-sodes of non-bloody and non-mucoid diarrhea that wereself-limited, and stool analysis were germ and blood free.

Serology tests were negative for: CMV, eBV, adeno-virus, parvovirus, AnA, rf, Anti-CCp, Anti-Scl, Anti-Sm,Anti-SS A/B, Anti-rnp, Anti-DnA and Anti-Jo. As a

result, a differential diagnosis of atypical KD and SoJiAwas made.

On the 10th day of admission, an echocardiogram re-vealed a left and right coronary artery dilatation (3-4 mm)and mild dilatation of the left ventricle (fig. 2). there-fore, a diagnosis of atypical KD was hypothesized basedon a prolonged fever for more than 5 days associated withone clinical diagnostic criteria (bilateral conjunctivitis),coronary artery dilatation, increased Crp and eSr with acomplementary laboratory criteria – anemia. After check-ing for the absence of thrombocytopenia, the patient wastreated with a first dose of iViG (2 gram/kg) along with ahigh dose of aspirin (100 mg/kg/day), and fever returnedto normal shortly before peaking again. Afterwards, ano-ther infusion of iViG (2 gram/kg) was given due to therecurrence of fever, but the child did not show improve-ment and continued to have high grade fever spikes.echocardiogram and abdominal ultrasounds were repeatedand the results remained unchanged. the persistence offever with two doses of iViG and lack of further clinicalcriteria to support the diagnosis of atypical Kawasakiraised the suspicion of SoJiA, and aspirin dose was shiftedto an antiplatelet dose (3-5 mg/kg/day).

On the 15th day of hospitalization, and after receivingiViG with no alleviation of pyrexia, a bone marrow aspi-rate was obtained and revealed rare hemophagocyticbodies with no evidence of underlying malignancies. how-ever, since the patient fulfilled both hlh-2004 criteria [4]as well as ravelli et al. criteria [5], he was diagnosed to

50 Lebanese Medical Journal 2018 • Volume 66 (1) E. HARIRI et al. – Macrophage activation syndrome

Tableau IlaboRatoRy investigations duRing Hospital stay and folloW-up

Day 3 Day 4 Day 6 Day 8 Day 12* Day 15* Day 17C Day 21 Day 24D Day 27 Day 34 Day 54

Hb 10 9.4 9 9.6 8.6 8.9 8.2 8.7 8.9 8.9 10.7 11.2WbC 13730 12490 12340 13880 12660 18510 12980 21170 24800 27710 26600 18470N (%) 33.6 - 44 47 50 50 45 43 30 45 - 35PlT (x 103) 51 42 61 102 165 287 274 391 491 522 420 252CRP 17.3 20.18 22.61 9.88 10.2 10.17 11.35 3.89 - 2.86 1.63 1.56eSR - - - - - 120 123 - 118 122 40 51alT 69 - 29 - - - 181 343 550 250 33 18aST - - 44 - - - 343 445 547 122 29 29alP - - 120 - - - - 197 277 - - -GGT - - 3 - - - 13 46 73 47 19 -Ferritin - - - - - 198 160 - - 75 - 21Fibrinogen - - - - - - 516 - - - - -D-Dimers - - - - - - 2.64 - - - - -TG - - - - - - 469 - - - 125 -albumin - - - - - - 2.4 - - - - -Sodium 133 131 134 136 135 - - 135 - - - -urine WbC - 1-2 1-2 1-2 - - - - - - -

*ivig infusion Csteroids treatment Ddischarge Hb: hemoglobin WbC: white blood cells N: neutrophils PlT: plateletsCRP: c-reactive protein eSR: erythrocyte sedimentation rate alT: alanine transaminase aST: aspartate transaminasealP: alkaline phosphatase GGT: gamma-glutamyl transferase TG: triglyceride

have MAS and subsequently, 1 mg/kg/day of prednisonewas initiated once daily, and a significant clinical im-provement was observed with no remitting fever. theanterior uveitis persisted and treatment with prednisoloneacetate ophthalmic suspension drops was initiated withthe prednisone dose increased to 2 mg/kg/day.

the child was discharged after one week, and follow-upwith the ophthalmologist two weeks later has shown reso-lution of the anterior uveitis. hence, prednisone dose wastapered off over the following three-week period. echocar-diography then revealed an improvement in the coronaryartery dilation, and the child is currently on follow-up forthe last four months with no recurrence of fever.

DiSCuSSiOn

the diagnosis and management of a fever of unknownorigin is one of the most difficult yet common cases fac-ing pediatricians. KD and juvenile idiopathic arthritis(JiA) are two major causes of prolonged and refractoryfever in children not sought early by physicians and con-

sidered as diagnoses of exclusion. JiA is the most com-mon chronic rheumatologic disease affecting children andconsidered a major cause of pain, depressed growth andmobility restriction in this age group [6]. it usually startsas general systemic symptoms that include sore throat,fever, lymphadenopathy, hepatosplenomegaly and recur-rent salmon-colored rash [7]. these symptoms may pre-cede the involvement of the joints and the development ofarthritis that may not appear until months or even yearsafter the pyrexia begins, hence delaying the diagnosis [7].Common laboratory abnormalities include anemia, leuko-cytosis elevated eSr, and children are usually AnA andrf negative.

MAS, known as reactive haemophagocytic lympho-histiocytosis, occurs in 6-7% of children with SoJiA,with a reported mortality rate of 20-30% [8], and aboutone-third of patients with active SoJiA may have mild,subclinical MAS [9]. it was first described by hadchouelet al. in 1985 [10], and is believed to be triggered by bac-terial or viral infections (hepatitis A, varicella zostervirus, eBV virus, etc.), or by the use of non-steroidal anti-

E. HARIRI et al. – Macrophage activation syndrome Lebanese Medical Journal 2018 • Volume 66 (1) 51

Figure 1. High spiking intermittent fever pattern during the hospital stay.Black arrows indicate time of administration of IVIG while gray arrow indicates time of administration of corticosteroids.

Figure 2. Echocardiography showing dilatation of the right coronary artery (RCA) of 3 mm in (a)and left coronary artery (LCA) of 4 mm in (b).

Time (Day)

Tem

per

atu

re (

ºC)

a b

inflammatory drugs (nSAiDs), methotrexate, gold salts orsulfasalazine [11]. the onset of MAS is usually in the earlystages of SoJiA and can commonly be the initial presenta-tion of this disease [12]. until now, there are no definite orvalidated diagnostic criteria for MAS, and establishingearly diagnosis is often difficult [5]. typically, patientswho develop MAS present with persistent unremittingfever, rash, jaundice, lymphadenopathy, hepatosplenomeg-aly, mental status changes, and laboratory analyses showcoagulopathy with fall in at least two of three blood celllines, elevated prothrombin time (pt) and partial thrombo-plastic time (ptt), reduced fibrinogen and raised D-dimerlevels, low erythrocyte sedimentation rate (eSr) and ele-vated serum liver enzyme values which can terminate inacute liver failure, coma and multiple organ failure.

in this case, we present a patient with SoJiA presentinginitially with MAS and treated for a considerable periodof time as incomplete KD due to the presence of coronaryartery dilatation. in fact, clinical features in patients withSoJiA, particularly in the initial stages, closely resembleKD. Both illnesses will present with fever, rash, thrombo-cytosis, and increased inflammatory markers. therefore,it is not surprising that most SoJiA patients with coronaryartery dilatation were all initially classified as KD or in-complete KD and treated with multiple doses of iViG.Differentiation from KD is important for three reasons: tohasten institution of appropriate treatment, to determinelong-term prognosis, and most importantly to avoid mul-tiple courses of iViG due to suspected refractory KD. thiswould dramatically increase expenditure given the exorbi-tant costs of iViG in addition to exposing the patient topotential harms of blood products. Such is demonstratedin our patient as well as other reports in literature [12,13],where multiple courses of iViG would be potentially de-laying therapy in this subset of SoJiA patients that need tobe treated more aggressively. however, Shin et al. hadsuggested that the implications of misdiagnosing SoJiApatients as KD were minimal since iViG treatment wouldbe beneficial in SoJiA patients as well [14]. in our patient,because the prolonged fever was unexplained, incompleteKD was considered, especially with the presence of cer-tain laboratory parameters (anemia, hypoalbuminemia,elevated liver enzymes) and abnormal echocardiography.it is well recognized that some patients do not fulfill theclassic diagnostic criteria of KD termed ‘incomplete’ or‘atypical’ KD, and the diagnosis is often based on echo-cardiographic findings of coronary artery abnormalitiesand laboratory findings according to the American heartAssociation guidelines [15]. it should be considered in allchildren with prolonged fever for ≥ 5 days associated with2 or 3 of the principal clinical features of KD [16,17].

the pattern of fever described as intermittent is moretypical to SoJiA than KD that usually has a remittent typeof fever, while thrombocytopenia along with hepatosple-nomegaly may exclude the diagnosis of KD. Besides,uveitis is not an uncommon feature of JiA and is found in12% of all types [18], thus the presence of uveitis does notfavor the diagnosis of KD in our patient. Additionally, KD

itself remains an acute, self-limiting illness, and evidenceof systemic inflammation is more persistent in SoJiA thanusually observed in KD.

hence, this patient has JiA undiagnosed previouslywith a family history of arthritis and Crohn’s disease, andthe ongoing fever that responded to steroids with absenceof response to a combination of iViG and aspirin. the pa-tient’s initial presentation of SoJiA appeared as a compli-cation of MAS in a milder form because he had throm-bocytopenia, anemia, deranged liver function tests, in-creased lactate dehydrogenase (lDh), pt and D-dimers,hypertriglyceridemia, hyponatremia with hepatospleno-megaly and dilated cardiac ventricles. Besides, promptrecognition of MAS as a severe complication associatedwith SoJiA is mandatory, treatment with high doses ofcorticosteroids as first line therapy has been shown to beeffective, followed by cyclosporine A if no response tosteroids is evident within 24-48 hours [8,19]. fortunate-ly, our patient recovered from it early with a low dose ofcorticosteroids despite the unfavorable prognosis of MAS.

Besides, the diagnosis of MAS is usually confirmed bythe demonstration of hemophagocytosis in the bone mar-row. however, the sensitivity of hemophagocytosis was83% in one study, with a specificity of only 60% [21].hence, in several instances of MAS [6], the bone marrowaspirate does not show hemophagocytosis, which is notdemonstrable in the initial stages of the disease, and re-peating bone marrow aspirate over time may eventuallydemonstrate hemophagocytosis. furthermore, although adecline in fibrinogen is expected in MAS, high fibrinogendoes not exclude this diagnosis, where a case study onnine patients with MAS found one patient with elevatedfibrinogen [10]. On the other hand, the child’s age madethe examination difficult to determine whether there wasjoint pain and to confirm the presence of arthritis. in addi-tion, the development of arthritis before 2 years of age isusually uncommon. therefore, MAS in our case is the ini-tial presentation of an underlying, undiagnosed JiA. SinceJiA can be a chronic, intermittent or transient disease, aclose follow-up of the child is warranted to ensure propermanagement and avoid progression of this disease.

COnCluSiOn

Similar to our case, there are several reports in literaturewhere an initial incorrect diagnosis of incomplete Kawa-saki is established in a patient with a prolonged fever ofunknown origin, followed by the diagnosis of SoJiA, withor without a complication of MAS [12, 20-23]. hence,even if guidelines may aid physicians towards the diagno-sis of incomplete KD, it remains difficult to establish thediagnosis of KD and differentiate it from SoJiA due tooverlapping features and absence of specific laboratorymarkers. All in all, given the prognosis of MAS and itsprevalence in SoJiA, a high index of suspicion is needed ina patient with prolonged unremitting fever, coagulopa-thies, pancytopenia and hepatosplenomegaly to initiateproper treatment and avoid fatal outcomes.

52 Lebanese Medical Journal 2018 • Volume 66 (1) E. HARIRI et al. – Macrophage activation syndrome

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