Cardiac Involvement and Prognosis in Acute Mucocutaneous Lymph Node Syndrome* Zenshiro Onouchi, M.D.; Nunehiko Tomizawa, M.D.; Masakatsu Goto, M.D.; Kazuyasu Nakata, M.D.; Masaru Fukuda, M.D.; and Motoko Goto, M.D.

Cardiac involvement and prognosis were studied in the acute febrile mucocutaneous lymph node syndrome which recently has been found among Japanese infants and younger children. The reason for its particular predilec-

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mucocutaneous lymph node syndrome ( MLNS) is a disease of unknown etiology and pathogenesis affecting most frequently infants and children under five years of age. Its onset produces an acute, febrile condition accompanied by swelling of cervical lymph nodes. Since MLNS was first established as a separate entity by Kawasaki 1 in 1967, much attention has been focused upon it by the Japanese Pediatric Society. According to a nationwide survey conducted by the MLNS Research Committee of the Ministry of Health and Welfare starting in 1970, more than 7,000 cases were reported by 1973. The syndrome has 1.4 percent mortality; 2 the death is caused either by rupture of an aneurysm of the main coronary artery, by thrombosis of same, 3 or mitral insufficiency4 due to papillary muscle dysfunction. We have recently determined, and report here, the relationship between the clinical findings in the active stage of the disease and the pathologic change in the main coronary artery. In addition, we discuss its pathogenesis and predisposing cause of invasion of the main coronary arteries. MATERIALS AND METHODS

We selected 21 from 60 patients who fulfilled the diagnostic criteria set forth by the MLNS Research Committee of Ministry of Heal~ and Welfare, whose coronary arteries to examine. After the diagnosis of MLNS was made, erythrocyte sedimentation rate, C-reactive protein levels, electrocardiogram, cardiothoratic ratio of chest x-ray films, complete blood count, urinalysis and blood chemistry were examined weekly, until acute reactants returned to normal. ECGs were analyzed with respect to P-Q intervals, corrected Q-T intervals'tagt•

There were no abnormal ECG findings in the "normal" group, hut flattening of T waves or QTc prolongation in the active stage was seen in the other groups. ~1orcover, PQ interval was elongated in some cases of the "stenosis" and "aneurysm" group. While only in the "aneurysm" group were significant ST depressions noted in leads 2, aVF, and all chest leads, especially the Vr. lead. Even if MLI\'S left a large aneurysm in the coronary artery as a sequela, the electrocardiographic changes returned to normal when the active stage had passed, except the QTc was prolonged ten months after the onset of the disease in one of the "aneurysm" group (Case 21). Stenosis or decreased blood flow involved the left circumflex or left anterior descending branch on the coronary arteriogram and the regional myocardium was perfused by the dilated branches of right coronary artery (Fig 1 ) . Aneurysms (Fig 2, 3, 4) tended to involve preferentially the main coronary arteries, but were never seen at a distance of 10 mm or more from the coronary ostium (Fig 5) . ~Ioreover, thrombosis was always noted in large aneurysms. Skin biopsies showed no remarkable change on light microscopic studies, but ultrastructural observations hy electronmicroscopy made this clear. The capillary lesion showed its basement membrane extremely thickened (Fig 6) . 298 ONOUCHI ET Al

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Histologic examinations of myocardiums obtained by biopsy revealed a small focus of Anitschkow ''myocytes" (Fig 7) which was considered to represent a microinfarct 11 even in one patient a year and

FIGURE 1. Dilated acute marginal artery as collateral circulation in a patient with narrowing of the ldt anterior descending artery.

CHEST, 68: 3, SEPTEMBER, 1975

FIGUHE

2. Large aneurysm at left main coronary artery.

a half after the active stage had passed. Electron microscopic investigation of myocardiocytes showed increased lipid droplets anti other degenerative changes.

Autopsy Filulings 12

FIGURE

4. Small aneurysms at both main coronary arteries.

nutrient arteries. The overall process is panarteritis. These lesions characteristically were in the same stage of development. The wall of the aneurysm showed massive necrosis due to the nutrient arteritis.

The patient was a 22-month-old boy. At necropsy, the enlarged heart was surrounded by large bleeding into the pericardium from a fissure of the aneurysmal wall which measured 3 x 2 x 1.5 em and was located at the left coronary artery 1.5 em distal to the ostium. The coronary arteries on both sides were very dilated and tortuous. Pathologic findings characteristically consisted of small and medium-sized muscular arteries. Although almost all organ systems were affected, these lesions were seen particularly in the coronary arteries in both the extra- and intramyocardium including its

FIGURE

.3. Large aneurysm at right main coronary artery.

CHEST, 68: 3, SEPTEMBER, 1975

FIGURE 5. Left side shows the right coronary aneurysm which is not displayed by aortography.

ACUTE MUCOCUTANEOUS LYMPH NODE SYNDROME 299

6. Capillary with thickened basement membrane at the eruption ( 22000 X ) . En == endothelial cell, Er == erythrocyte; B~l == basement membrane; NCl == nucleus. FtGUHE

Drsc.ussiON The etiology of this syndrome remains unknown. \lemhers of the study committee consider that many agents, such as microorganisms or drugs, may act as triggers for the attack. Hamashima, 13 a pathologist, insists that some form of rickettsia is the specific cause. Kawasaki'-"-'• described in detail the differentiation between this syndrome and other diseases with erythema and fever. The pathogenesis of MLNS has not been established yet, as mentioned. But, of known entities, infantile polyarteritis nodosa 14 seems to be similar to \1LNS as to clinical symptoms and pathologic findings, except the prognosis. In the former, the patients always have a downhill course to death, while, in the latter, most patients had been said to be completely recovered until the frequent involvement of the coronary arteries comes to light, leaving grave damage. 15 MLNS and infantile polyarteritis pathogenctically seem to be related to hypersensitivity or allergic angiitis 16 but differ pathologically from classic polyarteritis 17 in that ( 1) smaller caliber arteries and arterioles are primarily affected, ( 2) capillaries in addition to arteries are involved, and ( 3) vascular lesions are generally at the same stage of development. Infantile polyarteritis nodosa seems to represent the most severe form of MLl\S and displays the broad clinical spectrum. It has recently been established that almost all cases of MLNS 10 •18 reveal the ECG abnormalities and/ or cardiac enlargement in the active stage. Cardiac involvement may be divided into two groups: one resulting from myocardial ischemia and another resulting from myocarditis and pericarditis. 19 ·20 In reference to myocardial ischemia, cardiac involvement may be also divided into two groups: one resulting from arteritis of the main coronary arteries and another from focal necrosis of myocardium due to intramyocardial small arteritis. Especially in the "aneurysm" group, the ECG 300 ONOUCHI ET Al

showed horizontal or downward sloping of the STsegment combined with Q-T prolongation; these findings are generally regarded as ischemic type.~1."" Because ECG abnormalities disappeared in most cases when the active stage had passed, the inner caliber of the coronary arteries became narrow in the active stage, but myocardial ischemia may improve during the healing of the arteritis. On the other hand, with reference to myocarditis, the pathologic process is not due to direct invasion of causative agents but to cell infiltration into the myocardium from the periarteritis. When the arteritis of the main coronary artery is moderate, it becomes stenotic in the healing stage. If the inflammation is extensive, the arterial wall ruptures before it is replaced by fibrous tissue. Those that do not rupture still have the possibility of thrombosing. The extent of cardiac involvement is closely related to the degree and the extent of the acute reaction in the active phase of the disease. Steroid hormones given in sufficient doses started early in the course of the disease seem to be fairly effective as treatment and as preventive measures in cardiac involvement. If the aneurysm has already devel-

FIGURE 7 . Small focus of Anitchkow myocytes or myoc.:ardial histiocytes which may represent the mkroinfarct.

CHEST, 68: 3, SEPTEMBER, 1975

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J Pediat 24:2546, I97I Tanaka ;'\ : Study for autopsied cases of ML:.'\S (in Japanese) . Acta Paediat Jap 76:696, I972 Hamada I, Takao A, et a! : Cardiova~cular

Cardiac involvement and prognosis in acute mucocutaneous lymph node syndrome.

Cardiac involvement and prognosis were studied in the acute febrile mucocutaneous lymph node syndrome which recently has been found among Japanese inf...
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