EXPERIENCE AND REASON |
Longstanding Obliterative Panarteritis in Kawasaki Disease: Lack of Cyclosporin A Effect
Emma Children’s Hospital, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
Department of Immunopathology, Central Laboratory of the Dutch Red Cross Blood Transfusion Service, 1066 CX, Amsterdam, the Netherlands
Department of Cardiovascular Pathology, Academic Medical Center, 1105 AZ, Amsterdam, the Netherlands
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ABSTRACT |
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 TOP ABSTRACT CASE HISTORYMETHODSCONSIDERATIONSAUTOPSY FINDINGSDISCUSSIONREFERENCES |
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Kawasaki disease is a childhood vasculitis of medium-sized vessels, affecting the coronary arteries in particular. We have treated a therapy-resistant child who met all diagnostic criteria for Kawasaki disease. After the boy was given intravenous immunoglobulins and salicylates, as well as several courses of pulsed methylprednisolone, disease recurred and coronary artery lesions became progressively detectable. Cyclosporin A was started and seemed clinically effective. In contrast to the positive effect on inflammatory parameters, ie, C-reactive protein and white blood cell counts, a novel plasma marker for cytotoxicity (granzyme B) remained elevated. Coronary disease progressed to fatal obstruction and myocardial infarction. Echocardiography, electrocardiograms, and myocardial creatine phosphokinase did not predict impending death. At autopsy an obliterative panarteritis was observed resulting from massive fibrointimal proliferation, affecting the aorta and several large and medium-sized arteries. Immunophenotypic analysis of the inflammatory infiltrates in arteries revealed mainly granzyme-positive cytotoxic T cells and macrophages in the intima and media, as well as nodular aggregates of T cells, B cells, and plasma cells in the adventitia of affected arteries. These findings further endorse the role of specific cellular and humoral immunity in Kawasaki disease. Unremitting coronary arteritis and excessive smooth muscle hyperplasia resulted in coronary occlusion despite the use of cyclosporin A.
Key Words: Kawasaki disease • panarteritis • immunoglobulin • cyclosporin A • granzyme
Abbreviations: IVIG, intravenous immunoglobulin • CsA, cyclosporin A • CRP, C-reactive protein • WBC, white blood cell • LAD, left anterior descending • RCA, right coronary artery • ELISA, enzyme-linked immunosorbent assay • GrA, granzyme A • GrB, granzyme B • NK, natural killer • Ig, immunoglobulin • CTL cytotoxic T lymphocyte
Kawasaki disease is one of the most common forms of childhood vasculitis. It presents with prolonged fever and a polymorphic exanthem, oropharyngeal erythema, and bilateral conjunctivitis. Scarlet fever and measles are the closest clinical mimics. Its exact cause is not known, but exposure to a microbial superantigen has been suggested as a possible etiologic factor.1–3 However, other factors—in particular viral disease—have been claimed to evoke disease in certain patients as well.4–7
Diagnosis of Kawasaki disease still relies on clinical criteria,1,2 and investigations are done mainly to exclude other diseases and to detect early or established cardiac complications. It is a major cause of acquired heart disease in childhood in western society, although coronary complications can be reduced significantly by the use of intravenous immunoglobulin (IVIG) therapy combined with oral aspirin.2,8 The serious consequences of Kawasaki disease require a heightened awareness of this condition when dealing with childhood exanthems.
Some patients are unresponsive to standard therapy. In case of such therapy resistance, alternative treatment options are scarce and have been a subject of controversy.9–12 To date, most patients are treated with corticosteroids, orally for several weeks or in a short course of intravenous pulses of methylprednisolone, when IVIG infusions have failed. Raman et al13 reported 2 patients with Kawasaki disease resistant to IVIG and steroids who were subsequently treated successfully with cyclosporin A (CsA). We describe a patient who despite intensive multidrug treatment, including CsA, died after 5 to 6 months of obliterative panarteritis.
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CASE HISTORY |
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TOPABSTRACTCASE HISTORYMETHODSCONSIDERATIONSAUTOPSY FINDINGSDISCUSSIONREFERENCES |
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A previously healthy 16-month-old boy was admitted to a local hospital after persistent fever for 1 week. At presentation the boy showed generalized lymphadenopathy, meningism, irritability, and bilateral otitis media. Cerebrospinal fluid showed pleocytosis, was negative on Gram stains, and remained negative in microbiologic cultures. After paracentesis for additional culture, broad-spectrum antibiotics were started intravenously. After 2 to 3 days, the diagnosis of Kawasaki disease was made because of the appearance of strawberry tongue with blood-crusted lips, slight erythema palmare, and nonpurulent conjunctivitis. Apart from cow’s milk protein allergy, the family history was uneventful, particularly for autoimmunity and coronary disease or risk factors.
Laboratory values were as follows: erythrocyte sedimentation rate, 67 mm/h; C-reactive protein (CRP), 179 mg/L; white blood cell (WBC) count, 9.4 x 109/L (with 88% neutrophils and 7% lymphocytes); hemoglobulin level, 11.6 g/dL; platelet count, 475 x 109/L. Liver and kidney function was normal. Coomb’s test and antinuclear factor were negative. Antineutrophil cytoplasmic autoantibodies were negative. Urinalysis showed no abnormalities; anti-streptolysin O titer was not elevated; serologic tests for Epstein-Barr virus, cytomegalovirus, and parvovirus B19, and measles were negative. Bacterial and viral cultures from blood, throat, and feces were negative.
The patient received a single high dose of IVIG (2 g/kg) over 12 hours combined with oral aspirin (80 mg/kg/d). After 72 hours, fever and clinical symptoms persisted, a second IVIG infusion was administered at a dose of 1 g/kg, followed 3 days later by a third IVIG infusion (1 g/kg) because of recurrent fever and rising CRP. Initial echocardiography before the first and around the second IVIG infusion (day 12) showed no coronary artery aneurysms. Directly after the third IVIG infusion, the child was transferred (day 15) to our hospital. In clinical terms, he still showed signs of active Kawasaki disease, fulfilling the 5 criteria. On admission, aneurysmatic lesions were observed by echocardiography in the left anterior descending (LAD) coronary artery (LAD: 4 mm). Three pulses of methylprednisolone were given (30 mg/kg/d), and rapid clinical improvement was observed, being afebrile with minor conjunctivitis and red lips persisting for some time. Meanwhile, aneurysm formation progressed (LAD >8 mm; left coronary artery and right coronary artery [RCA] between 4–7 mm in diameter). After discharge (day 30) to the outpatient clinics for frequent echocardiography, a thrombus was detected in the LAD (day 42); warfarin was started for the forthcoming months (apart from oral low-dose salicylates). The thrombus resolved uneventful but the CRP values rose progressively and full-blown disease clinically recurred (day 60).
After readmission, the boy was retreated with two doses of IVIG (1 g/kg) and acetyl salicylates were increased up to 200 mg/kg to obtain optimal plasma levels. Because of the lack of clinical effect we started CsA (5 mg/kg) intravenously (day 70), switching to oral medication after 4 days to yield serum level of 
200 µg/L. The boy recovered completely within 2 weeks, and CsA dose was reduced slowly thereafter and stopped after 7 weeks of treatment (day 110). After 20 days (day 130), full-blown clinical disease was present again. CsA was restarted and symptoms subsided but the boy seemed lethargic and in pain, in particular after meals. Electrocardiograms, echocardiography, and blood levels of myocardial creatine phosphokinase were completely normal. Anticoagulation was adequate (international normalized ratio: 2.5–3.0). There was not any sign of ischemia or renewed disease activity at the coronary level. After admission for further evaluation of the gastrointestinal tract complaints, he suddenly died with an asystole and cardiogenic shock (3 months after the onset of symptoms; day 142). Resuscitation was unsuccessful despite atropine and epinephrine, and nitroprusside.
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METHODS |
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TOPABSTRACTCASE HISTORYMETHODSCONSIDERATIONSAUTOPSY FINDINGSDISCUSSIONREFERENCES |
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CRP and Cytokine Levels in Plasma
CRP was measured in blood samples with enzyme-linked immunosorbent assay (ELISA) (detection limit of 0.1 mg/L). This assay was performed as described before,14 using anti-CRP mAb KH61 (2 µg/mL) as the coating mAb, and biotinylated anti-CRP mAb 5G4 to detect bound CRP. Interleukin-6, IL-8, and tumor necrosis factor-
concentrations were analyzed using commercially available ELISAs with detection limits of 3.0 pg/mL, 15.0 pg/mL and 5.0 pg/mL, respectively (Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, the Netherlands).
Determination of Plasma Granzymes
Granzyme A (GrA) and granzyme B (GrB) were measured by ELISA, as described before.15 Purified GrB-Mab 11 was used as coating mAb. Plasma samples as well as the standard purified GrA or GrB were diluted in HPE-NMS buffer and detected with biotinylated GB10 mAb followed by SA-HRP for quantification and analysis. The ELISA for GrA was similarly performed, using GA-29 (0.5 µg/mL) as coating mAb, and biotinylated GA-28 was used to detect bound GrA.
Immunohistochemistry
Immunophenotypic analysis of vascular inflammatory infiltrates in postmortem material was conducted according to standard procedures, using a streptavidin-bioptin-complex method on paraffin-embedded sections and a 3-step indirect immunoperoxidase method on frozen sections.
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CONSIDERATIONS |
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TOPABSTRACTCASE HISTORYMETHODSCONSIDERATIONSAUTOPSY FINDINGSDISCUSSIONREFERENCES |
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Clinical symptoms—scored as the number of clinical criteria present—were indeed waxing and waning, until CsA was started (Fig 1A; day 70). The presence of coronary artery aneurysms from day 18 onward remained unchanged (added as 1 additional "Kawasaki criterion" in black). After tapering and ultimate stopping of CsA (day 120), rapid recurrence of clinical disease was observed. Although clinical symptoms were again sensitive to CsA (day 135), the patient died shortly afterward.
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Inflammatory parameters over time showed large fluctuations. When considered on cohort-basis, these parameters have proven their value,16,17 but at an individual base, its meaning for clinical decision-making remains to be established. We measured CRP, erythrocyte sedimentation rate, hemoglobin, WBC counts, platelet counts, and several cytokines, among which were interleukin-6, interleukin-8, and tumor necrosis factor-
. Granzymes were included as potential parameters and read-out of in vivo cytotoxic activity of lymphocytes.15 As was concluded initially from the CRP values that were prospectively determined, disease activity seemed to follow the clinical disease activity (Fig 1B). On the other hand, the levels of GrA and GrB, as retrospectively assessed, were increased and may hence reflect continuing immune activity, as shown for GrB in Fig 1B. This was also true in the later phase of the disease, when CsA had been added because of recurring clinical disease activity. CsA apparently did not influence the levels of plasma granzymes. Levels of CsA were adequate (range: 150–200 ng/mL). Cytokines were increased at single time points only and never more than 3-fold above the age-matched threshold levels. A relevant pattern was not recognized (data not shown).
The WBC and platelet counts were also altered as indicated in Fig 1C. The inverse correlation of platelet number and CRP levels in blood were obviously present in this patient, as has been often reported before.
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AUTOPSY FINDINGS |
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TOPABSTRACTCASE HISTORYMETHODSCONSIDERATIONSAUTOPSY FINDINGSDISCUSSIONREFERENCES |
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Permission for a full autopsy, excluding the brain was obtained. The heart was slightly hypertrophied (95 g) and showed dilation of both ventricles. Postmortem angiography of the heart revealed multiple stenosing lesions and aneurysmal dilations of all 3 major epicardial arteries (Fig 2A and B). The mitral valve leaflets showed nonbacterial thrombotic vegetations. On gross inspection the aorta and large arteries, including the carotid, iliac and renal arteries, showed multifocal lesions characterized by thickening of the vessel wall and wrinkling of the intimal surface. Histologically, there was a mononuclear infiltrate throughout the vascular intima, media, and adventitia of affected vessels with destruction of the media, which, however, varied in extent from site to site. In addition there was massive proliferation of anti-
actin-positive smooth muscle cells in the intima of arteries at all sites excised (Fig 2C), and which had caused subtotal occlusion of the lumen in the LAD, RCA, and left circumflex.
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The intimal and medial infiltrates were composed of T cells (CD3+) and macrophages (CD68+) with prominent HLA-DR expression (Fig 2D). Less than 50% of T cells were CD8 (Fig 2E), of which a small fraction showed distinct granular cytoplasmic staining of GrB (Fig 2F). Only sparse natural killer (NK) cells were found amid the infiltrate. Apart from the intimal and medial infiltrates in arteries, we noticed an adventitial inflammatory infiltrate at the inflamed sites which was composed of nodular infiltrates composed of B cells, including plasma cells and to a lesser extent T cells and macrophages (Figs 2G and H). Most B cells were immunoglobulin (Ig)M-positive admixed with a small number (<10%) of IgA-positive cells. No inflammatory lesions were noticed in veins or in the pulmonary vascular tree. Histologic sections of the myocardium revealed patchy areas of coagulative necrosis, in combination with infiltration of neutrophils consistent with recent myocardial infarction >1 day old. Additional findings at autopsy consisted of tubulointerstitial nephritis of the kidneys, pleural exudations, ascites, and generalized lymphadenopathy. There were no signs of ischemia/infarction in organs other than the heart.
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DISCUSSION |
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TOPABSTRACTCASE HISTORYMETHODSCONSIDERATIONSAUTOPSY FINDINGSDISCUSSIONREFERENCES |
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The mortality rate among boys with Kawasaki disease is 2-fold increased and most deaths occur within the first 1 to 2 months in the acute phase of the disease owing to heart failure.18 In a study on mycocardial infarction in Kawasaki disease, this complication occurred mostly in boys and usually within the first year during sleep or rest. Myocardial infarctions are asymptomatic in
40% of the patients.18,19 Symptoms of myocardial infarction in children are vomiting and abdominal pain.19,20 Our patient was in pain during the last week of admission, showed feeding problems, and had vomited on that fatal day. Histologically the myocardium showed areas of coagulative necrosis and polymorphonuclear infiltration consistent with a few-days-old myocardial infarction. This is of clinical interest because even a day before his death, a normal electrocardiogram was obtained without signs of arrhythmia or depressed Q waves and without elevation of cardiac enzymes [not shown].
Our case is reminiscent of 2 previous reports of fatal obliterative coronary vasculitis, resulting in sudden death attributable to myocardial infarction in the apparent absence of concomitant clinical symptoms.21,22 One child died 7 months after Kawasaki disease as a consequence of profound fibrointimal proliferation narrowing 95% of the LAD artery. In that patient, active lymphocytic inflammation was observed in all epicardial arteries without changes in any other organ.21 Two other patients had similar extensive fibrointimal thickening in combination with inflammation and infiltration without prior coronary lesions, yet with a protracted course of fever and rise in inflammatory parameters.22 All three cases had received a single IVIG infusion.21,22 One child had received systemic steroids because of his asthma 3 days before the onset of Kawasaki disease, and had an incomplete recurrence of disease 3 weeks after IVIG that resolved without further treatment.22
Mild fibrointimal proliferation disease has been reported as a long-term phenomenon in arteries of patients with Kawasaki disease.23,24 Suzuki et al25 studied immunohistochemically the stenotic segments of coronary artery lesions of 7 children with prior Kawasaki disease and demonstrated the expression of various growth factors, including platelet-derived growth factor-A, TGF-ß, and basic fibroblast growth factor by smooth muscle cells. These cells participate in the fibrointoimal proliferation and neovascularization in the intima. They concluded that active remodeling of the coronary arteries due to intimal proliferation may continue for several years after the onset of Kawasaki disease.
In our patient extensive vascular involvement had occurred, including the aorta at several levels (ascendens, thoracic descendens, abdominal) and the major branching arteries. We found at all sites evidence of the signs of a longstanding arteritis and an exuberant fibrointimal response. However, not all arteries showed the same extent of inflammatory activity. For example, in the thoracic descending aorta scarring (intimal hyperplasia and medial fibrosis) was present with only scant inflammatory infiltration, whereas all coronary artery sections and the abdominal aorta showed prominent active inflammation. Only in coronary arteries, subtotal occlusions due to massive intimal proliferation were noticed.
A remarkable finding was the presence of prominent nodular infiltrates in the adventitia of the arteries, at sites of intimal and medial inflammation. Brown et al26 reported recently that the infiltrate in acute Kawasaki disease was composed of mainly CD8+ T cells and macrophages. In our patient with longstanding arteritis, we also studied the adventitia of inflamed arteries that revealed the presence of prominent nodular infiltrates. These were composed of large amounts of B-cells and plasma cells (mainly polyclonal, ie, both 
and 
-positive, IgM-positive, and a small IgA-positive fraction of cells) in addition to T cells and macrophages. These infiltrates closely resemble the adventitial infiltrates observed in arteries with severe atherosclerotic plaque formation, previously interpreted as organized lymphoid tissue.27,28 Such infiltrates can represent prominent B cell reactivity leading to follicular lymphoid hyperplasia, as also seen in the course of severe autoimmune disease (eg, Crohn’s disease, Hashimoto thyroiditis, and rheumatoid arthritis).29–31
In normal lymphoid tissue the NK cells form the predominant cytolytic cell population. On activation also CD8+ T lymphocytes, these cells become GrB+ of cytotoxic T lymphocytes (CTLs). Granzymes are released from these cells to deliver a lethal hit during contact between the CTLs or NK cells and target cell.32 Plasma levels have been reported in patients with ongoing CTL response, ie, in patients suffering from various infections or active rheumatoid arthritis.15,33 The presence of CTLs (CD8+, GrB+) in the media of our patient combined with the GrB levels in plasma, may reflect CTL activity in the widespread vascular lesions. Granzymes can be detected in many if not all patients with Kawasaki disease, which is interesting in the light of co-existing damage of the coronary vasculature as determined by echocardiography [M. Biezeveld et al, unpublished data]. Although the obliterative fibrocellular response in Kawasaki disease bears several common features with coronary disease in heart transplants,34 the chronic use of immunosuppressive medication such as CsA may not influence the coronary inflammation and proliferation, as is illustrated by our case. The use of cyclophosphamide in Kawasaki disease has recently been described.35 However, it seems unlikely that this drug will be able to stop the over-exaggerated vascular smooth muscle response observed in our patient.
The course of the disease and the postmortem findings in our patient further underscore the wide spectrum of both clinical and, in particular, cardiological sequelae of Kawasaki disease. Although abnormal, neither echocardiography nor inflammatory parameters could retrospectively predict the boy’s impending death. Our patient illustrates the need for additional approaches in the early phase of therapy-resistant Kawasaki disease. Whether antioxidants36 or matrix-metalloproteinase inhibitors37 have such additional therapeutic potential in the standard treatment of Kawasaki disease is a possibility that warrants further study.
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ACKNOWLEDGMENTS |
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M Biezeveld is supported by a grant of the Netherlands Heart Foundation (NHS 99.189).
We thank Drs Jaap Ottenkamp and Dirk Roos for critically reading the manuscript.
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FOOTNOTES |
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Received for publication Feb 20, 2003; Accepted Jun 6, 2003.
Address correspondence to Taco W. Kuijpers, MD, PhD, Emma Children’s Hospital, Academic Medical Center (G8–205), Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail: t.w.kuijpers{at}amc.uva.nl
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