Kawasaki disease (KD) is an acute vasculitis of unknown etiology that predominantly affects children < 5 years of age. It is now the leading cause of acquired heart disease in the pediatric age group in developed countries1. The diagnosis of classic KD is based on the presence of ≥ 5 days of fever and the demonstration of ≥ 4 of 5 principal clinical features: erythematous rash, bilateral nonexudative conjunctival injection, changes in the lips and oral cavity, erythema and edema in the hands and feet, and cervical lymphadenopathy, usually unilateral2. However, many children with KD, especially infants, present with fewer than 4 of the principal clinical findings (so-called incomplete KD), and may experience significant delays in diagnosis. The main complication of KD is the development of coronary artery aneurysms, which occur in around 25% of untreated cases. High-dose intravenous immunoglobulin (IVIG) administration in the acute phase of the illness has been shown to reduce the prevalence of coronary artery abnormalities to 3–6%1,3. However, about 10% to 20% of patients develop persistent or recurrent fever after primary therapy with IVIG and are termed IVIG resistant4. Several studies have shown that patients who are refractory to initial IVIG are at increased risk of developing coronary artery abnormalities5. A number of therapeutic approaches have been proposed for children who have failed to respond to initial therapy, including IVIG retreatment, corticosteroids, infliximab, cyclosporine, anakinra, plasma exchange, and cytotoxic agents1.
Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic disorders that is part of the spectrum of secondary hemophagocytic lymphohistiocytosis (HLH)6. Although the pathophysiology of MAS is incompletely understood, it is thought to result from a dysfunctional immune response, which causes uncontrolled activation of the monocyte/macrophage system and ultimately leads to massive hypersecretion of proinflammatory cytokines7. Cardinal signs and symptoms of MAS are unremitting fever, hepatosplenomegaly, neurologic dysfunction, and hemorrhagic manifestations. Typical laboratory abnormalities include a drop in blood cell lines, increased ferritin, triglycerides, liver enzymes, lactate dehydrogenase, D-dimers, and soluble CD25, and decreased fibrinogen and natural killer cell function. A characteristic histopathologic feature is the accumulation of macrophages exhibiting hemophagocytic activity in bone marrow core biopsy specimens or aspirates. If untreated, MAS may result in progressive multiorgan failure and eventual death. Timely diagnosis and prompt institution of appropriate treatment are therefore imperative.
MAS is seen most commonly in systemic juvenile idiopathic arthritis (sJIA) and in its adult counterpart, adult-onset Still disease, but is increasingly reported in patients with other rheumatic illnesses, including KD8,9,10,11,12,13. The estimated prevalence of MAS in KD is 1.1–1.9%9,11. However, it has been argued that MAS in KD may be more common than generally thought11. Choi, et al14 have suggested that a fraction of patients who are refractory to a second dose of IVIG have subclinical (“occult”) MAS.
Detection of MAS in patients with KD can be challenging, because the 2 conditions share many clinical and laboratory features, including fever, rash, and elevated transaminases. Further, the frequent use of systemic glucocorticoids (GC), which are efficacious in a sizable proportion of patients with MAS, in the treatment of KD refractory to IVIG therapy1, might lead some cases of MAS presenting concurrently with KD to go unnoticed, owing to the suppression of MAS process by GC therapy. Thus, a high degree of suspicion is required for making an early diagnosis. The occurrence of MAS may affect the course and prognosis of KD, because patients with MAS were found to have a high rate of IVIG resistance11,13. Further, a 13% mortality rate has been reported13. A comparison of the typical clinical and laboratory features of KD and MAS is presented in Table 1.
Comparison of typical clinical and laboratory features of Kawasaki disease and macrophage activation syndrome (MAS).
One possible explanation for the underreporting of MAS in KD is the lack of specific diagnostic or classification criteria. Recent studies have shown that the HLH-2004 diagnostic guidelines15 and the 2016 classification criteria for MAS in sJIA16 do not have sufficient sensitivity and specificity for the detection of MAS in KD11,13. The inadequate performance of these criteria could be due to differences in MAS phenotype between KD, primary HLH and sJIA-associated MAS. To give an example, only 38% of patients with MAS in KD were found to have hypofibrinogenemia13, which is part of both HLH-2004 and 2016 sJIA-MAS criteria. Further, it is unlikely that patients with MAS in KD, which is often associated with thrombocytosis, reach the low threshold for platelet count (< 100 × 109/l) requested by the HLH-2004 guidelines. In addition, the frequent occurrence of liver transaminase increase in the acute stage of KD makes this laboratory abnormality, which is included in the 2016 criteria for MAS in sJIA16, unsuitable for identifying MAS in KD. Note that patients with KD and MAS may not show the decrease in erythrocyte sedimentation rate (ESR) typically seen in MAS. This phenomenon has been ascribed to the neutralization of red blood count zeta potential by immunoglobulin G (secondary to IVIG therapy), resulting in an artificial elevation of ESR counteracting the usual process associated with MAS9. These shortcomings highlight the need for a multinational collaborative effort aimed at developing classification criteria for MAS-complicating KD.
The underrecognition of MAS in the routine clinical setting could be partly due to the lack of awareness of the possible occurrence of this complication in KD. As a result, the classic laboratory markers for MAS (other than blood cell count) are not included in the routine tests for KD. Identification of the syndrome could be enhanced by recommending the inclusion of serum ferritin determination in the diagnostic blood work of all patients with KD, particularly those with IVIG resistance. It is well known that elevated serum ferritin level is an important, available, timely, and affordable diagnostic marker of MAS. In a review of 69 cases of KD-associated MAS, the frequency of hyperferritinemia was 95% with a cutoff level ≥ 500 ng/ml, as required by the HLH-2004 criteria15, and 92% with a cutoff level of ≥ 684 ng/ml, as required by the 2016 MAS-sJIA criteria16. Another alert sign for MAS is the decrease in platelet count, which contrasts with the tendency toward thrombocytosis that is typically observed in the acute stage of KD. Note that although the detection of hemophagocytosis in the bone marrow may confirm the diagnosis of MAS, this finding is frequently absent, particularly in the early stages9,11,13, and is not specific for HLH. Thus, in the presence of the classic clinical and laboratory manifestations, the diagnosis of MAS may not require the demonstration of this morphologic feature. Bone marrow aspiration might, however, be necessary in doubtful cases or to rule out a particular etiology, such as Leishmania infection.
Between March and May 2020, a rise in the number of children with some or all of the features that are seen in KD (although frequently accompanied by unusual or less common symptoms such as abdominal pain, diarrhea, and myocardial inflammation) has been noticed in some countries or country regions most seriously hit by the coronavirus disease 2019 (COVID-19) pandemic17,18. Some of these children needed urgent intensive care treatment because of the development of MAS or toxic shock–like syndrome19. Some, but not all, have tested positive for SARS-CoV-2. It is still unclear whether this emerging multisystem inflammatory syndrome represents true KD and whether it is triggered by the coronavirus. An alert has been issued by national health authorities and pediatric scientific societies to raise awareness of this condition among general practitioners and pediatricians. These observations have raised the interest of the media and are the subjects of investigation by several research groups.
It is critically important to identify MAS early, because this potentially devastating complication carries a high mortality rate and may require a more aggressive therapeutic approach than the traditional treatment protocol for KD. MAS suspicion should prompt treatment with additional IVIG and high-dose intravenous glucocorticoids. Failure to respond to this therapy should lead to consideration of additional medications used in MAS, such as cyclosporine, etoposide, or anakinra. More recently, early initiation of anakinra was found to be a rapid and effective treatment option in KD-associated MAS12. It is noteworthy that, based on experimental findings indicating that the interleukin 1 (IL1) signaling pathway is an essential driver of disease pathogenesis, IL1 blockade with anakinra or canakinumab is being examined in clinical trials with the aim of enhancing treatment of patients with severe inflammation in the setting of acute KD20.
There is now compelling evidence that MAS in KD is underdiagnosed. Owing to the importance of hyperferritinemia for raising the suspicion of MAS, it is suggested that serum ferritin determination be included in the laboratory investigation of all patients with KD, particularly those who have persistence or recurrence of fever after the first course of IVIG. The finding of increased level of ferritin, in conjunction with other suggestive clinical and laboratory features (Table 1), should prompt the physician to diagnose MAS and to start timely and appropriate treatment. A large-scale multinational collaborative effort is required to define the characteristics of MAS in KD, to develop criteria that help practitioners in its early detection, and to establish the optimal therapeutic approach.
- Copyright © 2021 by the Journal of Rheumatology
