Acute rheumatic fever associated with tenosynovitis and a unique cytokine profile.

Acute rheumatic fever (ARF), caused by group A ß-hemolytic streptococcus infection, is characterized by inflammation affecting several organs. There are few reports on magnetic resonance imaging (MRI) findings in patients with ARF. An 8-year-old Japanese boy presented with a prolonged fever of unknown cause and swelling of his right hand. MRI of his hand revealed tenosynovitis. Migratory arthritis and erythema marginatum appeared following the hand swelling. We diagnosed him as having ARF based on the clinical course and serological testing for group A ß-hemolytic streptococcus. His serum interleukin-18 levels were lower than those typically seen in cases of systemic juvenile idiopathic arthritis (sJIA). After treatment with naproxen, his symptoms improved immediately. In conclusion, MRI findings of tenosynovitis may be useful for the diagnosis of not only sJIA but also ARF in patients presenting with a fever of unknown origin. Subsequently, the diagnosis of ARF can be confirmed with specific serological tests. Serum interleukin-18 levels may be helpful in the differential diagnosis of ARF and sJIA. Although ARF is rare in developed countries, including Japan, early diagnosis and appropriate treatment are important to prevent rheumatic heart disease.

Adjunct cyclosporine therapy for refractory Kawasaki disease in a very young infant.

Herein we describe the case of a 6-week-old boy who developed complete Kawasaki disease (KD). The cytokine profile and activation of monocytes and subsequent T cells matched the typical feature of refractory KD. The patient received a total of three courses of i.v. immunoglobulin (IVIG), but did not achieve clinical relief. Adjunctive therapy with oral cyclosporine A (CsA) led to prompt defervescence. This was continued for 7 days without serious adverse events. Coronary artery dilatations regressed within 3 months of follow up. KD infants <3 months of age are at higher risk of coronary artery aneurysm than the older ones. To our knowledge, oral CsA treatment has not been reported in such young infants with KD. The diagnosis and treatment of very young infants with KD are challenging. Adjunctive use of CsA in IVIG treatment could be effective for refractory KD in infants <3 months of age.

Successful control of juvenile dermatomyositis-associated macrophage activation syndrome and interstitial pneumonia: distinct kinetics of interleukin-6 and -18 levels.

BACKGROUND: Macrophage activation syndrome (MAS) is the secondary hemophagocytic lymphohistiocytosis associated with rheumatic diseases. Recently, the different cytokine profiles between systemic juvenile idiopathic arthritis (sJIA)-associated MAS (sJIA-MAS) and juvenile systemic lupus erythematosus (JSLE)-associated MAS (JSLE-MAS) were reported. However, there is little information about juvenile dermatomyositis (JDM)-associated MAS (JDM-MAS). CASE PRESENTATION: A 4-year-old girl with JDM was hospitalized because of fever, erythema, hepatosplenomegaly, cytopenia, liver dysfunction and coagulopathy. Bone marrow aspiration revealed appreciable numbers of activated and hemophagocytosing macrophages. She was diagnosed as having JDM-MAS complicated with interstitial pneumonia (IP) based on the findings of the elevation of serum Krebs von den Lungen-6 (KL-6) levels and chest computed tomography findings. We analyzed circulating levels of interleukin (IL)-2,4,6,10,18, tumor necrosis factor-α and interferon-γ in the patient. Hypercytokinemia occurred at the diagnosis of MAS and IP, showing with the prominent elevations of IL-6 and IL-18 levels. The cytokine profiles were distinct from those reported in patients with sJIA-MAS or JSLE-MAS. High-dose corticosteroid and cyclosporine therapy led to a drastic improvement of MAS with decreased IL-6 levels. Subsequent cyclophosphamide therapy successfully controlled IP, paralleled with the declining pattern of IL-18 and KL-6 levels. CONCLUSION: This is the first report to describe a successful treatment and the cytokine profile of JDM-MAS and IP. Serum IL-6 and IL-18 levels may be useful for predicting the disease activity of JDM-MAS and IP, respectively.

Remission of autoimmune neutropenia after development of Kawasaki disease.

We report the second case of the association of Kawasaki disease (KD) and autoimmune neutropenia (AIN). A 21-month-old female diagnosed as having AIN of infancy developed a complete KD when severe neutropenia continued. The patient suffered from no coronary artery lesions, and well responded to a single high-dose gamma-globulin therapy. The cytokine profile of the neutropenic infant was representative of the typical KD. Neutrophil counts notably increased during the convalescent phase of KD, and were then normalized forthwith. The prompt resolutions of KD and AIN paralleled the increase of circulating transforming growth factor (TGF)-ß1 levels. The clinical course of the patient was contrasted to that of the first reported case of a patient who developed severe and refractory KD after the high dose granulocyte-colony stimulating factor (G-CSF) therapy.

Cytokine profile of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during seasonal H1N1 infection.

BACKGROUND: Several studies support the role of viral infections in the pathogenesis of asthma exacerbation. However, several pediatricians believe that influenza virus infection does not exacerbate bronchial asthma, except for influenza A H1N1 2009 pandemic [A(H1N1)pdm09] virus infection. We previously reported that A(H1N1)pdm09 infection possibly induces severe pulmonary inflammation or severe asthmatic attack in a mouse model of bronchial asthma and in asthmatic children. However, the ability of seasonal H1N1 influenza (H1N1) infection to exacerbate asthmatic attacks in bronchial asthma patients has not been previously reported, and the differences in the pathogenicity profiles, such as cytokine profiles, remains unclear in bronchial asthma patients after A(H1N1)pdm09 and H1N1 infections. METHODS: The cytokine levels and viral titers in the bronchoalveolar lavage (BAL) fluid from mice with and without asthma after H1N1 infection (A/Yamagata and A/Puerto Rico strains) were compared. RESULTS: The interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, IL-5, interferon (IFN)-α, IFN-ß, and IFN-γ levels were significantly higher in the BAL fluids from the control/H1N1 mice than from the asthmatic/H1N1 mice. The viral titers in the BAL fluid were also significantly higher in the control/H1N1mice than in the asthmatic/H1N1 mice infected with either A/Yamagata or A/Puerto Rico. CONCLUSIONS: A(H1N1)pdm09 infection, but not H1N1 infection, can induce severe pulmonary inflammation through elevated cytokine levels in a mouse model of asthma.

Serum and cerebrospinal fluid levels of visinin-like protein-1 in acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) has recently been recognized as an encephalopathy subtype. Typical clinical symptoms of AESD are biphasic seizures, and MRI findings show reduced subcortical diffusion during clustering seizures with unconsciousness after the acute phase. Visinin-like protein-1 (VILIP-1) is a recently discovered protein that is abundant in the central nervous system, and some reports have shown that VILIP-1 may be a prognostic biomarker of conditions such as Alzheimer's disease, stroke, and brain injury. METHODS: However, there have been no reports regarding serum and cerebrospinal fluid (CSF) levels of VILIP-1 in patients with AESD. We measured the serum and CSF levels of VILIP-1 in patients with AESD, and compared the levels to those in patients with prolonged febrile seizures (FS). RESULTS: Both serum and CSF levels of VILIP-1 were significantly higher in patients with AESD than in patients with prolonged FS. Serum and CSF VILIP-1 levels were normal on day 1 of AESD. CONCLUSIONS: Our results suggest that both serum and CSF levels of VILIP-1 may be one of predictive markers of AESD.

Analysis of bronchoalveolar lavage fluid in a mouse model of bronchial asthma and H1N1 2009 infection.

BACKGROUND: Bronchial asthma is known as a risk factor of admission to the intensive care unit. However, the mechanism by which pandemic 2009 H1N1 (A(H1N1)pdm09) infection increases the severity of symptoms in patients with bronchial asthma is unknown; therefore, we aimed at determining this mechanism. METHODS: Inflammatory cell levels in the bronchoalveolar lavage (BAL) fluid from the non-asthma/mock, non-asthma/A(H1N1)pdm09, asthma/mock, and asthma/A(H1N1)pdm09 groups were determined using BALB/c mice. Cell infiltration levels, cytokine levels, and viral titers were compared among the groups. RESULTS: Neutrophil, monocyte, interleukin (IL)-5, IL-6, IL-10, IL-13, and tumor necrosis factor (TNF)-α levels were significantly higher in the BAL fluid from the non-asthma/A(H1N1)pdm09 and asthma/A(H1N1)pdm09 groups than in the mock groups (p<0.05 for neutrophils and monocytes; p<0.01 for the rest). The number of eosinophils and CD8(+) lymphocytes and the level of transforming growth factor beta 1 (TGF-ß1) in BAL fluid in the asthma/A(H1N1)pdm09 group were significantly higher among all groups (p<0.05 for eosinophils and CD8(+) lymphocytes; p<0.01 for TGF-ß1). The levels of IL-6, IL-10, IL-13, and TNF-α were significantly higher in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group (p<0.05 for IL-6 and IL-10; p<0.01 for IL-13 and TNF-α). The level of IFN-γ in the asthma/A(H1N1)pdm09 group was significantly lower than that in the non-asthma/A(H1N1)pdm09 group (p<0.05). The viral titers in the BAL fluids were higher in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group (p<0.05). Histopathological examination showed more severe infiltration of inflammatory cells and destruction of lung tissue in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group. CONCLUSIONS: Severe pulmonary inflammation induced by elevated levels of cytokines, combined with increased viral replication due to decreased IFN-γ levels, may contribute to worsening respiratory symptoms in patients with bronchial asthma and A(H1N1)pdm09 infection.

Serum soluble CD163 levels in patients with influenza-associated encephalopathy.

BACKGROUND: Influenza-associated encephalopathy (IE) is a serious complication during influenza viral infection. Common clinical symptoms of IE include seizures and progressive coma with high-grade fever. We previously reported that hypercytokinemia and monocyte/macrophage activation may play an important role in the pathogenesis of IE. CD163 is a scavenger receptor for hemoglobin-haptoglobin complexes and is expressed by monocytes/macrophages. Proteolytic cleavage of monocyte-bound CD163 by matrix metalloproteinases releases soluble CD163 (sCD163). However, there have been no reports regarding serum sCD163 levels in IE patients. METHODS: We measured serum levels of sCD163 as a marker of monocyte/macrophage activation in IE patients with poor outcomes, those without neurological sequelae, influenza patients without IE, and control subjects. RESULTS: Serum sCD163 levels were significantly higher in IE patients with poor outcomes than in those without neurological sequelae. In particular, sCD163 levels in cases of death were significantly higher than those in other cases. CONCLUSIONS: Our results suggest that monocyte/macrophage activation is related to the pathogenesis of severe IE.