Pathogenic role and diagnostic utility of interferon-α in histiocytic necrotizing lymphadenitis.

PURPOSE: Histiocytic necrotizing lymphadenitis (HNL) is an inflammatory disease of unknown etiology clinically characterized by painful lymphadenopathy. This study aimed to investigate the role of interferon (IFN)-α in the pathogenesis of HNL and the clinical significance of serum IFN-α levels for the diagnosis and monitoring of HNL disease activity. METHODS: This study enrolled 47 patients with HNL and 43 patients with other inflammatory diseases that require HNL differentiation including malignant lymphoma (ML), bacterial lymphadenitis, and Kawasaki disease. Expression of IFN-stimulated genes (ISGs) and MX1 in the lymph nodes was measured by real-time quantitative reverse transcription polymerase chain reaction and immunofluorescence staining, respectively. Enzyme-linked immunosorbent assay was used to quantify serum cytokine levels. The results were compared with the clinical features and disease course of HNL. RESULTS: Patients with HNL had a significantly elevated ISG expression in the lymph nodes compared with those with ML. MX1 and CD123, a specific marker of plasmacytoid dendritic cells (pDCs), were colocalized. In patients with HNL, serum IFN-α levels were significantly elevated and positively correlated with disease activity. The serum IFN-α level cutoff value for differentiating HNL from other diseases was 11.5 pg/mL. CONCLUSION: IFN-α overproduction from pDCs may play a critical role in HNL pathogenesis. The serum IFN-α level may be a valuable biomarker for the diagnosis and monitoring of disease activity in patients with HNL.

Inspiratory Muscle Training Before Esophagectomy Increases Diaphragmatic Excursion: A Randomized Controlled Trial.

BACKGROUND: Inspiratory muscle training (IMT) has preventive effects against postoperative pulmonary complications (PPCs) after upper abdominal surgery. However, its impact on diaphragmatic function has not been evaluated. This study investigated the effect of preoperative IMT on diaphragmatic excursion (DE) and prevention of PPCs for patients with esophageal cancer. METHODS: This study was an unblinded, parallel, randomized controlled trial. Patients with thoracic or abdominal esophageal cancer scheduled for esophagectomy were randomized into the incentive spirometry (IS) or IMT group. During preoperative neoadjuvant chemotherapy, IS or IMT intervention was performed. The inspiratory resistance of the IMT group was consistently set at 50% maximal inspiratory pressure. The primary outcome was the amount of change in DE evaluated with ultrasonography, and the secondary outcome was the incidence of Clavien-Dindo grade II or higher PPCs. RESULTS: This study recruited 42 patients. Among these patients 21 were randomized into the IS or IMT group, and 2 patients dropped out from the study. Finally, 40 patients were included in this analysis. The DE of the IMT group increased significantly after the intervention. The IMT group had significantly larger DE changes than the IS group. Of the 39 patients analyzed for postoperative outcome, 5 experienced grade II PPCs. The IMT group had a lower incidence of PPCs than the IS group. CONCLUSIONS: Patients with thoracic and abdominal esophageal cancer scheduled for surgery who had preoperative IMT have increased DE, which may have an important role in prevention of PPCs.

Serum interleukin-18 levels can improve the diagnostic performance of the PRINTO and ILAR criteria for systemic juvenile idiopathic arthritis.

OBJECTIVE: Recently, the Pediatric Rheumatology International Trials Organization (PRINTO) has proposed revisions to the current International League of Associations for Rheumatology (ILAR) criteria for systemic juvenile idiopathic arthritis (s-JIA). Interleukin (IL)-18 overproduction plays a significant role in the pathogenesis of s-JIA. This study aimed to evaluate the performance of the PRINTO criteria compared with the ILAR criteria and determine whether serum IL-18 levels improve their diagnostic performances. METHODS: Overall, 90 patients with s-JIA and 27 patients with other febrile disease controls presenting with a prolonged fever of > 14 days and arthritis and/or erythematous rash were enrolled. The ILAR and PRINTO classification criteria were applied to all patients and examined with expert diagnoses. Enzyme-linked immunosorbent assay was used for measuring serum IL-18 levels. RESULTS: The PRINTO criteria had higher sensitivity but lower specificity than the ILAR criteria (sensitivity: PRINTO 0.856, ILAR 0.533; specificity: PRINTO 0.259, ILAR 0.851). With the addition of serum IL-18 levels ≥ 4,800 pg/mL, the sensitivity of the ILAR criteria and specificity of the PRINTO criteria were improved to 1.000 and 1.000, respectively. PRINTO plus serum IL-18 levels ≥ 4,800 pg/mL showed the highest value in Youden's index (sensitivity - [1 - specificity]). CONCLUSION: Serum IL-18 levels could improve the diagnostic performance of the PRINTO and ILAR criteria for s-JIA. The PRINTO criteria plus serum IL-18 levels ≥ 4,800 pg/mL could be the best diagnostic performance for s-JIA.

Efficacy of High-Density Three-Dimensional Mapping for Verapamil-Sensitive Left Posterior Fascicular Ventricular Tachycardia in Pediatric Patients.

In verapamil-sensitive left posterior fascicular ventricular tachycardia (LPF-VT), radiofrequency catheter ablation (RFA) is performed targeting mid-to-late diastolic potential (P1) and presystolic potential (P2) during tachycardia. This study included four patients who had undergone electrophysiological study (EPS) and pediatric patients with verapamil-sensitive LPF-VT who had undergone RFA using high-density three-dimensional (3D) mapping. The included patients were 11-14 years old. During EPS, right bundle branch block and superior configuration VT were induced in all patients. VT mapping was performed via the transseptal approach. P1 and P2 during VT were recorded in three of the four patients. All patients initially underwent RFA via the transseptal approach. In three patients, P1 during VT was targeted, and VT was terminated. The lesion size indices in which VT was terminated were 4.6, 4.6, and 4.7. For one patient whose P1 could not be recorded, linear ablation was performed perpendicularly in the area where P2 was recorded during VT. Among the three patients in whom VT was terminated, linear ablation was performed in two to eliminate the ventricular echo beats. In all patients, VT became uninducible in the acute phase and had not recurred 8-24 months after RFA. High-density 3D mapping with an HD Grid Mapping Catheter allows recording of P1 and P2 during VT and may improve the success rate of RFA in pediatric patients with verapamil-sensitive LPF-VT.

Clinical significance of serum cytokine profiles for differentiating between Kawasaki disease and its mimickers.

OBJECTIVES: To investigate the clinical significance of serum cytokine profiles for differentiating between Kawasaki disease (KD) and its mimickers. METHODS: Patients with KD, including complete KD, KD shock syndrome (KDSS), and KD with macrophage activation syndrome (KD-MAS), and its mimickers, including multisystem inflammatory syndrome in children, toxic shock syndrome, and Yersinia pseudotuberculosis infection, were enrolled. Serum levels of interleukin (IL)-6, soluble tumor necrosis factor receptor type II (sTNF-RII), IL-10, IL-18, and chemokine (C-X-C motif) ligand 9 (CXCL9) were measured using enzyme-linked immunosorbent assay and compared them with clinical manifestations. RESULTS: Serum IL-6, sTNF-RII, and IL-10 levels were significantly elevated in patients with KDSS. Serum IL-18 levels were substantially elevated in patients with KD-MAS. Patients with KD-MAS and KD mimickers had significantly elevated serum CXCL9 levels compared with those with complete KD. Area under the receiver operating characteristic curve analysis showed that serum IL-6 was the most useful for differentiating KDSS from the others, IL-18 and CXCL9 for KD-MAS from complete KD, and CXCL9 for KD mimickers from complete KD and KD-MAS. CONCLUSION: Serum cytokine profiles may be useful for differentiating between KD and its mimickers.

Calmodulinopathy in Japanese Children　- Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy.

BACKGROUND: Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like). CONCLUSIONS: Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.

Ablation index-guided high-power vs. moderate-power cavotricuspid isthmus ablation.

Ablation index (AI)-guided ablation is useful for pulmonary vein isolation (PVI) and cavotricuspid isthmus (CTI) ablation. However, the impact of radiofrequency (RF) application power on CTI ablation with a fixed target AI remains unclear. One-hundred-thirty drug-refractory atrial fibrillation and/or atrial flutter patients who underwent AI-guided CTI ablation with or without PVI between July 2020 and August 2021 were randomly assigned to high-power (45 W) and moderate-power (35 W) groups. We performed CTI ablation with the same target AI value in both groups: 500 for the anterior 1/3 segments and 450 for the posterior 2/3 segments. In total, first-pass conduction block of the CTI was obtained in 111 patients (85.4%), with 7 patients (5.4%) showing CTI reconnection. The rate of first-pass conduction block was significantly higher in the 45 W group (61/65, 93.8%) than in the 35 W group (50/65, 76.9%, P = 0.01). CTI ablation and CTI fluoroscopy time were significantly shorter in the 45 W group than in the 35 W group (CTI ablation time: 192.3 ± 84.8 vs. 319.8 ± 171.4 s, P < 0.0001; CTI fluoroscopy time: 125.2 ± 122.4 vs. 171.2 ± 124.0 s, P = 0.039). Although there was no significant difference, steam pops were identified in two patients from the 45 W group at the anterior segment of the CTI. The 45 W ablation strategy was faster and provided a higher probability of first-pass conduction block than the 35 W ablation strategy for CTI ablation with a fixed AI target.

Sternocleidomastoid Muscle Thickness Correlates with Exercise Tolerance in Patients with COPD.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have difficulties inhaling as the diaphragm becomes flattened and weakened due to lung hyperinflation. This weakened respiratory function is compensated for by the increased activity of the accessory respiratory muscles, such as the sternocleidomastoid muscle (SCM). OBJECTIVES: This study aimed to evaluate the difference in the SCM thickening fraction (SCM TF) of each respiratory phase (end-expiration, resting inspiration, and end-inspiration), as measured using ultrasonography (US), between patients with COPD and control subjects. We also evaluate the correlation between the SCM TF of each respiratory phase and exercise tolerance in patients with COPD. METHODS: Patients with COPD (n = 44) and age-matched controls (n = 20) underwent US for determination of the SCM TF. Ventilation parameters, including the peak oxygen uptake (peak VO2) and the change in the inspiratory capacity, were measured during cardiopulmonary exercise testing. The SCM thickness and TF was measured during end-expiration, resting breathing, and end-inspiration. RESULTS: The SCM was significantly thinner in patients with COPD than in controls at end-expiration. The increase in the SCM TF from end-expiration to end-inspiration in patients with COPD did not differ significantly from that in control subjects. In contrast, the SCM TF from end-expiration to resting inspiration was significantly greater in patients with COPD than in control subjects. The peak VO2 was strongly positively correlated with the SCM TF from end-expiration to end-inspiration in patients with COPD (r = 0.71, p < 0.01). CONCLUSIONS: The SCM may be thinner in patients with COPD than in controls. The SCM TF may also be associated with exercise tolerance.

Prediction of atrioventricular conduction disturbance after ablation of persistent atrial fibrillation.

The prevalence of atrioventricular conduction disturbance (AVCD) in patients with persistent atrial fibrillation (AF) has not yet been fully investigated. We sought to identify the predictors of AVCD in patients with AF by analyzing the relationship between pre-ablation heart rate during AF and the PR interval in sinus rhythm after ablation. We analyzed pre-ablation 24-h Holter electrocardiogram (ECG) and 12 lead ECG 12 months after ablation of 121 consecutive patients with persistent AF who underwent their first ablation procedure and maintained sinus rhythm at 12 months. AVCD was defined as a first-degree atrioventricular block (AVB), second-degree AVB, high-degree AVB, or third-degree AVB observed on ECG at 12 months after ablation. Seventeen out of 121 patients (14.0%) had AVCD at 12 months. In the group with AVCD, total heartbeat (THB) and maximum heart rate (Max HR) were significantly lower, and the prevalence of concomitant Cavo-tricuspid isthmus-dependent atrial flutter before ablation and the appearance of macro reentrant atrial tachycardia (AT) during the procedure were significantly higher than those in the group without AVCD. Multiple regression analysis revealed that maximum HR and macro reentrant AT were significant predictors of AVCD. Receiver operating characteristic curve analysis revealed that Max HR of <165.0 bpm predicts AVCD with a sensitivity of 76.47% and a specificity of 74.00%. In patients with persistent AF, low Max HR and the presence of macro reentrant AT during the ablation procedure were predictors of AVCD.

One-year-old boy with refractory Listeria monocytogenes meningitis due to persistent hypercytokinemia.

We had a case of Listeria monocytogenes (LM) meningitis complicated with hypercytokinemia and hemophagocytic lymphohistiocytosis in a healthy 22-month-old boy. He was admitted to our hospital with a fever, vomiting, mild consciousness disturbances, and extraocular muscle paralysis. Magnetic resonance imaging (MRI) revealed bilateral deep white matter lesions. After receiving ampicillin, meropenem, and gentamicin, his cerebrospinal fluid (CSF) culture results turned negative on the third day of hospitalization. However, the fever intermittently persisted, and it took approximately 40 days to completely resolve. During this period, various inflammatory cytokine levels, particularly neopterin, in the blood and CSF remained elevated. Therefore, long-term administration of corticosteroids in addition to antibiotics was required. The use of dexamethasone appeared to be effective for neurological disorders such as consciousness disturbance and extraocular muscle paralysis associated with abnormal brain MRI findings. LM meningitis may present with encephalopathy and persistent fever due to hypercytokinemia. In such cases, corticosteroid therapy should be considered.