Additional Intravenous Immunoglobulin Research Articles

Early combined treatment with steroid and immunoglobulin is effective for serious Kawasaki disease complicated by myocarditis and encephalopathy

Severe-type Kawasaki disease (KD) complicated by serious myocarditis and encephalopathy can be successfully treated without abnormality of the coronary arteries by steroid pulse treatment and intravenous immunoglobulin (IVIg). A 4-year-old Japanese girl was diagnosed with KD due to a 6-day history of fever, rash, flushed lips, conjunctival hyperemia, palmar edema, and cervical lymphadenopathy. The day after initiation of IVIg and aspirin, cardiac gallop rhythm was identified. Cardiac ultrasonography revealed severe left ventricular dysfunction. Disturbance of consciousness, hallucinations, and slurred speech were also observed. Magnetic resonance imaging showed no abnormalities, but electroencephalography revealed high-voltage slow waves. Despite this serious disease, cardiac function and neurological abnormalities showed complete recovery without dilatation of the coronary arteries by steroid pulse treatment and additional IVIg. Follow-up at 15 months revealed no abnormality of the coronary arteries. In conclusion, we suggest that early combined treatment with steroid and IVIg is effective for serious KD complicated by myocarditis and encephalopathy.

Clinical outcome of patients with refractory Kawasaki disease based on treatment modalities.

PurposeAlthough a significant number of reports on new therapeutic options for refractory Kawasaki disease (KD) such as steroid, infliximab, or repeated intravenous immunoglobulin (IVIG) are available, their effectiveness in reducing the prevalence of coronary artery lesions (CAL) remains controversial. This study aimed to define the clinical characteristics of patients with refractory KD and to assess the effects of adjuvant therapy on patient outcomes.MethodsWe performed a retrospective study of 38 refractory KD patients from January 2012 to March 2015. We divided these patients into 2 groups: group 1 received more than 3 IVIG administration+ steroid therapy, (n=7, 18.4%), and group 2 patients were unresponsive to initial IVIG and required steroid therapy or second IVIG (n=31, 81.6%). We compared the clinical manifestations, laboratory results, and echocardiographic findings between the groups and examined the clinical utility of additional therapies in both groups.ResultsA significant difference was found in the total duration of fever between the groups (13.0±4.04 days in group 1 vs. 8.87±2.30 days in group 2; P=0.035). At the end of the follow-up, all cases in group 1 showed suppressed CAL. In group 2, coronary artery aneurysm occurred in 2 patients (6.4 %). All the patients treated with intravenous corticosteroids without additional IVIG developed CALs including coronary artery aneurysms.ConclusionNo statistical difference was found in the development of CAL between the groups. Prospective, randomized, clinical studies are needed to elucidate the effects of adjunctive therapy in refractory KD patients.

WITHDRAWN: Infliximab versus intravenous pulse methylprednisolone treatment for immunoglobulin-resistant kawasaki disease: a systematic review and adjusted indirect comparison metaanalysis

// Han Chan 1,2,* ,Yuhao Wang 1,* , Junli Yan 1,2,* , Gaofu Zhang 1,2 , Mo Wang 1,2 , Haiping Yang 1,2 and Qiu Li 1,2 1 Department of Nephrology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China 2 Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China * These authors have contributed equally to this work Correspondence to: Haiping Yang, email: oyhp0708@163.com Qiu Li, email: liqiu809@126.com Keywords : infliximab; methylprednisolone; intravenous immunoglobulin; mucocutaneous lymph node syndrome Received: September 01, 2017     Accepted: November 16, 2017     Epub: December 14, 2017     Abstract Background: Infliximab, intravenous pulse methylprednisolone (IVMP), and intravenous immunoglobulin (IVIG) retreatment are commonly used for the management of immunoglobulin-resistant Kawasaki disease (KD). Objective: To evaluate the safety and efficacy of these three therapies in pediatric patients with IVIG-resistant KD by performing an adjusted indirect comparison meta-analysis. Materials and Methods: PubMed, Embase, Web of Science, Clinicaltrials.gov, and Cochrane databases were searched on August 10, 2017. The main outcomes analyzed were coronary artery lesions (CALs) (e.g., coronary artery aneurysm or coronary artery dilatation), treatment resistance, adverse events (AEs) associated with drug infusion and antipyretic effects. Results: Eleven studies involving 341 immunoglobulin-resistant KD patients were identified and analyzed. The total incidence rate of CALs for infliximab versus IVMP was 0.78 (0.29–2.05), and the rates of coronary artery aneurysm (4.13, 0.38–45.22) and coronary artery dilatation (0.45, 0.10–1.99) did not differ significantly between groups. The rate of treatment resistance for infliximab versus IVMP was 0.22 (0.03– 1.47), and antipyretic effects for infliximab versus IVMP was 1.14 (0.63–2.05). The total rate of AEs for infliximab versus IVMP was 2.54 (1.003–6.411). Conclusions: No significant differences were observed among the 3 conventional therapies in the cardioprotective effect or the rate of treatment resistance. Infliximab and IVMP were more effective than additional IVIG due to antipyretic effects. IVMP treatment may have an advantage due to its lower total rate of AEs associated with drug infusion.

Abstract 131: Retrospective Study of The Timing Of Additional Therapy For Severe Kawasaki Disease Before And After The Induction Of Raise Study Protocol

Background: The RAISE study showed that combination therapy with intravenous immunoglobulin (IVIg) and prednisolone (PSL) improved coronary artery outcomes in patients with severe Kawasaki disease (KD). We encountered KD cases in which fever and findings such as WBC were masked by the steroid administration in combination therapy. We hypothesized that combination therapy might delay second- and third-line therapy for severe KD. Purpose: The goal of the study was to investigate whether combination therapy with IVIg and PSL might delay second- and third-line therapy for severe KD patients. Methods: We retrospectively investigated clinical data from acute KD patients admitted to our hospital from January 2011 to September 2014. We examined the following: 1) prediction score for refractory KD 2) first-line therapy for KD (IVIg group, n=10; IVIg/PSL group, n=11); 3) additional rescue therapy such as additional IVIg, steroid pulse therapy, plasma exchange, and so on 4) period from KD onset to end of main therapy for KD; 5) day of increased albumin from previous examination; and 6) day of CRP reaching <1.0 mg/l. Results: Seventy-four acute KD patients were admitted to our hospital during the study period. Only 1 KD patient had coronary artery lesions (CAL) at 1 month after onset. Detailed data were as follows: 1) Twenty-one patients were at high risk for refractory KD. 2) number of patients with additional IVIg (IVIg, 6/10; IVIg/PSL, 6/11); 3) number of patients with steroid pulse therapy (IVIg, 4/10; IVIg/PSL, 4/11); 4) period from KD onset to end of main therapy (IVIg, 8.3 days; IVIg/PSL, 8.7 days); 5) day of increased albumin (IVIg, 12.0 days; IVIg/PSL, 11.8 days); 6) day of CRP reaching <1.0 mg/l (IVIg, 13.7 days; IVIg/PSL, 11.4 days). No differences between IVIg and IVIg/PSL groups were seen for any factor. Discussion and conclusion: In this study, overall frequency of CAL was 1.3%, lower than that reported from nationwide surveillance in Japan. This study found no differences between groups in regard to frequency or timing of additional therapy and response. We concluded that combination therapy with IVIg and PSL did not delay the timing of additional therapy for acute KD. The cohort for this retrospective study was small, and further investigation is thus needed.

Abstract 62: Functional mechanism of cyclosporin A therapy for immunoglobulin-resistant Kawasaki disease

Background: We have reported that cyclosporin A (CsA) therapy may be a promising and safe option for patients with Kawasaki disease (KD) resistant to initial and additional intravenous immunoglobulin (IVIG). Up to now, it has been considered that CsA exerts effects on the intracellular phosphatase calcineurin, and subsequently inhibits activation of nuclear factor of activated T cells (NFAT). However, the functional mechanism of CsA therapy in KD patients has remained unclear. Methods: The KD patients enrolled in this study were treated with CsA between April 2012 and December 2013. In accordance with our treatment protocol, KD patients are initially treated with IVIG and aspirin. If there is no response, a further course of IVIG is given, and if there is no response to this additional IVIG, the patients are treated with CsA. Peripheral blood samples were obtained just before and after the initial course of IVIG, additional IVIG, and CsA therapy. To evaluate the NFAT pathway and activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, we examined the gene expression of cytokines and intracellular signal transducers using real-time RT-PCR and phospho-STAT3 (pSTAT3) and STAT5 (pSTAT5) using flow cytometry. Results: Thirty-six KD patients were divided into three groups: responsive to initial IVIG (n=19), responsive to additional IVIG (n=7), and treated with CsA group (n=10). In the CsA group, expression of mRNAs for interleukin (IL)-2, NFATc1 and NFATc2 was significantly increased, whereas the mean fluorescence intensity (MFI) of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased after CsA treatment. In the group responsive to initial IVIG, the expression of mRNAs for IL-2, IL-6, NFATc1 and NFATc2 was significantly increased, whereas that for STAT3, 5A, 5B was decreased after IVIG treatment; on the other hand, the MFI of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased, and that of pSTAT5 (CD16b+ granulocyte) was increased, after IVIG. Conclusion: In patients with refractory KD, CsA exerts effects on the activity of the NFAT and JAK-STAT pathways. However, our results suggest that in patients with immunoglobulin-resistant KD, CsA may act through a mechanism other than the NFAT pathway.

Abstract 147: Coronary artery aneurysms on day 4 after onset of Kawasaki Disease: A Case report

Background: Coronary artery aneurysm (CAA) in patients with Kawasaki disease (KD) almost always occurs after day 8, and the most early detection report of CAA was in an autopsy case on day 6 after onset. The possibility of CAA formation prior to day 6 has not been documented. Case report: A 10-month-old Japanese boy presented with a 4-day fever, conjunctival injection, erythema of the lips, erythema of the palms and soles, erythematous rush, and induration at a Bacillus Calmette-Guerin inoculation site. On day 4, echocardiography revealed coronary artery dilatation (right coronary artery [RCA], 4.6 mm; left main trunk [LMT], 4.6 mm; left anterior descending [LAD] artery, 3.4 mm). Laboratory data were as follows: white blood cell count, 19,400/μL; C-reactive protein, 15.2 mg/dL; albumin, 3.2 g/dL; high-density lipoprotein cholesterol, 20 mg/dL, and erythrocyte sedimentation rate, 48 mm/h. He was diagnosed with KD and treated with oral aspirin 30 mg/kg/day and intravenous immunoglobulin (IVIG) 2 g/kg. His fever subsided the next day. On day 17, periungual peeling of the fingers and toes was noted. His fever recurred and he treated with additional IVIG 1 g/kg, after which his fever subsided again. On day 20, the aneurysms had not increased in size (RCA, 3.3 mm; LMT, 3.6 mm; LAD, 2.4 mm). On day 44, although echocardiography showed a mild coronary artery dilatation, a coronary angiogram showed no apparent abnormality. He had no obvious fever or symptoms of KD prior to this course of KD. This case may help clarify the pathophysiology of CAA in patients with KD.

Abstract 81: A retrospective analysis of 274 cases of Kawasaki disease

Purpose: Haematological, biochemical and clinical parameters were retrospectively analysed in a group of patients with Kawasaki disease, to determine predictive variables on the effect of intravenous immunoglobulin (IVIG) therapy. Methods: We studied 274 cases of Kawasaki disease between October 2006 and September 2013 at a single centre (Kawasaki Municipal Tama Hospital, Japan). These cases were analysed on the basis of: (1) Requirement of additional therapy post IVIG (41 cases vs 200 cases not requiring additional therapy) (2) Presence of coronary artery lesions (CAL: Z score≧2.5) within a month (15 cases with CAL, 220 cases without CAL) Haematological, biochemical and clinical parameters including white blood cell, percentage of neutrophils, platelet, total-bilirubin, AST, ALT, Albumin, Sodium, C-reaction protein, Fibrinogen and D-dimmer as well as time to first post-IVIG treatment were compared in the categories shown above. Statistical analysis was performed with Mann-Whitney U test. Differences were considered to be significant when the two-tailed p-value was < 0.05. Results: The percentage of neutrophils, total-bilirubin, AST, ALT, Albumin, Sodium, C-reaction protein, D-dimmer and time to first treatment show significant difference between the groups stratified on the requirement of post-IVIG therapy. In the stratification based on acute CAL- AST, ALT, Albumin and Sodium show significant difference between the groups. Conclusion: We suggest that ratio of neutrophil, total-bilirubin, AST, ALT, Albumin, Sodium, C-reaction protein, D-dimmer and time to first treatment are predictive factors of resistance to single IVIG therapy. Similarly, levels of AST, ALT, Albumin and Sodium are predictive factors of acute coronary artery lesions in Kawasaki disease.

Abstract 142: Plasma Exchange Therapy in a Patient with Refractory Kawasaki Disease Initially Treated with Intravenous Immunoglobulin and Prednisolone

Prednisolone combined with intravenous immunoglobulin (IVIG) is the standard option for the initial treatment of Kawasaki disease (KD) in Japan, as described in the 2012 Japanese guidelines for KD. However, there is still debate regarding treatment in patients with refractory KD initially treated with IVIG plus prednisolone, especially in those with comorbid coronary artery aneurysm (CAA). Here, we present the case of a 3 year-old-girl initially treated with IVIG plus prednisolone, whose clinical and laboratory parameters improved after plasma exchange therapy (PE). She was admitted to a local hospital on day 4 of illness and diagnosed as having severe KD (Kobayashi score, 7). Therefore, prednisolone plus IVIG was administered as initial treatment. The initial course was ineffective. She was treated with methylprednisolone pulse therapy, and a second and third round of additional IVIG, but low-grade fever persisted. After these treatments the patient’s general condition had improved and major KD symptoms improved by day 13 of illness, despite a high serum C-reactive protein level (19.9 mg/dl) and hypoalbuminemia (1.8 g/dl). Expanding medium-sized aneurysm was detected on the same day, so she was immediately referred to our hospital for further treatment. The CAA continued to expand, so PE was performed for 3 consecutive days and prednisolone was gradually reduced from day 15 of illness. After that, she became afebrile and CAA progression stopped. Laboratory findings such as serum C-reactive protein and albumin levels were dramatically improved after PE. This case suggests that PE might be effective for refractory KD initially treated with IVIG plus glucocorticoids and may stop the CAA development. Doctors must remain aware that patients treated with glucocorticoids may have masked clinical conditions, and take care not to underestimate the signs of refractory KD.

Abstract 196: The Characteristics of Patients with Kawasaki disease Presented with Fever and Cervical Lymphadenopathy at Admission

Purpose: Of the principal diagnostic criteria of Kawasaki disease (KD), cervical lymphadenopathy is the least common. However, it may be misdiagnosed as bacterial cervical lymphadenitis. We evaluated the characteristics of patients with KD presenting with only fever and cervical lymphadenopathy at admission. Methods: This study enrolled patients diagnosed KD from January 2013 to May 2014. All of patients were divided to three groups: group 1 had only fever and cervical lymphadenopathy at admission; group 2 had typical manifestations with cervical lymphadenopathy; group 3 had typical manifestations without cervical lymphadenopathy. Results: Ninety eight patients (group 1 in 13, group 2 in 31, group 3 in 54) were examined. The median age of group 1 was significantly older than group 2 and 3 ( P =0.001). The duration of fever before admission at our hospital was more prolonged in group 1 than in group 2 and 3 ( P =0.001). In comparison between groups, the laboratory results at the admission day were not significantly different. However, group 1 showed significantly elevated white blood cell counts, elevated neutrophil counts, and decreased lymphocyte counts after first intravenous immunoglobulin administration ( P =0.001, P =0.001, and P =0.003). The frequency of additional intravenous immunoglobulin treatment did not have significant difference. Group 1 had significantly increased duration of hospitalization, and frequency of second line treatment such as systemic steroid or infliximab than group 2 and 3 ( P =0.000, P =0.024, and P =0.007). The development of a coronary artery dilatation (z score >2.5) was higher in group 1 than in group 3 ( P =0.008). Conclusions: KD with cervical lymphadenopathy as main presentation indicates a severe form of KD associated with increased risks of second line treatment such as systemic steroid or infliximab and coronary artery dilatation. KD should be suspected in the older children with antibiotics non-responsive, prolonged fever and cervical lymphadenopathy. For differentiation between responder and non-responder for first line treatment, white blood cell counts and their subset after first intravenous immunoglobulin administration may be beneficial.

Background Factors Associated with the Complications of Coronary Artery Lesions Caused by Kawasaki Disease

Appropriate therapy during the acute phase of Kawasaki disease to prevent large coronary artery lesions (CAL) has not been established. The aim of this retrospective study was to investigate the usefulness of an initial single intravenous immunoglobulin (IVIG) therapy. In this study, I included a total of 200 pediatric patients who had received 2g/kg/day IVIG therapy for Kawasaki disease between 1999 and 2015 at the Department of Pediatrics, Aomori Prefectural Central Hospital. An initial IVIG therapy starting on day 5 was used as first-line therapy when possible. The second-line therapy was additional IVIG therapy, and the third-line therapy was an urinastatin infusion or plasma exchange. All patients received an initial single IVIG therapy with delayed or with concomitant administration of aspirin or flurbiprofen. Initial IVIG therapy resistance occurred in 48 of 200 patients (24%), and 17 patients (9%) received additional IVIG therapy. Four patients received urinastatin and one patient received plasma exchange as the third-line therapy. Before the 30th day, the prevalence of CAL was 5% (10/200); after 30 days, it was 2% (4/200). The maximal internal CAL diameter was 4.8 mm (Z score = 6.3) among all patients. Variable factors including IVIG resistance, responsiveness, and relapse of disease were associated with CAL complications. An initial single IVIG therapy may be useful for the prevention of large CAL caused by different factors of Kawasaki disease.

Study of tumor necrosis factor-α, soluble tumor necrosis factor receptor-1 levels and its role in intravenous immunoglobulin non-responsive children with Kawasaki disease

Objective To investigate the outcome of intravenous immunoglobulin (IVIG) therapy in children with Kawasaki disease(KD), and to study serum tumor necrosis factor-α (TNF-α), soluble tumor necrosis factor receptor-1 (sTNFR1) levels in these patients, and to explore further treatment of IVIG non-responsive. Methods Eighty-three patients with KD received initial IVIG and aspirin therapy within 10 days.Patients were divided into non-responsive group and sensitive group, while the clinical experiences and the outcome of them were recorded.Thirty-three health children were also recruited in this study, and the levels of serum TNF-α, sTNFR1 in KD patients were compared with health children and within different groups. Results 1.In non-responsive group, the rate of coronary artery lesions(CALs) was 45.4%(5/11 cases) in non-responsive group, but 33.3%(24/72 cases) in sensitive group, there was a statistical difference between them(P 0.05).3.Serum sTNFR1 concentration was (4.6±1.9) μg/L in non-responsive group, (4.7±2.9) μg/L in sensitive group, (5.4±1.9) μg/L in health children, so there was no statistical difference between them(P>0.05).4.In non-responsive group, serum TNF-α contentrations of CALs were significantly higher than non-CALs[(266.8±117.3) ng/L vs (126.2±93.7) ng/L], also significantly higher than serum TNF-α contentions of CALs in sensitive group[(118.8±96.1) ng/L], there was a statistical difference between them(P<0.05).5.In non-responsive group, but the levels of C-reactive protein(CRP) and lactate dehydrogenase(LDH) were higher than sensitive group, the levels of hemoglobin(Hb) and albumen were lower than sensitive group, so there was a statistical difference between them(P<0.05). Conclusions The high elevation of TNF-α levels existed in KD, also accompanied with abnormal sTNFR1 levels.The elevation of TNF-α levels had continually existed in non-responsive group after initial IVIG therapy.IVIG could let serum TNF-α concentrations down, so non-responsive group need additional IVIG therapy.The rate of CALs is more common in IVIG non-responsive group, but the outcome would be improved by using additional IVIG therapy.The high levels of CRP, LDH and low levels of Hb, albumen are closely asso-ciated with risk factors of IVIG re-treatment and inflammation reaction, so timely therapy is necessary to prevent damages in children with KD. Key words: Kawasaki disease; Intravenous immunoglobulin non-responsive; Tumor necrosis factor-α; Soluble tumor necrosis factor receptor; Coronary artery lesions

Plasma exchange therapy for severe gastrointestinal involvement of Henoch Schonlein purpura in children

The aim of this report is to evaluate the plasma exchange as a choice for the management of life-threating gastrointestinal system (GIS) involvement in Henoch-Schönlein purpura (HSP) when refractory to conventional therapies. We retrospectively reviewed the medical records of HSP patients who had plasma exchange therapy due to massive GIS involvement. We reported age, gender, initial HSP presentation, etiological or triggering factors and disease course. Treatment modalities, side effects and their outcomes were noted. We reported 7 cases of childhood HSP with severe gastrointestinal involvement refractory to common immunosuppression with systemic steroid and cytotoxic therapy. All patients gave inadequate response to pulse methyl prednisolone or oral prednisolone therapy with ongoing GIS bleeding and severe abdominal pain. Therefore, pulse cyclophosphamide was added to the treatment. Two patients received additional intravenous immunoglobulin (IVIG) therapy. Gastrointestinal manifestations continued and plasma exchange was performed. All patients improved after plasma exchange treatment. Treatment of GI involvement in HSP with plasma exchange has been mainly based on case reports. According to our data, we propose that, plasma exchange may be a safe and efficient management choice in paediatric HSP patients with massive GIS involvement that are refractory to other therapies.

Infliximab Plus Plasma Exchange Rescue Therapy in Kawasaki Disease

To evaluate infliximab (IFX) in patients with Kawasaki disease (KD) that was unresponsive to additional intravenous immunoglobulin (IVIG) therapy and subsequent rescue with supplementary plasma exchange (PE) in patients unresponsive to treatment. We studied 76 patients with KD who received IVIG therapy twice and were unresponsive to additional IVIG. Seventy were treated with IFX alone (92.1%). Six patients who were unresponsive IFX (7.9%) were further treated by PE. This resulted in disappearance of fever and other clinical symptoms, and improvement of laboratory data. There was no severe life-threatening adverse events.Twelve of the 76 cases had developed coronary artery dilatation, and 3 had coronary artery aneurysm within 1month of disease onset. At the end of follow-up, in all cases, coronary artery lesions were suppressed or reversed. Treatment of intractable KD with sequential IVIG, IFX, and PE treatments in a step-wise protocol was effective.

Effect of dalteparin, a low-molecular-weight heparin, as adjunctive therapy in patients with Kawasaki disease: a retrospective study

BackgroundDalteparin, a low-molecular-weight heparin, has anticoagulant and anti-angiogenic activity. This study investigated whether dalteparin reduced coronary artery lesion (CAL) prevalence, and resistance to intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD).MethodsThis retrospective study comprised two parts. In the first cohort, 126 patients with KD (68 male, 58 female; median age: 22 months, range: 1–67 months) admitted to Nihon University Nerima-Hikarigaoka Hospital from January 2004 to June 2008, received either dalteparin 75 IU/kg/day, IVIG 400 mg/kg/day for 5 consecutive days, and aspirin 30 mg/kg/day, or dalteparin 75 IU/kg/day and aspirin 30 mg/kg/day, until clinical improvement. Control data came from the 2005–6 Nationwide KD survey. In the second cohort, 112 patients with KD (59 male, 53 female; median age: 19 months, range: 1–66 months) admitted from June 2010 to February 2012, received either dalteparin 75 IU/kg/day, IVIG 2.0 g/kg over 12 h, and aspirin 30 mg/kg/day, or dalteparin 75 IU/kg/day and aspirin 30 mg/kg/day. Control data came from the 2009–10 Nationwide KD survey. No patients enrolled in the nationwide surveys received dalteparin. All patients at our institution were given dalteparin in their combination therapy.ResultsA comparison of the first cohort with controls in the nationwide survey showed that the prevalence of initial administration of IVIG was 80.2% versus 86.0%; the rate of additional IVIG administration was 7.1% versus 14.0% (p = 0.03); CAL prevalence in the acute period was 4.8% versus 11.9% (p < 0.01); and the prevalence of cardiovascular sequelae was 0% versus 3.8% (p < 0.05). A comparison of the second cohort with controls in the nationwide survey showed that the rate of initial administration of IVIG was 92.9% versus 89.5%; the rate of additional IVIG administration was 8.9% versus 17.1% (p = 0.02); the prevalence of resistance to IVIG was 3.6% versus 14.9% (p < 0.001); and CAL prevalence in the acute period was 2.7% versus 8.6% (p = 0.03).ConclusionsThis study found that adjunctive dalteparin was associated with a lower prevalence of IVIG resistance and CAL in young children with KD.Trial registrationUMIN-CTR: UMIN000010349.

High-dose intravenous immunoglobulin therapy for eosinophilic granulomatosis with polyangiitis.

BackgroundRegulatory T (Treg) cells are implicated in the development and progression of eosinophilic granulomatosis with polyangiitis (EGPA). We previously showed beneficial effects of intravenous immunoglobulin (IVIG) therapy combined with corticosteroid and immunosuppressant treatment on clinical symptoms, including mononeuritis multiplex and cardiac dysfunction, and Treg cell frequency, during EGPA. Whether the timing of administration (during initial treatment or at relapse after remission) or previous treatment affects the clinical and immunologic efficacy of IVIG is unknown. We evaluated whether the frequency of Treg cells varied depending on when IVIG was provided relative to the start of conventional therapy for EGPA.MethodsThe patient population for this retrospective analysis comprised 17 patients with severe mononeuritis multiplex or heart failure whose EGPA did not respond to corticosteroids combined with immunosuppressant therapy. Ten patients first received IVIG during initial treatment, whereas the remaining 7 patients first received IVIG on relapse after remission. We measured the percentage of Treg cells, defined as FOXP3+CD4+ T cells, present before the first round of IVIG and at 1 month after the last IVIG treatment.ResultsFOXP3+CD4+ T cells were increased in patients who required only a single course of IVIG to achieve remission compared with those who needed two or more courses. The dosage of prednisolone at initial IVIG was inversely correlated with the ratio of the number of FOXP3+CD4+ T cells before IVIG and that at 1 month thereafter.ConclusionPatients with severe EGPA who receive IVIG after nonresponse to high-dose prednisolone during initial treatment may need multiple courses of IVIG to achieve remission. An increase in the frequency of Treg cells after IVIG may predict the need for additional IVIG in EGPA.

The role of IgM-enriched intravenous immunoglobulin in transplantation

After organ transplantation, gamma globulin and intravenous immunoglobulin enriched with IgM are most frequently used in septic shock as early immune-support. If the explanted organ is infected, the transplantation, as a life-saving operation, can be performed if there is no systemic inflammation and the patient receives IgM enriched immunoglobulin prophylaxis during surgery. The period after transplantation can be divided into three parts from the infection point of view: the first month after transplantation, the first sixth months and the following six months. Infections within the first month are basically related to the surgical procedure. Because of the immunosuppressive therapy, the opportunistic and fungal infections are more common during the first sixth months. After this period, the occurrence and the type of infections are similar to that of the non-transplant population except for pulmonary infections. The latter is two to three times more frequent. This is explained by the secondary hypogammaglobulinaemia (lower blood levels of IgM and IgG) which is caused by the steroids but most of mycophenolate mofetil by inhibition of the T and B lymphocyte proliferation. Septic shock develops with a continuing fall of IgM levels. Under these circumstances additional intravenous immunoglobulin therapy with IgM can be lifesaving. Besides, immunoglobulin concentrates with IgM may also be used in the case of viral infections without prophylaxis and/or without etiological therapy such as in the case of West Nile virus infection. As a result of the increase in antibiotic resistance, the application of immunotherapy, including immunoglobulins may become the mainstream in the treatment of septic shock.

Clinical Manifestation of Necrotizing Pneumonia in Healthy Children

were revealed in two patients; Streptococcus pneumonia (S. pneumonia) was revealed in one patient and S. pneumonia and Mycoplasma pneumonia in the other patient. Three patients were treated with additional intravenous immunoglobulin. Clinical improvement was prolonged: fever lasted 10 to 23 days, and length of hospitalization was 15 to 36 days. NP or pneumatocele were completely resolved on the follow-up radiographic studies in all of the patients. Conclusion: Although the previously healthy young children with NP had protracted clinical course, they recovered without any problematic sequelae. Our results suggest that the immunopathogenesis of NP in children may be associated with the exaggerated immune reaction of the host to insults from initial bacterial infections, rather than the pathogen-induced cytopathies.

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

Late development of coronary artery abnormalities could be associated with persistence of non-fever symptoms in Kawasaki disease.

BackgroundPersistent fever after intravenous immunoglobulin (IVIG) is considered to be a major criterion of IVIG resistance in Kawasaki disease (KD), and a risk factor for the development of coronary artery abnormalities (CAA). However, the importance of persistent non-fever symptoms after defervescence has not yet been investigated. We examined the relationship between persistent non-fever symptoms and CAA in KD.MethodsWe conducted a retrospective cohort study of patients hospitalized with KD at the National Center for Child Health and Development between 1 April 2008 and 31 March 2009. Patients were divided into two groups; group A included patients who still had non-fever symptoms one month after onset of the illness and group B included patients who did not have persistent non-fever symptoms. Demographic, clinical variables were compared between the groups.ResultsSeventy-seven KD patients treated with IVIG were retrospectively analyzed. Patients were divided into two groups; group A included 12 (15.6%) patients and group B 65 (84.4%) patients. Demographic data, baseline laboratory data, and fever duration did not differ between the groups. In group A patients the most common persistent non-fever symptoms were lip erythema (n = 6) and bulbar conjunctivitis (n = 8). One month after onset of the illness CAA developed in seven of 77 patients (9.1%), four (33%) in group A and three (4.6%) in group B (odds ratio 10.3; 95% CI 1.9-54.8). Three patients in group A and one patient in group B developed CAA after the resolution of fever.ConclusionsPersistence of non-fever symptoms after IVIG may suggest persistence of latent inflammation, which may increase the risk of CAA. Therefore, patients with persistent non-fever symptoms may be at risk of developing CAA, even after defervescence. A prospective trial of additional IVIG for such patients should be considered.

Preemptive intravenous immunoglobulin allows safe and timely administration of antineoplastic therapies in patients with multiple myeloma and parvovirus B19 disease

Parvovirus B19 (B19) disease is a rare cause of anemia in cancer patients and often goes unrecognized, causing delays in anticancer therapy. A retrospective review was carried out of the records of patients with multiple myeloma who underwent melphalan-based autologous stem cell transplantation (MEL-ASCT) and developed B19 infection (January 2009-December 2011). Cases were defined by the presence of clinical and laboratory findings consistent with B19 disease in patients with repeatedly positive plasma quantitative polymerase chain reaction for parvovirus. Six patients qualified as cases; 5 presented with trilineage cytopenias (chronic in 1) and 1 with anemia later progressing to pancytopenia. Transfusion-dependent thrombocytopenia led to testing in 5 patients. Two of these patients also had manifestations of autoimmune disease. Therapy with intravenous immunoglobulin (IVIG) resulted in clinical and hematologic response in all; however, 1 patient, whose white blood cell counts and serum hemoglobin levels improved, required splenectomy for persistent thrombocytopenia. All patients required additional IVIG for recurrent B19 disease. Although viral load at diagnosis did not correlate with the severity of cytopenia, its decrease was associated with response during 17 of 20 evaluable episodes (P=0.02). Preemptive IVIG allowed the safe administration of chemotherapy in 3 patients, including MEL-ASCT in 1. Parvovirus B19 can cause severe disease in myeloma patients including ASCT recipients. Thrombocytopenia - not anemia - was the leading presentation and may be associated with autoimmune conditions. Patients with unexplained cytopenias, particularly when prolonged, should undergo testing for circulating parvovirus. A reduction in viral load was associated with response to IVIG, although additional therapy was needed for recurrent disease. Most importantly, preemptive IVIG allowed for safe and timely administration of antineoplastic therapy in patients with ongoing B19 disease.