Gammaglobulin Treatment Research Articles

Randomized Controlled Study of Intravenous Gamma-globulin Products in Treatment of Kawasaki Disease

Background: The efficacy of high-dose intravenous gamma-globulin (IVGG) treatment in Kawasaki disease (KD) is well known. But it is unclear whether the IVGG products manufactured by various companies are equally efficacious in treatment of KD and whether they are equally safe. Purpose: To compare the efficacy and safety of various IVGG products in patients with KD. Methods: We studied 142 patients with KD who had no coronary artery complications on admission and within the first 9 days of illness. Using a random number table, 50 patients were selected to receive freeze-dried, sulfonated product (Venilon-I; product A), 56 patients were selected to receive pH4-treated product (Polyglobin-N; product B), and the remaing 36 patients were selected to receive polyethyleneglycol-treated product (Venoglobulin-IH; product C). The doses of IVGG (2g/kg X 1 day or 1g/kg X 1 day) were determined by Harada's score. All patients were treated with IVGG in combination with aspirin. Results: There were no significant differences among the 3 groups in regard to age, gender, Harada's score, and illness days when IVGG was initiated. The incidence rate of patients who needed additional IVGG treatment was similar in all groups (product A.26.0%, B 21.4%, C 30.6%). The incidence of coronary artery complications was similar in all groups (product A 10.0%, B 8.9%, C 2.8%). The adverse effects of IVGG were seen in 4 patients, but all patients recovered after IVGG was discontinued. There were no significant differences among the 3 groups in regard to adverse effects (product A 0%, B 1.8%, C 5.6%). Conclusion: We concluded that there are no significant differences among 3 IVGG products in regard to their efficacy and safety.

Estimation of “Selective” Intravenous Gamma Globulin Treatment Indicated by Harada Score

Harada score, which was originally constructed as a guideline for indication of intravenous gamma globulin (IVGG) in research group of Kawasaki disease promoted by the Ministry of Health (Kouseishou), had been applied to consecutive 258 cases of Kawasaki disease between 1989 and 1998. Each item of score are regarded as positive when patient is male, 12-month-old or younger, white blood cell count is 12,000/mm3 or more, platelet count is less than 350,000/mm4C-reactive protein is 4.0mg/dl or more, hematocrit is less than 35%, serum albumin is less than 3.5g/dl. Concerning to these items, 203 cases (78.7%) fulfilled 4 or more items and were treated with IVGG. Among them, coronary artery lesion (CAL) developed in 28 cases (13.8%) at 30th day after onset and remained after 1 year in 19 cases (7.4%). Giant aneurysm larger than 8mm in diameter developed in 3 cases (1.5%). Fifty-five cases fulfilled 3 or fewer items and were not treated with IVGG. CAL developed in 2 cases (3.6%) at 30th day and both of them regressed to discontinue medication until 1 year after onset. Frequency of blood examinations while patient is in hospital were done every 3.13±0.87 days in cases during 3 years from 1986 to 1988 before Harada score was evaluated, while during 10 years of this study examinations were done every 3.06±0.46 days in cases that IVGG was indicated, and 2.81±0.68 days in cases that IVGG was not indicated. Harada score has utility with 93.3% and 100% of sensitivity at 30th day and over 1 year respectively, for selection of cases which IVGG is absolutely necessary for prevention of CAL. Though frequency of blood tests tends to increase, statistics concerning to it was not significant.

CTLA-4 (CD152) Expression in T Cells during the Acute Stage of Kawasaki Disease

Although we have already reported that the activation of monocytes/macrophages plays a central role in acute Kawasaki disease (KD), the role of T cells in KD remains under debate. The kinetics of T cell activation in acute KD was investigated with emphasis on cytotoxic T lymphocytes-associated antigen 4 (CTLA-4, CD152). CTLA-4 is a surface molecule of activated T cells with sequence homology to CD28. Both molecules bind to the same ligands, but have antagonistic functions. While CD28 is an important costimulator, CTLA-4 has an essential inhibitory function in maintaining the homeostasis of the immune system. CTLA-4 is a negative regulator of T cell activation. Using flow cytometry, we investigated intracellular expression of CTLA-4 in CD3+ and CD4+T cells of 13 patients with KD and 13 healthy children. The percentages of intracellular CTLA-4 positive CD3+ and CD4+T cells were 6.6±3.7% and 4±3.8% in KD before treatment during the acute stage (Mean Illness Day: 3.9). These levels were significantly higher than the levels during the convalescent stage (1.8±1.4%, p<0.01 and 1.0±0.9%, p<0.05) and were significantly higher than the levels in healthy children (2.4±1.0%, p<0.01 and 1.0±0.6%, p<0.05). The percentages of CTLA-4+CD3+T cells and CD4+T cells were reduced after intravenous gammaglobulin treatment (3.9±4.2% and 3.3±4.2%, respectively). In this study, we found increases in CTLA-4 expression in T cells during acute KD. Since CTLA-4 is an inhibitory molecule of T cell activation, peripheral blood T cell activation seemed to have terminated by the time KD patients were diagnosed. Peripheral blood T cells might activate before symptoms appear in KD patients.

Vaccination Against Infections in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a well-defined mature B-cell neoplasm associated with increased susceptibility to infections. Two major options in prevention of infections in CLL, intravenous gammaglobulin treatment and antimicrobial chemoprophylaxis, have not resulted in satisfactory outcome. A third strategy, antimicrobial vaccination, is the topic of this minireview. We collected articles and their references concerning CLL vaccination from the Medline database starting from 1966 and thirteen relevant studies were found. Plain bacterial polysaccharide vaccines would seem to be ineffective in antibody formation in patients with CLL. However, protein and conjugate vaccines appear to be more immunogenic and their responses may be further enhanced with ranitidine adjuvant treatment. New well-designed investigations are needed to develop appropriate vaccination strategies and evaluate vaccination efficacy in infection morbidity and mortality in CLL.

Comparison of thrombopoiesis during ITP and HIV-ITP and response to intravenous gammaglobulin treatment

Immune thrombocytopenic purpura's diagnosis (ITP) is based on low platelet count and exclusion of clinical conditions rather than a specific diagnostic test. We used the reticulated platelet (RP) assay to study ITP and thrombocytopenia associated with HIV infection (HIV-ITP). Data from 96 ITP and 23 HIV-ITP patients showed low platelet counts (PC) with both high or low %RP suggesting that individuals have different degrees of thrombopoiesis. About 20% of ITP and 46% of HIV-ITP patients had %RP in the 'low' or 'normal' ranges. Grouped by platelet count <30 x 109/L, 24% ITP and 36% HIV-ITP patients had 'low' & 'normal' %RP. The patient population did not show correlation between PC and %RP, but individuals showed an inverse relationship. Within a week of receiving IVIG, 18 ITP and 9 HIV-ITP patients' PC increased, %RP decreased. Patients with %RP measured within 24 h of IVIG treatment had lower %RP than expected, suggesting dilution by an older platelet population. ITP and HIV-ITP patients' responses to i.v. gammaglobulins were similar. Thrombopoietin levels of ITP patients did not correlate with PC, %RP, or RP count. Estimation of thrombopoiesis by RP assay provides useful information for differentiation among thrombocytopenias.

Factors relating to the cardiac sequelae of Kawasaki disease one month after initial onset

This study aimed to determine the risk factors related to the presence of cardiac sequelae 1 mo after initial onset and to examine the preventive effect of the early administration of high‐dose gamma‐globulin (GG) on cardiac sequelae in patients with Kawasaki disease. Patients treated with high‐dose GG of 2000 ± 100 mg kg‐1 were selected as subjects from the 15th nation‐wide survey in Japan. Univariate and logistic multiple variable analyses were used to test the effects of background variables such as age and gender, variables relating to laboratory findings such as the percentage of neutrophil leucocytes, and variables relating to the GG treatment on the presence of cardiac sequelae. The odds ratios were significantly higher for males (1.48), those younger than 1 y of age (1.71), recurrent cases (2.42), and those with a low haematocrit (&gt;32.5%) (1.45) and high percentage of neutrophil leucocytes (&lt;68%) (1.63). The odds ratio was low for those who started GG administration in less than 6 d from onset between the patients with and without cardiac sequelae. The odds ratio for the duration of GG treatment was not significantly different between those with and without cardiac sequelae. Conclusion: Patients who received early administration of GG, less than 6 d from onset of the disease, had a lower risk than those received GG more than 6 d from the onset. The percentage of neutrophil leucocytes and the haematocrit level are useful indicators in predicting the development of cardiac sequelae.

Factors relating to the cardiac sequelae of Kawasaki disease one month after initial onset.

This study aimed to determine the risk factors related to the presence of cardiac sequelae 1 mo after initial onset and to examine the preventive effect of the early administration of high-dose gamma-globulin (GG) on cardiac sequelae in patients with Kawasaki disease. Patients treated with high-dose GG of 2000 +/- 100 mg kg(-1) were selected as subjects from the 15th nation-wide survey in Japan. Univariate and logistic multiple variable analyses were used to test the effects of background variables such as age and gender, variables relating to laboratory findings such as the percentage of neutrophil leucocytes, and variables relating to the GG treatment on the presence of cardiac sequelae. The odds ratios were significantly higher for males (1.48), those younger than 1 y of age (1.71), recurrent cases (2.42), and those with a low haematocrit (<32.5%) (1.45) and high percentage of neutrophil leucocytes (>68%) (1.63). The odds ratio was low for those who started GG administration in less than 6 d from onset between the patients with and without cardiac sequelae. The odds ratio for the duration of GG treatment was not significantly different between those with and without cardiac sequelae. Patients who received early administration of GG, less than 6 d from onset of the disease, had a lower risk than those received GG more than 6 d from the onset. The percentage of neutrophil leucocytes and the haematocrit level are useful indicators in predicting the development of cardiac sequelae.

Incidence survey of Kawasaki disease in 1997 and 1998 in Japan.

To describe the results of a nationwide epidemiologic survey of Kawasaki disease for the 2-year period 1997 and 1998. We sent a questionnaire to all hospitals with 100 beds or more throughout Japan (2663 hospitals) requesting data on patients with Kawasaki disease. Study items included name, sex, date of birth, date of initial hospital visit, diagnosis, address, recurrence, sibling cases, gammaglobulin treatment, and cardiac lesion in the acute stage or 1 month after onset. Of the 2663 hospitals, 68.5% responded, reporting 12 966 patients-7489 males and 5477 females. Of the total patients reported, 6373 (incidence rate of 108.0 per 100 000 children <5 years old) occurred in 1997, and 6593 (111.7) in 1998. More than one half of the patients (54.9%) were <2 years old and 81.6% were <4 years old. In males, the incidence rates of cardiac lesions were 27.2 in the acute stage and 10.1 a month after onset. In females, the rates were 16.7 and 5.2, respectively. The incidence rates of cardiac lesions were highest in the youngest age group (<6 months old) both in the acute stage and 1 month after onset. The rates decreased with increasing ages. Although frequency of giant aneurysms was not high at the acute stage, it did not decrease 1 month after onset. The incidence rates have been steadily increasing for 11 years since 1987. The rate in 1998 was over 1.5 times higher than that in 1987. The age and sex distributions were identical in each survey. Although most of the cardiac lesions at the acute stage decreased to half or less 1 month after onset, giant aneurysms did not decrease and existed persistently after 1 month.

The Profiles of Kawasaki Disease in China

Kawasaki disease in China was described for the first time in 1976 in Taiwan, and in 1978 in mainland, respectively. Questionnaire surveys had been conducted in both of the area of China and showed that the Kawasaki disease patients increased year by year. No data on incidence rates were available for these surveys because the problem of representativeness. However, it showed that there were many similar characteristics of Kawasaki disease in China comparing with those in Japan. Although a series of infectious agents were suspected, the etiology of Kawasaki disease remained unclear. High dose of gamma globulin treatment was also adopted commonly in China.

Indices of progression of IgA nephropathy are modulated by α-tocopherol in rats

Background. We have previously shown that α-tocopherol prevents oxidative stress in experimental IgA nephropathy (IgAN) when administered before or concurrent with the induction of IgAN. We now seek to determine whether α-tocopherol can ameliorate the disease after IgAN is established. Methods. Using the classic IgAN model, 25 male Lewis rats were sorted into five groups of five animals each: 4-week control, 4-week bovine gamma globulin (BGG) treatment, 6-week control, 6-week BGG treatment, and 6-week BGG treatment with α-tocopherol administration started after 4 weeks. Serum α-tocopherol concentrations, kidney and plasma malondialdehyde concentrations, and kidney transforming growth factor beta-1 (TGFβ1) mRNA were analyzed. Results.α-Tocopherol modulated IgAN after the disease was established in the 4-week BGG model, as indicated by the reduction in tissue oxidative stress, dampening of fibrogenic cytokine (TGFβ1), and abatement of proteinuria in α-tocopherol-treated animals compared with untreated rats. Conclusions. These results substantiate the anti-oxidant role of α-tocopherol in diminishing the indices associated with progression of experimental IgAN. The ability of α-tocopherol to reduce the progression of injury after establishment of the disease reflects the clinical situation, and thus holds promise for human therapy.

The Effect on MRI of Gammaglobulin Treatment in Relapsing Multiple Sclerosis

A number of uncontrolled studies and randomised, placebo-controlled trials have shown that treatment with intravenous gammaglobulin (IVIG) reduces the exacerbation rate in relapsing multiple sclerosis (MS). Two randomised studies from Denmark and Israel, respectively have used MRI as efficacy endpoint. In a Danish crossover trial, the number of gadolinium-enhancing lesions in serial cranial MRI was significantly reduced by approximately 60% during IVIG treatment compared to placebo. Neither the Danish study nor an Israeli study were able to show significant reductions in the total lesion load on T2-weighted cranial MRI. However, the studies were either too short or comprised too few patients for showing significant differences in T2-weighted MRI. In conclusion, IVIG is of benefit to patients with relapsing MS, but larger studies are required before the place of IVIG in the treatment of MS can be established.

Initial intravenous gammaglobulin treatment failure in Kawasaki disease.

To determine initial intravenous gammaglobulin (IVIG) treatment failures in Kawasaki disease (KD) and to report the outcome of retreatment and our use of pulse intravenous (IV) methylprednisolone and cyclophosphamide in patients with persistent KD. Retrospective analysis of the treatment and response of children with KD over 3 years. Fifty (77%) of 65 patients completely responded to a single treatment with IVIG (2 g/kg). Fifteen patients (23%) required retreatment; 10 patients fully responded but 5 had persistent disease (3 developed coronary aneurysms and 4 developed coronary artery thrombosis). Four of these 5 patients with persistent disease were treated with pulse IV methylprednisolone and 2 were also treated with IV cyclophosphamide. There was no progression of coronary aneurysms and no deaths. No initial patient characteristics predicted IVIG treatment failure or the development of coronary aneurysms. Nearly 23% of patients with KD may require retreatment and 8% may develop coronary aneurysm. Additional antiinflammatory therapy, such as IV methylprednisolone and IV cyclophosphamide, may be helpful in treating persistent KD.

Selective high dose gamma-globulin treatment in Kawasaki disease: Assessment of clinical aspects and cost effectiveness

Selective high dose gamma-globulin treatment in Kawasaki disease: Assessment of clinical aspects and cost effectiveness

Selective high dose gamma-globulin treatment in Kawasaki disease: Assessment of clinical aspects and cost effectiveness

High-dose intravenous gamma-globulin (IVGG) plus aspirin (ASA) treatment is effective in preventing coronary artery complications in acute Kawasaki disease (KD). However, gamma-globulin is very expensive, especially in Japan. Furthermore the indication for IVGG treatment and the optimal dose of gamma-globulin remain controversial. To examine these two issues, we used Harada's scoring system to investigate whether a single 2 g/kg dose therapy has any advantage over the 5 day 400 mg/kg per day therapy. We studied 203 patients with KD who had no coronary artery complications on admission. Of these, 145 patients scored 4 or more on Harada score within the first 9 days of illness and were treated with IVGG treatment. Using a random number table, 72 patients were selected to receive a single 2 g/kg dose (2 g group), while the remaining 73 patients were treated with 400 mg/kg per day for 5 consecutive days (400 mg group). Those who had a Harada score of three or less received no IVGG (non-IVGG group) treatment (58 patients). The incidence rate of coronary artery complications in the 2 g group was significantly lower than in the 400 mg group. The duration of high fever, positive duration of C-reactive protein and the number of hospital days in the 2 g group were each significantly shorter than in the 400 mg group. The total medical expense in the 2 g group was significantly lower than in the 400 mg group. There were no coronary artery complications in the non-IVGG group. It was found to be clinically more effective and more cost effective to select a patient by Harada's scoring system and, where a score of four or more was obtained, to administer a single 2 g/kg intravenous dose of gamma-globulin for acute KD.

#719 Response to endovenous gammaglobulin treatment in children with idiopathic thrombocytopenic purpura (ITP)

#719 Response to endovenous gammaglobulin treatment in children with idiopathic thrombocytopenic purpura (ITP)

Labeled WBC cardiac imaging and two-dimensional echocardiography to evaluate high-dose gamma globulin treatment in Kawasaki disease.

Twenty-eight children (5 girls, 23 boys; age, 20.3 +/- 16.2 months) with Kawasaki disease (KD) were included in this study. The children were treated with aspirin plus intravenous injection of gamma globulin (IVGG). Both Tc-99m HMPAO labeled WBC heart imaging (Tc-WBC) and two-dimensional echocardiograms (2D-Echo) were used to evaluate the effects of IVGG on the most common cardiac presentations--carditis and dilated coronary arteries--in KD. After IVGG therapy, the results showed that 32.1% (9/28) carditis patients had improved; 39.3% (11/28) of patients had no significant change; 28.6% (8/28) of patients had severe changes, and there was no significant difference among the three groups by the evidences of Tc-WBC. Dilated coronary arteries (CA) became smaller in 32.1% (9/28) of patients; 53.6% (15/28) of patients had no definite change; 14.3% (4/28) of patients had dilated LCA that became larger; and borderline difference existed among the three groups, proved by 2D-Echo. Between the Tc-WBC and 2D-Echo, 35.7% (10/28) of patients had similar changes, and 64% (18/28) of patients showed incongruous changes; and there was little difference. In conclusion, Tc-WBC and 2D-Echo provide strong evidence of the existence of carditis and dilated coronary arteries in certain patients, even after IVGG treatment. The improvements of carditis and dilated coronary arteries were not correlated with each other after IVGG therapy.

Intravenous gammaglobulin treatment in multiple sclerosis and experimental autoimmune encephalomyelitis: delineation of usage and mode of action.

Multiple sclerosis (MS) is a central nervous system demyelinating disease of implicated autoimmune aetiology. The effect was evaluated of intravenous gammaglobulin (IVIg), a successful therapy in various autoimmune diseases, in relapsing-remitting MS patients treated for three years. IVIg treatment significantly reduced the number and severity of acute exacerbations and resulted in a lesser neurological disability. There were no significant short or long-term adverse effects to IVIg treatment. To clarify the putative therapeutic effects of IVIg, this treatment was examined in the animal model of experimental autoimmune encephalomyelitis (EAE) in the rat. IVIg suppressed active EAE in relation to disease severity and duration, despite the presence of T-cell reactivity to specific antigens, while the treatment had no effect on passive EAE induced by adoptive transfer of myelin basic protein specific CD4 + T-cells. It is concluded that IVIg treatment may be a promising treatment in relapsing-remitting MS as it can alter the natural course of the disease.

Equilibrium multigated blood pool ventriculography to evaluate the effects of high-dose gamma-globulin treatment for left ventricular functions in Kawasaki disease.

Twenty-one patients with acute state Kawasaki disease (15 boys, 6 girls; age range, 1-8 years) had equilibrium multigated blood pool ventriculography (EMBPV) before treatment. The symptoms and signs subsided after the administration of aspirin and the intravenous injection of high-dose (400 mg/kg per day x 5 days) gamma-globulin (IVGG) treatment. Then, a second EMBPV was arranged to evaluate the effects of the treatment on left ventricular functions. Left ventricular function was analyzed based on the following parameters: (systolic phase) ejection fraction, ejection time, peak ejection rate, first 1/3 ejection rate mean; and (diastolic phase) peak filling rate, fast filling fraction, time to peak filling rate, first 1/3 filling rate mean. The results showed that there were no significant differences in the parameters of left ventricular function before and after treatment (P > 0.05, paired Student's t-tests).

Gamma-globulin treatment of acute myocarditis in the pediatric population.

Myocardial damage in myocarditis is mediated, in part, by immunological mechanisms. High-dose intravenous gamma-globulin (IVIG) is an immunomodulatory agent that is beneficial in myocarditis secondary to Kawasaki disease, as well as in murine myocarditis. Since 1990, the routine management of presumed acute myocarditis at Children's Hospital, Boston, and Children's Hospital, Los Angeles, has included administration of high-dose IVIG. We treated 21 consecutive children presenting with presumed acute myocarditis with IVIG, 2 g/kg, over 24 hours, in addition to anticongestive therapies. A comparison group comprised 25 recent historical control patients meeting identical eligibility criteria but not receiving IVIG therapy. Left ventricular function was assessed during five time intervals: 0 to 7 days, 1 to 3 weeks, 3 weeks to 3 months, 3 to 6 months, and 6 to 12 months. At presentation, the IVIG and non-IVIG groups had comparable left ventricular enlargement and poor fractional shortening. Compared with the non-IVIG group, those treated with IVIG had a smaller mean adjusted left ventricular end-diastolic dimension and higher fractional shortening in the periods from 3 to 6 months (P = .008 and P = .033, respectively) and 6 to 12 months (P = .072 and P = .029, respectively). When adjusting for age, biopsy status, intravenous inotropic agents, and angiotensin-converting enzyme inhibitors, patients treated with IVIG were more likely to achieve normal left ventricular function during the first year after presentation (P = .03). By 1 year after presentation, the probability of survival tended to be higher among IVIG-treated patients (.84 versus .60, P = .069). We observed no adverse effects of IVIG administration. These data suggest that use of high-dose IVIG for treatment of acute myocarditis is associated with improved recovery of left ventricular function and with a tendency to better survival during the first year after presentation.

Gamma-globulin modulates growth of EBV-derived B-cell tumors in SCID mice reconstituted with human lymphocytes.

The effect of weekly gamma-globulin injection on the development of human B-cell tumors was studied in 120 mice with severe combined immunodeficiency (SCID). The mice were injected intraperitoneally (i.p.) with human peripheral mononuclear cells (PBMC) from 6 different Epstein-Barr virus (EBV)-seropositive donors. Animals repopulated with cells from 5 donors received gamma-globulin or saline for 20 weeks and were followed up to 24 weeks after reconstitution. A delay in the appearance of fata EBV-derived human B-cell tumors was noticed in the gamma-globulin-treated groups as compared to the controls. In a separate experiment, the effect of gamma-globulin treatment during the initial 4 weeks after reconstitution was compared to treatment from week 5 to week 8 as well as to a continuous 20-week treatment. The results from this experiment showed that B-cell tumor growth could be prevented just as efficiently when the animals were treated only during the first 4 weeks. In contrast, no preventive effect was seen when the first gamma-globulin dose was given at the beginning of week 5 after reconstitution. Our results indicate that gamma-globulin reduces the frequency of EBV-derived B-cell tumor development and suggest that SCID mice repopulated with human cells represent a useful in vivo model for evaluation of the prophylactic and/or therapeutic effects of immunomodulatory treatments in lympho-proliferative disorders associated with immunosuppression.