CLINICAL CASE
Severe steroid-dependent asthma with IgG-2 deficiency and recurrent sinusitis: response to treatment with high-dose intravenous immunoglobulin
C. Loza Cortina
Hospital de Jarrio. Pediatric Service. Unit of Allergy. Jarrio (Asturias). Spain.
Correspondence:
C. Loza Cortina
Hospital de Jarrio
Pediatric Service (Unit of Allergy)
Jarrio-Coaña
33719 Jarrio (Asturias) (Spain)
SUMMARY
Patients with severe asthma pose a dilemma to the physician since the treatment they need, namely high doses of oral steroids, has serious side effects, especially among the pediatric population. Deficiency in one or more of the IgG subclasses has been associated with abnormal pulmonary function, as well as with recurrent sinopulmonary infections in adults and children. In the last years attention has been focused on alternative therapies for these patients. One of these alternatives is the treatment with intravenous immunoglobulin (IVIG). We report an 11-year-old boy with severe asthma since the age of two years and multiple hospital admissions due to asthmatic crisis even more frequent and severe, to the point of needing, in the last year, daily treatment with high doses of oral steroids (20 mg). During six months the patient was given high doses of intravenous immunoglobulin. After one month of treatment a clinical and spirometric improvement was apparent allowing to taper down the oral steroids until their complete substitution by inhaled budesonide (1,600 µg/day). The only side effects noted were severe headaches after gammaglobulin infusions which responded well to oral paracetamol. This improvement was sustained throughout the treatment period, but few weeks after the IVIG was suspended the clinical and spirometric parameters started to worsen again.
Key words: Asthma. Sinusitis. Children. IgG-2 deficiency. Intravenous gammaglobulin.
RESUMEN
Los pacientes con asma grave suponen un serio problema médico puesto que el tratamiento que necesitan, altas dosis de corticoides orales, tiene importantes efectos secundarios, especialmente entre la población pediátrica. Las deficiencias de una o más subclases de IgG han sido asociadas a una mala función pulmonar así como a infecciones sinopulmonares recurrentes, tanto en niños como en adultos. Durante los últimos años se han venido ensayando alternativas terapéuticas para estos pacientes. Una de estas alternativas es el tratamiento con inmunoglobulina intravenosa ((IVIG). Presentamos el caso de un niño de once años de edad, con asma grave desde los dos años y múltiples ingresos hospitalarios debido a crisis asmáticas cada vez más intensas y frecuentes, hasta el punto de necesitar, en el último año, tratamiento diario con altas dosis de corticoides orales (20 mg). Durante seis meses el paciente recibió altas dosis de IVIG. Después de un mes de tratamiento comenzó a notarse una mejoría clínica y espirométrica, permitiendo la retirada gradual de los corticoides orales hasta su completa sustitución por budesonida inhalada (1.600 µg diarios). Los únicos efectos secundarios observados fueron cefaleas después de las infusiones de gammaglobulina que respondían bien al paracetamol oral. Esta mejoría se mantuvo durante todo el período de tratamiento, pero a las pocas semanas de suspender la IVIG los parámetros clínicos y espirométricos comenzaron a empeorar de nuevo.
Palabras clave: Asma. Sinusitis. Niños. Déficit de IgG-2. Gammaglobulina intravenosa.
INTRODUCTION
Patients with severe asthma pose a dilemma to the physician since the treatment they need, namely high doses of oral steroids, has serious side effects, especially among the pediatric population.
In the last years attention has been focused on alternative therapies for these patients. One of these alternatives is the treatment with intravenous immunoglobulin (IVIG). Since the first placebo-controlled study on immunoglobulin treatment in children by Abernathy (1) several papers have appeared regarding this issue.
Here we report the results obtained with the treatment of one patient with severe asthma with high doses of IVIG according to the protocol described by Mazer and Gelfand (2).
CASE REPORT
The case report is an 11-year-old boy with severe asthma since the age of two years and multiple hospital admissions due to asthmatic crisis ever more frequent and severe, to the point of needing, in the last year, daily treatment with high doses of oral steroids (20 mg). Besides this treatment, the patient received daily inhaled salmeterol and ipratropium bromide (a trial with retarded theophyllines had to be suspended because of severe headaches). On the other hand, this patient suffered from recurrent episodes of sinusitis. He had been two years on immunotherapy (house dust mites), showing no improvement, in an attempt to reduce the the high doses of inhaled steroids (1,200 µg/day) that had been receiving since he was first attended in our office at the age of seven. In the previous years, the child had been poorly controlled and did not receive any regular treatment, having on average a monthly crisis, according to the report of the mother.
The following tests were carried out: skin prick test: D. Pteronyssinus and Farinae strongly positive (4+); IgE: 743 UI/ml.; alfa-1-antitrypsin, sweat electrolites (three determinations) and metabolic checkup normal; X-ray studies: thorax (inspiration-expiration) and esophagogram normal; maxillary sinuses: recurrent infections; pulmonary scintigraphy negative; immunologic studies: IgG total 646 mg/dl, (723-1685), IgG-1 421 mg/dl, IgG-2 48 mg/dl, (147-493), IgG-3 24 mg/dl, IgG-4 29 mg/dl, IgM 76 mg/dl, IgA 59 mg/dl (70-382), anti IgA-antibodies negative; functional response to polysaccharide antigens after vaccination against neumococcus and hemophilus normal.
During six months the patient was given high doses of intravenous immunoglobulin (human gammaglobulin 5%, pH 4,25: Polyglobin® N, Bayer), 2 g/kg every four weeks, seven courses in total. The correspondent dose to each course, 100 g, was given in two consecutive days, 1,000 cc (50 g) each day, at a maximun rate of 240 cc/h, keeping the patient monitored during the seven hours that lasted the infusion.
After one month of treatment a clinical and spirometric improvement was apparent (Fig. 1) allowing to taper down the oral steroids until their total substitution by topical budesonide (1,600 µg/day). During the six months of treatment with immunoglobulin, the inhaled salmeterol and ipratropium bromide that the patient was receiving were kept. The only side effect noted were severe headaches after gammaglobulin infusions that responded well to oral paracetamol. This improvement was sustained throughout the treatment period, but few weeks after the IVIG was suspended, the clinical and spirometric parameters started to worsen again.
Figure 1.--Spirometric evolution in %.
After the cessation of the IVIG treatment the immunoglobulin values were: IgG 863 mg/dl, IgG-1 466 mg/dl, IgG-2 241 mg/dl, IgG-3 24 mg/dl, IgG-4 22 mg/dl, IgA 82 mg/dl and IgM 79 mg/dl.
DISCUSSION
Some children with severe asthma need high doses of oral steroids to keep a quality of life as normal as possible. Unfortunately, this treatment, as is well known, has very serious side effects including growth retardation through the suppression of the hypothalamus-pituitary-adrenal axis. Other alternatives have been tried with agents such as gold and methotrexate in an effort to reduce the dose of steroids, but these medications have important side effects, too, mainly hematologic supression.
Deficiency in one or more of the IgG subclasses has been associated with abnormal pulmonary function, as well as with recurrent sinopulmonary infections in adults and children (3-7).
Over the last years several authors have reported on their experience with the treatment of severe bronchial asthma (with or without IgG-2 deficiency and/or recurrent sinus infections) with IVIG. Whereas some authors found positive results (2, 8-12) others did not (1, 13). The authors of the last paper published on the subject to date, who did not find positive results, pointed out, nevertheless, that: "IVIG exerts its effect on a long-term basis; therefore a longer treatment period than the three months chosen (6 months or more) and a longer follow-up period could result in a greater efficacy of the treatment"(13).
Our patient had a deficiency of IgG-2 with good functional response to polysaccharide antigens, a subtle diminution of IgA and recurrent maxillary sinusitis. As in the trial carried out by Mazer and Gelfand we noted a quick positive response both in clinical and spirometric parameters; the pulmonary function tests that showed a greater improvement were those measuring the small airway disease, as was the case in other studies (9). Similarly to the experience of other authors (12, 13) the only side effects suffered by the patient were severe headaches after the infusions; these headaches responded well to oral paracetamol.
Several mechanisms of action have been proposed to explain the effectiveness of the IVIG: 1) reduction of the sino-pulmonary infections by passively increasing the immunity, thus reducing one of the exacerbating causes of asthmatic crisis (9); 2) immunomodulatory action of the immunoglobulins diminishing the immune response to allergens (2); 3) external source of antiidiotype antibodies that acting against the antigenic determinants responsible of the hypersensitivity response would modulate the immune function (14); 4) diminishing of mast cell degranulation (14); 5) Inhibition of periferal mononuclear cells proliferation (15).
Unfortunately, the positive effects of the IVIG treatment, as happened in the study of Mazer and Gelfand, disappeared five to six weeks after the cessation of the therapy and the patient had to resume the treatment with oral steroids.
In summary, the treatment of severe, steroid-dependent asthma with high doses of intravenous immunoglobulin is well tolerated by children but has a positive effect during the treatment period only.
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