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Asthma and selective immunoglobulin subclass deficiency: Improvement of asthma after immunoglobulin replacement therapy
Clinical and laboratory observations Asthma and selective immunoglobulin subclass deficiency: Improvement of asthma after immunoglobulin replacement therapy Richard Page, MD, Gilbert Friday, MD, Paul Stillwagon, MD, David Skoner, MD, L a w r e n c e Caliguiri, MD, a n d Philip Fireman, MD From the Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh
Several reports document a selective IgG subclass deficiency in patients with chronic pulmonary disease. 13 Other authors have shown the benefit of IgG replacement in IgG subclass-deficient patients with chronic sinopulmonary infections. 4'5 Since asthma has been suggested to be an inflammatory airway disease,6,7 controlling bronchial inflammation initiated by recurrent or persistent infections may diminish the severity of asthma. We have evaluated the effect of IgG replacement therapy on the severity of asthma and infections in five patients with asthma, recurrent sinopulmonary infections, and concomitant IgG subclass deficiencies. METHODS Patient selection. Patients were followed either in Children's Hospital of Pittsburgh Asthma and Allergic Disease Center or referred by physicians in the Pittsburgh area. Human Right Committee approval for this clinical trial with an approved drug was not required; these patients had clinical indications for use of the medication, which was requested by the referring physicians or the family. Children with recurrent or chronic asthma triggered by repeated infections of the upper or lower respiratory tract were evaluated for immunologic competence from 1983 to 1986. Quantitative serum immunoglobulins were measured in all patients; if the total serum IgG concentration was low or if it was normal but a clinical concern about
Supported by National Institutes of Health Grant 2M01 RR00084, Clinical Associate Physician Award, and National Institutes of Health Grant R01 AI19262. Submitted for publication May 6, 1987; accepted July 10, 1987. Reprint requests: Philip Fireman, MD, Children's Hospital of Pittsburgh, 125 DeSoto St., Pittsburgh, PA 15213.
undue susceptibility to infection persisted, serum IgG subclasses and functional antibody titers to diphtheria, tetanus, 12 pneumococcal serotypes, and rubella were measured. Many patients also had influenza viral antibody measured. If these antibody titers were low, patients were immunized or reimmunized with the appropriate vaccine (except rubella vaccine), and antibody titers were measured 4 weeks later. Of approximately 500 patients evaluated for asthma exacerbated by recurrent sinopulmonary infections, we measured lgG subclasses and functional antibodies in approximately 75. Of these, five patients had a selective deficiency of IgG subclass l, 2, and/or 3 that was unrelated to possible transient hypogammaglobulinemia of infancy. IgG SD FEVa MMEFR MEF
Immunoglobulin G Standard deviation Forced expiratory volume in 1 second Maximum midexpiratory flow rate Mean expiratory flow
Patient population. All five patients fulfilled the American Thoracic Society definition of asthma. All patients required daily theophylline therapy, five used /3-agonists daily, three required cromolyn, and three were steroid dependent (two received prednisone on alternate days and one daily). All patients had intermittently received brief courses of prednisone for severe acute episodes of asthma. All patients had recurrent sinopulmonary infections requiring frequent antibiotic therapy; two had been unsuccessfully managed with prophylactic antibiotics before "y-globulin therapy. Three of the five patients had a history of allergic rhinitis confirmed by positive skin tests, but these allergens did not trigger the asthma. All three
127
1 28
Clinical and laboratory observations
The Journal of Pediatrics January 1988
Table. Summary of the laboratory results of the five study patients with IgG subclass deficiency Immunoglobulins
Functional antibodies
IgG subclasses
Age IgG IgA IgM IgG1 IgG2 IgG3 IgG4 Patient (yr) (mg/dl.) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) 1
1
2 3
14 19
4
5
13
17
375 405 (~) 300 (~)
389 (~)
299 (~)
41' <1 (~) 120
98
76
90
243 (~)
13 (~)
80 155
367 340 (~)
5 (~) 163
154
220
215 ($)
113 (~,)
212 (~)
45 (~)
13 29 15 (~,)
56
<5 (~)
3 0 (~) 13
42
8
Vaccines Diphtheria (IU/mL) Pneumococcal Diphtheria (IU/mL), tetanus IU/mL) Diphtheria (IU/mL), tetanus (IU/mL) Diphtheria (IU/mL), pneumococcal
PrePostvaccine vaccine ND
0.03
(~,) 0.03
(~)* 0.3
(~)
(~)*
ND
0.05
ND
0.5
0,001 (~)
0.01
($)
(~)*
ND, not done, IU, internationalunits. values >2 SD belowmean. *No increasein antibodyafter vaccine.
patients had received immunotherapy for their allergic rhinitis without diminution in the frequency of either sinopulmonary infections or asthma. Laboratory assays. IgG, IgA, and IgM were measured by nephelometry in the University of Pittsburgh Immunopathology Laboratory. Low values were defined as >2 SD below the arithmetic mean for age. IgG subclasses were measured by either radioimmunodiffusion at Brigham and Women's Hospital in Boston or by radioimmunoassay at Specialty Laboratories in Los Angeles. The former considered low IgG subclasses those >2 SD below the geometric mean; the latter were those in the bottom 5% of a normal group of children. Influenza titers were performed by hemagglutination-inhibition assay. Diphtheria titers were determined by radioimmunoassay, and tetanus and pneumococcal titers were determined by enzyme-linked immunosorbent assay. Low diphtheria and tetanus titers were >2 SD below the geometric mean; pneumococcal titers were compared with those of a normal population of adults with prevaccination titers. Pulmonary function testing was performed by spirometry. Patients repeated the tests until three acceptable efforts were obtained. 8 Using the best curve, percentage predicted was calculated with a formula that considered height, weight, age, race, and sex. 9 3,-Globulin therapy. After the diagnosis of IgG subclass deficiency was established, each patient initially received 200 to 400 mg/kg of intravenous -y-globulin as a loading dose. Subsequent doses were 100 to 300 mg/kg intravenously every 4 weeks.
Clinical evaluation To assess changes after 7-globulin therapy, we studied the following: (1) pulmonary function tests, (2) medication diary, (3) hospital admissions for status asthmaticus, (4) school attendance, and (5) clinical signs and symptoms of sinopulmonary infections. Sinusitis was defined as either positive sinus radiographs or purulent rhinorrhea associated with cough, fever, headache, or halitosis. Pulmonary infections were documented by either infiltrates on chest radiograph or rales, tachypnea, and cough. RESULTS
Laboratory values. As outlined in the Table, IgG subclass deficiencies were diagnosed in five patients with asthma as follows: Two patients had both IgG1 and IgG2 deficiency, and one each had one of the following deficiencies: IgG2, IgG4, and IgA; IgG1 and IgG3; and IgG1, IgG2, and IgG3. Four of five patients had low-total IgG values. Functional antibody deficiencies corresponding to their subclass deficiency were found in four of the five patients, whereas one patient had normal functional antibodies to diphtheria and tetanus despite a documented IgG subclass deficiency. Clinical course. The patients were examined on a regular basis for 2 to 18 months by one of the authors before intravenous 7-globulin therapy and 10 to 30 months after 7-globulin therapy was instituted. One patient developed mild bronchospasm during the initial infusion, which was treated with 0.3 mL 1:1000 epinephrine; she was free of
Volume 112 Number 1
Clinical and laboratory observations
12 9
n=4 160 140,
120 ~O
I00 o
80
0
o
60
o
4 0 84
O
~
T
I O
FEV= o=Pre
O
0
0 0
9
MMEFR
MEFzs
9 = Post
Figure. Pulmonary function values in the four patients older than 6 years of age. Pre (O) refers to the individual values before patients received 3,-globulin, and post (e) refers to these values 6 to 14 months after 7-globulin therapy was begun. Arithmetic mean is indicated by the bar. Pulmonary function assessments (FEV, MMEFR, and MEF25) are expressed as percentage predicted based on height, weight, age, sex, and race.
symptoms during subsequent infusions. Improvement was documented by the following: 1. Pulmonary function values. Of four patients who were more than 6 years of age, three had improved pulmonary function test results 6 to 14 months after 7-globulin therapy (Figure) was instituted. Whereas the average FEVI increased only marginally from 90% to 100% of the predicted value, the mean M M E F R increased from 51% to 82%, and the mean MEF25 doubled from 37% to 78%, of predicted values. 2. Hospital admissions. Two patients with four admissions for status asthmaticus in the year before therapy had none after intravenous 3,-globulin therapy. The patient who did not improve had eight admissions before and nine admissions in the year after therapy. 3. School absenteeism. The three patients regularly attending school missed a total of 20 school days before therapy; none missed any school days because of asthma after therapy was instituted. 4. Medication requirements. Four of the five patients required fewer drugs after -y-globulin therapy was begun. Two of five patients stopped theophylline, and three of five patients stopped daily use of beta-agonists. One of three patients discontinued daily inhaled steroids, and both patients discontinued use of alternate-day steroids, but the one patient with multiple hospitalizations kept taking daily prednisone therapy.
4. Signs and symptoms. The total number of sinopulmonary infections decreased by 80% from 20 in the year preceding 3,-globulin therapy to four the year after therapy. The 20 infections consisted of 16 cases of sinusitis (six documented radiographically), three cases of penumonia (two documented radiographical!y), and one episode of acute otitis media; all four cases after therapy were episodes of clinical sinusitis in patient 5, in whom treatment with intravenous -r-globulin failed. Four of the five patients noticed significant diminution in their asthma symptoms and the number of asthma attacks after 7globulin therapy was begun. They wheezed less often and rarely needed emergency therapy by a physician. Orie patient (No. 4), Who improved after 1 year of intravenous 3,-globulin therapy, had a recurrence of asthma and sinopulmonary infections within 4 months after treatment was stopped. These symptoms resolved after intravenous -r-globulin was resumed. In patient 5, who failed to improve clinically with intravenous 3~-g!obulin, we reassessed trough immunoglobulins and functional antibodies 12 months after therapy. Initially treated with 100 mg/kg, his total IgG and IgG1 increased slightly to 347 and 256 mg/dL, respectively. His IgG2 (43 mg/dL) remained low; his IgG3, diphtheria, and tetanus titers reached normal values. Increasing his intravenous dose of 7-globulin to 300 mg/kg every 4 weeks for four doses increased his IgG to 759 mg/dL, but his sYmptoms continued.
130
Clinical and laboratory observations
DISCUSSION Chronic pulmonary diseases and recurrent sinopulmonary infections have been associated with low immunoglobulin levels not only in agammaglobulinemia5but in patients with IgG subclass deficiency1-3 and asthma, l~ Although 3,-globulin replacement therapy can decrease the incidence of recurrent infections in patients with IgG deficiency,4,5 no studies have documented an improvement in asthmatic symptoms after initiation of 3,-globulin. This group of asthmatic children with recurrent sinopulmonary infections and selective IgG subclass deficiencies demonstrated not 0nly a decrease in recurrent sinopulmonary symptoms, as previously reported by Rolfman et al., 5 but also a marked decrease in the severity of asthma and medication requirements. Pulmonary function tests that measured predominantly Small airway disease improved after 7globulin therapy. The one patient who did not improve has very severe, steroid-dependent asthma. He received 100 mg/kg of intravenous 3,-globulin every 4 weeks, a dose some authors believe is inadequate,5,11.12but increasing his dose to 300 mg/kg has not diminished his symptoms. Although spontaneous improvement in these patients' asthmatic symptoms unrelated to the 3,-globulin therapy cannot be completely ruled out, one patient developed a recurrence of sinopulmonary infections and exacerbation of her asthma 4 months after voluntarily stopping 7globulin therapy. When intravenous 3,-globulin therapy was resumed, the asthma improved. The possibility of a placebo-controlled study was considered, but it was considered inappropriate to withhold 7-globulin replacement therapy in patients with documented immunodeficiency. Some authors might criticize beginning 3,-globulin therapy in such patients, but others recommend a therapeutic trial of 3,-globulin for patients with asthma with recurrent sinopulmonary infections and IgG subclass deficiencies.H The mechanism for the improvement in these patients' asthma is not certain. Since asthma is considered an inflammatory disease of the airways,6,7 clinical or subclinical infection with respiratory pathogens, especially in those patients with concomitant immunodeficiency, could perpetuate this inflammation. Viral infections are frequently associated with asthma in children and may play a role in initiating airway inflammation?3,14 Providing passive immunity may be one way to reduce sinopulmonary infections and inflammation?5,16 Chronic sinusitis, which can cause asthma to become refractory to bronchodilator therapy, may be another significant factor. 17,18 Through transfer of passive immunity, reduction of bacterial and viral infections, or other mechanisms that improve host defenses, 7-globulin therapy reduces sinopulmonary infections and may thereby diminish bronchial hyperreactivity,
The Journal of Pediatrics January 1988
with subsequent improvement in asthma in patients with IgG subclass deficiency. Despite low IgG subclasses, two of the five patients had normal functional antibody titers. Some authors believe that patients with selective IgG subclass deficiencies but protective functional antibody titers should not receive 7-globulin replacement therapy, so we have considered randomizing such patients into a treatment and control study protocol to address this issue. We thank Jackie Suttner, Clinical Research Center Nurse Coordinator, Marsha Rueter and Michele Joos, Asthma and Allergic Disease Center nurses, and our laboratory technicians, Linda Gillen and Sharon Boehm. REFERENCES
1. Smith TF, Morris EC, Bain RP. IgG subclassesin nonallergic children with chronic chest symptoms. J PEDIATR 1984; 105:896. 2. Bjorkander J, Bake B, Oxelius V-A, Hanson LA. Impaired lung function in patients with IgA deficiencyand low levelsof igG2 or IgG3. N Engl J Med 1985;313:720. 3. Stanley PJ, Corbo G, Cole PJ. Serum IgG subclasses in chronic and recurrent respiratory infections. Clin Exp Immunol 1984;58:703. 4. Sehur PH, Borel H, Gelfand EW, Alper CA, Rosen FS. Selective -r-globulin deficiencies in patients with recurrent pyogenic infections. N Engl J Med 1970;283:631. 5. Rolfman CM, Lederman HM, Lavi S, Stein LD, Levison H, Gelfand EW. Benefit of intravenous IgG replacement in hypogammaglobulinemicpatients with chronic sinopulmonary disease. Am J Med 1985;79:171. 6. Kay AB, Lee TH, Durham SR, et al. Mediators of hypersensitivity and inflammatory cells in early- and late-phase asthmatic reactions. In: Kay AB, Austen KF, Lichtenstein LM, eds. Asthma: physiology. Immunopharmacology and treatment. Orlando, Florida: Academic Press, 1984:211. 7. Murphy KR, Irvin CG, Glezen LS, Marsh WR, Larsen GL. The effect of polymorphonuclear leukocyte depletion on the late asthmatic response and changes in airway reactivity [Abstract]. Am Rev Respir Dis 1985;131:A6. 8. Gardner R, et al. ATS statement-Snowbird workshop on standardization of spirometry. ARRD 1979;119:831. 9. Schoenberg JB, Beck GJ, Bouhuys A. Growth and decay of pulmonary function in healthy blacks and whites. Respir Physiol 1978;33:367. 10. Berger W, Pollock J, Kiechel F, Dunning M, Pearlman D. Immunoglobulin levels in children with chronic severe asthma. Ann Allergy 1978;41:67. 11. Smith TF. Immunodeficiencyin chronic pediatric respiratory illness. Hosp Pract [Off] 1986;21;143. 12. Pirofsky B. Intravenous immune globulin therapy in hypogammaglobulinemia.A review. Am J Med 1984;76:53. 13. Mclntosh K, Ellis EF, Hoffman LS, Lybass TG, Eller J J, Fulginiti VA. The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J PEDIATR1973;82:578. 14. Hudgel DW, Langston L, Selner JC, Mclntosh K. Viral and
Volume 112 Number 1
bacterial infections in adults with chronic asthma, Am Rev Respir Dis 1979;120:393. 15. Prince GA, Hemming VG, Chanock RM. The use of purified immunoglobulin in the therapy of respiratory syncytial virus infection. Pediatr Infect Dis 1986;5:$201. 16. Hemming VG, Prince G A. Intravenous immunoglobulin G in viral respiratory infections for newborns and infants. Pediatr Infect Dis 1986;5:$204.
Clinical and laboratory observations
13 !
17. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway disease in children. Pediatrics 1984;73:526. 18. Friedman R, Ackerman M, Wald E, Casselbrant M, Friday G, Fireman P. Asthma and bacterial sinusitis in children. J Allergy Clin Immunol 1984;74:185.
Comparison of two methods of rapid theophylline testing in clinical practice K a t h y N. S h a w , MD, G a r y R. Fleisher, MD, a n d J. S a n f o r d S c h w a r t z , MD From the Department of Pediatrics, Division of General Pediatrics, The Children's Hospital of Philadelphia; the Clinical Epidemiology Unit, Department of Medicine, Section of General Medicine, and the Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia; and the Department of Pediatrics, Division of Emergency Medicine, The Children's Hospital, Harvard Medical School, Boston
Rapid availability of serum theophylline levels may facilitate the management of acute asthmatic attacks in children, because standard treatment often involves intravenous administration of theophylline, a drug with a relatively narrow therapeutic window, potential toxicity, and a clearance that varies widely among individual patients. 1-3 However, serum theophylline values are often not available at a clinically useful time because of the long turnaround time required by conventional laboratory methods. Two rapid immunoassays, the Seralyzer reagent-strip test (Ames Division, Miles Diagnostics, Elkhart, Ind.) and the AccuLevel strip test (Syntex Medical Diagnostics, Palo Alto, Calif.), have shown close correlation to reference levels in controlled research trials, 49 but no similar evaluations have been reported in clinical situations. The purpose of this study was to assess and compare the clinical accuracy of these rapid assays in an emergency department setting.
Presented in a preliminary form at the 1987 Annual Meeting, The Ambulatory Pediatric Association, April 30, 1987, Anaheim, Calif. Submitted for publication May 11, 1987; accepted July 9, 1987. Reprint requests: Kathy N. Shaw, MD, Department of Emergency Medicine, The Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104.
METHODS
The study was conducted in the emergency department of The Children's Hospital of Philadelphia over a 3-month period during the hours of 3 to 11 P.M., when laboratory personnel were available to run the rapid theophylline assays. Venipuncture blood samples were obtained from all acutely wheezing children who reported taking theophylline and for whom a determination of serum theophylline levels had been ordered during their emergency department visit. Resident physicians estimated the serum theHPLC
High-pressure liquid chromatography
]
ophylline levels on the basis of the child's clinical history and physical examination findings before obtaining laboratory results. Three serum theophylline levels in each sample were determined by the hospital clinical laboratories with methods described in detail elsewhere: (1) highpressure liquid chromatography, 1~ (2) the Seralyzer dry reagent-strip immunoassay, 4 which uses serum and requires a spectrophotometer for reading, and (3) the AccuLevel test strip immunoassay, 5 which involves capillary migration that uses whole blood and does not require instrumentation. During the study period, all serum theophylline levels
Several reports document a selective IgG subclass deficiency in patients with chronic pulmonary disease. 13 Other authors have shown the benefit of IgG replacement in IgG subclass-deficient patients with chronic sinopulmonary infections. 4'5 Since asthma has been suggested to be an inflammatory airway disease,6,7 controlling bronchial inflammation initiated by recurrent or persistent infections may diminish the severity of asthma. We have evaluated the effect of IgG replacement therapy on the severity of asthma and infections in five patients with asthma, recurrent sinopulmonary infections, and concomitant IgG subclass deficiencies. METHODS Patient selection. Patients were followed either in Children's Hospital of Pittsburgh Asthma and Allergic Disease Center or referred by physicians in the Pittsburgh area. Human Right Committee approval for this clinical trial with an approved drug was not required; these patients had clinical indications for use of the medication, which was requested by the referring physicians or the family. Children with recurrent or chronic asthma triggered by repeated infections of the upper or lower respiratory tract were evaluated for immunologic competence from 1983 to 1986. Quantitative serum immunoglobulins were measured in all patients; if the total serum IgG concentration was low or if it was normal but a clinical concern about
Supported by National Institutes of Health Grant 2M01 RR00084, Clinical Associate Physician Award, and National Institutes of Health Grant R01 AI19262. Submitted for publication May 6, 1987; accepted July 10, 1987. Reprint requests: Philip Fireman, MD, Children's Hospital of Pittsburgh, 125 DeSoto St., Pittsburgh, PA 15213.
undue susceptibility to infection persisted, serum IgG subclasses and functional antibody titers to diphtheria, tetanus, 12 pneumococcal serotypes, and rubella were measured. Many patients also had influenza viral antibody measured. If these antibody titers were low, patients were immunized or reimmunized with the appropriate vaccine (except rubella vaccine), and antibody titers were measured 4 weeks later. Of approximately 500 patients evaluated for asthma exacerbated by recurrent sinopulmonary infections, we measured lgG subclasses and functional antibodies in approximately 75. Of these, five patients had a selective deficiency of IgG subclass l, 2, and/or 3 that was unrelated to possible transient hypogammaglobulinemia of infancy. IgG SD FEVa MMEFR MEF
Immunoglobulin G Standard deviation Forced expiratory volume in 1 second Maximum midexpiratory flow rate Mean expiratory flow
Patient population. All five patients fulfilled the American Thoracic Society definition of asthma. All patients required daily theophylline therapy, five used /3-agonists daily, three required cromolyn, and three were steroid dependent (two received prednisone on alternate days and one daily). All patients had intermittently received brief courses of prednisone for severe acute episodes of asthma. All patients had recurrent sinopulmonary infections requiring frequent antibiotic therapy; two had been unsuccessfully managed with prophylactic antibiotics before "y-globulin therapy. Three of the five patients had a history of allergic rhinitis confirmed by positive skin tests, but these allergens did not trigger the asthma. All three
127
1 28
Clinical and laboratory observations
The Journal of Pediatrics January 1988
Table. Summary of the laboratory results of the five study patients with IgG subclass deficiency Immunoglobulins
Functional antibodies
IgG subclasses
Age IgG IgA IgM IgG1 IgG2 IgG3 IgG4 Patient (yr) (mg/dl.) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) 1
1
2 3
14 19
4
5
13
17
375 405 (~) 300 (~)
389 (~)
299 (~)
41' <1 (~) 120
98
76
90
243 (~)
13 (~)
80 155
367 340 (~)
5 (~) 163
154
220
215 ($)
113 (~,)
212 (~)
45 (~)
13 29 15 (~,)
56
<5 (~)
3 0 (~) 13
42
8
Vaccines Diphtheria (IU/mL) Pneumococcal Diphtheria (IU/mL), tetanus IU/mL) Diphtheria (IU/mL), tetanus (IU/mL) Diphtheria (IU/mL), pneumococcal
PrePostvaccine vaccine ND
0.03
(~,) 0.03
(~)* 0.3
(~)
(~)*
ND
0.05
ND
0.5
0,001 (~)
0.01
($)
(~)*
ND, not done, IU, internationalunits. values >2 SD belowmean. *No increasein antibodyafter vaccine.
patients had received immunotherapy for their allergic rhinitis without diminution in the frequency of either sinopulmonary infections or asthma. Laboratory assays. IgG, IgA, and IgM were measured by nephelometry in the University of Pittsburgh Immunopathology Laboratory. Low values were defined as >2 SD below the arithmetic mean for age. IgG subclasses were measured by either radioimmunodiffusion at Brigham and Women's Hospital in Boston or by radioimmunoassay at Specialty Laboratories in Los Angeles. The former considered low IgG subclasses those >2 SD below the geometric mean; the latter were those in the bottom 5% of a normal group of children. Influenza titers were performed by hemagglutination-inhibition assay. Diphtheria titers were determined by radioimmunoassay, and tetanus and pneumococcal titers were determined by enzyme-linked immunosorbent assay. Low diphtheria and tetanus titers were >2 SD below the geometric mean; pneumococcal titers were compared with those of a normal population of adults with prevaccination titers. Pulmonary function testing was performed by spirometry. Patients repeated the tests until three acceptable efforts were obtained. 8 Using the best curve, percentage predicted was calculated with a formula that considered height, weight, age, race, and sex. 9 3,-Globulin therapy. After the diagnosis of IgG subclass deficiency was established, each patient initially received 200 to 400 mg/kg of intravenous -y-globulin as a loading dose. Subsequent doses were 100 to 300 mg/kg intravenously every 4 weeks.
Clinical evaluation To assess changes after 7-globulin therapy, we studied the following: (1) pulmonary function tests, (2) medication diary, (3) hospital admissions for status asthmaticus, (4) school attendance, and (5) clinical signs and symptoms of sinopulmonary infections. Sinusitis was defined as either positive sinus radiographs or purulent rhinorrhea associated with cough, fever, headache, or halitosis. Pulmonary infections were documented by either infiltrates on chest radiograph or rales, tachypnea, and cough. RESULTS
Laboratory values. As outlined in the Table, IgG subclass deficiencies were diagnosed in five patients with asthma as follows: Two patients had both IgG1 and IgG2 deficiency, and one each had one of the following deficiencies: IgG2, IgG4, and IgA; IgG1 and IgG3; and IgG1, IgG2, and IgG3. Four of five patients had low-total IgG values. Functional antibody deficiencies corresponding to their subclass deficiency were found in four of the five patients, whereas one patient had normal functional antibodies to diphtheria and tetanus despite a documented IgG subclass deficiency. Clinical course. The patients were examined on a regular basis for 2 to 18 months by one of the authors before intravenous 7-globulin therapy and 10 to 30 months after 7-globulin therapy was instituted. One patient developed mild bronchospasm during the initial infusion, which was treated with 0.3 mL 1:1000 epinephrine; she was free of
Volume 112 Number 1
Clinical and laboratory observations
12 9
n=4 160 140,
120 ~O
I00 o
80
0
o
60
o
4 0 84
O
~
T
I O
FEV= o=Pre
O
0
0 0
9
MMEFR
MEFzs
9 = Post
Figure. Pulmonary function values in the four patients older than 6 years of age. Pre (O) refers to the individual values before patients received 3,-globulin, and post (e) refers to these values 6 to 14 months after 7-globulin therapy was begun. Arithmetic mean is indicated by the bar. Pulmonary function assessments (FEV, MMEFR, and MEF25) are expressed as percentage predicted based on height, weight, age, sex, and race.
symptoms during subsequent infusions. Improvement was documented by the following: 1. Pulmonary function values. Of four patients who were more than 6 years of age, three had improved pulmonary function test results 6 to 14 months after 7-globulin therapy (Figure) was instituted. Whereas the average FEVI increased only marginally from 90% to 100% of the predicted value, the mean M M E F R increased from 51% to 82%, and the mean MEF25 doubled from 37% to 78%, of predicted values. 2. Hospital admissions. Two patients with four admissions for status asthmaticus in the year before therapy had none after intravenous 3,-globulin therapy. The patient who did not improve had eight admissions before and nine admissions in the year after therapy. 3. School absenteeism. The three patients regularly attending school missed a total of 20 school days before therapy; none missed any school days because of asthma after therapy was instituted. 4. Medication requirements. Four of the five patients required fewer drugs after -y-globulin therapy was begun. Two of five patients stopped theophylline, and three of five patients stopped daily use of beta-agonists. One of three patients discontinued daily inhaled steroids, and both patients discontinued use of alternate-day steroids, but the one patient with multiple hospitalizations kept taking daily prednisone therapy.
4. Signs and symptoms. The total number of sinopulmonary infections decreased by 80% from 20 in the year preceding 3,-globulin therapy to four the year after therapy. The 20 infections consisted of 16 cases of sinusitis (six documented radiographically), three cases of penumonia (two documented radiographical!y), and one episode of acute otitis media; all four cases after therapy were episodes of clinical sinusitis in patient 5, in whom treatment with intravenous -r-globulin failed. Four of the five patients noticed significant diminution in their asthma symptoms and the number of asthma attacks after 7globulin therapy was begun. They wheezed less often and rarely needed emergency therapy by a physician. Orie patient (No. 4), Who improved after 1 year of intravenous 3,-globulin therapy, had a recurrence of asthma and sinopulmonary infections within 4 months after treatment was stopped. These symptoms resolved after intravenous -r-globulin was resumed. In patient 5, who failed to improve clinically with intravenous 3~-g!obulin, we reassessed trough immunoglobulins and functional antibodies 12 months after therapy. Initially treated with 100 mg/kg, his total IgG and IgG1 increased slightly to 347 and 256 mg/dL, respectively. His IgG2 (43 mg/dL) remained low; his IgG3, diphtheria, and tetanus titers reached normal values. Increasing his intravenous dose of 7-globulin to 300 mg/kg every 4 weeks for four doses increased his IgG to 759 mg/dL, but his sYmptoms continued.
130
Clinical and laboratory observations
DISCUSSION Chronic pulmonary diseases and recurrent sinopulmonary infections have been associated with low immunoglobulin levels not only in agammaglobulinemia5but in patients with IgG subclass deficiency1-3 and asthma, l~ Although 3,-globulin replacement therapy can decrease the incidence of recurrent infections in patients with IgG deficiency,4,5 no studies have documented an improvement in asthmatic symptoms after initiation of 3,-globulin. This group of asthmatic children with recurrent sinopulmonary infections and selective IgG subclass deficiencies demonstrated not 0nly a decrease in recurrent sinopulmonary symptoms, as previously reported by Rolfman et al., 5 but also a marked decrease in the severity of asthma and medication requirements. Pulmonary function tests that measured predominantly Small airway disease improved after 7globulin therapy. The one patient who did not improve has very severe, steroid-dependent asthma. He received 100 mg/kg of intravenous 3,-globulin every 4 weeks, a dose some authors believe is inadequate,5,11.12but increasing his dose to 300 mg/kg has not diminished his symptoms. Although spontaneous improvement in these patients' asthmatic symptoms unrelated to the 3,-globulin therapy cannot be completely ruled out, one patient developed a recurrence of sinopulmonary infections and exacerbation of her asthma 4 months after voluntarily stopping 7globulin therapy. When intravenous 3,-globulin therapy was resumed, the asthma improved. The possibility of a placebo-controlled study was considered, but it was considered inappropriate to withhold 7-globulin replacement therapy in patients with documented immunodeficiency. Some authors might criticize beginning 3,-globulin therapy in such patients, but others recommend a therapeutic trial of 3,-globulin for patients with asthma with recurrent sinopulmonary infections and IgG subclass deficiencies.H The mechanism for the improvement in these patients' asthma is not certain. Since asthma is considered an inflammatory disease of the airways,6,7 clinical or subclinical infection with respiratory pathogens, especially in those patients with concomitant immunodeficiency, could perpetuate this inflammation. Viral infections are frequently associated with asthma in children and may play a role in initiating airway inflammation?3,14 Providing passive immunity may be one way to reduce sinopulmonary infections and inflammation?5,16 Chronic sinusitis, which can cause asthma to become refractory to bronchodilator therapy, may be another significant factor. 17,18 Through transfer of passive immunity, reduction of bacterial and viral infections, or other mechanisms that improve host defenses, 7-globulin therapy reduces sinopulmonary infections and may thereby diminish bronchial hyperreactivity,
The Journal of Pediatrics January 1988
with subsequent improvement in asthma in patients with IgG subclass deficiency. Despite low IgG subclasses, two of the five patients had normal functional antibody titers. Some authors believe that patients with selective IgG subclass deficiencies but protective functional antibody titers should not receive 7-globulin replacement therapy, so we have considered randomizing such patients into a treatment and control study protocol to address this issue. We thank Jackie Suttner, Clinical Research Center Nurse Coordinator, Marsha Rueter and Michele Joos, Asthma and Allergic Disease Center nurses, and our laboratory technicians, Linda Gillen and Sharon Boehm. REFERENCES
1. Smith TF, Morris EC, Bain RP. IgG subclassesin nonallergic children with chronic chest symptoms. J PEDIATR 1984; 105:896. 2. Bjorkander J, Bake B, Oxelius V-A, Hanson LA. Impaired lung function in patients with IgA deficiencyand low levelsof igG2 or IgG3. N Engl J Med 1985;313:720. 3. Stanley PJ, Corbo G, Cole PJ. Serum IgG subclasses in chronic and recurrent respiratory infections. Clin Exp Immunol 1984;58:703. 4. Sehur PH, Borel H, Gelfand EW, Alper CA, Rosen FS. Selective -r-globulin deficiencies in patients with recurrent pyogenic infections. N Engl J Med 1970;283:631. 5. Rolfman CM, Lederman HM, Lavi S, Stein LD, Levison H, Gelfand EW. Benefit of intravenous IgG replacement in hypogammaglobulinemicpatients with chronic sinopulmonary disease. Am J Med 1985;79:171. 6. Kay AB, Lee TH, Durham SR, et al. Mediators of hypersensitivity and inflammatory cells in early- and late-phase asthmatic reactions. In: Kay AB, Austen KF, Lichtenstein LM, eds. Asthma: physiology. Immunopharmacology and treatment. Orlando, Florida: Academic Press, 1984:211. 7. Murphy KR, Irvin CG, Glezen LS, Marsh WR, Larsen GL. The effect of polymorphonuclear leukocyte depletion on the late asthmatic response and changes in airway reactivity [Abstract]. Am Rev Respir Dis 1985;131:A6. 8. Gardner R, et al. ATS statement-Snowbird workshop on standardization of spirometry. ARRD 1979;119:831. 9. Schoenberg JB, Beck GJ, Bouhuys A. Growth and decay of pulmonary function in healthy blacks and whites. Respir Physiol 1978;33:367. 10. Berger W, Pollock J, Kiechel F, Dunning M, Pearlman D. Immunoglobulin levels in children with chronic severe asthma. Ann Allergy 1978;41:67. 11. Smith TF. Immunodeficiencyin chronic pediatric respiratory illness. Hosp Pract [Off] 1986;21;143. 12. Pirofsky B. Intravenous immune globulin therapy in hypogammaglobulinemia.A review. Am J Med 1984;76:53. 13. Mclntosh K, Ellis EF, Hoffman LS, Lybass TG, Eller J J, Fulginiti VA. The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J PEDIATR1973;82:578. 14. Hudgel DW, Langston L, Selner JC, Mclntosh K. Viral and
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bacterial infections in adults with chronic asthma, Am Rev Respir Dis 1979;120:393. 15. Prince GA, Hemming VG, Chanock RM. The use of purified immunoglobulin in the therapy of respiratory syncytial virus infection. Pediatr Infect Dis 1986;5:$201. 16. Hemming VG, Prince G A. Intravenous immunoglobulin G in viral respiratory infections for newborns and infants. Pediatr Infect Dis 1986;5:$204.
Clinical and laboratory observations
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17. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway disease in children. Pediatrics 1984;73:526. 18. Friedman R, Ackerman M, Wald E, Casselbrant M, Friday G, Fireman P. Asthma and bacterial sinusitis in children. J Allergy Clin Immunol 1984;74:185.
Comparison of two methods of rapid theophylline testing in clinical practice K a t h y N. S h a w , MD, G a r y R. Fleisher, MD, a n d J. S a n f o r d S c h w a r t z , MD From the Department of Pediatrics, Division of General Pediatrics, The Children's Hospital of Philadelphia; the Clinical Epidemiology Unit, Department of Medicine, Section of General Medicine, and the Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia; and the Department of Pediatrics, Division of Emergency Medicine, The Children's Hospital, Harvard Medical School, Boston
Rapid availability of serum theophylline levels may facilitate the management of acute asthmatic attacks in children, because standard treatment often involves intravenous administration of theophylline, a drug with a relatively narrow therapeutic window, potential toxicity, and a clearance that varies widely among individual patients. 1-3 However, serum theophylline values are often not available at a clinically useful time because of the long turnaround time required by conventional laboratory methods. Two rapid immunoassays, the Seralyzer reagent-strip test (Ames Division, Miles Diagnostics, Elkhart, Ind.) and the AccuLevel strip test (Syntex Medical Diagnostics, Palo Alto, Calif.), have shown close correlation to reference levels in controlled research trials, 49 but no similar evaluations have been reported in clinical situations. The purpose of this study was to assess and compare the clinical accuracy of these rapid assays in an emergency department setting.
Presented in a preliminary form at the 1987 Annual Meeting, The Ambulatory Pediatric Association, April 30, 1987, Anaheim, Calif. Submitted for publication May 11, 1987; accepted July 9, 1987. Reprint requests: Kathy N. Shaw, MD, Department of Emergency Medicine, The Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104.
METHODS
The study was conducted in the emergency department of The Children's Hospital of Philadelphia over a 3-month period during the hours of 3 to 11 P.M., when laboratory personnel were available to run the rapid theophylline assays. Venipuncture blood samples were obtained from all acutely wheezing children who reported taking theophylline and for whom a determination of serum theophylline levels had been ordered during their emergency department visit. Resident physicians estimated the serum theHPLC
High-pressure liquid chromatography
]
ophylline levels on the basis of the child's clinical history and physical examination findings before obtaining laboratory results. Three serum theophylline levels in each sample were determined by the hospital clinical laboratories with methods described in detail elsewhere: (1) highpressure liquid chromatography, 1~ (2) the Seralyzer dry reagent-strip immunoassay, 4 which uses serum and requires a spectrophotometer for reading, and (3) the AccuLevel test strip immunoassay, 5 which involves capillary migration that uses whole blood and does not require instrumentation. During the study period, all serum theophylline levels