Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: A retrospective survey of 31 patients

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Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: A retrospective survey of 31 patients

Pierre Quartier, MD, Marianne Debré, MD, Jacques De Blic, MD, Rodolphe de Sauverzac, MD, Natacha Sayegh, MD, Nada Jabado, MD, PhD, Elie Haddad, MD, Stéphane Blanche, MD, Jean-Laurent Casanova, MD, PhD, C. I. Edvard Smith, MD, PhD, Françoise Le Deist, MD, PhD, Geneviève de Saint Basile, MD, PhD, and Alain Fischer, MD, PhD Objective: To evaluate the outcome of children who received prolonged intravenous immunoglobulin (IVIg) replacement therapy early in life for Xlinked agammaglobulinemia (XLA). Study design: We performed a retrospective study of the clinical features and outcome of patients with genetic and/or immunologic results consistent with XLA. Patients receiving IVIg replacement therapy within 3 months of the diagnosis and for at least 4 years between 1982 and 1997 were included. Results: Thirty-one patients began receiving IVIg replacement therapy at a median age of 24 months and were followed up for a median time of 123 months. IVIg was given at doses >0.25 g/kg every 3 weeks, and mean individual residual IgG levels ranged from 500 to 1140 mg/dL (median, 700 mg/dL). During IVIg replacement, the incidence of bacterial infections requiring hospitalization fell from 0.40 to 0.06 per patient per year (P < .001). However, viral or unidentified infections still developed, including enteroviral meningoencephalitis (n = 3) causing death in one patient, exudative enteropathy (n = 3), and aseptic arthritis (n = 1). At last follow-up, 30 patients were alive at a median age of 144 months (range, 58 to 253 months). Among 23 patients who were evaluated by respiratory function tests and computed tomography, 3 had an obstructive syndrome, 6 had bronchiectasis, and 20 had chronic sinusitis. Conclusion: Early IVIg replacement therapy achieving residual IgG levels >500 mg/dL is effective in preventing severe acute bacterial infections and pulmonary insufficiency. More intensive therapy may be required to fully prevent the onset of bronchiectasis, chronic sinusitis, and nonbacterial infections, particularly enteroviral infections, in all cases. (J Pediatr 1999;134:589-96)

From the Pediatric Immunology and Hematology Unit and Institut National de la Santé et de la Recherche Médicale U429, Pediatric Pneumology Unit, Department of Pediatrics, Department of Oto-rhino-laryngology, and Department of Radiology of Hôpital Necker-Enfants Malades, Paris, France; and Center for BioTechnology, Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.

Submitted for publication Aug 25, 1998; revision received Jan 8, 1999; accepted Feb 23, 1999. Reprint requests: Pierre Quartier, MD, Unité d’Immuno-hématologie Pédiatrique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/98206

X-linked agammaglobulinemia, first described by Bruton,1 is characterized by a block in B-cell development at the pre-B-cell stage, typically resulting in See related article, p. 584. markedly decreased levels or absence of both mature B cells and immunoglobulin production in affected male subjects. T-cell and myeloid functions are intrinsically normal, although neutropenia has been described under conditions of stress.2,3 The gene encoding the cytoplasmic Bruton tyrosine kinase is defective in XLA.4,5 Mutations of the BTK gene have also been reported in male subjects with milder clinical forms and incomplete B-cell defects.6-11 In female XLA carriers, B cells display a skewed inactivation of the mutated X chromosome.12-14 BTK BTK CT IVIg SSCP XLA

Bruton tyrosine kinase (protein) Bruton tyrosine kinase (gene) Computed tomography Intravenous polyvalent immunoglobulin Single-strand conformational polymorphism X-linked agammaglobulinemia

Before the era of immunoglobulin replacement therapy, patients with XLA had early-onset, severe, and recurrent infections, mainly caused by encapsulated bacteria.2,3,11 Initially, replacement with intramuscular immunoglobulins 589

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was attempted, which led to improvements in clinical status. However, acute infections persisted and chronic infections developed, particularly chronic sinusitis and bronchitis leading to bronchiectasis and eventually to cor pulmonale.2 A number of patients also had severe enteroviral infections, particularly meningoencephalitis.2,3,11,15-19 Death frequently ensued before the age of 25 years.2 In the early 1980s, replacement with intravenous immunoglobulins was introduced. The incidence of bacterial and nonbacterial infections was significantly reduced when residual serum IgG levels were maintained over 500 mg/dL14,15,20,21; this approach therefore became standard therapy. Similar data were reported for patients with XLA who received replacement therapy with subcutaneous immunoglobulins.22,23 The most striking results were observed when IVIg replacement was initiated early in life.11,15,20 We report a retrospective study of the course of XLA in patients diagnosed and/or investigated at a single pediatric center and treated with IVIg within 3 months of diagnosis to maintain residual serum IgG levels above 500 mg/dL. Patients were followed up for a minimum of 4 years. We describe their long-term outcome.

PATIENTS AND METHODS Inclusion Criteria The inclusion criteria were: (1) diagnosis of XLA by genetic investigations (detection of BTK mutations and linkage analysis if relatives had been documented as cases) or B-cell–specific primary immunodeficiency defined as mature B-cell (surface Ig+, CD19+) counts below 1% of circulating blood lymphocytes, profoundly reduced levels of serum IgG, IgA, IgM, and normal Tcell counts and function as assessed by in vitro mitogen- and antigen-induced proliferation assays; (2) IVIg replacement initiated within 3 months of diagnosis and administered for at least 48 months. 590

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Collection of Data Records of patients referred to the Pediatric Immunology and Hematology Unit of Necker-Enfants Malades Hospital (Paris) between 1982, when intact IVIg preparations became available, and 1993 were retrospectively studied. In addition, a questionnaire was sent to physicians at other centers administering IVIg replacement therapy to the patients. We tried to collect at least one residual serum IgG titer per trimester of IVIg replacement for each patient. Residual IgG levels were measured at the beginning of an IVIg infusion. When several residual IgG levels were available for the same trimester for a patient, only the lowest value was considered. Only infections requiring hospitalization were included in the analysis of the incidence of severe infections. At last follow-up, between April and December 1997, pulmonary function tests (spirometry and flow-volume curves) and computed tomography of the thorax and the sinuses were performed. Also, the patients themselves or their parents were requested by mail to answer simple questions regarding the consequences of the disease and its treatment on physical status, quality of life, and school attendance.

Statistical Analysis The number of infections requiring hospitalization were adjusted according to the period at risk before or after IVIg treatment. A paired t test was used for comparisons.

Immunologic Tests Serum IgG, IgA, and IgM levels were quantified by nephelometry. Circulating B cells were counted by detection of membrane-bound IgM and by immunofluorescence labeling by monoclonal antibodies to B-cell antigens (CD19, CD20; Immunotech, France). T-cell and T-cell subpopulation counts were determined by using immunofluorescent monoclonal antibodies to CD3, CD4, and CD8. Normal T-cell

functions were assessed by using mitogen-induced (phytohemagglutinin) and antigen-induced (Candida, tetanus toxoid) T-cell proliferation assays in vitro.24

BTK Gene and Linkage Analysis BTK gene mutations were identified by single-strand conformational polymorphism analysis, followed by sequencing as previously described.25 Patients with negative SSCP results were tested for BTK protein by Western blot analysis. Linkage analysis was performed by using closely linked microsatellites.26

Therapeutic Features Treatment factors analyzed included age at initiation of IVIg therapy, immunoglobulin doses as a function of weight, residual serum IgG levels, adverse effects, and associated treatments such as antibiotics, chest physiotherapy, and surgery.

RESULTS Patients’ Characteristics at Initiation of IVIg Replacement Thirty-one patients from 23 unrelated kindreds fulfilled the inclusion criteria (Table I). Five patients were either not studied for BTK mutations or had no mutation of BTK identified. These patients may therefore have agammaglobulinemia that is not due to a BTK mutation, as previously described.27-29 Five children received a diagnosis of XLA before the appearance of any clinical symptoms because of family history. In the 26 other patients, infections requiring hospitalization developed (Table II) at a median age of 7 months (range, 1 to 30 months). At the onset of IVIg replacement therapy, bronchiectasis was clearly documented in only 2 patients, but recurrent bronchitis had developed in 15 other patients. Chronic sinusitis was documented by radiography in 4 children, and 21 others had recurrent ear-nose-throat infections. Four chil-

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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 5 Table I. Characteristics of the patients at diagnosis and duration of IVIg replacement therapy

Patient No.

Age (mo)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Median

10 16 31 87 56 44 28 45 4 23 111 111 18 5 13 35 11 13 5 56 56 9 18 44 28 19 33 13 2 14 7 19

Family history

BTK gene mutation

0 0 + + + 0 + Brother of 19 + 0 Twin of 12 Twin of 11 Brother of 14 Brother of 13 Brother of 16 Brother of 15 Cousin of 26 + Brother of 8 Twin of 21 Twin of 20 + Half brother of 29 0 + Cousin of 17 0 0 Half brother of 23 0 0

Not found* Exon 10† ND Not found* ND R288W R288W R525X R641H G594R R562W R562W 1242ins-T 1242ins-T V561D V561D 1429N In15 + lg→t R525X E59ins-T E59ins-T G313del-G G54del-G In6 - 2a→c ND‡ 1429N E277X Not found* G54del-G L369F N526K

Serum Ig levels (mg/dL) IgG IgA IgM 52 10 46 50 126 3 59 49 120 100 ND 46 0 118 45 233 ND 10 69 0 0 0 0 0 22 12 0 0 0 10 39

0 7 13 1 50 7 44 38 50 10 0 0 0 0 4 1 11 0 0 0 0 0 0 0 0 7 0 0 0 0 4

0 0 18 2 44 8 7 44 50 30 0 0 0 49 188 50 17 28 42 16 0 44 22 0 25 14 0 15 0 28 12

B cells (%)

Duration of IVIg therapy (mo)

1 0 0 0 0 0 0 0 0 0 0 0 1 0 <1 <1 0 0 0 0 0 0 0 <1 0 0 0,1 1 0 0 1 Median

186 180 179 166 158 166 159 158 135 123 135 135 126 135 137 123 107 112 122 116 116 107 76 83 80 82 68 49 56 55 60 123

For Patients 4 and 25, Western blot analysis showed the absence of BTK protein. For patients 1 and 3, Western blot analysis for the presence of BTK protein is ongoing. ND, Not documented (in the case of serum IgG because of previous intramuscular Ig replacement therapy); X, stop codon; ins, insertion; del, deletion; In, intronic mutation. *No BTK mutation found by SSCP. †BTK mutation mapped to exon 10 by SSCP but not further characterized. ‡XLA diagnosis by linkage analysis.

dren failed to thrive (height and weight <2 SD). Three children presented with mild impairment of neurocognitive development of unknown origin.

Characteristics of IVIg Replacement There were 3690 cumulated months of IVIg therapy. Twenty-four patients

received replacement therapy predominantly with IVIg preparations from the “Etablissements de Transfusion Français,” renamed “Laboratoire Français du Fractionnement et des Biotechnologies” (Les Ulis) in 1994. The other preparations used were Sandoglobulin (Novartis Institute, Basel) and Endobulin (Immuno France, Mar-

seilles). IVIg replacement therapy was systematically administered every 3 weeks or more frequently in all but 3 patients. In these 3 patients, IVIg therapy was administered every 4 weeks for 10, 15, and 15 months, respectively; but residual serum IgG levels fell below 500 mg/dL, and infections requiring hospitalization developed. 591

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Table II. Infections requiring hospitalization before and during IVIg replacement therapy

Before IVIg

During IVIg

No. of infections/patients

Annual infection incidence*

No. of infections/patients

Annual infection incidence*

21:15 3:3 3:3 1:1 1:1 2:2 32:17

0.261 0.037 0.037 0.012 0.012 0.025 0.398

15:9 1:1 0 0 0 2:1 18:9

0.049 0.003

1:1 0‡ 1:1 7:7 9:9 41:19

0.012

0 3:3 3:3 1:1 6:6 25:11

Bacterial infections Pneumonia Septicemia Meningitis Arthritis Osteomyelitis Dermatitis, cellulitis Total bacterial infections Nonbacterial infections Myocarditis Meningoencephalitis Exudative enteropathy§ Aseptic arthritis Total nonbacterial infections Total (all events)

0.012 0.087 0.112 0.510

0.007 0.059†

0.010 0.010 0.003 0.020 0.083

*Number of infections/number of years accumulated by the 31 patients before or during IVIg therapy. †P < .001; ‡Two patients may have had the enteroviral infection before IVIg therapy (see text). §Exudative enteropathy was defined as the association of diarrhea, increased alpha-1 antitrypsin clearance, and requirement for IVIg replacement therapy to be administered more frequently than every 2 weeks to maintain serum residual IgG levels at above 500 mg/dL.

These patients received treatment every 3 weeks during the rest of the study period. The median and mean IVIg doses administered to the 31 patients during the study were 380 and 390 mg/kg every 3 weeks, respectively. The mean individual IVIg doses varied from 260 to 1120 mg/kg every 3 weeks. During IVIg therapy, at least one residual serum IgG level per trimester was available for 995 of the 1230 cumulated trimesters studied (Table III). Residual serum IgG levels were above 500 mg/dL for 824 trimesters and above 800 mg/dL for 240. Thirteen patients received more than 4 trimesters of replacement therapy with residual serum IgG levels under 500 mg/dL. From the onset of IVIg replacement therapy to the last follow-up, the mean individual residual IgG levels were between 500 and 1140 mg/dL (mean, 609 mg/dL and median, 700 mg/dL for the whole population). Mild adverse reactions to IVIg replacement therapy were documented in 8 patients. 592

Infections During IVIg Replacement Therapy

Incidence of Infections Relative to Clinical Status at Diagnosis

Infections requiring hospitalization before and during IVIg replacement therapy are reported in Table II. The overall incidence of acute bacterial infection was significantly lower after routine IVIg therapy had been initiated than before (0.06 and 0.40 per patient per year, respectively, P < .001). Enteroviral meningoencephalitis was diagnosed in 3 patients during IVIg replacement therapy by specific polymerase chain reaction assay on cerebrospinal fluid (2 cases) or on a cerebral biopsy sample (1 case); viral cultures were negative. Two of these 3 patients had unexplained impairment of neurocognitive development and neutropenia before diagnosis and treatment of XLA. One also had unexplained myocarditis at the age of 3 months. Their symptoms may have been caused by enteroviral infection before initiation of IVIg therapy.

Among the 5 patients treated with IVIg at young ages (between 2 and 7 months) before any complications occurred, only one subsequently had infections requiring hospitalization after the first 3 months of IVIg replacement therapy. However, the annual incidence of infections requiring hospitalization after the first 3 months of IVIg therapy was not significantly lower in these 5 patients than in the 26 others (0.05 and 0.06, respectively). During IVIg replacement therapy, 8 of the 15 episodes of pneumonia requiring hospitalization occurred in patients with preexisting bronchiectasis. Bronchiectasis was documented only after IVIg replacement therapy was initiated in 4 patients, and 3 of them had no history of recurrent bronchitis before the diagnosis of XLA. Both patients who had bacterial infections outside the lungs had additional predisposing fac-

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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 5

Table III. Annual incidence of bacterial infections requiring hospitalization during IVIg replacement therapy relative to residual serum IgG levels

Residual serum IgG levels*

Not documented <500 mg/dL

Cumulative trimesters of replacement therapy Annual incidence of bacterial infections Pneumonia Septicemia Dermatitis, cellulitis

235 0.05 0.05 0.00 0.00

171 0.16 0.12 0.02 0.02

500-800 mg/dL

>800 mg/dL

Total

584 0.05 0.05 0.00 0.01

240 0.00† 0.00† 0.00 0.00

1230 0.06 0.05 0.00 0.01

*At least one residual serum IgG value was collected for each trimester of IVIg therapy, and in cases for which several levels were available, only the lowest was considered. †Annual incidence significantly lower than for the periods when residual serum IgG levels were between 500 and 800 mg/dL (P < .001) or under 500 mg/dL (P < .001).

tors (ie, persistent neutropenia and presence of a central venous catheter, respectively).

Incidence of Infections Relative to Residual Serum IgG Levels (Table III) The median serum IgG level at the onset of infection was 550 mg/dL (range, 130 mg/dL, in 1 patient who received IVIg replacement for only 2 months, to 710 mg/dL; with residual IgG levels between 400 and 500 mg/dL in 5 cases, between 500 and 600 mg/dL in 8, and not documented in 3). The annual incidence of bacterial infections requiring hospitalization was significantly lower for the periods when patients had residual IgG levels >800 mg/dL than for the periods when IgG levels were between 500 and 800 mg/dL or <500 mg/dL (P < .001). There were 212 trimesters of replacement therapy with residual IgG levels between 800 and 1000 mg/dL and only 28 trimesters with levels >1000 mg/dL. Nonbacterial infections including meningoencephalitis, exudative enteropathy, and aseptic arthritis were diagnosed in 7 patients during IVIg replacement therapy. The residual serum IgG level before diagnosis was <500 mg/dL in 4 patients, between 500 and 800 mg/dL in 2, and >800 mg/dL in 1 patient. However, these infections may have developed months before they were diagnosed because they were all subacute or chronic.

Outcome of Infections Relative to Residual Serum IgG Levels In the 8 patients who had aseptic arthritis before IVIg replacement (7 cases) or shortly thereafter (1 case), there were recurrences if residual serum IgG levels were between 500 and 800 mg/dL. Higher-dose IVIg was given to these patients for 16 to 125 months (median, 95 months) to attain residual IgG levels >800 mg/dL. This was associated with improvement in clinical symptoms. In 3 patients who had enteroviral meningoencephalitis, IVIg was administered at doses of 0.4 g/kg every 48 hours to 1 g/kg per day for 3 to 12 months. Residual IgG values consequently increased to 3100 to 6300 mg/dL. The specific serotype of the infecting enterovirus was not determined in our patients, so it was not possible to select IVIg with high titers of neutralizing antibody. In 2 patients, clinical symptoms and cerebrospinal fluid abnormalities resolved; both patients are alive and well with a follow-up of 15 and 78 months, respectively. The third patient died despite intraventricular infusion of immunoglobulins through an Omaya reservoir.

Additional Treatments and Patient Outcome Surgical treatment (meatotomy and infundibulectomy) of symptomatic chronic sinusitis was performed in 5 patients and resulted in clinical im-

provement that lasted for 6 to 18 months. Pulmonary lobectomy was performed shortly after diagnosis of XLA in one child with localized bronchiectasis. He remained free of bronchitis and pneumonia during the following 10 years. The effect of prophylactic antibiotics and daily chest physiotherapy, in combination with intensification of IVIg replacement, was assessed for 6 patients who had previously experienced recurrent bronchitis and bronchiectasis. Lesions did not progress as assessed by CT during the following 24 to 96 months. In 3 patients, pulmonary function tests showed evidence of obstruction, which resolved within 24 to 96 months.

Status of the Patients at Last Follow-up At last follow-up, 30 of the 31 patients were alive (Table IV). Of the 6 patients with diffuse or localized bronchiectasis, 2 had documented lesions before diagnosis of XLA and 1 patient presented with recurrent bronchitis. Three patients may have had bronchiectasis after IVIg therapy was initiated because they had no history of recurrent bronchitis at the onset of IVIg replacement therapy. Among 20 patients with documented chronic sinusitis at last follow-up, 17 had experienced recurrent ear-nose-throat infections before initiation of IVIg therapy. School performance was good in all cases, except for 2 patients whose neu593

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Table IV. Status of the 30 patients alive at last follow-up

General features Age (mo) Duration of IVIg therapy (mo) Height (SDs) Weight (SDs) Bronchopulmonary status and pulmonary function Recurrent bronchitis (>3/y) or daily cough CT scan Disseminated bronchiectasis Localized (1 lobe) bronchiectasis Absence of bronchiectasis Not done Pulmonary function tests Obstructive syndrome* Normal Not done Chronic sinusitis Clinical symptoms† CT scan Chronic sinusitis Absence of lesions Not done

58-253 (median, 144) 55-186 (median, 123) –1 to +3 (median, +0.5) –2 to +3 (median, +1.5) n = 15 n=3 n=3 n = 17 n=7 n=3 n = 20 n=7 n = 21 n = 20 n=3 n=7

*Obstructive syndrome is defined as forced expiratory volume in 1 second/forced vital capacity <80% of the theoretical value.30 †Presence of 2 of the 3 major clinical signs: rhinorrhea, postnasal drip, and cough for at least 3 months.31

rocognitive development was impaired before the diagnosis of XLA was made. According to the questionnaire filled in by 21 patients or their parents, it appears that physical activity was slightly limited in 2 cases, school attendance was not affected, and IVIg therapy was well accepted. In addition to IVIg therapy, 16 patients were receiving daily oral prophylactic antibiotic therapy for chronic bronchitis or sinusitis, 2 had sequential courses of intravenous antibiotics, and 7 had daily chest physiotherapy.

DISCUSSION In 31 children with genetic or immunologic results or both that were consistent with XLA, IVIg replacement therapy initiated within 3 months of diagnosis yielding residual serum IgG levels over 500 mg/dL was effec594

tive in preventing acute bacterial infections, diffuse bronchiectasis, and pulmonary insufficiency. However, most patients had chronic sinusitis, and a few had serious nonbacterial infections, including life-threatening enteroviral meningoencephalitis. The observation of a marked decrease in the incidence of infections, particularly bacterial infections, requiring hospitalization once IVIg therapy was initiated, confirms previously reported results.15,20,21 The incidence we report (0.08/patient/year) is similar to that reported by Skull et al20 (0.11/patient/year) in 18 Australian patients, 10 with XLA and 8 with other humoral immunodeficiencies who began receiving, at a median age of 13 months, IVIg therapy at doses over 0.25 g/kg every 3 weeks. The incidence of pneumonia in our patients (0.05/patient/year) was similar to that in the study by Skull et al20 and to that of 8

German patients with XLA described by Liese et al15 who were given IVIg doses of over 0.35 g/kg every 3 weeks before the age of 5 years. The occurrence of severe enteroviral infections despite IVIg replacement in our series is in accordance with previous reports.11,16 It suggests that IVIg therapy achieving residual serum IgG levels above 500 mg/dL before the age of 5 years does not prevent such complications.15 However, it is possible that the enterovirus infections occurred before the onset of IVIg replacement therapy in these patients. Indeed, 2 of our patients had already experienced clinical symptoms and neutropenia, which may have been due to early enteroviral infection. It is still not entirely clear whether IVIg replacement ensures favorable long-term outcome in patients with XLA. In our series IVIg was well tolerated, enabled most children to reach adolescence with normal physical development and school attendance, and was highly effective in preventing chronic obstructive respiratory syndrome, as other authors have reported.21 On the other hand, IVIg therapy generally failed to prevent chronic bronchitis and sinusitis as indicated by the high prevalence of clinical symptoms and lesions revealed by sensitive radiologic methods. More intensive replacement therapy, achieving residual serum IgG levels above 800 mg/dL, may improve functional outcome. Severe bacterial and nonbacterial infections, including life-threatening enteroviral meningoencephalitis, can occur when residual IgG levels are between 500 and 800 mg/dL, as indicated in this study and others.11,16 This and the absence of bacterial infections requiring hospitalization while patients had residual serum IgG levels over 800 mg/dL strongly encourages more intensive replacement therapy. To prevent enteroviral infections, early diagnosis and prompt treatment are necessary; the higher the residual IgG level, the better are the chances of

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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 5 maintaining an antibody level that protects against enteroviruses. In addition, higher residual IgG levels might ensure a more efficient prevention of the recurrent infections that lead to chronic inflammatory lesions because the incidence of bronchitis and sinusitis has been shown by various authors to correlate inversely with IVIg doses and residual IgG levels.15,21 Also, the favorable outcome of nonbacterial infections is dependent on residual IgG level being high, as demonstrated in this study and others.11,17,21,32 A wider use of ancillary treatments should also be investigated. Indeed, the high prevalence of chronic sinusitis in our series, similar to that reported in patients with XLA treated with intramuscular immunoglobulin2,3 shows that the sinus cavities have poor access to IVIg. In addition, intensive chest physiotherapy and antibiotics have been shown to decrease the incidence of infections33 and to improve pulmonary function in cases of chronic sinusitis and bronchiectasis.21 In patients with chronic sinusitis, medical treatments generally are ineffective.34 Surgical procedures such as meatotomy and infundibulectomy should be considered, although their clinical effect may only be transient. In conclusion, further follow-up of the patients reported and prospective analysis of the clinical course of future patients with XLA should provide more information about the ability of optimized prophylactic treatment, including more intensive immunoglobulin replacement, to ensure long-term survival without major complications. Particular attention to adherence to treatment and effect on quality of life will also be required. We thank Dr P. Landais, Service d’Informatique et de Statistiques Médicales, Hôpital Necker-Enfants Malades, for statistical analysis, and Dr J Peake, INSERM U429, Hôpital Necker-Enfants Malades, for critical reading. We are grateful to the following physicians who provided data about the patients: Drs A. Bazin and T. Martin, Centre Hospitalier Louis Pasteur, Cherbourg; Dr B. Blanchard,

Centre Hospitalier Général, Longjumeau; Dr G. Blondin, Centre Hospitalier de Cornouaille, Quimper; Dr R. Carbajal, Centre Hospitalier Général, Poissy; Dr P. de Lumey, Centre Hospitalier Universitaire, Limoges; Dr G. de Schrevel, Centre Hospitalier Universitaire, Caen; Dr J.-P. Drain, Centre Hospitalier, Valenciennes; Drs J. Furioli and Ch. Tcherkes, Centre Hospitalier Général, Mantes la Jolie; Dr O. Hermine, Hôpital Necker-Enfants Malades, Paris; Dr B. Kiffer, Centre Hospitalier Régional Notre Dame du Bon Secours, Metz; Dr F. Kirch, Hôpital de Freyming-Merlebach, Freyming-Merlebach; Dr M. Morin, Hôpital Monod, Flers; Dr B. Ntuyahaga, Centre Hospitalier Victor Dupouy, Argenteuil; Drs D. Quillerou and M. Jullien, Centre Hospitalier, Troyes; Drs D. Roybet and H. Taramasco, Centre Hospitalier Intercommunal de ToulonLa Seine sur Mer, Toulon; Dr H. Rubie, Centre Hospitalier Universitaire Purpan, Toulouse; Dr J. Rudler, Centre Hospitalier Général, Chateauroux; Drs C. Saint Aimé and A. Ponsar, Centre Hospitalier Universitaire, Fort de France; and Dr J.-P. Vannier, Centre Hospitalier Régional Universitaire, Rouen.

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