0
Clinical Investigations: IMMUNOLOGY |

Pulmonary Interstitial Disease in Ig Deficiency* FREE TO VIEW

Valentin Popa, MD, FCCP; Thomas V. Colby, MD, FCCP; Stanley B. Reich, MD
Author and Funding Information

*From the Department of Medicine (Dr. Popa), Methodist Hospital, Sacramento, and University of California at Davis, Davis, CA; the Department of Pathology (Dr. Colby), Mayo Clinic Scottsdale, Scottsdale, AZ; and Department of Radiology (Dr. Reich), Oakland Veterans Administration Medical Center, University of California at Davis, Davis, CA.

Correspondence to: Valentin Popa, MD, 8100 Timberlake Way, Sacramento, CA 95823



Chest. 2002;122(5):1594-1603. doi:10.1378/chest.122.5.1594
Text Size: A A A
Published online

Study objectives: To determine the frequency and type of interstitial lung disease (ILD) in consecutive subjects with symptomatic Ig deficiency.

Patients: One hundred forty-eight consecutive subjects with repeated respiratory infections and Ig deficiency.

Measurements: Ig classes and IgG subclasses (IgGSCs), the response to vaccination, pulmonary function tests, chest radiography, CT scan, Ga scan and, when possible, BAL and lung biopsy.

Results: Twenty-nine of 148 subjects (19 men and 10 women aged 18 to 72 years) had evidence of ILD. In 20 subjects, no cause of ILD was apparent. The remaining nine cases were ostensibly due to identifiable causes. Twenty subjects had IgGSC deficiency, 8 subjects had common variable immunodeficiency, and 1 subject had combined IgM plus IgGSC deficiency. No isotype deficiency was consistently related to a specific ILD. After administration of IV Ig, eight subjects, all with IgGSC deficiency, improved clinically, physiologically, radiologically, and occasionally histologically, regardless of immunologic or radiologic features. In this selective sample, the prevalence of ILD in consecutive subjects with recurrent respiratory infections and Ig deficiency (29 of 148 subjects; 19.6%) was higher than in the general population (0.8%; p < 0.05).

Conclusions: ILD in Ig deficiency is frequent and usually involves IgGSC deficiency.

Figures in this Article

Ig deficiencies comprise a diverse group of clinical entities that include common variable immunodeficiency (CVID), selective IgG subclass (IgGSC) deficiency, IgA or IgM deficiency, X-linked agammaglobulinemia, and other rare conditions. The diagnosis relies on laboratory demonstration of decreased serum Ig(s) and a poor response to vaccination mediated via IgG1 and/or IgG2 in a patient with manifestations consistent with Ig deficiency.12

The most common clinical manifestations of antibody deficiency syndromes are repeated and prolonged infections usually involving the respiratory system. Thus, rhinosinusitis, bronchitis, asthma, bronchiectasis, and pneumonia are all well recognized. Patients with Ig deficiencies may also have radiologic3and/or functional4evidence of interstitial lung disease (ILD), but their frequency and type are incompletely appreciated. Several histologic patterns have been reported in the lungs of patients with CVID, including lymphocytic interstitial pneumonitis (LIP),56 granulomatous interstitial pneumonitis,79 bronchiolitis obliterans organizing pneumonia (BOOP),10and usual interstitial pneumonitis (UIP).11 For the most part, these descriptions come from small series or individual case reports1011 that are difficult to interpret. Indeed, in individual patients, the link between Ig deficiency and repeated infections is usually argued by measuring the response to vaccination. However, the relevance of this immune deficiency for ILD calls for statistical analysis and/or IV Ig treatment since no diagnostic test can suggest this relationship.

In studying recurrent respiratory infections and Ig deficiency,1213 one of us (V.P.) was impressed by the frequency of radiologic3and/or functional4 evidence of ILD. This is not a unique experience. Some authors have found a restrictive ventilatory abnormality in 20 to 30% of adults with CVID.14In Ig deficiencies other than IgGSC deficiency,1519 several authors have reported many CT scan abnormalities of the large bronchi (bronchial wall thickening, bronchiectasis), small bronchi, alveoli (bullae, segmental or lobar collapse due to small airways obstruction), and interstitium. The interstitial changes were usually listed descriptively and included scattered nodules; septal and nonseptal lines; ground-glass consolidation, presumably a lesion involving both the alveolar lumen and wall18; and occasionally honeycombing.19 Their asymmetrical localization and frequent association with bronchiectasis suggest a relation with previous infections and, for lack of a better term, we will call these lesions seen on CT scan, chronic postinfectious pneumonitis. These complex changes are much more frequent than the diffuse ILD mentioned above.

Herein we report a consecutive series of patients initially seen because of symptomatic primary Ig deficiency who also had radiologic evidence of ILD3or BAL with physiologic findings4 consistent with ILD.

Materials

The subjects included in this study were observed consecutively by V.P. either at the Veterans Administration Sacramento outpatient clinic (from 1984 to 1987) or, subsequently, in his practice of pulmonary, allergy, and internal medicine (from 1987 to 1999).

Selection Criteria

From 1984 to 1999, all subjects who had recurrent respiratory infections (see below), underwent a workup for Ig deficiency along with pulmonary function tests and lung imaging. Included in this series were all cases with radiologic evidence of ILD or, in its absence, with BAL and physiologic findings consistent with ILD. These findings had to be stationary or progressive over 1 month and unexplained by evolving infections or hemodynamic or lymphangitic processes.20 Since adults with CVID or IgGSC deficiency usually have bronchial respiratory infections,1214,21 the concomitant presence of asthma, bronchitis, or bronchiectasis associated with an obstructive abnormality on physiologic testing did not constitute grounds for exclusion.

Methods

Recurrent respiratory infections were defined arbitrarily as five upper or lower respiratory catarrhal manifestations other than pneumonia occurring five times per year in the past 2 years and lasting each time at least 2 weeks; pneumonia was considered recurrent if it occurred once a year in the past 2 years.1213,21This frequency represents two to three times the number of average episodes of bronchitis, sinusitis, or otitis, and five times the average number of pneumonia cases encountered in healthy blood donors.22 The respiratory infections that did not fulfill the criteria for recurrence were considered to be occasional. Asthma, chronic bronchitis, bronchiectasis, and restrictive and obstructive ventilatory abnormalities4 were diagnosed according to current criteria.

Studies
Lung Imaging:

These studies included chest radiography, CT scan of the lung (with thin sections after 1990), and Ga scan. The radiologic diagnosis of ILD was based on the presence of nodules, lines, honeycombing, and ground-glass opacity on the chest radiograph and the following abnormalities on CT scan of the chest: nodules (including centrilobular nodules), lines (thickened septa, intralobular, curvilinear, and parenchymal bands), cysts (including honeycombing), parenchymal opacification (ground-glass attenuation and consolidation), decreased lung attenuation, and mosaic pattern.3 The CT scans were interpreted by S.B.R.

Pulmonary Function Tests:

We measured flow-volume curves, static lung volumes by He dilution, and diffusing capacity of the lung for carbon monoxide (Dlco) with the single-breath method as indicated by Morris et al,4 and arterial blood gases.23 The data of Morris et al4 were used to determine the eventual type of functional abnormality. In the absence of ILD by chest imaging, restrictive impairment of ventilation4 was considered suggestive of ILD if associated with abnormal findings on BAL.

Ig:

These studies included circulating total IgA, IgG, IgM by nephelometric method, total IgE by radioimmunoassay, and IgGSCs by radial immunodiffusion using either the commercial Immunology Laboratory of Peter Bent Brigham Hospital (from 1984 to 1987) or a commercial kit (Binding Site; ARUP Laboratory, Salt Lake City, UT). Values < 450 mg/dL for IgG, < 5 mg/dL for IgA, and < 20 mg/dL for IgM, all substantially below the 95% confidence limit,1,24 were used to define CVID,1213 IgA, and IgM deficiency,2 respectively. Similar to IgA and IgM deficiency, in which the values between the lower 95% confidence limit and the value defining arbitrarily the deficiency are called partial deficiency, the values of IgG between 650 mg/dL, the lower 95% confidence limit,24 and 450 mg/dL,1214 the defining value of CVID, were called partial CVID (PCVID).1213 Values of IgGSC below the 95% confidence limits were considered abnormal: 422 mg/dL for IgG1, 117 mg/dL for IgG2, 41 mg/dL for IgG3,25and 11 mg/dL for IgG4.26 In addition, to diagnose isolated IgGSC deficiency, we required an IgG > 450 mg/dL and planned to determine (every time it was possible) an impaired IgG response to vaccination.12 For IgG1-mediated pathway, we determined the change in specific IgG antibodies against tetanus toxoid in both veterans and nonveterans; for IgG2-mediated pathway, we measured IgG antibodies against Haemophilus influenzae in veterans and, in nonveterans, against Streptococcus pneumoniae antigens 3, 7A, 9, and 14. The measurements were performed in Dr. Heiner’s research laboratory at Harbor-UCLA Medical Center for veterans,12 and at Specialty Laboratory (Santa Monica, CA) for nonveterans.21 Failure to double the preimmunization level of the specific antibody was considered a subnormal response.1,1213

Lymphocyte Phenotyping:

These studies included lymphocyte phenotyping for B cells, and CD4 and CD8 T lymphocytes. Values < 9% for B cell, CD4 count < 500/μL, and a CD4/CD8 ratio < 0.8 were considered abnormal.1

Biopsy and BAL:

Open-lung or closed-lung biopsy and BAL were considered every time the etiologic diagnosis of ILD could not be established by CT scan. The biopsy specimens were evaluated by the same observer (T.V.C.) using standard criteria.27

Statistical Analysis

We used nonparametric methods for comparison of groups, and the Fisher exact test for comparing proportion of events in two groups.

Of 148 patients, a total of 29 patients were included in this study: 25 patients with radiologic findings of ILD and 4 patients with neutrophil alveolitis (> 25% neutrophils, > 10 × 106 cells/mL) and restriction abnormality. Since in many cases of ILD with clear chest radiographs, as for instance in collagen vascular diseases or sarcoidosis, the presence of restrictive abnormality is taken as a sign of interstitial involvement, the four patients with neutrophil alveolitis were considered to have ILD and were combined with the 25 patients displaying radiologic findings. These 29 cases are summarized in Table 1 . There were 20 male and 9 female patients (age range, 18 to 72 years); 23 patients were ≥ 40 years old. None of them had extrapulmonary manifestations characteristic of IgG deficiency. The onset of repeated respiratory infection, except in one patient (subject 16), was in adulthood.

The Ig deficiencies associated with ILD included 8 cases of CVID; 2 cases of IgM deficiency, combined with IgGSC deficiency or PCVID; and 21 cases representing IgGSC deficiency. To indicate the degree of IgG deficiency, the subjects with PCVID, all qualifying as CVID according to Cunningham-Rundles28 but not according to Watts et al,14 will be identified as PCVID in Table 1. In the text, for the sake of simplicity, these subjects will be included in CVID. No patient had CD4/CD8 abnormality.

The prevalence of ILD in Ig deficiency, 29 of 148 patients (19,600/100,000), is 240 times higher (p < 0.05) than the prevalence of ILD in the general population of Bernalillo County, New Mexico29 (80.9/100,000). The later study included a variety of ILD along with isolated restrictive abnormality without lung infiltrates. The 29 cases of ILD associated with Ig deficiency represented 20.7% of the total cases of ILD (n = 140) seen concurrently by V.P.

No pulmonary function tests other than arterial blood gas analysis could be performed in five subjects (two subjects with mental retardation and three subjects with acute illness). Ga scan findings, performed in 20 subjects, were positive in seven patients: three of four subjects with neutrophil alveolitis (subjects 2, 3, and 4), all three subjects with exposure to irritants (subjects 22, 23, and 24), and one subject with radiation pneumonitis (subject 25).

Except for the three patients seen exclusively in the hospital, all patients were followed up for at least 6 months; four subjects were followed up for 4 to 12 years. In these patients, the Ig measurements were repeated at 3 to 6 months, and the results confirmed the presence of the same Ig deficiency.

With the intention of preventing the recurrent respiratory infections associated with antibody deficiency, IV Ig was administered to eight subjects. The dose varied from 150 mg/kg/mo in six subjects to 400 mg/kg/mo in two subjects. All had IgGSC deficiency, IgG3, IgG4, combined IgG3 plus IgG4, and one patient had IgG3 plus IgG1. Their ILD was documented by BAL and physiologically (subjects 1 and 2), radiologically (subject 21 with bronchiectasis and chronic postinfectious pneumonitis), or histologically (subjects 5 and 6 with LIP, and subjects 7, 9, and 15 with UIP, nonspecific interstitial pneumonitis [NSIP], and—descriptive diagnosis—with interstitial pneumonitis with few scattered granulomas without vasculitis but with antiproteinase-3 antibody, homogeneous antinuclear antibody, and antiribonucleoprotein, respectively). The immune treatment lasted 4 months in subjects 6, 7, 15, and 21; 4 years in subject 9; and 10 to 12 years in subjects 1, 2, and 5. On the average, per patients’ rating, the recurrent respiratory infections decreased by 75% in frequency, duration, and severity; dyspnea on exertion (Borg scale) improved by 50 to 75%; while the rate of hospitalizations decreased by 68%. Unanimously, the subjects claimed that IV Ig increased their general well-being. All subjects improved radiologically, as illustrated in Figures 1234 and, with the exception of a mentally retarded subject who could not perform pulmonary function tests reliably, physiologically as well (Fig 5 ). No isotype deficiency was reversed when the isotypes were measured 6 weeks after IV Ig administration. In four subjects receiving 4 months of treatment (subjects 6, 7, 15, and 21), the physiologic and radiologic improvement lasted at least 12 months (Fig 1). Subject 1 had repeated episodes of respiratory infection with clear chest radiograph, CT scan, or Ga scan, which were associated with acute, reversible restriction. These episodes (occult pneumonia?) together with the intercritical, mild restrictive abnormality improved during his many years of treatment with IV Ig (Fig 5). One of the two subjects with LIP, subject 5 (Fig 2) acquired a severe abdominal infection, followed by sepsis and ARDS after 10 years of IV Ig; a few months later, this subject died receiving mechanical ventilation. The autopsy showed chronic diffuse alveolar damage but no evidence of LIP (Fig 6 ). Subject 15 died during an episode of acute respiratory infection; autopsy revealed interstitial fibrosis and bronchopneumonia but no granulomas.

The main findings of this article are the following: (1) in Ig deficiency with repeated respiratory infections, ILD is frequent (29 of 148 subjects; 19.6%), much more prevalent than expected from general population surveys and polymorphic clinically, histologically, and immunologically; (2) the most common Ig abnormality is low IgGSC; (3) no particular histologic or radiologic aspect is consistently related to a particular immune deficiency, CVID, IgA, IgM, or IgGSC deficiency, the serum level of the deficient Ig(s), or the IgG pathway of response to vaccination; (4) regardless of the type of immune deficiency or histologic aspects, the administration of IV Ig in some cases of ILD leads to clinical, physiologic, radiologic and, when checked, histologic improvement as well.

ILD appears to be much more prevalent in patients with repeated respiratory infections and Ig deficiency than in the general population. The comparison of a selected series of patients with the general population is valid for two reasons. First, in a pulmonary and allergy practice, the separate prevalence of ILD and immune deficiency should be higher than the prevalence of these diseases in the general population. However, unless these two diseases are mechanistically interrelated, the proportion in which they are associated should be the same in the specialty practice and the general population. That the prevalence of ILD is higher in Ig-deficient patients than in the general population points to a relationship between these two diseases. Second, this series is not the product of a systematic encounter with patients harboring ILD and recurrent respiratory infections with Ig deficiency. Such an uninterrupted bias during a 15-year period seems unlikely both intuitively and factually. Indeed, the prevalence of Ig deficiency in recurrent respiratory infections is not higher when ILD is present (19.6%) than when it is not (25 to 33%).1213

From a demographic standpoint, this report confirms that recurrent infections, the characteristic manifestation of Ig deficiencies, may first appear in adulthood.2,1214,28 The associated ILD is usually diagnosed several years later, after age 40 years (23 of 29 patients). Among patients with bronchiectasis and chronic postinfectious pneumonitis, the severity of B-cell deficiency may influence the apparent onset: early childhood in X-linked hypogammaglobulinemia,30 late childhood or adolescence in CVID (15 to 19 years; subject 19), and in the fourth to sixth decade in IgGSC deficiency (Table 1).

Because of respiratory infections, the chronic symptomatology of ILD associated with Ig deficiency may acquire a “bronchitic-asthmatic” character, often with low FEV1/FVC (7 of 24 subjects) or increase in residual volume (RV) and/or functional residual capacity with normal FEV1/FVC (5 of 24 subjects).

The pathologic and radiologic spectrum of ILD associated with Ig deficiency is remarkably wide. This is reminiscent of collagen vascular diseases, in which the same disease and the same immune abnormalities can be associated with many different types of ILD.27 With the exception of granulomatous pneumonitis, which could not be confidently catogorized in subject 15, all diffuse ILD and the chronic postinflammatory pneumonitis previously related to CVID are now shown to coexist with IgG isotype deficiency. In addition, NSIP, apparently not reported before in CVID, may also be associated with IgGSC deficiency.

Two of the ILD cases mentioned in this article deserve special mention. Neutrophil alveolitis represents a nonspecific inflammatory reaction. It may be associated with a clear chest radiograph (eg, systemic lupus erythematosus), radiologic ILD, or CVID with bronchiectasis in free interval.3132 Pleading for interstitial involvement, despite a normal CT scan finding of the chest, was an occasionally positive Ga scan finding (subjects 2, 3, and 4) and mild restrictive abnormality on pulmonary function testing.

Bronchiectasis with chronic postinfectious pneumonitis was described in antibody deficiency by means of high-resolution CT scan or chest radiograph and labeled interstitial disease, chronic lung disease, fibrosis, etc.1519 As shown by CT scans2930(Fig 4), the lesions are complex, involving the bronchi, alveoli, and the interstitium. In agreement with the literature,1519,30 bronchiectasis with chronic interstitial pneumonitis was usually diagnosed by CT scan (subjects 16 through 21) and only exceptionally by biopsy (subject 11). Radiologic16 and pathologic aspects (subject 11) suggest that BOOP may constitute an important part of chronic pneumonitis.

In several patients (subjects 22 through 29), ILD seems to be related to a specific etiopathogenic entity, but the observed low Ig levels may still participate in the genesis of interstitial inflammation. In the patient with systemic lupus erythematosus, a low IgG1 is totally unexpected since IgG1, the isotype carrying most of the antinuclear activity,33is usually increased rather than decreased. In the patient with myotonic dystrophy, a low IgG1 resulting from its increased catabolism in this disease34was expected, but the bibasilar interstitial infiltrates were not. In the remaining cases, the presence of an associated IgG deficiency was never investigated. It is possible that the case of radiation pneumonitis, the two cases of granulomatous ILD associated with exposure to talc by inhalation or IV, and the case with restrictive abnormality that developed after acute exposure to respiratory irritants might have been related to Ig deficiency. Although there are insufficient data for a definitive conclusion, it is known that experimentally many environmental agents may elicit immunologic response and, apparently via transforming growth factor-β1, pulmonary fibrosis.35 Cigarette smoke may favor or produce immunodeficiency.1213

The effect of therapy with IV Ig in ILD confers practical relevance to this study. The study documents that IV Ig benefits chronic postinfectious pneumonitis when this disease is associated not only with CVID,17,19 but also with a much more frequent immune deficiency, IgGSC deficiency. Second, this form of therapy also improves diffuse ILD associated with various IgGSC deficiencies. The theoretical implications of the study seem at least as important as its practical relevance. Currently, the manifestations of Ig deficiency are blamed on antibody deficiency. It is the deficiency in a class or, for IgG, subclasses, particularly IgG1 or IgG2, which shapes the clinical form of disease. This study suggests that the manifestations of ILD associated with Ig deficiency and their favorable influence by IV Ig reflect a dual process: an antibody deficiency explaining the recurrent infections, and a modulating effect of IgG on pulmonary inflammation.

Many pretreatment features of ILD associated with Ig deficiency would not be expected in a pure antibody deficiency syndrome. No specific ILD is invariably connected to a particular IgG deficiency (Table 1), and no aspect of immune deficiency, serum levels of isotype, or response to vaccination heralds the interstitial involvement. Indeed, the range of serum concentrations of IgGSC (in 85% of the subjects between 60% and 35% of predicted values) and the patterns of impaired response to vaccination were similar to those seen in subjects with recurrent respiratory infections but no ILD.1213 Also, similar to noninfectious, autoimmune manifestations of CVID, in ILD associated with CVID, no concentration of IgG is consistently related to interstitial involvement. The effect of IV Ig in ILD is particularly suggestive of an anti-inflammatory action. First, the improvement relates to inflammatory lesions that are either pathogenically unrelated to infections36 or, in the case of bronchiectasis with chronic postinfectious pneumonitis,17,19 impossible to improve by simply preventing the infections. Second, the effect exceeds the half-life of IgG, persisting for many months. Third, the type of diffuse ILD improved by IgG treatment often responds to steroids, anti-inflammatory agents par excellence. The immunomodulatory, anti-inflammatory action of IV Ig in ILD is an extension of the therapeutic effect of IV Ig in various inflammatory diseases with immune mechanisms.37 Fourth, Fc-gamma receptors have been demonstrated on many cells participating in inflammation and IgG modulates various cytokines,35 including transforming growth factor-β1,38a potent regulator of collagen tissue synthesis in the lung.39 It is not clear how Ig(s) modulate interstitial inflammation. The isotype deficiency, as in the case of Ig deficiency without ILD, may be a marker of another immune abnormality, still unidentified, that modulates inflammation. If this factor is actually a circulating Ig, its concentration may be too low to lead to a quantitative deficiency in the corresponding IgGSC.1213

This report is observational in nature and analyzes a relatively small number of subjects. However, because it contains the largest number of ILD associated with low Ig(s) mentioned in the literature and collected serially from the largest pool of adults with IgGSC deficiency reported in this country, it is for now a reasonable surrogate for an epidemiologic survey of Ig deficiencies associated with ILD. It is with this caution that we advance the hypothesis that at times, there is a link between ILD and IgGSC deficiency.

Abbreviations: BOOP = bronchiolitis obliterans organizing pneumonia; CVID = common variable immunodeficiency; Dlco = diffusing capacity of the lung for carbon monoxide; IgGSC = IgG subclass; ILD = interstitial lung disease; LIP = lymphocytic interstitial pneumonitis; NSIP = nonspecific interstitial pneumonitis; PCVID = partial common variable immunodeficiency; RV = residual volume; UIP = usual interstitial pneumonitis

Supported in part by a grant-in-aid from Schering Co. and Methodist Hospital, Sacramento, CA.

Table Graphic Jump Location
Table 1. Demographic, Clinical, Immunologic, Radiologic, and Pathologic Aspects of ILD Associated With Ig Deficiency*
* 

BMI = body mass index; M = male; F = female; S = smoker; NS = nonsmoker; FRC = functional residual capacity; TLC = total lung capacity; A = asthma; TT = tetanus toxicity; HIB = Haemophilus influenzae B; PN = pneumococcus; WNL = within normal limits; N/D = not determined; Neutr. Alv. = neutrophil alveolitis; Abs = absent; Brct = bronchiectosis; Ret. = reticular; S/P = status past; SLE = systemic lupus erythematosus; f/u = follow-up; LUL = left upper lobe; RUL = right upper lobe.

Figure Jump LinkFigure 1. Changes in CT scan of the chest in subject 7 (NSIP) before (left and central upper panels) during (right upper panel), and after treatment with IV Ig at 6, 12, and 24 months (lower panels, in successive order). B = before IV Ig; A = after IV Ig.Grahic Jump Location
Figure Jump LinkFigure 2. Changes in CT scan of the chest in subject 5 (LIP). The images were obtained before beginning treatment with IV Ig (left), after 6 months (middle), and after 2 1/2 years (right). See Figure 1 legend for definition of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Changes in CT scan of the chest in subject 15. The images were obtained before treatment with IV Ig (left panel) and 2 months and 4 months after the end of this treatment (center and right panels, respectively). See Figure 1 legend for definition of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Changes in CT scan of the chest in subject 21 (bronchiectasis with associated alveolar, linear and nodular interstitial involvement). In view of the heterogeneity of lung changes at different lung levels, the figure compares images obtained at two different levels (upper and lower panels), 4 months and 1 month before treatment (left and central panels, respectively), and 7 months after treatment (right panels). See Figure 1 legend for definition of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Pulmonary function changes in seven subjects administered IV Ig. The figure shows the percentage changes in lung volumes and Dlco, and the absolute changes in FEV1/FVC percentage and Pao2 as related to the corresponding baseline values (Table 1). Triangles indicate FVC; circles indicate RV; closed symbols are measurements during the administration of IV Ig; open symbols are measurements after this treatment has ended. Note the isolated improvement in subject 3, who had only an isolated decrease in Dlco at baseline. In subject 21 with chronic pneumonitis, airway obstruction, and hyperinflation, IV Ig improved the restriction much more than the obstruction as shown by an increase in FVC and RV and decrease in FEV1. The smallest physiologic improvement was seen in subject 9 with UIP, who continued to smoke. Abs = absolute.Grahic Jump Location
Figure Jump LinkFigure 6. LIP (subject 8) at the time of diagnosis (left panels) and at autopsy (right panel) [hematoxylin-eosin]. Left upper panel: high-power microscopy in the area of infiltrate shows lymphocytes and plasma cells in the alveolar septa. Left lower panel: lower-power microscopy of a bronchiole shows adjacent lymphoid hyperplasia with germinal center. Right panel: high-power microscopy showing organizing diffuse alveolar damage with dilated alveolar ducts and alveolar septal thickening without significant inflammation.Grahic Jump Location

Drs. Deborah Douglas and Walter Finkelbein have kindly allowed the review of slides made from biopsy specimens or autopsy materials at Mercy General Hospital or University of California at Davis, respectively.

Conley, ME, Stiehm, RE (1996) Immunodeficiency disorders: general considerations. Stiehm, RE eds.Immunologic disorders in infants and children 4th ed. ,201-215 Saunders. Philadelphia, PA:
 
Ochs, HD, Winkelstein, J Disorders of the B-cell system. Stiehm, RE eds.Immunologic disorders in infants and children 4th ed.1996,296-338 Saunders. Philadelphia, PA:
 
Lynch, D, Gamsu, G Imaging of diffuse parenchymal lung disease. Schwartz, MI King, TE eds.Interstitial lung disease 3rd ed.1988,71-102 Decker. Hamilton, Canada:
 
Morris, AH, Kanner, RE, Crapo, RO, et al Clinical pulmonary function testing1984,2-20 Intermountain Thoracic Society. Salt Lake City, UT:
 
Liebow, A, Carrington, CB Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia.Med Clin North Am1973;37,809-821
 
Strimlan, CV, Rosenow, EC, Weiland, LH, et al Lymphocytic interstitial pneumonitis.Ann Intern Med1978;88,616-621. [PubMed]
 
Sharma, OP, James, DG Hypogammaglobulinemia, depression of delayed-type hypersensitivity, and granuloma formation.Am Rev Respir Dis1971;104,228-231. [PubMed]
 
Mechanic, LJ, Dikman, S, Cunningham-Rundles, C Granulomatous disease in common variable immunodeficiency.Ann Intern Med1997;127,613-617. [PubMed]
 
Fasano, MB, Sullivan, KE, Sarpong, SB, et al Sarcoidosis and common variable immunodeficiency: report of 8 cases and review of the literature.Medicine1996;75,251-261. [PubMed] [CrossRef]
 
Kaufman, J, Komorowski, R Bronchiolitis obliterans organizing pneumonia in common variable immunodeficiency syndrome.Chest1991;100,552-553. [PubMed]
 
Walker, JC, O’Connel, MA, Pluss, JL Usual interstitial pneumonitis in a patient with common variable immunodeficiency.J Allergy Clin Immunol1997;99,847-851. [PubMed]
 
Popa, V, Kim, K, Heiner, D IgG deficiency in adults with recurrent respiratory infections.Ann Allergy1993;70,418-423. [PubMed]
 
Popa, V Airway obstruction in adults with recurrent respiratory infections and IgG deficiency.Chest1994;105,1006-1012
 
Watts, WJ, Watts, MB, Dai, W, et al Respiratory dysfunction in patients with common variable hypogammaglobulinemia.Am Rev Respir Dis1986;134,699-703. [PubMed]
 
Manson, D, Reid, B, Dalal, I, et al Clinical utility of high resolution pulmonary computed tomography in children with antibody deficiency disorders.Pediatr Radiol1997;27,794-798. [PubMed]
 
Feydya, A, Sibilia, J, De Kerviler, E, et al Chest high resolution CT in adults with primary humoral immunodeficiency.Br J Radiol1996;69,1108-1116. [PubMed]
 
Roifman, CM, Levison, H, Gelfand, EW High-dose vs low-dose immunoglobulin in hypogammaglobulinemia and chronic lung disease.Lancet1987;1,1075-1077. [PubMed]
 
Obregon, RG, Lynch, DA, Kaske, T, et al Radiologic findings of adult primary immunodeficiency disorders: contribution of CT.Chest1994;106,490-495. [PubMed]
 
Kainulainen, L, Varpula, M, Lippo, K, et al Pulmonary abnormalities in patients with primary hypoglobulinemia.J Allergy Clin Immunol1999;104,1031-1036. [PubMed]
 
Reynolds, HY Interstitial lung diseases. Fauci, AS Braunwald, E Isselbacher, KJet al eds.Harrison’s principles of internal medicine 14th ed.1998,1460 McGraw-Hill. New York, NY:
 
Popa, V, Nagy, SM Immediate hypersensitivity in adults with IgG deficiency and recurrent respiratory infections.Ann Allergy Asthma Immunol1999;82,567-573. [PubMed]
 
Soderstrom, T, Soderstrom, R, Enskog, A Immunoglobulin subclasses and prophylactic use of immunoglobulin in immunoglobulin G subclass deficiency.Cancer1991;68,1426-1429. [PubMed]
 
Malmagaard, K Alveolo-arterial oxygen difference: size and components in normal man.Acta Physiol Scand1966;66,10-20
 
Silverman, LM, Christensen, RH, Grant, GH Amino acids and proteins. Tietz, NW eds.Textbook of clinical chemistry1986,573-580 Saunders. Philadelphia, PA:
 
Oxelius, V-A IgG subclass levels in infancy and childhood.Acta Paediatr Scand1979;68,23-27. [PubMed]
 
Schur, P IgG subclasses: a review.Ann Allergy1987;58,89-96. [PubMed]
 
Colby, TV, Swensen, SJ Anatomic distribution and histopathologic patterns in interstitial lung disease. Schwarz, MI King, TE eds.Interstitial lung disease1998,31-50 Decker. Hamilton, Canada:
 
Cunningham-Rundles, C Clinical and immunological analyses of 103 patients with common variable immunodeficiency.J Clin Immunol1989;9,22-33. [PubMed]
 
Coultas, DB, Zumwalt, RE, Black, WC, et al The epidemiology of interstitial lung diseases.Am J Respir Crit Care Med1994;150,967-972. [PubMed]
 
Curtin, JJ, Webster, ADB, Farrant, J, et al Bronchiectasis in hypogammaglobulinemia: a computed tomography assessment.Clin Radiol1991;44,82-84. [PubMed]
 
Kainulainen, L, Nikoskelainen, J, Vuorinen, T, et al Viruses and bacteria in bronchial samples from patients with primary hypogammaglobulinemia.Am J Respir Crit Care Med1999;159,1199-1204. [PubMed]
 
Wells, AU, du Bois, RM Bronchiolitis in association with connective tissue disorders.Clin Chest Med1993;4,655-665
 
Yount, WJ, Cohen, P, Eisenberg, RA Distribution of IgG subclasses among human autoantibodies to Sm, RNP, dsDNA, SS-B and IgG rheumatoid factor.Monogr Allergy1988;23,41-56. [PubMed]
 
Wochner, RD, Drews, G, Strober, W, et al Accelerated breakdown of immunoglobulin G (IgG) in myotonic dystrophy: a hereditary error of immunoglobulin catabolism.J Clin Invest1966;45,321-329. [PubMed]
 
Chan, ED, Worthen, GS, Augustin, A, et al Inflammation in the pathogenesis of interstitial lung disease. Schwarz, MI King, TE eds.Interstitial lung disease1998,135-164 Decker. Hamilton, Canada:
 
Schwarz, MI Interstitial lung disease following pulmonary infections. Schwarz, MI King, TE eds.Interstitial lung disease1998,697-750 Decker. Hamilton, Canada:
 
Kazatchkine, MD, Kaveri, SV Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin.N Engl J Med2001;345,747-755. [PubMed]
 
Andersson, U, Bjork, L, Skansen-Ssaphir, U, et al Pooled human IgG modulates cytokine production in lymphocytes and monocytes.Immunol Rev1994;139,21-42. [PubMed]
 
Khalil, N, Parekh, TV, O’Connor, R, et al Regulation of the effects of TGF-β1 by activation of latent TGF-β1 and differential expression of TGF-β receptors (TβR-I and TβR-II) in idiopathic pulmonary fibrosis.Thorax2001;56,907-915. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Changes in CT scan of the chest in subject 7 (NSIP) before (left and central upper panels) during (right upper panel), and after treatment with IV Ig at 6, 12, and 24 months (lower panels, in successive order). B = before IV Ig; A = after IV Ig.Grahic Jump Location
Figure Jump LinkFigure 2. Changes in CT scan of the chest in subject 5 (LIP). The images were obtained before beginning treatment with IV Ig (left), after 6 months (middle), and after 2 1/2 years (right). See Figure 1 legend for definition of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Changes in CT scan of the chest in subject 15. The images were obtained before treatment with IV Ig (left panel) and 2 months and 4 months after the end of this treatment (center and right panels, respectively). See Figure 1 legend for definition of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Changes in CT scan of the chest in subject 21 (bronchiectasis with associated alveolar, linear and nodular interstitial involvement). In view of the heterogeneity of lung changes at different lung levels, the figure compares images obtained at two different levels (upper and lower panels), 4 months and 1 month before treatment (left and central panels, respectively), and 7 months after treatment (right panels). See Figure 1 legend for definition of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Pulmonary function changes in seven subjects administered IV Ig. The figure shows the percentage changes in lung volumes and Dlco, and the absolute changes in FEV1/FVC percentage and Pao2 as related to the corresponding baseline values (Table 1). Triangles indicate FVC; circles indicate RV; closed symbols are measurements during the administration of IV Ig; open symbols are measurements after this treatment has ended. Note the isolated improvement in subject 3, who had only an isolated decrease in Dlco at baseline. In subject 21 with chronic pneumonitis, airway obstruction, and hyperinflation, IV Ig improved the restriction much more than the obstruction as shown by an increase in FVC and RV and decrease in FEV1. The smallest physiologic improvement was seen in subject 9 with UIP, who continued to smoke. Abs = absolute.Grahic Jump Location
Figure Jump LinkFigure 6. LIP (subject 8) at the time of diagnosis (left panels) and at autopsy (right panel) [hematoxylin-eosin]. Left upper panel: high-power microscopy in the area of infiltrate shows lymphocytes and plasma cells in the alveolar septa. Left lower panel: lower-power microscopy of a bronchiole shows adjacent lymphoid hyperplasia with germinal center. Right panel: high-power microscopy showing organizing diffuse alveolar damage with dilated alveolar ducts and alveolar septal thickening without significant inflammation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Demographic, Clinical, Immunologic, Radiologic, and Pathologic Aspects of ILD Associated With Ig Deficiency*
* 

BMI = body mass index; M = male; F = female; S = smoker; NS = nonsmoker; FRC = functional residual capacity; TLC = total lung capacity; A = asthma; TT = tetanus toxicity; HIB = Haemophilus influenzae B; PN = pneumococcus; WNL = within normal limits; N/D = not determined; Neutr. Alv. = neutrophil alveolitis; Abs = absent; Brct = bronchiectosis; Ret. = reticular; S/P = status past; SLE = systemic lupus erythematosus; f/u = follow-up; LUL = left upper lobe; RUL = right upper lobe.

References

Conley, ME, Stiehm, RE (1996) Immunodeficiency disorders: general considerations. Stiehm, RE eds.Immunologic disorders in infants and children 4th ed. ,201-215 Saunders. Philadelphia, PA:
 
Ochs, HD, Winkelstein, J Disorders of the B-cell system. Stiehm, RE eds.Immunologic disorders in infants and children 4th ed.1996,296-338 Saunders. Philadelphia, PA:
 
Lynch, D, Gamsu, G Imaging of diffuse parenchymal lung disease. Schwartz, MI King, TE eds.Interstitial lung disease 3rd ed.1988,71-102 Decker. Hamilton, Canada:
 
Morris, AH, Kanner, RE, Crapo, RO, et al Clinical pulmonary function testing1984,2-20 Intermountain Thoracic Society. Salt Lake City, UT:
 
Liebow, A, Carrington, CB Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia.Med Clin North Am1973;37,809-821
 
Strimlan, CV, Rosenow, EC, Weiland, LH, et al Lymphocytic interstitial pneumonitis.Ann Intern Med1978;88,616-621. [PubMed]
 
Sharma, OP, James, DG Hypogammaglobulinemia, depression of delayed-type hypersensitivity, and granuloma formation.Am Rev Respir Dis1971;104,228-231. [PubMed]
 
Mechanic, LJ, Dikman, S, Cunningham-Rundles, C Granulomatous disease in common variable immunodeficiency.Ann Intern Med1997;127,613-617. [PubMed]
 
Fasano, MB, Sullivan, KE, Sarpong, SB, et al Sarcoidosis and common variable immunodeficiency: report of 8 cases and review of the literature.Medicine1996;75,251-261. [PubMed] [CrossRef]
 
Kaufman, J, Komorowski, R Bronchiolitis obliterans organizing pneumonia in common variable immunodeficiency syndrome.Chest1991;100,552-553. [PubMed]
 
Walker, JC, O’Connel, MA, Pluss, JL Usual interstitial pneumonitis in a patient with common variable immunodeficiency.J Allergy Clin Immunol1997;99,847-851. [PubMed]
 
Popa, V, Kim, K, Heiner, D IgG deficiency in adults with recurrent respiratory infections.Ann Allergy1993;70,418-423. [PubMed]
 
Popa, V Airway obstruction in adults with recurrent respiratory infections and IgG deficiency.Chest1994;105,1006-1012
 
Watts, WJ, Watts, MB, Dai, W, et al Respiratory dysfunction in patients with common variable hypogammaglobulinemia.Am Rev Respir Dis1986;134,699-703. [PubMed]
 
Manson, D, Reid, B, Dalal, I, et al Clinical utility of high resolution pulmonary computed tomography in children with antibody deficiency disorders.Pediatr Radiol1997;27,794-798. [PubMed]
 
Feydya, A, Sibilia, J, De Kerviler, E, et al Chest high resolution CT in adults with primary humoral immunodeficiency.Br J Radiol1996;69,1108-1116. [PubMed]
 
Roifman, CM, Levison, H, Gelfand, EW High-dose vs low-dose immunoglobulin in hypogammaglobulinemia and chronic lung disease.Lancet1987;1,1075-1077. [PubMed]
 
Obregon, RG, Lynch, DA, Kaske, T, et al Radiologic findings of adult primary immunodeficiency disorders: contribution of CT.Chest1994;106,490-495. [PubMed]
 
Kainulainen, L, Varpula, M, Lippo, K, et al Pulmonary abnormalities in patients with primary hypoglobulinemia.J Allergy Clin Immunol1999;104,1031-1036. [PubMed]
 
Reynolds, HY Interstitial lung diseases. Fauci, AS Braunwald, E Isselbacher, KJet al eds.Harrison’s principles of internal medicine 14th ed.1998,1460 McGraw-Hill. New York, NY:
 
Popa, V, Nagy, SM Immediate hypersensitivity in adults with IgG deficiency and recurrent respiratory infections.Ann Allergy Asthma Immunol1999;82,567-573. [PubMed]
 
Soderstrom, T, Soderstrom, R, Enskog, A Immunoglobulin subclasses and prophylactic use of immunoglobulin in immunoglobulin G subclass deficiency.Cancer1991;68,1426-1429. [PubMed]
 
Malmagaard, K Alveolo-arterial oxygen difference: size and components in normal man.Acta Physiol Scand1966;66,10-20
 
Silverman, LM, Christensen, RH, Grant, GH Amino acids and proteins. Tietz, NW eds.Textbook of clinical chemistry1986,573-580 Saunders. Philadelphia, PA:
 
Oxelius, V-A IgG subclass levels in infancy and childhood.Acta Paediatr Scand1979;68,23-27. [PubMed]
 
Schur, P IgG subclasses: a review.Ann Allergy1987;58,89-96. [PubMed]
 
Colby, TV, Swensen, SJ Anatomic distribution and histopathologic patterns in interstitial lung disease. Schwarz, MI King, TE eds.Interstitial lung disease1998,31-50 Decker. Hamilton, Canada:
 
Cunningham-Rundles, C Clinical and immunological analyses of 103 patients with common variable immunodeficiency.J Clin Immunol1989;9,22-33. [PubMed]
 
Coultas, DB, Zumwalt, RE, Black, WC, et al The epidemiology of interstitial lung diseases.Am J Respir Crit Care Med1994;150,967-972. [PubMed]
 
Curtin, JJ, Webster, ADB, Farrant, J, et al Bronchiectasis in hypogammaglobulinemia: a computed tomography assessment.Clin Radiol1991;44,82-84. [PubMed]
 
Kainulainen, L, Nikoskelainen, J, Vuorinen, T, et al Viruses and bacteria in bronchial samples from patients with primary hypogammaglobulinemia.Am J Respir Crit Care Med1999;159,1199-1204. [PubMed]
 
Wells, AU, du Bois, RM Bronchiolitis in association with connective tissue disorders.Clin Chest Med1993;4,655-665
 
Yount, WJ, Cohen, P, Eisenberg, RA Distribution of IgG subclasses among human autoantibodies to Sm, RNP, dsDNA, SS-B and IgG rheumatoid factor.Monogr Allergy1988;23,41-56. [PubMed]
 
Wochner, RD, Drews, G, Strober, W, et al Accelerated breakdown of immunoglobulin G (IgG) in myotonic dystrophy: a hereditary error of immunoglobulin catabolism.J Clin Invest1966;45,321-329. [PubMed]
 
Chan, ED, Worthen, GS, Augustin, A, et al Inflammation in the pathogenesis of interstitial lung disease. Schwarz, MI King, TE eds.Interstitial lung disease1998,135-164 Decker. Hamilton, Canada:
 
Schwarz, MI Interstitial lung disease following pulmonary infections. Schwarz, MI King, TE eds.Interstitial lung disease1998,697-750 Decker. Hamilton, Canada:
 
Kazatchkine, MD, Kaveri, SV Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin.N Engl J Med2001;345,747-755. [PubMed]
 
Andersson, U, Bjork, L, Skansen-Ssaphir, U, et al Pooled human IgG modulates cytokine production in lymphocytes and monocytes.Immunol Rev1994;139,21-42. [PubMed]
 
Khalil, N, Parekh, TV, O’Connor, R, et al Regulation of the effects of TGF-β1 by activation of latent TGF-β1 and differential expression of TGF-β receptors (TβR-I and TβR-II) in idiopathic pulmonary fibrosis.Thorax2001;56,907-915. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543