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The HRCT appearances of granulomatous pulmonary disease in common variable immune deficiency
European Journal of Radiology 54 (2005) 359–364
The HRCT appearances of granulomatous pulmonary disease in common variable immune deficiency J.E.S. Park, I. Beal, J.P. Dilworth, V. Tormey, J. Haddock ∗ Royal Free and Hampstead NHS Trust, Pond Street, London NW3 2QG, UK Received 13 April 2004; received in revised form 8 September 2004; accepted 10 September 2004
Abstract Approximately 10% of patients with common variable immune deficiency have systemic granulomatous disease with associated interstitial lung disease. From a population of patients with CVID attending a large tertiary referral clinic for primary immunodeficiency diseases we selected a cohort who had a restrictive defect or impaired gas transfer on pulmonary function testing and/or histologically proven granulomatous disease. HRCT scans of the thorax were reviewed retrospectively in 18 patients by two radiologists. Thirteen patients had diffuse reticulation, which varied from fine to coarse with features of fibrosis. Nodules were found in eight patients. In seven, these were associated with reticulation and in one they were an isolated finding. Bronchiectasis was found as the only abnormality in three and in addition to diffuse reticulation or nodules in another three patients. Greater appreciation of the spectrum of the radiological abnormalities in CVID patients with interstitial lung disease is important. Deteriorating lung function in patients with granulomatous CVID may be secondary to interstitial lung disease rather than bronchiectasis, and treatment should be tailored accordingly. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: HRCT; Common variable immunodeficiency (CVID); Granulomatous
1. Introduction Common variable immunodeficiency (CVID) is the commonest severe primary immunodeficiency disorder with a prevalence of 1:25,000–1:50,000. Affected patients have hypogammaglobulinaemia with a marked reduction in IgG and IgA, a variable decrease in IgM and frequently have low numbers of circulating CD4+ T-cells [1]. Although a minority of CVID patients may have an undiagnosed single gene disorder, a substantial proportion appears to have a complex disorder of immune dysregulation, the major susceptibility locus being in the MHC complex on chromosome 6 [2,3]. Clinically it is a heterogeneous disorder characterised by recurring bacterial infections as well as an increased risk of autoimmune disease and malignancy [4,5]. ∗
Corresponding author. Fax: +44 20 7830 2316. E-mail address: [email protected] (J. Haddock).
0720-048X/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2004.09.005
Symptoms of recurring infections start at any age but there are peaks of onset at 1–5 and 16–20 years. More than 95% of patients present with recurrent sinopulmonary infection and progress gradually to develop bronchiectasis. The mean delay between onset of symptoms and diagnosis is 6 years. A subgroup of patients with CVID develops granulomatous disease [4,6]. The liver and spleen are most commonly involved, but about 10% develop interstitial lung disease. Within the primary antibody deficiencies this feature is probably unique to CVID but the spectrum of lung disease is not well defined with some isolated reports and few large studies. Interstitial lung disease does not occur in X-linked hypogammaglobulinaemia and is most likely to be related to the pathogenesis of the immunodeficiency in CVID. In patients with hypogammaglobulinaemia, bronchiectasis is known to be a common cause for deteriorating lung function with several reports describing the radiological fea-
360
J.E.S. Park et al. / European Journal of Radiology 54 (2005) 359–364
tures. Curtin et al. [7] described the pattern of bronchiectasis and bronchial wall thickening seen in patients with CVID and X-linked agammaglobulinaemia (XLA). Feydy et al. [8] reported in detail the CT findings in 19 patients (16 of whom had CVID), including lobar/segmental collapse, scars, interstitial lesions, nodules and lobular air trapping in addition to bronchiectasis and bronchial wall thickening. The occurrence of a ‘sarcoid-like’ syndrome in combination with CVID has been widely reported [4,6,13,14], yet there have only been a few reports on the radiographic findings in this specific subset of patients. Thickett et al. [9] described the respiratory complications, lung function and HRCT findings in CVID; although only 2 out of 34 patients had CT scans consistent with granulomatous lung disease. There have also been isolated reports of respiratory complications in CVID that have included CT findings [10–12]. Walsh et al. [15] describe the pulmonary CT findings of histologically proven granulomatous disease in two patients with primary hypogammaglobulinaemia who had multiple nodules with a variable degree of interstitial change. Further to this, Fasano et al. [14] evaluated eight patients with CVID, in whom clinical findings consistent with sarcoidosis were present and reviewed the literature on other reported cases. Chest X-ray and CT findings included hilar adenopathy, scarring, fibrosis, interstitial changes and nodules. Most larger series describe the spectrum of lung disease associated with antibody deficiency, predominantly bronchiectasis [4,9,14]. However, with earlier diagnosis the incidence of established bronchiectasis may be decreasing. To date, most reports of interstitial lung disease in CVID are either isolated cases or reports of small numbers included among other patients with respiratory disease in CVID. The spectrum of interstitial lung disease in CVID requires further characterisation as well as attempts at classification. The purpose of this study is to describe the radiological spectrum of interstitial lung disease on HRCT in 16 patients with granulomatous or sarcoid-like variant of CVID and correlate this with pulmonary function and clinical features.
2. Patients and methods The primary immunodeficiency clinic at the Royal Free Hospital is a large tertiary referral centre for patients with known or suspected immunodeficiency disease. CVID was diagnosed using the World Health Organisation criteria based on recurrent bacterial infections associated with hypogammaglobulinaemia, and the exclusion of other known causes of humoral deficiency [1]. All patients were receiving regular intravenous or subcutaneous immunoglobulin infusions to maintain an IgG level of greater than 8 g/l. All patients have pulmonary function tests performed yearly or more frequently if previously abnormal or they have developed respiratory symptoms. High resolution CT scan of the thorax was performed on patients with progressive symptoms of shortness of breath, impaired gas transfer on
pulmonary function testing and/or an abnormal chest radiograph suggesting fibrosis. We selected 18 patients as having the ‘sarcoid’ variant of CVID based on the following criteria: tissue diagnosis of granulomas from biopsy of lymph node, lung, liver, skin, kidney gut or splenectomy; cholestatic pattern of increased liver function tests (alkaline phosphatase and ␥-glutamyl transferase) with splenomegaly and progressive abnormality in pulmonary function testing with impaired gas transfer and/or restrictive pattern on spirometry. To allow comparison, the pulmonary function tests most closely related in time to CT scanning were recorded. Clinical features were determined by review of the medical notes. CT scans were available for all 18 patients with granulomatous CVID. These were performed at the Royal Free Hospital using GE Medical Systems Prospeed Imation Dryview, High Speed and Light Speed Plus (n = 15) and at a variety of referring hospitals on a Somatom Plus 4 or a Somatom Arsac system (n = 3). Ten of the scans were high resolution with collimation of one or 1.25 mm. Six scans had 5 mm collimation and have been included in the study. Two patients had scans of 10 mm thickness and were considered ineligible. All scans were obtained at end inspiration. Images were obtained at standard window and level settings to demonstrate lung parenchyma and mediastinal structures. Two radiologists independently reviewed CT scans retrospectively in 16 patients. The radiologists were unaware of the clinical condition of the patients or their pulmonary function tests. The pattern of disease was described according to Fleishner Society criteria [16] in terms of reticulation (fine linear, interlobular, coarse linear), traction bronchiectasis, architectural distortion, nodules (size <5 mm, 6–10 mm, >10 mm; definition and distribution) bronchiectasis, zonal predominance and lymphadenopathy. The presence of each abnormality was analysed for the three different lobes of each lung with the lingula considered as a separate lobe. The zonal Table 1 Demographics of the group with reticular and/or nodular changes on HRCT Number of patients Male Female
14 6 8
Median age (range) Mean (range) age at CVID diagnosis Mean time to respiratory diagnosis
50 (25–64) years 29.3 (4–53) years 12.6 (0–45) years
Table 2 Summary of HRCT findings Upper
Middle
Lower
Reticulation Fine Interlobular Coarse
8/32 1/32 12/32
7/32 4/32 14/32
10/32 2/32 17/32
Nodules Bronchiectasis Architectural distortion Traction bronchiectasis
10/32 4/32 15/32 3/32
8/32 7/32 14/32 6/32
12/32 6/32 20/32 4/32
J.E.S. Park et al. / European Journal of Radiology 54 (2005) 359–364
Fig. 1. Bilateral coarse reticulation.
predominance of the CT findings was also recorded as upper, lower or random. Upper lung zone predominance was present when most of the abnormalities were above the level of the tracheal carina and lower zone predominance was present when most of the abnormalities were below this level. Lymphadenopathy was considered present if there were nodes measuring >1 cm in short axis diameter and the site of these was recorded (anterior mediastinal, pretracheal, right or left hilar). 3. Results Patient demographics are summarised in Table 1 and HRCT findings in Table 2. Thirteen of the 16 patients had reticulation. This occurred in 75 out of the possible 96 lobes. There was lower zone predominance with the upper lobe involved in 64% of cases, the middle lobe in 74% and the lower lobe in 91%. The reticulation was coarse in 57% of the affected lobes (Fig. 1) compared with 33% of lobes, which showed fine linear reticulation and 10% with interlobular reticulation. The more coarse reticulation was associated with features of fibrosis. Architectural distortion was evident in 47% of the upper lobes, 44% of the middle lobes and 62% of the lower lobes. Traction bronchiectasis was seen in 10% of the upper lobes, 20% of the middle lobes and 13% of the lower lobes.
Fig. 2. Coarse reticulation in association with ill-defined nodules.
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Eight of the 16 patients had nodules (in seven of these eight the nodules were associated with reticulation (Fig. 2)). The nodules were seen in 31% of the upper lobes, 25% of the middle lobes and 38% of the lower lobes. The smaller nodules (<5 mm) tended to be randomly distributed and well defined and the larger nodules tended to be ill-defined and were bronchocentric in distribution (Fig. 3). Six of the 16 had pre-tracheal adenopathy. In two patients this was in conjunction with hilar adenopathy. The adenopathy was seen in conjunction with reticulation in five of these patients. The other patient had no reticulation and only widespread bronchiectasis was seen (Fig. 4). Six of the 16 patients had bronchiectasis (in three this was present with a separate component of reticulation elsewhere (Fig. 5)). Bronchiectasis was found in 13% of the upper lobes, 22% of the middle lobes and 19% of the lower lobes. Table 1 shows that in our series lung involvement in a reticular and/or nodular pattern affected men and women similarly (eight women and six men). A large range for time to diagnosis of lung involvement from the time of diagnosis of CVID is also seen. Clinically all of our patients with reticular and/or nodular changes had recurrent sinopulmonary infections. Tables 3 and 4 summarise the pulmonary function tests (PFTs) in this group. The majority (11 patients) have ab-
Fig. 3. Small, well-defined and randomly distributed nodules and larger, ill-defined, bronchocentric nodules in same patient.
Fig. 4. Isolated bronchiectasis.
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Fig. 5. Bronchiectasis in addition to reticulation.
normal PFTs, either restrictive or both obstructive and restrictive. None had an isolated obstructive picture. All with abnormal PFTs had shortness of breath, persistent cough or both.
4. Discussion High resolution CT is an accurate and reliable technique in the evaluation of many chronic interstitial and obstructive lung diseases [17–19]. The CT findings in sarcoid include small, well-defined nodules, a peribronchovascular distribution, fibrosis and a mid-and upper-zone distribution [20,21]. We have defined the HRCT findings of a specific sub-group of patients who have granulomatous (previously labeled as sarcoid-like) CVID. Of the patients with interstitial lung disease, 80% had a generalised diffuse reticular pattern on HRCT with lower zone predominance. Large ill-defined bronchocentric nodules or small randomly distributed nodules were found in 50% of patients. In all but one patient, the nodules were seen in association with reticular changes. The HRCT features described are different to those described in classical sarcoidosis or primary antibody deficiency. A further observation is that of enlarged nodes occurring in 38% of CT scans, a proportion similar to that previously reported for patients with granulomatous or interstitial lung disease [22]. All patients with lymphadenopathy also had
interstitial changes. As patients with CVID have approximately a thirty-fold risk of developing lymphoma compared to healthy individuals [23], this emphasises the difficulty in interpreting lymphadenopathy in granulomatous CVID. Two of the five patients with lymphadenopathy in this study subsequently developed B cell lymphomas suggesting that lymph node biopsy should be considered even in histologically confirmed granulomatous CVID. Recognition of the spectrum of interstitial lung disease in CVID is essential to distinguish these patients from those with classical sarcoid. Two patients in this series were diagnosed and treated for sarcoidosis prior to the detection of hypogammaglobulinemia and CVID. Measurement of serum immunoglobulins in suspected sarcoidosis may avoid adverse consequences of immunosuppressive treatment in undiagnosed CVID. In patients with CVID, respiratory symptoms and deteriorating lung function, particularly restrictive Table 3 Pulmonary function within 12 months of CT scanning, grouped by percentage of predicted value, for patients with reticular and/or nodular changes on HRCT Range (% of predicted value)
FVC
FEV1
TLCO
KCO
>75 60–75 40–59 <40
7 2 5 0
5 3 5 1
3 3 6 2
9 5 0 0
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Table 4 Numbers of patients with reticular and/or nodular changes at CT scanning in each pulmonary function group Pulmonary function Normal Restrictive Obstructive and restrictive Total
[4]
Number of patients 3 8 3
[5] [6]
14 [7]
changes may be a result of the pathogenesis of CVID itself and not due to recurrent infections and subsequent bronchiectasis. Treatment can then be tailored appropriately. Bronchiectasis was found in 38% (in isolation in 19% and in addition to diffuse reticulation in 19%). This compares to other series that report bronchiectasis in 42–73% of patients with primary immunodeficiency disorders [7–9]. With earlier diagnosis of hypogammaglobulinemia and commencement of immunoglobulin replacement severe bronchiectasis may become less common. The coexistence of bronchiectasis with interstitial lung disease in some patients emphasises the important role of HRCT in the complete assessment of respiratory complications. Our study was retrospective on a selected group of patients within a CVID population and consequently has certain weaknesses in design. Not all patients without respiratory symptoms or signs, or abnormal PFTs had a CT scan due to concerns regarding radiation sensitivity in CVID [24], hence our study does not address the prevalence of interstitial lung disease in CVID. It is also possible that some patients who are asymptomatic with normal lung function have some degree of interstitial lung disease. We have described the spectrum of HRCT changes in the lung in a selected group of CVID patients with features suggestive of interstitial lung disease. Greater appreciation of the spectrum of the radiological abnormalities may help reduce morbidity in this disease. Despite some concerns about radiation sensitivity in CVID, these findings support HRCT scanning of the chest at time of diagnosis of CVID as a baseline assessment of pulmonary disease [24]. Deteriorating lung function in patients with granulomatous CVID may be secondary to interstitial lung disease rather than bronchiectasis and treatment should be tailored accordingly. References [1] Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol 1999; 118 Suppl 1:1–28. [2] Kralovicova J, Hammarstrom L, Plebani A, Webster AD, Vorechovsky I. Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate HLA-DQ/DR as a major susceptibility locus in selective IgA deficiency and common variable immunodeficiency. J Immunol 2003;170:2765–75. [3] Vorechovsky I, Webster AD, Plebani A, Hammarstrom L. Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance
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[22]
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[24]
differences, and the role of anti-IgA antibodies in disease predisposition. Am J Hum Genet 1999;64:1096–109. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999;92:34–48. Webster AD. Common variable immunodeficiency. Immunol Allergy Clin North Am 2001;21:1–22. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997;127:613–7. Curtin JJ, Webster AD, Farrant J, Katz D. Bronchiectasis in hypogammaglobulinaemia—a computed tomography assessment. Clin Radiol 1991;44:82–4. Feydy A, Sibilia J, De Kerviler E, et al. Chest high resolution CT in adults with primary humoral immunodeficiency. Br J Radiol 1996;69:1108–16. Thickett KM, Kumararatne DS, Banerjee AK, Dudley R, Stableforth DE. Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings. QJM 2002;95:655–62. Kainulainen L, Varpula M, Liippo K, Svedstrom E, Nikoskelainen J, Ruuskanen O. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol 1999;104:1031–6. Duddridge M, West KP, Wales J, Browning MJ. A coughing policeman. Lancet 2000;355:804. Sutor G, Fabel H. Sarcoidosis and common variable immunodeficiency A case of a malignant course of sarcoidosis in conjunction with severe impairment of the cellular and humoral immune system. Respiration 2000;67:204–8. Matucci A, Rossi O, Cecchi L, et al. ‘Sarcoidosis-like’ granulomatous disease in patients with common variable hypogammaglobulinemia. Ann Ital Med Int 2002;17:108–16. Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency report of 8 cases and review of the literature. Medicine (Baltimore) 1996;75:251–61. Walsh G, Flower CD, Nasser S, Ewan PW. Granulomatous interstitial pneumonitis in association with primary hypogammaglobulinemia: computed tomography appearances. J Thorac Imaging 1999;14:207–9. Austin JH, Muller NL, Friedman PJ, et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996;200:327–31. Muller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology 1995;196:3–12. Swensen SJ, Aughenbaugh GL, Douglas WW, Myers JL. Highresolution CT of the lungs: findings in various pulmonary diseases. AJR Am J Roentgenol 1992;158:971–9. Webb WR. High resolution lung computed tomography Normal anatomic and pathologic findings. Radiol Clin North Am 1991;29:1051–63. Hansell DM. High resolution computed tomography in sarcoidosis and extrinsic allergic alveolitis: imaging insights. Sarcoidosis 1992;9:21–8. Muller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of 25 patients. AJR Am J Roentgenol 1989;152:1179–82. Curtin JJ, Murray JG, Apthorp LA, Franz AM, Webster AD. Mediastinal lymph node enlargement and splenomegaly in primary hypogammaglobulinaemia. Clin Radiol 1995;50:489–91. Kinlen LJ, Webster AD, Bird AG, et al. Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet 1985;1: 263–6. Vorechovsky I, Scott D, Haeney MR, Webster DA. Chromosomal radiosensitivity in common variable immune deficiency. Mutat Res 1993;290:255–64.
The HRCT appearances of granulomatous pulmonary disease in common variable immune deficiency J.E.S. Park, I. Beal, J.P. Dilworth, V. Tormey, J. Haddock ∗ Royal Free and Hampstead NHS Trust, Pond Street, London NW3 2QG, UK Received 13 April 2004; received in revised form 8 September 2004; accepted 10 September 2004
Abstract Approximately 10% of patients with common variable immune deficiency have systemic granulomatous disease with associated interstitial lung disease. From a population of patients with CVID attending a large tertiary referral clinic for primary immunodeficiency diseases we selected a cohort who had a restrictive defect or impaired gas transfer on pulmonary function testing and/or histologically proven granulomatous disease. HRCT scans of the thorax were reviewed retrospectively in 18 patients by two radiologists. Thirteen patients had diffuse reticulation, which varied from fine to coarse with features of fibrosis. Nodules were found in eight patients. In seven, these were associated with reticulation and in one they were an isolated finding. Bronchiectasis was found as the only abnormality in three and in addition to diffuse reticulation or nodules in another three patients. Greater appreciation of the spectrum of the radiological abnormalities in CVID patients with interstitial lung disease is important. Deteriorating lung function in patients with granulomatous CVID may be secondary to interstitial lung disease rather than bronchiectasis, and treatment should be tailored accordingly. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: HRCT; Common variable immunodeficiency (CVID); Granulomatous
1. Introduction Common variable immunodeficiency (CVID) is the commonest severe primary immunodeficiency disorder with a prevalence of 1:25,000–1:50,000. Affected patients have hypogammaglobulinaemia with a marked reduction in IgG and IgA, a variable decrease in IgM and frequently have low numbers of circulating CD4+ T-cells [1]. Although a minority of CVID patients may have an undiagnosed single gene disorder, a substantial proportion appears to have a complex disorder of immune dysregulation, the major susceptibility locus being in the MHC complex on chromosome 6 [2,3]. Clinically it is a heterogeneous disorder characterised by recurring bacterial infections as well as an increased risk of autoimmune disease and malignancy [4,5]. ∗
Corresponding author. Fax: +44 20 7830 2316. E-mail address: [email protected] (J. Haddock).
0720-048X/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2004.09.005
Symptoms of recurring infections start at any age but there are peaks of onset at 1–5 and 16–20 years. More than 95% of patients present with recurrent sinopulmonary infection and progress gradually to develop bronchiectasis. The mean delay between onset of symptoms and diagnosis is 6 years. A subgroup of patients with CVID develops granulomatous disease [4,6]. The liver and spleen are most commonly involved, but about 10% develop interstitial lung disease. Within the primary antibody deficiencies this feature is probably unique to CVID but the spectrum of lung disease is not well defined with some isolated reports and few large studies. Interstitial lung disease does not occur in X-linked hypogammaglobulinaemia and is most likely to be related to the pathogenesis of the immunodeficiency in CVID. In patients with hypogammaglobulinaemia, bronchiectasis is known to be a common cause for deteriorating lung function with several reports describing the radiological fea-
360
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tures. Curtin et al. [7] described the pattern of bronchiectasis and bronchial wall thickening seen in patients with CVID and X-linked agammaglobulinaemia (XLA). Feydy et al. [8] reported in detail the CT findings in 19 patients (16 of whom had CVID), including lobar/segmental collapse, scars, interstitial lesions, nodules and lobular air trapping in addition to bronchiectasis and bronchial wall thickening. The occurrence of a ‘sarcoid-like’ syndrome in combination with CVID has been widely reported [4,6,13,14], yet there have only been a few reports on the radiographic findings in this specific subset of patients. Thickett et al. [9] described the respiratory complications, lung function and HRCT findings in CVID; although only 2 out of 34 patients had CT scans consistent with granulomatous lung disease. There have also been isolated reports of respiratory complications in CVID that have included CT findings [10–12]. Walsh et al. [15] describe the pulmonary CT findings of histologically proven granulomatous disease in two patients with primary hypogammaglobulinaemia who had multiple nodules with a variable degree of interstitial change. Further to this, Fasano et al. [14] evaluated eight patients with CVID, in whom clinical findings consistent with sarcoidosis were present and reviewed the literature on other reported cases. Chest X-ray and CT findings included hilar adenopathy, scarring, fibrosis, interstitial changes and nodules. Most larger series describe the spectrum of lung disease associated with antibody deficiency, predominantly bronchiectasis [4,9,14]. However, with earlier diagnosis the incidence of established bronchiectasis may be decreasing. To date, most reports of interstitial lung disease in CVID are either isolated cases or reports of small numbers included among other patients with respiratory disease in CVID. The spectrum of interstitial lung disease in CVID requires further characterisation as well as attempts at classification. The purpose of this study is to describe the radiological spectrum of interstitial lung disease on HRCT in 16 patients with granulomatous or sarcoid-like variant of CVID and correlate this with pulmonary function and clinical features.
2. Patients and methods The primary immunodeficiency clinic at the Royal Free Hospital is a large tertiary referral centre for patients with known or suspected immunodeficiency disease. CVID was diagnosed using the World Health Organisation criteria based on recurrent bacterial infections associated with hypogammaglobulinaemia, and the exclusion of other known causes of humoral deficiency [1]. All patients were receiving regular intravenous or subcutaneous immunoglobulin infusions to maintain an IgG level of greater than 8 g/l. All patients have pulmonary function tests performed yearly or more frequently if previously abnormal or they have developed respiratory symptoms. High resolution CT scan of the thorax was performed on patients with progressive symptoms of shortness of breath, impaired gas transfer on
pulmonary function testing and/or an abnormal chest radiograph suggesting fibrosis. We selected 18 patients as having the ‘sarcoid’ variant of CVID based on the following criteria: tissue diagnosis of granulomas from biopsy of lymph node, lung, liver, skin, kidney gut or splenectomy; cholestatic pattern of increased liver function tests (alkaline phosphatase and ␥-glutamyl transferase) with splenomegaly and progressive abnormality in pulmonary function testing with impaired gas transfer and/or restrictive pattern on spirometry. To allow comparison, the pulmonary function tests most closely related in time to CT scanning were recorded. Clinical features were determined by review of the medical notes. CT scans were available for all 18 patients with granulomatous CVID. These were performed at the Royal Free Hospital using GE Medical Systems Prospeed Imation Dryview, High Speed and Light Speed Plus (n = 15) and at a variety of referring hospitals on a Somatom Plus 4 or a Somatom Arsac system (n = 3). Ten of the scans were high resolution with collimation of one or 1.25 mm. Six scans had 5 mm collimation and have been included in the study. Two patients had scans of 10 mm thickness and were considered ineligible. All scans were obtained at end inspiration. Images were obtained at standard window and level settings to demonstrate lung parenchyma and mediastinal structures. Two radiologists independently reviewed CT scans retrospectively in 16 patients. The radiologists were unaware of the clinical condition of the patients or their pulmonary function tests. The pattern of disease was described according to Fleishner Society criteria [16] in terms of reticulation (fine linear, interlobular, coarse linear), traction bronchiectasis, architectural distortion, nodules (size <5 mm, 6–10 mm, >10 mm; definition and distribution) bronchiectasis, zonal predominance and lymphadenopathy. The presence of each abnormality was analysed for the three different lobes of each lung with the lingula considered as a separate lobe. The zonal Table 1 Demographics of the group with reticular and/or nodular changes on HRCT Number of patients Male Female
14 6 8
Median age (range) Mean (range) age at CVID diagnosis Mean time to respiratory diagnosis
50 (25–64) years 29.3 (4–53) years 12.6 (0–45) years
Table 2 Summary of HRCT findings Upper
Middle
Lower
Reticulation Fine Interlobular Coarse
8/32 1/32 12/32
7/32 4/32 14/32
10/32 2/32 17/32
Nodules Bronchiectasis Architectural distortion Traction bronchiectasis
10/32 4/32 15/32 3/32
8/32 7/32 14/32 6/32
12/32 6/32 20/32 4/32
J.E.S. Park et al. / European Journal of Radiology 54 (2005) 359–364
Fig. 1. Bilateral coarse reticulation.
predominance of the CT findings was also recorded as upper, lower or random. Upper lung zone predominance was present when most of the abnormalities were above the level of the tracheal carina and lower zone predominance was present when most of the abnormalities were below this level. Lymphadenopathy was considered present if there were nodes measuring >1 cm in short axis diameter and the site of these was recorded (anterior mediastinal, pretracheal, right or left hilar). 3. Results Patient demographics are summarised in Table 1 and HRCT findings in Table 2. Thirteen of the 16 patients had reticulation. This occurred in 75 out of the possible 96 lobes. There was lower zone predominance with the upper lobe involved in 64% of cases, the middle lobe in 74% and the lower lobe in 91%. The reticulation was coarse in 57% of the affected lobes (Fig. 1) compared with 33% of lobes, which showed fine linear reticulation and 10% with interlobular reticulation. The more coarse reticulation was associated with features of fibrosis. Architectural distortion was evident in 47% of the upper lobes, 44% of the middle lobes and 62% of the lower lobes. Traction bronchiectasis was seen in 10% of the upper lobes, 20% of the middle lobes and 13% of the lower lobes.
Fig. 2. Coarse reticulation in association with ill-defined nodules.
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Eight of the 16 patients had nodules (in seven of these eight the nodules were associated with reticulation (Fig. 2)). The nodules were seen in 31% of the upper lobes, 25% of the middle lobes and 38% of the lower lobes. The smaller nodules (<5 mm) tended to be randomly distributed and well defined and the larger nodules tended to be ill-defined and were bronchocentric in distribution (Fig. 3). Six of the 16 had pre-tracheal adenopathy. In two patients this was in conjunction with hilar adenopathy. The adenopathy was seen in conjunction with reticulation in five of these patients. The other patient had no reticulation and only widespread bronchiectasis was seen (Fig. 4). Six of the 16 patients had bronchiectasis (in three this was present with a separate component of reticulation elsewhere (Fig. 5)). Bronchiectasis was found in 13% of the upper lobes, 22% of the middle lobes and 19% of the lower lobes. Table 1 shows that in our series lung involvement in a reticular and/or nodular pattern affected men and women similarly (eight women and six men). A large range for time to diagnosis of lung involvement from the time of diagnosis of CVID is also seen. Clinically all of our patients with reticular and/or nodular changes had recurrent sinopulmonary infections. Tables 3 and 4 summarise the pulmonary function tests (PFTs) in this group. The majority (11 patients) have ab-
Fig. 3. Small, well-defined and randomly distributed nodules and larger, ill-defined, bronchocentric nodules in same patient.
Fig. 4. Isolated bronchiectasis.
J.E.S. Park et al. / European Journal of Radiology 54 (2005) 359–364
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Fig. 5. Bronchiectasis in addition to reticulation.
normal PFTs, either restrictive or both obstructive and restrictive. None had an isolated obstructive picture. All with abnormal PFTs had shortness of breath, persistent cough or both.
4. Discussion High resolution CT is an accurate and reliable technique in the evaluation of many chronic interstitial and obstructive lung diseases [17–19]. The CT findings in sarcoid include small, well-defined nodules, a peribronchovascular distribution, fibrosis and a mid-and upper-zone distribution [20,21]. We have defined the HRCT findings of a specific sub-group of patients who have granulomatous (previously labeled as sarcoid-like) CVID. Of the patients with interstitial lung disease, 80% had a generalised diffuse reticular pattern on HRCT with lower zone predominance. Large ill-defined bronchocentric nodules or small randomly distributed nodules were found in 50% of patients. In all but one patient, the nodules were seen in association with reticular changes. The HRCT features described are different to those described in classical sarcoidosis or primary antibody deficiency. A further observation is that of enlarged nodes occurring in 38% of CT scans, a proportion similar to that previously reported for patients with granulomatous or interstitial lung disease [22]. All patients with lymphadenopathy also had
interstitial changes. As patients with CVID have approximately a thirty-fold risk of developing lymphoma compared to healthy individuals [23], this emphasises the difficulty in interpreting lymphadenopathy in granulomatous CVID. Two of the five patients with lymphadenopathy in this study subsequently developed B cell lymphomas suggesting that lymph node biopsy should be considered even in histologically confirmed granulomatous CVID. Recognition of the spectrum of interstitial lung disease in CVID is essential to distinguish these patients from those with classical sarcoid. Two patients in this series were diagnosed and treated for sarcoidosis prior to the detection of hypogammaglobulinemia and CVID. Measurement of serum immunoglobulins in suspected sarcoidosis may avoid adverse consequences of immunosuppressive treatment in undiagnosed CVID. In patients with CVID, respiratory symptoms and deteriorating lung function, particularly restrictive Table 3 Pulmonary function within 12 months of CT scanning, grouped by percentage of predicted value, for patients with reticular and/or nodular changes on HRCT Range (% of predicted value)
FVC
FEV1
TLCO
KCO
>75 60–75 40–59 <40
7 2 5 0
5 3 5 1
3 3 6 2
9 5 0 0
364
J.E.S. Park et al. / European Journal of Radiology 54 (2005) 359–364
Table 4 Numbers of patients with reticular and/or nodular changes at CT scanning in each pulmonary function group Pulmonary function Normal Restrictive Obstructive and restrictive Total
[4]
Number of patients 3 8 3
[5] [6]
14 [7]
changes may be a result of the pathogenesis of CVID itself and not due to recurrent infections and subsequent bronchiectasis. Treatment can then be tailored appropriately. Bronchiectasis was found in 38% (in isolation in 19% and in addition to diffuse reticulation in 19%). This compares to other series that report bronchiectasis in 42–73% of patients with primary immunodeficiency disorders [7–9]. With earlier diagnosis of hypogammaglobulinemia and commencement of immunoglobulin replacement severe bronchiectasis may become less common. The coexistence of bronchiectasis with interstitial lung disease in some patients emphasises the important role of HRCT in the complete assessment of respiratory complications. Our study was retrospective on a selected group of patients within a CVID population and consequently has certain weaknesses in design. Not all patients without respiratory symptoms or signs, or abnormal PFTs had a CT scan due to concerns regarding radiation sensitivity in CVID [24], hence our study does not address the prevalence of interstitial lung disease in CVID. It is also possible that some patients who are asymptomatic with normal lung function have some degree of interstitial lung disease. We have described the spectrum of HRCT changes in the lung in a selected group of CVID patients with features suggestive of interstitial lung disease. Greater appreciation of the spectrum of the radiological abnormalities may help reduce morbidity in this disease. Despite some concerns about radiation sensitivity in CVID, these findings support HRCT scanning of the chest at time of diagnosis of CVID as a baseline assessment of pulmonary disease [24]. Deteriorating lung function in patients with granulomatous CVID may be secondary to interstitial lung disease rather than bronchiectasis and treatment should be tailored accordingly. References [1] Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol 1999; 118 Suppl 1:1–28. [2] Kralovicova J, Hammarstrom L, Plebani A, Webster AD, Vorechovsky I. Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate HLA-DQ/DR as a major susceptibility locus in selective IgA deficiency and common variable immunodeficiency. J Immunol 2003;170:2765–75. [3] Vorechovsky I, Webster AD, Plebani A, Hammarstrom L. Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance
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