ORIGINAL ARTICLE

Chest CT findings in pediatric Wegener’s granulomatosis

Daniel Levine & Jonathan Akikusa & David Manson &

Earl Silverman & Rayfel Schneider

Received: 29 June 2006 /Revised: 20 September 2006 /Accepted: 27 September 2006 / Published online: 28 October 2006# Springer-Verlag 2006

AbstractBackground Although pulmonary involvement occurs in themajority of children and adolescents with Wegener’s gran-ulomatosis (WG), relatively little has been published regard-ing the CT imaging manifestations in this group of patients.Objective To determine the frequency and types of chestCT abnormalities in active pediatric WG (pWG).Materials and methods The study was a retrospectiveexamination of 29 chest CT examinations performed atdiagnosis (n=14) and during disease flares (n=15) in 18children.Results The most common abnormalities were nodules(seen in 90% of examinations), ground-glass opacification(52%), and air-space opacification (45%). Of examinationswith nodules, 73% demonstrated nodules >5 mm indiameter and 69% demonstrated more than five nodules;17% had cavitary lesions. The only abnormality with asignificant difference in prevalence between diagnosis and

disease flares was air-space opacification, present in 71%and 20%, respectively (P<0.01).Conclusions In accordance with the findings of publishedadult studies and at variance with those of prior pediatricstudies, our findings indicate that chest CT abnormalities inactive pWG are frequent, most commonly comprisingnodules and ground-glass opacification, which may bedifficult to detect on plain radiography. We thereforeadvocate the routine use of chest CT for all affected patients,both at the time of presentation and during disease flares.

Keywords Wegener’s granulomatosis . Chest . CT.

Children

Introduction

In 1931, Heinz Klinger of the University of Berlin firstreported the cases of two patients who died of systemicvasculitis. Five years later, Friedrich Wegener, a Germanpathologist from Breslau, described three patients withnecrotizing granulomata involving both the upper andlower respiratory tract; he was the first to recognize thisdisorder as a distinct form of vasculitis, which now bearshis name. More recently, the Chapel Hill Conference on thenomenclature of systemic vasculitides defined Wegener’sgranulomatosis (WG) as a necrotizing granulomatousinflammation involving the respiratory tract and affectingsmall- to medium-sized vessels, with necrotizing glomeru-lonephritis being a common association [1]. Although theetiology remains obscure, both exogenous and geneticfactors have been implicated [2] and there is evidence thatthe disease process is initiated with damage to the vascularendothelium [3]. Classically affecting the upper respiratorytract, lungs, and kidneys, the disease may affect almost any

Pediatr Radiol (2007) 37:57–62DOI 10.1007/s00247-006-0341-9

D. Levine (*)Department of Radiology and Nuclear Medicine,British Columbia Children’s Hospital,4480 Oak Street,Vancouver, British Columbia, CanadaV6H 3V4e-mail: daniel.levine@mac.com

J. AkikusaDepartment of Rheumatology,Royal Children’s Hospital Melbourne,Melbourne, Australia

D. MansonDepartment of Radiology, Hospital for Sick Children,Toronto, Canada

E. Silverman :R. SchneiderDepartment of Rheumatology, Hospital for Sick Children,Toronto, Canada

organ system, including the eye, brain, skin, gastrointestinaltract, and spleen; joint involvement may also occur [4–7]. Inthe past, the diagnosis was usually made by histopathologicdemonstration of vasculitis, necrosis, and granulomatousinflammation [8], but more recently the presence of serumantineutrophil cytoplasmic antibodies (ANCA) has reducedthe requirement for histologic confirmation. The mainstay oftreatment comprises cytotoxic and immunosuppressantagents including corticosteroids. Although the majority ofpatients with pediatric WG (pWG) survive longer than5 years following diagnosis, prolonged disease-free remis-sion remains rare [8].

As lower airway involvement is common in WG, bothchest radiography and CT are important in establishing thediagnosis. The spectrum of WG abnormalities on chest CThas been well documented within the adult population andincludes nodules, air-space and ground-glass opacification,airway involvement, pleural effusions, and lymphadenopa-thy [9–17]. However, only one prior study has investigatedthe pattern of abnormalities seen in a small cohort of fivepWG patients, finding it to be at variance with that of adultdisease [18]. We reviewed the medical records and chestCT examinations of 25 pWG patients seen at our institutionover a 21-year period and describe the imaging findings inthis larger patient cohort with emphasis on the prevalenceand patterns of CT abnormalities during active disease.

Materials and methods

With Research Ethics Board approval, 25 patients diagnosedwith pWG at the Hospital for Sick Children in TorontobetweenMarch 1984 and January 2005 were identified from apreexisting database maintained by the Division of Rheuma-tology. All patients had at least two of the four disease featuresof the 1990 American College of Rheumatology criteria forclassification ofWG,which are: (1) nasal or oral inflammation,(2) abnormal chest radiograph, (3) urinary sediment, and (4)granulomatous inflammation on biopsy [19]. In the absence offormal documentation of the state of a patient’s nasal or oralmucosa, CT evidence of turbinate mucosal thickening withassociated sinusitis was accepted as evidence of nasalinvolvement, provided there were other features suggestiveof WG. From 18 of these patients, 29 CT examinations wereavailable for review, one examination for each of 14 patientsat presentation and 15 examinations for 8 patients duringdisease flares. Four patients had examinations included inboth groups. For those patients who had more than one chestCT scan at presentation or during a disease flare, only theinitial examination was included.

For the purposes of this study, disease flares weredefined as one or more of the following: new or recurrentclinical features considered to be related to active pWG, a

prednisone dose increase (other than for reasons of stressdosing), and/or a sustained increase in serum creatinine(≥30%) over immediately preceding values documented notmore than 6 months before in nondialysis-dependentpatients.

CTchest examinations were performed on General Electric9800, HiLight Advantage, HiSpeed, Lightspeed QXI andLightspeed Ultra systems (GE Medical Systems, Milwaukee,Wis.). Examinations performed prior to 1999 were viewed onhard copy film; all later examinations were viewed on adedicated PACS workstation (GE Centricity, GE MedicalSystems). All examinations were independently read by twopediatric radiologists blinded to the phase of disease at whichthe examinations were obtained (i.e. presentation or flare), andthe findings were entered into a specially prepared database.For each examination the presence or absence of the followingon axial lung window and, where available, mediastinalwindow images was recorded: ground-glass opacification,uni- or multifocal air-space opacification, mosaic attenuation(alternating areas of relatively increased and decreasedparenchymal attenuation), pleural effusion, pleural thickening,endobronchial abnormality (comprising luminal irregularity,stenosis, or mass lesion), lymphadenopathy, and parenchymalnodules. The latter were further assessed by number (less thanor more than five), by size (less than or more than 5 mm indiameter), and for the presence of cavitation. Where differ-ences in findings occurred between the two radiologists, therelevant examinations were reassessed and a consensusopinion recorded.

In cases where clinical questions arose in relation to theexplanation of the radiologic findings, reference was made to adatabase established by the Division of Rheumatology doc-umenting the clinical features of pWG patients followed at ourinstitution at the onset of their disease and during follow-up.

Data were analyzed using simple descriptive statistics.The prevalences of specific radiologic findings in exami-nations performed at presentation were compared withthose in examinations obtained during disease flares usingFisher’s exact test. The number of findings per examinationat presentation was compared with that during disease flaresusing the two-sample t-test.

Results

The cohort consisted of 18 patients; 5 were male and 13 werefemale. The median age at the time of CT examination was14.9 years. The majority of presentation CT examinationswere non-high-resolution CT (non-HRCT) whilst thoseobtained at times of disease flare were fairly evenly splitbetween HRCT and non-HRCT (Table 1).

The most common abnormalities identified were nodules(seen in 89.7% of examinations), ground-glass opacifica-

58 Pediatr Radiol (2007) 37:57–62

tion (51.7%), and air-space opacification (44.8%) (Table 2).In 84.6% of the examinations exhibiting air-space opacifi-cation, the abnormality was multifocal. Combinations ofabnormalities were common. Of those examinations withnodules, 73.1% demonstrated nodules >5 mm in diameterand 69.2% demonstrated more than five nodules. Overall,17.3% had cavitary lesions, 21.4% at presentation and13.3% during disease flares. Mediastinal lymphadenopathywas seen in 21.4% of examinations at presentation but innone during disease flares. One patient alone exhibitedendobronchial abnormality (3.4% of all examinations),demonstrating subtle tracheal mural irregularity on adisease flare examination. The only abnormality with asignificant difference in prevalence between examinationsobtained at diagnosis and times of disease flare was air-space opacification, which was present in 71.4% and 20%,respectively (P<0.01; Table 2). In five patients thisabnormality at presentation was associated with clinicalevidence of pulmonary hemorrhage (falling hemoglobinlevel and/or hemoptysis) whereas only one patient hadclinically evident pulmonary hemorrhage during a diseaseflare. Although the prevalences of specific findings atpresentation and flare were generally similar, there weresignificantly more abnormalities per examination at presen-tation than during disease flares (median 3.5 at presentation

versus 2.0 during flares, P<0.02). Figures 1, 2, 3 and 4illustrate some typical examples of chest CT imagingfindings in the study cohort.

Discussion

Although pulmonary involvement has been documented in74% to 87% of children and adolescents withWG [4, 20, 21],relatively little has been published in the radiologic literaturewith regard to the relevant imaging manifestations—likely areflection of the rarity of the condition. In 1994, Wadsworthet al. [22] documented the chest radiographic manifestationsin 11 children with WG, finding that diffuse alveolar andinterstitial opacities were the most common abnormality,occurring in 64%, with nodular disease being identified inonly 27% of the patient cohort. In a 1990 case report, Singeret al. [23] described the chest radiographic findings in an 11-year-old female with biopsy-confirmed WG as comprisingfour large, well-defined nodules, with one demonstratingcavitation. Other case reports have described infiltrates,pleural effusions, and nodular disease on chest radiography[21, 24]. However, the increased sensitivity of CT ascompared to radiography for the often subtle abnormalitiesthat comprise the imaging manifestations of pulmonary WGis both intuitive and established [11, 14, 17, 25, 26].

The most common CT findings reported in adult WGpatients are nodules, which are present in approximately 63%to 89% of patients, with cavitating nodules present inapproximately 22% to 50% of patients. Air-space andground-glass opacification are present in approximately 50%of patients; airway involvement (such as bronchial narrowing)is present in up to 59% of patients. Pleural effusions are lesscommon, being present in up to 12% of patients; mediastinal

Table 1 Technical details of CT examinations

HRCT Non-HRCT

Total HRCT asproportionof total (%)

Presentation examinations 5 9 14 35.7Flare examinations 8 7 15 53.3Total examinations 13 16 29 44.8

Table 2 Prevalence of chestCT findings at presentationversus during disease flares.The values presented are thepercentage of examinationswith the specific abnormality(NS not significant)

a Some examinations exhibitednodules within both sizecategories.

Abnormality Allexaminations

Presentationexaminations

Flareexaminations

P value(Fisher’s exacttest)

Nodules 89.7 92.9 86.7 NSWith cavitation 17.3 21.4 13.3 NSDiameter >5 mm 73.1 76.9 69.2 NSDiameter <5 mm 50.0a 46.2 53.8 NSMore than five 69.2 61.5 76.9 NSLess than five 30.8 38.5 23.1 NSGround-glass opacification 51.7 35.7 66.7 NSAir-space opacification 44.8 71.4 20.0 0.0092Multifocal air space opacification 84.6 90.0 66.7 NSMediastinal lymphadenopathy 10.3 21.4 0.0 NSSeptal thickening 6.9 7.1 6.7 NSPleural thickening 6.9 7.1 6.7 NSPleural effusion 6.9 14.3 0.0 NSParenchymal calcification 3.4 0.0 6.7 NSEndobronchial abnormality 3.4 0.0 6.7 NS

Pediatr Radiol (2007) 37:57–62 59

adenopathy, present in up to 15% of patients, tends to coexistwith lung parenchymal abnormalities. The studies describingthese abnormalities each comprised cohorts of between 8 and77 adult patients [9–17].

Large, rapidly cavitating nodules have been described onCT imaging in a 13-year-old Turkish male with WG [27], butthe only published study detailing the chest CT findings in apediatric cohort were reported in 1991 by McHugh et al.[18], In a series of 22 examinations of five patients, the mostcommon CT abnormality was multifocal parenchymalinfiltrates, which occurred in 32% of examinations; 27%exhibited nodules and 10% exhibited pleural disease, and nopatients with cavitating lesions, airway involvement, ormediastinal adenopathy were identified. The results of ourreview are in agreement with the adult studies rather thanthis prior pediatric review; this may be a reflection of the factthat our CT examinations were spread across a larger patientcohort, thereby providing a more accurate representation of

the true spectrum of disease. The single abnormality forwhich our data differs markedly from the published adultdata is that of thoracic airway involvement. A small numberof case reports have been published describing subglotticstenosis in pWG [22, 28, 29], and incidences of 58–91% forupper airway involvement (including ear, tracheal, nasal, andparanasal sinus disease) have been described in largerpediatric cohorts [4, 20, 21], but only four case reports ofthoracic tracheal or bronchial involvement in pWG wereidentified on review of the literature [30–33]. While it isconceivable that thoracic airway involvement in pWG mayhave been under-reported, the possibility that this particulardisease manifestation truly differs in incidence between adultand pediatric populations cannot be excluded.

A striking observation from our data is that of thestatistically significant difference in the incidence of air-space opacification between those CT examinations per-formed at initial presentation and those obtained duringdisease flares. A plausible explanation for this observationis that patients had significantly more active disease atpresentation than during disease flares and were thereforemore likely to demonstrate a wider spectrum of pulmonarymanifestations. Indeed, those patients in whom a diagnosisof pWG has been established undergo close clinical follow-up and are consequently likely to have symptoms of diseaseflare recognized and treated early. The observations (1) thatthere were significantly more abnormalities present onexaminations obtained at presentation as opposed to duringdisease flares, and (2) that pulmonary hemorrhage wasfrequently present as a clinical correlate of air-spaceopacification at presentation would support this idea.

Since follow-up CT examinations were not routinelyobtained in those patients in whom abnormalities weredocumented, it is not possible to make any generalizationsregarding the natural history of these abnormalities basedon our data. However, in those patients in whom follow-upexaminations were obtained, near-complete interval resolu-

Fig. 1 Axial images from the HRCT scan of the chest in a 12-year-oldgirl show multiple nodules of various sizes

Fig. 2 Axial images from the HRCT scan of the chest in a 13-year-oldgirl show a diffusely distributed pattern of centrilobular perivascularground-glass opacities similar to that seen in a “tree-in-bud” pattern ofnodules

Fig. 3 Axial image from CT volume acquisition of the chest in an 8-year-old girl shows multifocal air-space opacification within the rightlung

60 Pediatr Radiol (2007) 37:57–62

tion occurred, with only minor residual scarring at sites ofprior large cavitating nodules noted.

During the course of this study, some methodologicalproblems were encountered. First, not all presentation anddisease-flare CT examinations performed on the 25 patientsdiagnosed during the review period were available forevaluation. However, the missing studies tended to be olderexaminations, recorded on film rather than stored digitally;selection bias seems unlikely since all older examinationsshould have had an equal chance of being lost regardless ofthe findings that those studies contained. Second, althoughdrawing data from a relatively large patient cohort over along period of time has the advantage of increasing thestatistical power of the data, this comes at a cost—namely,the lack of uniformity of CT examination technique. Overall,the examinations were approximately evenly divided be-tween conventional (axial or volume) acquisitions andHRCT. While this may conceivably reduce confidence inthe study results on the one hand, it is also a reflection of realclinical practice since, in many institutions, imaging tech-

niques typically vary with individual radiologists’ prefer-ences, often without a consistent approach being taken.

Third, four patients were too unwell to undergo CT at thetime of presentation and all of these presented withpulmonary hemorrhage. The incidence of air-space andground-glass opacification may therefore have been under-estimated within our patient cohort. However, by virtue ofthe fact that these patients were excluded from thepresentation CT data, our results are more likely to reflectthose that would be seen in real clinical practice. Fourth,since the acquisition of disease-flare CT examinations wasnot driven by a standard clinical protocol, it is likely that atleast some of the patients who underwent imaging at thosetimes did so as a consequence of their chest symptoms,potentially artificially elevating the prevalence of abnor-malities in this group as compared to those patientsexperiencing a disease flare in the absence of chestsymptoms. It must be remembered, however, that the lungsremain the organ system most commonly affected in WG.

Finally, there is a difference between the prevalence of aspecific abnormality within a cohort of patients versus acohort of examinations. This distinction is not clearly madein some of the published data and makes comparison withour findings more difficult. Conceivably, an abnormalitymay have a low incidence amongst a cohort of WG patientsbut a much higher incidence amongst the cohort of CTexaminations of those patients. This would be true if thatparticular abnormality were present in those patients with amore severe clinical course, requiring a greater number ofCT examinations and contributing disproportionately to thesize of the examination cohort. For example, in the earlierreview of imaging findings in a pWG cohort of five patients,the fact that 18 out of a total of 22 examinations wereperformed on only two patients may render conclusionsbased on the prevalence of specific findings unreliable [18].

Conclusions

These findings, collected from patients presenting over a21-year period and representing the largest cohort of pWGpatients undergoing radiologic review, in contradistinctionto earlier work, suggests that chest CT findings areessentially the same as within the adult population, withnodules being the most common abnormality demonstrated.The statistically significant difference in the prevalence ofair-space opacification between presentation and disease-flare examinations requires the pediatric radiologist to beaware of the differing expected findings at various stageswithin the history of the disease. Finally, since CT isaccepted as being more sensitive than radiography indetecting abnormalities of the organ system most common-ly affected by WG, we advocate the routine use chest CT

Fig. 4 Axial images from CT volume acquisition of the chest in a 15-year-old girl show a large focus of near-confluent nodular air-spacedisease within the right lung (a) and a single large cavitary nodulewith several smaller ill-defined nodules also present, predominantlyaffecting the right lung (b)

Pediatr Radiol (2007) 37:57–62 61

for all affected patients both at the time of presentation andat times of disease flare. The examination obtained atpresentation will enable an assessment of baseline chestdisease against which the efficacy of therapeutic interven-tions may be considered at later stages in the diseasehistory. Although the diagnostic accuracy of HRCT versusconventional axial or volume acquisitions was not evaluat-ed here, use of the former rather than the latter is suggestedon the basis of radiation dose considerations.

References

1. Jennette JC, Falk RJ, Andrassy K, et al (1994) Nomenclature ofsystemic vasculitides. Proposal of an international consensusconference. Arthritis Rheum 37:187–192

2. Segelmark M, Elzouki AN, Wieslander J, et al (1995) The PiZgene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis. Kidney Int 48:844–850

3. Weiss MA, Crissman JD (1984) Renal biopsy findings inWegener’s granulomatosis: segmental necrotizing glomerulone-phritis with glomerular thrombosis. Hum Pathol 15:943–956

4. Belostotsky VM, Shah V, Dillon MJ (2002) Clinical features in 17paediatric patients with Wegener granulomatosis. Pediatr Nephrol17:754–761

5. Haas JP, Metzler M, Ruder H, et al (2002) An unusualmanifestation of Wegener’s granulomatosis in a 4-year-old girl.Pediatr Neurol 27:71–74

6. McHugh K, Manson D, Eberhard BA, et al (1991) Splenicnecrosis in Wegener’s granulomatosis. Pediatr Radiol 21:588–589

7. Provenzale JM, Allen NB (1996) Wegener granulomatosis: CTand MR findings. AJNR 17:785–792

8. Frosch M, Foell D (2004) Wegener granulomatosis in childhoodand adolescence. Eur J Pediatr 163:425–434

9. Aberle DR, Gamsu G, Lynch D (1990) Thoracic manifestations ofWegener granulomatosis: diagnosis and course. Radiology174:703–709

10. Cordier JF, Valeyre D, Guillevin L, et al (1990) PulmonaryWegener’s granulomatosis. A clinical and imaging study of 77cases. Chest 97:906–912

11. Kuhlman JE, Hruban RH, Fishman EK (1991) Wegener gran-ulomatosis: CT features of parenchymal lung disease. J ComputAssist Tomogr 15:948–952

12. Lee KS, Kim TS, Fujimoto K, et al (2003) Thoracic manifestationof Wegener’s granulomatosis: CT findings in 30 patients. EurRadiol 13:43–51

13. Lohrmann C, Uhl M, Kotter E, et al (2005) Pulmonary manifes-tations of wegener granulomatosis: CT findings in 57 patients and areview of the literature. Eur J Radiol 53:471–477

14. Papiris SA, Manoussakis MN, Drosos AA, et al (1992) Imagingof thoracic Wegener’s granulomatosis: the computed tomographicappearance. Am J Med 93:529–536

15. Pretorius ES, Stone JH, Hellman DB, et al (2004) Wegener’sgranulomatosis: CT evolution of pulmonary parenchymal findingsin treated disease. Crit Rev Comput Tomogr 45:67–85

16. Sheehan RE, Flint JD, Muller NL (2003) Computed tomographyfeatures of the thoracic manifestations of Wegener granulomatosis.J Thorac Imaging 18:34–41

17. Weir IH, Muller NL, Chiles C, et al (1992) Wegener’sgranulomatosis: findings from computed tomography of the chestin 10 patients. Can Assoc Radiol J 43:31–34

18. McHugh K, Manson D, Eberhard BA, et al (1991) Wegener’sgranulomatosis in childhood. Pediatr Radiol 21:552–555

19. Leavitt RY, Fauci AS, Bloch DA, et al (1990) The AmericanCollege of Rheumatology 1990 criteria for the classification ofWegener’s granulomatosis. Arthritis Rheum 33:1101–1107

20. Rottem M, Fauci AS, Hallahan CW, et al (1993) Wegenergranulomatosis in children and adolescents: clinical presentationand outcome. J Pediatr 122:26–31

21. Stegmayr BG, Gothefors L, Malmer B, et al (2000) Wegenergranulomatosis in children and young adults. A case study of tenpatients. Pediatr Nephrol 14:208–213

22. Wadsworth DT, Siegel MJ, Day DL (1994) Wegener’s granulo-matosis in children: chest radiographic manifestations. AJR163:901–904

23. Singer J, Suchet I, Horwitz T (1990) Paediatric Wegener’sgranulomatosis: two case histories and a review of the literature.Clin Radiol 42:50–51

24. Pradhan M, Meyers KE, Guttenberg M, et al (2000) Wegenergranulomatosis – an atypical case. Pediatr Nephrol 14:862–871

25. Anderson M, O’Driscoll BR, Chisholm R, et al (2000) Clinicalimages: high-resolution computed tomography in the diagnosis andmanagement of pulmonary Wegener’s granulomatosis in a patientwith normal chest radiography findings. Arthritis Rheum 43:698

26. Maskell GF, Lockwood CM, Flower CD (1993) Computedtomography of the lung in Wegener’s granulomatosis. Clin Radiol48:377–380

27. Haliloglu M, Karcaaltincaba M, Toru M, et al (2000) CT presentationof Wegener’s granulomatosis in a child: rapidly progressive changesof pulmonary nodules to cavities. Eur J Radiol 35:12–14

28. Hall SL, Miller LC, Duggan E, et al (1985) Wegener granuloma-tosis in pediatric patients. J Pediatr 106:739–744

29. Neumann G, Benz-Bohm G, Rister M (1984) Wegener’s gran-ulomatosis in childhood. Review of the literature and case report.Pediatr Radiol 14:267–271

30. Cohen MI, Gore RM, August CZ, et al (1984) Tracheal and bronchialstenosis associated with mediastinal adenopathy in Wegener gran-ulomatosis: CT findings. J Comput Assist Tomogr 8:327–329

31. Cohen SR, Landing BH, King BK, et al (1978) Wegener’sgranulomatosis causing laryngeal and tracheobronchial obstructionin an adolescent girl. Ann Otol Rhinol Laryngol Suppl 87:15–19

32. Matt BH (1996) Wegener’s granulomatosis, acute laryngotrachealairway obstruction and death in a 17-year-old female: case reportand review of the literature. Int J Pediatr Otorhinolaryngol37:163–172

33. Park KJ, Bergin CJ, Harrell J (1998) MR findings of trachealinvolvement in Wegener’s granulomatosis. AJR 171:524–525

62 Pediatr Radiol (2007) 37:57–62