Pediatric Radiology

Hyperimmunoglobulinemia E Syndrome: Radiographic Observations 1 David F. Merten, M.D., Rebecca H. Buckley, M.D., Philip C. Pratt, M.D., Eric L. Elfmann, M.D., and Herman Grossman, M.D.

Susceptibility to recurrent staphylococcal cutaneous and respiratory infections beginning in infancy associated with extreme hyperimmunoglobulinemia E is a recently described primary immunodeficiency syndrome. Other clinical features include depressed cellular immunity and deficient antibody formation. Recurrent pneumonia and cyst formation with variable persistence and expansion characterized the radiographic course in 11 patients. Five cysts resolved with continuous antistaphylococcal therapy; 2 were resected without recurrence; and 4 persisted after surgery and/or antibiotics (2-8 years). The cysts had dense, necrotic surfaces with fibrous walls, eosinophilic and other inflammatory cell infiltrates, and frequent, persistent, bronchial connections. Sinusitis (9/9) and mastoiditis (3/4) were also observed radiographically. INDEX TERMS: Aspergillosis. Immunity • Lungs, cysts. Lungs, infection • Lungs, surgery. Pneumonia • (Lung, immune defect with recurrent infection, 6 [0] .250) • (Lung, infection with primary immunoglobulin aberration, 6[0].2512). (Paranasal sinuses, sinusitis, 2[3].250) • (Ear, temoporal bone, mastoiditis, 2[1].260) Radiology 132:71-78, July 1979

TABLE I: CLINICAL FINDINGS IN HYPER-IGE SYNDROME (11 PATIENTS)

1972, Buckley et a/. (1) described an immunodeficiency syndrome characterized by a lifelong history of recurrent severe staphylococcal infections associated with extreme elevation of serum IgE concentration, occasionally in excess of 40,000 IU/ml (N5-621). Additional immunological features included depressed cellular immunity and deficient antibody formation, despite normal or elevated concentrations of other immunoglobulins. Over the past 10 years, 11 patients with the hyper-lgE syndrome have been referred to the Duke University Medical Center (DUMC) for diagnosis and treatment. Recurrent pneumonia, pneumatocele formation and, in many cases, persistence and expansion of these acquired cysts were noted. Description of the radiologic findings in these 11 patients constitutes the basis for this report. N

I

Age Sex Race Familial occurrence Infantile dermatitis Infection Onset Site

Organism

Course

CLINICAL FINDINGS (TABLE I)

At the time of this study the patients ranged in age from 4 to 39 years; however, in all cases manifestations of the immunodeficiency developed in infancy. A predominance of males was noted in this series (1OMI1F), and racial background was varied. There was sporadic familial occurrence of the syndrome, as well as involvement of both sexes and succeeding generations, suggesting an autosomal dominant form of inheritance with incomplete penetrance. In early infancy, all patients had a pruritic rash that either persisted into childhood or disappeared altogether. AI-

4-39 Years (Mean 18) 10 Male/ 1 female 8 White/3 black 2 11 Newborn (1-15 d) Infancy (1-22 mo) Skin Lungs Sinus Ear/mastoid Mouth (Candida) Septicemia Septic arthritis Staphylococcus aureus Candida albicans H. influenzae Living Dead

4 7 11 11 9 8

6 2 1 11 6 2 9 2

TABLE II: IMMUNOLOGICAL FEATURES IN HYPER-IGE SYNDROME IgE elevation (100 % ) Depressed cell-mediated immunity (100 % ) Deficient antibody formation (90 % ) Blood and sputum eosinophilia (100%) Normal phagocytic cell killing (100 %) Normal complement function (100 % ) Reproducible chemotactic abnormalities (27 %)

1 From the Departments of Radiology (D.F.M., E.L.E., H.G.), Pediatrics (R.H.B.) and Pathology (P.C.P.), Duke University Medical Center, Durham NC 27710. Presented at the Sixty-fourth Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, lll., Nov. 26-Dec. 1, 1978. Submitted for publication 26 Nov. 1978; revision requested 20 Feb. 1979; received 12 March 1979. Supported by grants RR-30, the General Clinical Research Center Program; AI 12026-05, Asthma and Allergic Diseases Center; and K07 A 170830, Allergic Diseases Academic Award. shan

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media and/or mastoiditis, and oral moniliasis were also frequently seen. Septicemia and arthritis were rarely encountered; infection of the urinary or gastrointestinal tracts, meninges, or skeletal structures was not seen. In addition to infections with staphylococci, infections with Hemophilus influenzae, pneumococci, streptococci, and fungi also were occasionally present. All patients have received long-term antibiotic therapy. Four have undergone surgical resection of persistent lung cysts. Nine patients are currently living; 2 have died. In one case (BS) esophageal perforation of unknown etiology occurred in a patient then free of infection, while in the other case (SE), death was due to massive pulmonary hemorrhage following resection of an infected lung cyst. Immunological findings are summarized in TABLE II. Marked elevation of IgE serum levels (5000-46,000 IU/ml, N 5-621) characterized the laboratory picture. A complete description and discussion of the immunological features of the hyper-lgE syndrome have been published elsewhere (2) . Fig. 1. (PT). At age 6 years. following an episode of recurrent staphylococcal pneumonia. there is a well-defined. unilocular cyst in the right upper lobe. The cyst lining is smooth and the wall is relatively thin. The cyst resolved over the course of a yearon constant antistaphylococcal therapy and at age9 years. the lungs remain clearof disease. though the rash was an eczematoid dermatitis. the distribution and character of the lesions were not those typical of atopic eczema. There was little or no evidence of respiratory allergy in these patients. Pyogenic infections began before two years of age in all patients and as early as the newborn period in 4. Severe recurrent furunculosis and pneumonia secondary to Staphylococcus aureus. coagulase positive. characterized the clinical course of all patients. Recurrent sinusitis, otitis

RADIOLOGY (TABLE III)

Radiological findings consist of recurrent pneumonia, pulmonary cyst formation with variable persistence and expansion of these acquired cysts. The onset of pneumonia ranged from the newborn period to eight years, with the initial pulmonary infection presenting before three years of age in the majority of patients. In all cases, the acute episodes of staphylococcal pneumonia were observed and treated elsewhere. Review of the available material indicates a segmental or lobar distribution of pneumonia. Pulmonary cyst formation was quite variable and could not [with the exception of 2 cases (TF, JB)] always be related to the initial bout of pneumonia. The interval until cyst formation ranged from two to eight years after the initial episode of pneumonia in 5 cases. Location

TABLE III: RADIOLOGIC FINDINGS (CHEST) IN HYPER IGE SYNDROME Lung S;yst Initial Appearance Single/Multiple Course (M) (Age) (Duration) (S) Location

Patient

Initial Pneumonia (Age)

BS

3 mo

12.5y

RB

5 mo

4y

AY CC TF PT LH JB

1d 5y 8y 2y 1y 1 mo

1.5 mo

OS SE

2.5 y 3y

10.5 Y 6y

EN

5y

LUL

S M

LLL

M

RUL RUL RLL RUL RUL LLL RLL LLL LLL RUL RLL LUL RLL LUL

S

S 8y 6y

S S S

S

M

M

Persistent (2y) Persistent (-) Persistent (8y) Resolved (-) Persistent (4y) Resolved (2y) Resolved (1y) Persistent (3y) Resolved (1-5y) Persistent (2.5y) Resolved (2y) Persistent (1 y) Recurrence (2y) Resolved (2y)

Surgery Lobectomy (Ll Lobectomy/ Pneumonectomy (L)

Lobectomy (L) Lobectomy (R) Lobectomy (L)

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2a,b

14YR

c

Fig. 2. (8S) a. A well-def ined multilocular cyst with airfluid levels is present in the left upper lobe. b. One year later the cyst has expanded and there are persisting air-fluid levels . c. Following left upper lobectomy and chronic antistaphylococcal therapy , the patient remained free of pulmonary disease.

17 YR

of the cysts was variable. They were single in 7 cases and multiple in 4 others. The cyst walls were variable in thickness, the lining was smooth, and occasionally, air-fluid levels were noted. The acquired pulmonary cysts resolved spontaneously following continuous antibiotic therapy in 5 cases (Fig. 1). The cysts disappeared 1-2 years after their appearance in the 3 patients in whom the initial appearance of the cyst could be established. None of these cysts showed evidence of chronic infection (i.e ., persistent air-fluid levels, thickened cyst wall). In 6 cases the cysts persisted or recurred despite antibiotic therapy. Persistent cysts were noted in 4 of these cases: one patient (BS) underwent resection of an infected cyst two years after onset (Fig. 2); one patient (JB) had spontaneous resolution of a right basilar cyst while left lower lobe cysts became chronically

infected and persisted until resection two and a half years after onset (Fig. 3); another 2 patients (CC, LH) have persistent cysts during a three- and four-year follow-up at OUMC. Recurrent cysts developed in other lung locations in 2 cases following resection of initial acquired cysts; in one patient (RB), a recurrent RUL cyst formed one year after left pneumonectomy and has persisted for eight years . In another patient (SE), recurrent bilateral lung cysts developed three years after right upper lobectomy and persisted until the child's death two years later (Fig. 4). Only 1 patient (RB) had radiographic suggestion of bronchiectasis on the plain radiograph of the chest. In another patient (OS), bronchography failed to show bronchiectasis or communication with the cystic lesion. In addition to pulmonary abnormalities, 9 patients had radiographic evidence of chronic sinusitis with diffuse and

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Fig. 3. (JB) a. At 2 mon ths of age. followi ng bilateral lower lobe staphy lococc al pneumo nia and left empyema. there is a small thin-walled cyst in the righ t car diophr enic angle. III-defined retrocardiac cystic lucen cies are present at the left base. b. At 5 months of age. the cy st at the right base remai ns thin -walled but has expanded . Multiple cysts are present in the retrocardiac area of the left lower lobe . c and d. By 18 months . the cys t on the right has res olved while the left lower lobe cy sts have expanded. Air-flu id levels indica te chronic infection. These pers isted for one year (d) and at age 30 month s the left lower lobe was resected. The ch ild has rem ained well in the two years since surgery .

variable involvement of the sinuses, ranging from mucosal thickening to complete opacification. Mastoid air cells

were radiographically examined in 4 cases and changes of chronic inflammatory disease were noted in 3.

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PATHOLOGY

Lung tissue from surgical or autopsy specimens was available for examination in 4 patients. All specimens were described as having single or multiple cystic spaces varying in diameter from 1 to 12 em. All appeared to have fibrotic walls and were lined by exudate. Bronchial communications were described in some cases but not in others; however, it is not clear from the gross notes whether they were specifically sought. Bronchiectasis was not described. On microscopic study the lesions generally had the characteristics of chronic abscesses. The cyst lining in all cases consisted of a dense necrotic layer of exudate with leukocytic infiltration. Moderate-to-heavy infiltration with eosinophils was observed in 2 cases. Granulation tissue with chronic mononuclear infiltration was noted beneath the exudative lining. The outer wall was fibrotic in all cases (Figs. 5 and 6). A definite bronchial communication was identified In 2 cases (Fig. 6). Hyphae of aspergillus species were found in 2 cases; in one of these a fungus mass was present. Lymph node tissue available in 2 cases was hyperplastic. DISCUSSION

The increased susceptibility to recurrent episodes of staphylococcal pneumonia appears to be the basis for cyst formation in patients with the hyper-lgE syndrome, although the precise pathogenesis is not clearly defined. Some cysts may begin as pneumatoceles, while others represent true cavitary abscesses. A pneumatocele can be defined as an acquired cyst resulting from an inflammatory process which causes central necrosis, with a cystic expansion of loculated air, either airspace or interstitial, being due to elastic retraction of the surrounding lung tissue. Caffey (3) suggested that these cysts result from an inflammatory endobronchial ball-valve mechanism associated with distension of peripheral bronchioles. This concept does not, however, account for the increased frequency of pneumatoceles in children. Since the elastic recoil pressure and hence tissue traction force at any level above residual volume is greater in children (4,5), necrosis and retraction with and without a ball-valve endobronchial obstruction appear to be important factors in pneumatocele formation in children. It has also been proposed that such cysts are subpleural collections of air which have dissected through lobular septa from a point of small airway rupture (6). While this may be true, many of the cysts seen in the present series appeared initially to be intraparenchymal. Pulmonary cysts may also follow interstitial emphysema in premature infants; however, cyst formation is complicated by positive pressure ventilation in such cases. Pneumatoceles often appear overnight in patients in whom only a small area of consolidation previously was present. The cyst is frequently larger than the preceding infiltrate and characteristically has thin walls. These fea-

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tures distinguish pneumatoceles from abscess cavities, which develop slowly in an area of consolidation and are thick walled. When serial films were available in our series (Fig. 3), pneumatocele formation appeared to be the basis for the patients' acquired cysts. Initially there is a bronchial communication with a pneumatocele, as there is with an abscess. However, the communication for the typical pneumatocele, which begins in a small focus of consolidation, is with a small bronchus or bronchiole. Communication with larger bronchi was seen in some cases in this series (Fig. 6), however, and was probably due to erosion of a chronically infected cyst into a bronchus. It is not clear whether frequent pneumatocele formation in these patients is simply due to the increased incidence ef staphylococcal infections or results from a specific defect in their handling of infectious processes. The presence of large numbers of eosinophils in the inflammatory exudates of hyper-lgE patients may be indicative that the latter is the case. Normally, with control of infection or resolution of the inflammatory reaction, the bronchial communication disappears and the air in the cyst is absorbed. In hyper-lgE patients, recurrent staphylococcal infection presumably leads to persistent bronchial connection with consequent persistence and even expansion of the acquired cyst. Chronic infection leads to thickening and fibrosis of the cyst walls, so that eventually they are indistinguishable from abscesses. Aspergillus super infection appeared to playa significant role in perpetuating the cysts in 2 cases. Although aspergillus is a frequent opportunistic contaminant of cystic pulmonary lesions in immunologically intact individuals, this does not imply a basic defect in these patients' ability to handle aspergillus infection. Chronic infection is not the only cause of pathogenesis of persistent lung cysts since these cysts are not seen in most of the other primary immunodeficiency diseases, including the various forms of agammaglobulinemia. One recent report (7) pictured pneumatoceles radiographically similar in appearance to those in the present report. Two of the 4 patients described in that report may well have had the hyper-lgE syndrome, as they had recurrent staphylococcal infections and their clinical courses were quite similar; however, there is no mention of their serum IgE concentrations. In the third patient, who had acute myelogenous leukemia and received immunosuppressive agents, the pneumatocele developed following Klebsiella pneumonia, and the fourth was a patient with staphylococcal pneumonia secondary to chronic granulomatous disease of childhood (CGO). Although the authors postulated neutrophil abnormalities as the common feature of the 4 patients, it should be noted that patients with CGO do not commonly develop lung cysts, whereas all patients with the hyper-lgE syndrome in the present report had this feature. It seems more likely that the common characteristic of the 4 patients described by Wood and Young (7) was infection with organisms that commonly lead to pneumatocele formation. Several reports have appeared describing patients

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Fig. 5. (SE) The cyst is lined by a dense layer of necrotic fibrinopurulent exudate. Granulomatous tissue with inflammation merges with the densely fibrotic wall at the left. Aspergillus hyphae are present in the lumen (H + E stain, 40X). The insert shows the septate hyphae in the cyst lumen . There is no invasion into the underlying tissue (methanamine silver stain , 250X).

Fig. 6. (RB) The cyst lumen contains fragments of purulent exudate. There is dense inflammatory infiltration of the cavity lining and the wall is fibrotic. Bronchial communication is noted (center white arrow). The bronchus, extending to the upper left is lined by respiratory epithelium . There are many goblet cells and the submucosa shows dense inflammatory infiltration (H + E stain, 40X).

with clinical features resembling the hyper-lgE syndrome (8-10) who were said to have had defective polymorphonuclear chemotactic responsiveness. The descriptions of many patients reported to have chemotactic defects are more in keeping with superficially infected atopic dermatitis rather than this syndrome. In our series, chemotactic studies were done several times in the same patients and only 3 of the 11 had reproducible defects in either polymorphonuclear or mononuclear chemotaxis (2). Such abnormalities (in all probability epiphenomena) are not the basic defect in these patients. The hyper-lgE syndrome is a rare disorder and does not represent simple recurrent infection of atopic dermatitis. Although the hyper-lgE syndrome cannot be defined by the presence or absence of chemotactic defects , other aspects of the syndrome are more constant (TABLES I and II). The major feature that distinguishes it from other conditions accompanied by elevated IgE (such as the usual atopic disorders) is the lifelong history of severe, deepseated infections with staphylococci and other organisms. The primary biologic error is unknown for this syndrome; however, in addition to striking elevation of serum IgE, patients had depressed specific cell-mediated immune responses, deficient antibody-forming capacity, and pronounced blood and

sputum eosinophilia. The role of the marked eosinophilia in the pathogenesis of an unusual inflammatory reaction remains to be elucidated. The relationship of these patients' excessive IgE production to depressed host-defense function or to the increased susceptibility to staphylococcal infections remains unknown. Susceptibility to infection may be related in part to other associated deficiencies, particularly those involving the thymus-dependent system. Rodent studies have provided strong evidence that IgE synthesis, while requiring T helper cells for initiation, is also under active T suppressor cell control (11) . The most convincing evidence favoring an association between immunodeficiency and augmented IgE production in man derives from the consistent finding of excessive IgE antibody production in certain of the well-defined primary immunodeficiency diseases. These include Wiskott-Aldrich, hyper-lgE. Oi George and Nezelof syndromes, all of which have in common a partial deficiency in thymus-dependent immune function (12). Such patients may, therefore, have sufficient numbers of T helper cells for initiation of IgE antibody formation but an inadequate number of T suppressor cells resulting in augmented IgE biosynthesis (13). The prognosis of patients with the hyper-lgE syndrome

Fig. 4. (SE) a-d. The initial episode of staphylococcal pneumonia was at age 3 years. At age 6 years, a lobulated multilocular cyst is present in the right upper lobe (a). The cyst wall is relatively thick, but there are no air-fluid levels. The right upper lobe was resected and, despite recurrent pneumonia, no cysts developed in the ensuing four years (b). Bilatera l cysts (RLL, LUL) were noted at age 11 years and 1 year later (e) the right lung cyst showed evidence of chronic infection (air-fluid level); the left upper lobe cyst wall remains thin. Tube drainage of the right lung was established . By 13 years of age (d), there is some decrease in the overall size of the right pulmonary cyst but air-fluid levels persist. The cyst wall on the left is now thickened and air-fluid levels are present indicating chronic infection. When the left upper lobe was resected, a mass (arrows) at the base of the cyst proved to be a fungus (aspergillus) ball adherent to the cyst wall.

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depends upon early recognition of the immunodeficiency and adequate chronic antistaphylococcal therapy (dicloxacillin). With such therapy and careful surgical management, the prognosis appears to be quite good. Some patients have even reached maturity. If the diagnosis is not made early in life, however, crippling chronic lung disease may develop and problems with infectious agents other than staphylococci become more frequent. SUMMARY AND CONCLUSIONS

The hyperimmunoglobulinemia E syndrome is characterized by a lifelong history of severe staphylococcal infections, primarily of the skin and lungs. The most striking radiographic feature of this syndrome is recurrent pneumonia with the frequent formation of acquired lung cysts. These cysts persist and expand, in some cases becoming chronically infected with saprophitic bacteria and various fungi. While continuous, adequate, antistaphylococcal antibiotic therapy may in some cases effect spontaneous remission of the cysts, recurrent infection and persistent bronchial communication may lead to chronically superinfected cysts. Persistence of the acquired cysts in such cases may necessitate surgical resection. ACKNOWLEDGMENT: We thank Mrs. Jacqueline D. Wright for her secretarial support in the preparation of this manuscript.

REFERENCES 1. Buckley RH, Wray BB, Belmaker EZ: Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 49: 59-70, Jan 1972

July 1979

2. Buckley RH: Hyperimmunoglobulinemia E, undue susceptibility to infection and depressed immunologic function. [In] Kagan BN, Hodes H, ed: Pediatric Immunology. New York, Science and Medicine Publishing Co., Inc. (in press) 3. Caffey J: On the natural progression of pulmonary cysts during early infancy. Pediatrics 11:48-64, Jan 1953 4. Helliesen PJ, Cook CD, Friedlander L, et al: Studies of respiratory physiology and children. I. Mechanics of respiration and lung volumes in 85 normal children 5 to 17 years of age. Pediatrics 22:80-93, Jul 1958 5. Avery ME, Cook CD: Volume-pressure relationships in the lungs and thorax of fetal, newborn and adult goats. J Appl Physiol 16: 1034-1038, Nov 1961 6. Boisset GF: Subpleural emphysema complicating staphylococcal and other pneumonias. J Pediatr 81:259-266, Aug 1972 7. Wood BP, Young LW: Persistent pneumatoceles associated with systemic leukocyte abnormalities. Pediatr Radiol 5: 10-13, Oct

1976 8. Clark RA, Root RK, Kimball HR, et al: Defective neutrophil chemotaxis and cellular immunity in a child with recurrent infections. Ann Intern Med 78:515-519, Apr 1973 9. Hill HR, Ochs HD, Quie PG, et al: Defect in neutrophil granulocyte chemotaxis in Job's syndrome of recurrent "cold" staphylococcal abscesses. Lancet 2:617-619, 14 Sep 1974 10. Blum R, Geller G, Fish LA: Recurrent severe staphylococcal infections, eczematoid rash, extreme elevations of IgE, eosinophilia and divergent chemotactic responses in two generations. J Pediatr 90:607-609, Apr 1977 11. Tada T: Regulation of reaginic antibody formation in animals. Prog Allergy 19:122-124, 1975 12. Buckley RH, Fiscus SA: Serum IgD and IgE concentrations in immunodeficiency diseases. J Clin Invest 55:157-165, Jan 1975 13. Buckley RH, Becker WG: Abnormalities in the regulation of human IgE synthesis. Immunol Rev 41:288-314, 1978

David F. Merten, M.D. Department of Radiology Duke University Medical Center Box 3834 Durham, NC 27710