Pneumatocele Complicating Hyperimmunoglobulin E Syndrome (Job’s Syndrome) Robert C. Shamberger, MD, Mary Ellen Wohl, MD, Antonio Perez-Atayde, MD, and W. Hardy Hendren, MD Departments of Surgery, Pediatrics (Division of Pulmonary Medicine), and Pathology, Children’s Hospital and Harvard Medical School, Boston, Massachusetts The case of a boy with hyperimmunoglobulin E syndrome or Job’s syndrome is presented to demonstrate the occurrence of pneumatoceles in this syndrome as well as their unusual natural history and failure to spontaneously resolve. Surgical resection was required for two complications in this patient, persistent bronchopleural fistula and a pulmonary abscess that destroyed one lung and required pneumonectomy. Pathologic examination of the specimens demonstrated the wall of the cysts
H
yperimmunoglobulin E syndrome (HIE)or Job’s syndrome is a complex disorder characterized by extremely high levels of serum immunoglobulin (Ig) E, recurrent infections (particularly resulting from Stupkylococcus uureus and fungus), and chronic dermatitis. We report an unusual case in which a boy with HIE presented with two major complications of pneumatoceles, each of which required surgical intervention. The unusual natural history of pneumatoceles in patients with this syndrome is stressed as well as the need for surgical intervention when complications occur. The patient was the product of an uncomplicated pregnancy. He had an episode of tachypnea in the first day of life for which a chest radiograph was obtained. It was completely normal. He had multiple episodes of otitis media and a papulovesicular rash on his face and neck during his first 3 years of life. When he was 3 years old a tonsillectomy and adenoidectomy were performed, which produced only temporary relief of his recurrent middle ear infections. Tests for cystic fibrosis (sweat chloride) were negative, and initial Ig levels were within normal limits (IgG, 9.7 g/L; IgA, 2.38 g/L; and IgM, 0.9 g/L). At age 5 years he had a spontaneous pneumothorax resulting from rupture of a previously unrecognized pneumatocele in the right upper lobe, which was believed initially to be an apical bleb on the chest radiograph. A right upper lobectomy was performed when the bronchopleural fistula did not resolve with tube thoracostomy drainage. At thoracotomy a single large cyst was identified in the right upper lobe. Pathologic examination demonstrated the cyst lacked an epithelial lining and had several bronchi opening directly into the cyst. Chronic active inflammaAccepted for publication Feb 28, 1992. Address reprint requests to Dr Shamberger, Department of Surgery, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115.
0 1992 by The Society of Thoracic Surgeons
consisted of granulation tissue with chronic active inflammation surrounded by infarcted pulmonary parenchyma with coagulative necrosis. The mechanism responsible for increased immunoglobulin E production in this syndrome is unknown, as is the manner in which elevated immunoglobulin E levels impair normal immune function. (Ann Tkoruc Surg 1992;54:1206-8)
tion was present in the wall of the cyst, and there was arteritis of adjacent medium-sized vessels. He did well after this resection, but bronchospastic pulmonary disease developed and was treated with theophylline. When he was 8 years old the diagnosis of HIE was established as the cause of his recurrent episodes of otitis media and S uureus infections in the skin. The serum IgE level was 5,100 U/mL. He was then treated long-term with dicloxacillin. At 10 years of age a pneumatocele was first identified in the right middle lobe, and at 10% years of age a pneumatocele developed in the right lower lobe after a Huernopkilus influenzue pneumonia. These pneumatoceles were followed up expectantly and remained thin-walled and stable in size until he was 19 years of age, when he was seen with an abscess in the pneumatocele in the right lower lobe (Fig 1).Initial attempts at another institution to manage the infection by antibiotics and subsequently by percutaneous catheter drainage of the pneumatocele were unsuccessful, and the area of involvement progressively enlarged (Fig 2). Pulmonary function tests and radioisotope perfusion and ventilation scans demonstrated no function of the entire right lung. A right pneumonectomy was performed. Pathologic examination revealed extensive necrotizing, suppurative, predominantly eosinophilic bronchopneumonia with necrotizing bronchiolitis and suppurative bronchiectasis with partial destruction of bronchiolar epithelium (Fig 3 ) . The pneumatocele had no epithelial lining, and the wall was made of granulation tissue, necrosis, and marked inflammation and appeared sharply demarcated from the compressed lung parenchyma. The interior of the cyst contained necrotic amorphous material with numerous Charcot-Leyden crystals, inflammatory cells with a predominance of eosinophils, and numerous septated branching fungi. Aspergillus furnigutus was cultured from the cyst contents. The Aspergillus was thought to represent colonization of the pneumatocele, however, 0003-4975/92/$5.00
Ann Thorac Surg 1992;54:12064
CASE REPORT SHAMBERGER ET AL PNEUMATOCELE AND HIE
1207
Fig 1. Chest radiograph obtained when the patient was seen with acute infection of the pneumatocele. The wall of the pneumatocele was thickened, and a fluid level was present.
Fig 2. Chest radiograph taken 7 weeks after Figure 2 demonstrates progressive enlargement of the pneurnatocele and destruction of surrounding pulmona y parenchyma.
as there was no histologic evidence of invasive infection. In areas the cyst contained the outlines of infarcted pulmonary parenchyma with coagulative necrosis. Adjacent to the cyst occasional necrotizing active arteritis with organizing thrombosis was noted (Fig 4). The pneumatocele extended very close to the lower lobe bronchus. He has done well in the 15 months following this resection. He continues to receive dicloxacillin, and intravenous y-globulin has been added to his treatment.
abscesses" were notable for their lack of surrounding inflammation. Davis and associates suggested the term Job's syndrome to describe their patients based on the Book of Job 2:7, "So went Satan forth from the presence of the Lord, and smote Job with some boils from the sole of his feet unto his crown." Buckley and co-workers [2] linked these clinical findings with markedly elevated serum IgE levels and coarse facies. The mechanisms responsible for increased IgE production in HIE are unknown. A decreased population of suppressor CD8+ lymphocytes has been demonstrated in this syndrome [3, 41. The elevated IgE levels have been postulated to reflect a T-cell imbalance resulting in T-cell activation and a deficiency of suppressor T cells to inhibit IgE production. It has recently been demonstrated that the cells producing IgE in HIE are largely independent of cell to cell interactions and
Comment Hyperimmunoglobulin E syndrome is an extremely rare disorder first reported by Davis, Schaller, and Wedgwood in 1966 [l].Their patients had recurrent sinopulmonary infections, dermatitis, and S aureus abscesses. These "cold
Fig 3 . Part of the large pneurnatocele outlined by a wall of inflammation and necrosis. The cyst contents are made up of cougulative necrotic pulmonary parenchyma, cellular and inflammatory debris, and fungal colonies. (Hematoxylin and eosin; x l 0 0 before 20% reduction.) The inset displays branching septate Aspergillus fumigatus stained with methenamine silver ( ~ 2 0 0 0before 20% reduction). (C = cyst, P = pulmonary parenchyma.)
1208
CASE REPORT SHAMBERGER ET AL PNEUMATOCELE AND HIE
Ann Thorac Surg 1992;54:1206-8
Fig 4. Wall of medium-sized artery showing necrotizing mixed inflammation with lymphocytes, plasma cells, neutrophils, and eosinophils. The inner elastic membrane appears focally disrupted (arrows). (Hematoxylin and eosin; ~ 4 0 0before 20% reduction.)
a r e n o t responsive t o the normal regulatory signals such as y-interferon and interleukin G [5]. T h e patients produce high levels of IgE directed against S aureus and other organisms w i t h a deficit i n synthesis of IgG antibody against these organisms (61. The neutrophils are normal i n n u m b e r and can ingest a n d kill bacteria normally, b u t their function and chemotaxis a p p e a r s to be impaired by t h e extremely h i g h levels of IgE. Patients with HIE are particularly susceptible t o infections of S aureus and Candida albicans, b u t also t o o t h e r suppurative infections from H influenzae, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas. Deep-seated infections other than pneumonias are unusual. In a previous report 6 of 13 patients had lobectomies performed for recurrent hemoptysis secondary t o bronchiectasis and recurrent pneumonias [7]. Staphylococcal p n e u m o n i a i n t h e era before antibiotics frequently produced pneumatoceles [8, 91. These would generally resolve w i t h fibrosis and did not persist. In o u r patient t h e middle and lower lobe pneumatoceles w e r e present over a 9-year period w i t h a gradual increase i n their size. Pneumatoceles h a v e been reported previously i n o t h e r patients w i t h HIE [7, 10, 111, b u t t h e natural history of t h e pneumatoceles has n o t been well described. In a remarkable series of 11 patients w i t h HIE reported by Merten and associates [ l l ] , all h a d ”lung cysts” and in 4 patients t h e y were multiple. In 5 patients t h e “cysts” w e r e reported t o h a v e spontaneously resolved after continuous antibiotic therapy. No evidence of chronic infection was seen i n these patients. I n t h e remaining 6 patients t h e ”cysts” persisted, and in 4 resections were performed. This case is presented t o increase recognition of t h e occurrence of pneumatoceles i n HIE as well a s to establish t h e frequent failure of s p o n t a n e o u s resolution despite long-term observation. Pathologic examination demonstrated necrosis of t h e s u r r o u n d i n g pulmonary parenchyma w i t h necrotizing bronchiolitis and arteritis a s t h e mechanism of rapid increase i n size of t h e lesion. I n this patient t h e T-cell n u m b e r and measurable function were normal a s was t h e antibody response when assessed 6
m o n t h s before he was seen w i t h t h e pulmonary abscess. Thus, i n t h e face of normal i m m u n e parameters, t h e pneumatocele persisted a n d became infected. This is the second report of Aspergillus colonization complicating t h e course of a pneumatocele i n HIE [12]. ~
We thank Raif S. Geha, MD, of the Department of Immunology for his assistance in the preparation of the manuscript.
References 1. Davis SD, Schaller J, Wedgwood RJ. Job’s syndrome: recurrent, “cold,” staphylococcal abscesses. Lancet 1966;1:1013-5. 2. Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 1972;49:59-70. 3. Katona IM, Tata G, Scanlon RT, Bellanti JA. Hyper IgE syndrome: a disease with suppressor T cell deficiency. Ann Allergy 1980;45:295-300. 4. Geha RS, Reinherz E, Leung D, McKee KT Jr, Schlossman S, Rosen FS. Deficiency of suppressor T cells in the hyperimmunoglobulin E syndrome. J Clin Invest 1981;68:783-91. 5. Vercelli D, Jabara HH, Cunningham-Rundles C, et al. Regulation of immunoglobulin (1g)E synthesis in the hyper-IgE syndrome. J Clin Invest 1990;85:1666-71. 6. Leung DYM, Ambrosino DM, Arbeit RD, et al. Impaired antibody responses to hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol 1988;81:1082-7. 7. Donabedian H, Gallin JI. The hyperimmunoglobulin E recurrent-infection (Job’s) syndrome: a review of the NIH experience and the literature. Medicine 1983;62:195-208. 8. Hendren WH 111, Haggerty RJ. Staphylococcic pneumonia in infancv and childhood: analysis of seventv-five cases. JAMA 1958;1k8:6-16. 9. Sabiston DC lr. HoDkins EH, Cooke RE, Bennett IL Ir. The surgical managemint of complications of staphylococcal pneumonia in infancy and childhood. J Thorac Cardiovasc Surg 1959;38:421-34. 10. Geha RS, Leung DYM. Hyper immunoglobulin E syndrome. Immunodefic Rev 1989;1:15572. 11. Merten DF, Buckley RH, Pratt PC, Effmann EL, Grossman H. Hyperimmunoglobulinemia E syndrome: radiographic observations. Radiology 1979;132:71-8. 12. Lui RC, Inculet RI. Job’s syndrome: a rare cause of recurrent lung abscess in childhood. Ann Thorac Surg 1990;50:992-4. I
.
H
yperimmunoglobulin E syndrome (HIE)or Job’s syndrome is a complex disorder characterized by extremely high levels of serum immunoglobulin (Ig) E, recurrent infections (particularly resulting from Stupkylococcus uureus and fungus), and chronic dermatitis. We report an unusual case in which a boy with HIE presented with two major complications of pneumatoceles, each of which required surgical intervention. The unusual natural history of pneumatoceles in patients with this syndrome is stressed as well as the need for surgical intervention when complications occur. The patient was the product of an uncomplicated pregnancy. He had an episode of tachypnea in the first day of life for which a chest radiograph was obtained. It was completely normal. He had multiple episodes of otitis media and a papulovesicular rash on his face and neck during his first 3 years of life. When he was 3 years old a tonsillectomy and adenoidectomy were performed, which produced only temporary relief of his recurrent middle ear infections. Tests for cystic fibrosis (sweat chloride) were negative, and initial Ig levels were within normal limits (IgG, 9.7 g/L; IgA, 2.38 g/L; and IgM, 0.9 g/L). At age 5 years he had a spontaneous pneumothorax resulting from rupture of a previously unrecognized pneumatocele in the right upper lobe, which was believed initially to be an apical bleb on the chest radiograph. A right upper lobectomy was performed when the bronchopleural fistula did not resolve with tube thoracostomy drainage. At thoracotomy a single large cyst was identified in the right upper lobe. Pathologic examination demonstrated the cyst lacked an epithelial lining and had several bronchi opening directly into the cyst. Chronic active inflammaAccepted for publication Feb 28, 1992. Address reprint requests to Dr Shamberger, Department of Surgery, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115.
0 1992 by The Society of Thoracic Surgeons
consisted of granulation tissue with chronic active inflammation surrounded by infarcted pulmonary parenchyma with coagulative necrosis. The mechanism responsible for increased immunoglobulin E production in this syndrome is unknown, as is the manner in which elevated immunoglobulin E levels impair normal immune function. (Ann Tkoruc Surg 1992;54:1206-8)
tion was present in the wall of the cyst, and there was arteritis of adjacent medium-sized vessels. He did well after this resection, but bronchospastic pulmonary disease developed and was treated with theophylline. When he was 8 years old the diagnosis of HIE was established as the cause of his recurrent episodes of otitis media and S uureus infections in the skin. The serum IgE level was 5,100 U/mL. He was then treated long-term with dicloxacillin. At 10 years of age a pneumatocele was first identified in the right middle lobe, and at 10% years of age a pneumatocele developed in the right lower lobe after a Huernopkilus influenzue pneumonia. These pneumatoceles were followed up expectantly and remained thin-walled and stable in size until he was 19 years of age, when he was seen with an abscess in the pneumatocele in the right lower lobe (Fig 1).Initial attempts at another institution to manage the infection by antibiotics and subsequently by percutaneous catheter drainage of the pneumatocele were unsuccessful, and the area of involvement progressively enlarged (Fig 2). Pulmonary function tests and radioisotope perfusion and ventilation scans demonstrated no function of the entire right lung. A right pneumonectomy was performed. Pathologic examination revealed extensive necrotizing, suppurative, predominantly eosinophilic bronchopneumonia with necrotizing bronchiolitis and suppurative bronchiectasis with partial destruction of bronchiolar epithelium (Fig 3 ) . The pneumatocele had no epithelial lining, and the wall was made of granulation tissue, necrosis, and marked inflammation and appeared sharply demarcated from the compressed lung parenchyma. The interior of the cyst contained necrotic amorphous material with numerous Charcot-Leyden crystals, inflammatory cells with a predominance of eosinophils, and numerous septated branching fungi. Aspergillus furnigutus was cultured from the cyst contents. The Aspergillus was thought to represent colonization of the pneumatocele, however, 0003-4975/92/$5.00
Ann Thorac Surg 1992;54:12064
CASE REPORT SHAMBERGER ET AL PNEUMATOCELE AND HIE
1207
Fig 1. Chest radiograph obtained when the patient was seen with acute infection of the pneumatocele. The wall of the pneumatocele was thickened, and a fluid level was present.
Fig 2. Chest radiograph taken 7 weeks after Figure 2 demonstrates progressive enlargement of the pneurnatocele and destruction of surrounding pulmona y parenchyma.
as there was no histologic evidence of invasive infection. In areas the cyst contained the outlines of infarcted pulmonary parenchyma with coagulative necrosis. Adjacent to the cyst occasional necrotizing active arteritis with organizing thrombosis was noted (Fig 4). The pneumatocele extended very close to the lower lobe bronchus. He has done well in the 15 months following this resection. He continues to receive dicloxacillin, and intravenous y-globulin has been added to his treatment.
abscesses" were notable for their lack of surrounding inflammation. Davis and associates suggested the term Job's syndrome to describe their patients based on the Book of Job 2:7, "So went Satan forth from the presence of the Lord, and smote Job with some boils from the sole of his feet unto his crown." Buckley and co-workers [2] linked these clinical findings with markedly elevated serum IgE levels and coarse facies. The mechanisms responsible for increased IgE production in HIE are unknown. A decreased population of suppressor CD8+ lymphocytes has been demonstrated in this syndrome [3, 41. The elevated IgE levels have been postulated to reflect a T-cell imbalance resulting in T-cell activation and a deficiency of suppressor T cells to inhibit IgE production. It has recently been demonstrated that the cells producing IgE in HIE are largely independent of cell to cell interactions and
Comment Hyperimmunoglobulin E syndrome is an extremely rare disorder first reported by Davis, Schaller, and Wedgwood in 1966 [l].Their patients had recurrent sinopulmonary infections, dermatitis, and S aureus abscesses. These "cold
Fig 3 . Part of the large pneurnatocele outlined by a wall of inflammation and necrosis. The cyst contents are made up of cougulative necrotic pulmonary parenchyma, cellular and inflammatory debris, and fungal colonies. (Hematoxylin and eosin; x l 0 0 before 20% reduction.) The inset displays branching septate Aspergillus fumigatus stained with methenamine silver ( ~ 2 0 0 0before 20% reduction). (C = cyst, P = pulmonary parenchyma.)
1208
CASE REPORT SHAMBERGER ET AL PNEUMATOCELE AND HIE
Ann Thorac Surg 1992;54:1206-8
Fig 4. Wall of medium-sized artery showing necrotizing mixed inflammation with lymphocytes, plasma cells, neutrophils, and eosinophils. The inner elastic membrane appears focally disrupted (arrows). (Hematoxylin and eosin; ~ 4 0 0before 20% reduction.)
a r e n o t responsive t o the normal regulatory signals such as y-interferon and interleukin G [5]. T h e patients produce high levels of IgE directed against S aureus and other organisms w i t h a deficit i n synthesis of IgG antibody against these organisms (61. The neutrophils are normal i n n u m b e r and can ingest a n d kill bacteria normally, b u t their function and chemotaxis a p p e a r s to be impaired by t h e extremely h i g h levels of IgE. Patients with HIE are particularly susceptible t o infections of S aureus and Candida albicans, b u t also t o o t h e r suppurative infections from H influenzae, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas. Deep-seated infections other than pneumonias are unusual. In a previous report 6 of 13 patients had lobectomies performed for recurrent hemoptysis secondary t o bronchiectasis and recurrent pneumonias [7]. Staphylococcal p n e u m o n i a i n t h e era before antibiotics frequently produced pneumatoceles [8, 91. These would generally resolve w i t h fibrosis and did not persist. In o u r patient t h e middle and lower lobe pneumatoceles w e r e present over a 9-year period w i t h a gradual increase i n their size. Pneumatoceles h a v e been reported previously i n o t h e r patients w i t h HIE [7, 10, 111, b u t t h e natural history of t h e pneumatoceles has n o t been well described. In a remarkable series of 11 patients w i t h HIE reported by Merten and associates [ l l ] , all h a d ”lung cysts” and in 4 patients t h e y were multiple. In 5 patients t h e “cysts” w e r e reported t o h a v e spontaneously resolved after continuous antibiotic therapy. No evidence of chronic infection was seen i n these patients. I n t h e remaining 6 patients t h e ”cysts” persisted, and in 4 resections were performed. This case is presented t o increase recognition of t h e occurrence of pneumatoceles i n HIE as well a s to establish t h e frequent failure of s p o n t a n e o u s resolution despite long-term observation. Pathologic examination demonstrated necrosis of t h e s u r r o u n d i n g pulmonary parenchyma w i t h necrotizing bronchiolitis and arteritis a s t h e mechanism of rapid increase i n size of t h e lesion. I n this patient t h e T-cell n u m b e r and measurable function were normal a s was t h e antibody response when assessed 6
m o n t h s before he was seen w i t h t h e pulmonary abscess. Thus, i n t h e face of normal i m m u n e parameters, t h e pneumatocele persisted a n d became infected. This is the second report of Aspergillus colonization complicating t h e course of a pneumatocele i n HIE [12]. ~
We thank Raif S. Geha, MD, of the Department of Immunology for his assistance in the preparation of the manuscript.
References 1. Davis SD, Schaller J, Wedgwood RJ. Job’s syndrome: recurrent, “cold,” staphylococcal abscesses. Lancet 1966;1:1013-5. 2. Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 1972;49:59-70. 3. Katona IM, Tata G, Scanlon RT, Bellanti JA. Hyper IgE syndrome: a disease with suppressor T cell deficiency. Ann Allergy 1980;45:295-300. 4. Geha RS, Reinherz E, Leung D, McKee KT Jr, Schlossman S, Rosen FS. Deficiency of suppressor T cells in the hyperimmunoglobulin E syndrome. J Clin Invest 1981;68:783-91. 5. Vercelli D, Jabara HH, Cunningham-Rundles C, et al. Regulation of immunoglobulin (1g)E synthesis in the hyper-IgE syndrome. J Clin Invest 1990;85:1666-71. 6. Leung DYM, Ambrosino DM, Arbeit RD, et al. Impaired antibody responses to hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol 1988;81:1082-7. 7. Donabedian H, Gallin JI. The hyperimmunoglobulin E recurrent-infection (Job’s) syndrome: a review of the NIH experience and the literature. Medicine 1983;62:195-208. 8. Hendren WH 111, Haggerty RJ. Staphylococcic pneumonia in infancv and childhood: analysis of seventv-five cases. JAMA 1958;1k8:6-16. 9. Sabiston DC lr. HoDkins EH, Cooke RE, Bennett IL Ir. The surgical managemint of complications of staphylococcal pneumonia in infancy and childhood. J Thorac Cardiovasc Surg 1959;38:421-34. 10. Geha RS, Leung DYM. Hyper immunoglobulin E syndrome. Immunodefic Rev 1989;1:15572. 11. Merten DF, Buckley RH, Pratt PC, Effmann EL, Grossman H. Hyperimmunoglobulinemia E syndrome: radiographic observations. Radiology 1979;132:71-8. 12. Lui RC, Inculet RI. Job’s syndrome: a rare cause of recurrent lung abscess in childhood. Ann Thorac Surg 1990;50:992-4. I
.
