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Wegener's Granulomatosis : Report of a Case with Rapidly Progressive Glomerulonephritis and Diabetes Mellitus
Auris' Nasus' Larynx (Tokyo) 13, 177-189 (1986)
WEGENER'S GRANULOMATOSIS: REPORT OF A CASE WITH RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS AND DIABETES MELLITUS Hiroyuki KAKOI, M. D., Fumihisa HIRAIDE, M. D., Shinji NISHIZAWA, M. D.,* Tetsuzo INOUYE, M. D.,** and Nobuyuki YOSHIZAWA, M. D.*** Department of Otolaryngology, Jichi Medical School, Tochigi, Japan
*Department of Otolaryngology, Social Health Insurance Hospital, Tokyo, Japan ** Department of Otolaryngology, and *** Department of 2nd Intestinal Medicine, National Defense Medical College, Saitama, Japan
A patient with the classic form of Wegener's granulomatosis with severe dabetes mellitus and rapidly progressive glomerulonephritis is described. This 61-year-old male presented with epistaxis and nasal pain and obstruction. The nasal cavities were filled with crusts covering eroded mucosa. The diagnosis was made by biopsy of nasal and bronchial mucosa, and laboratory data. The epistaxis was stopped by 10 Gy irradiation over the nasal cavities. The patient had severe diabetes mellitus. His blood sugar was not controlled by diet and insulin injection. His general condition worsened rapidly as the growth of granuloma in the nose and lung. Accordingly, prednisolone therapy reinitiated to suppress the granuloma although it has a reverse effect on diabetes mellitus. Approximately one month after admission, he died of acute renal failure. Autopsy was carried out. Granulomatous lesions were noted in the nasal cavities, lungs and spleen. Many petechiae were found macroscopically over the cortex of the kidney. Hyalinization or sclerosis with crescent formation was found microscopically in estimated 85 % of the glomeruli. Immunohistologic analysis of the renal tissue demonstrated an irregular linear pattern deposition of IgG, IgA and C3 and a granular pattern deposition of IgM and Clq. Wegener's granulomatosis has been considered a rare disease. In Japan approximately 400 cases have been reported. Recently the concept of a limited form of Wegener's granulomatosis was established. Most patients with this disease Recieved for publication February 20, 1986 177
178
H. KAKOI et at.
first consult otorhinolaryngologists complanining of nasal obstruction and bleeding. This disease is thought to be one of the causes of progressive necrotizing rhinitis. While its etiology is still unknown, it is considered similar to autoimmune disease. The necrotizing vasculitis of Wegener's granulomatosis resembles that of periarteritis nodosa and both diseases have elevation of serum immunoglobulins with deposition of immune complexes in tissues. Treatment with adrenal corticosteroids or immunosuppressants benefits most patients with this disease as is also true with autoimmune disease. We present in this paper our experience of treating a patient with a classic form of Wegener's granulomatosis complicated by severe diabetes mellitus. After about two months' hospitalization he died of acute renal failure. Our report includes the autopsy findings and one review of the appropriate literature. CASE REPORT
A 61-year-old male taxi driver was first seen in the Department of Otolaryngology, National Defense Medical College Hospital, on November 15, 1982, with complaints of nasal obstruction, epistaxis and pain at the root of the nose. Approximately one month earlier, he first noted constant nasal obstruction and bloody discharge after blowing his nose. He had lost 14 kg weight in the preceding two months. On examination abundant crusts which obstructed the nasal cavities were seen. When these crusts were removed the underlying surface was eroded and friable. Necrotizing granulomatous lesions were found on the nasal mucosa. The fundoscopic examination revealed no signs of diabetes mellitus or hypertension. The audiogram showed about 20 dB hearing loss with an A-B gap in both ears. There was no fluid or discharge seen on otoscopy. Roentgenographic findings of the nose and paranasal sinuses revealed diffuse shadows in the right maxillary sinus and in both ethmoid sinuses. The mucous membranes of the inferior turbinates and the nasal septum were thickened. On tomographic films of the nasal cavities, a partial defect of the nasal septal cartilage without bone destruction was observed (Fig. 1). The chest X-ray film showed multiple irregular cavitating nodules, 2 to 3 cm in diameter, in the right upper lobe. Thickening of the bronchial wall around the right B3a branch suggested an inflammation (Fig. 2). The laboratory findings at the first visit were: erythrocyte sedimentation rate, 37 mm per hr; WBC count, 14,100/cu mm, with 71 % neutrophils, 2 % eosinophils, 5 % monocytes, and 22 % lymphocytes; blood sugar, 451 mg/dl; alkaline phosphatase, 125 KAU; urinalysis: sugar 3+, with no white or red cells and no crystals. About 10% of the phenolsulfonphthalein was excreted in 15 min and 70.1 % in 120 min. The glomerular filtration rate (GFR) was normal. The renal blood flow (RBF) was 375.8 ml/min. The immunological study data included the fol-
WEGENER'S GRANULOMATOSIS CASE
179
Fig. 1. Tomographic film of the nose, Diffuse infiltrative shadow is noted in the right maxillary sinus and nasal septal cartilage is partly eroded.
--
Fig. 2. Tomographic film of the chest. Infiltrative shadow with multiple cavities is shown in the right upper lung.
lowing values: CRP; 6+; CH50, 60.5 V/ml; IgG, 2,999 mg/dl; IgM, 195 mg/dl; IgA, 309 mg/dl and IgE, 368IV/ml. The T and B lymphocyte subpopulation was 7.9 to 30.1 %. The lymphocyte blast formation was 28,072 cpm (control 23,000 cpm) with concanavalin A and 28,057 cpm (control 25,000 cpm) with phytohemoagglutinin. The purified protein derivative skin test (PPD) measured 9x8mm. Bronchoscopic examination found a granulomatous lesion, which bled easily, that spread from the trachea to the orifices of the right upper, the right middle,
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Fig. 3. Bronchoscopic finding,
H. KAKOI et al.
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Easily bleeding granulomatous lesion is revealed.
and the left upper bronchi. The orifices of the B3b and B6 were stenosed. Transbronchial lung biopsy (TBLB) could not be performed because of the friable bronchial wall. Tracheal and bronchial biopsies were done instead of TBLB (Fig. 3). A nasal mucosa biopsied specimen showed non-specific chronic inflammatory changes with infiltration of lymphocytes and plasma cells, and proliferation of capillaries. The tracheal mucosa specimen exhibited mucosal necrosis surrounded with infiltration of lymphocytes, polymorphonuclear neutrophils and multi-nuclear giant cells. Some areas revealed reactive hyperplasia of the bronchial cells and squamous epithelization. Tissue specimens from the nose and trachea showed necrotizing inflammatory changes. No renal biopsy was performed. Wegener's granulomatosis was suspected from the history and the physical findings in the nose. Oral prednisolone was started at a daily dose of 20 mg on November 15, 1982, but this was discontinued on November 27 since the initial blood sugar was elevated to 450 mgjdl. The patient was admitted to our hospital on December 6 to regulate his diabetes mellitus. He was put on a 1,500 cal diet and on the 6th hospital day treatment with Novolente insulin MC 22 Ujday was initiated. The dosage of insulin was regulated by the sliding scale method. On the 13th hospital day the patient's nausea, vomiting and anorexia became more severe and an intravenous drip containing Actorapid insulin MC and glucose, I unit to 4 g, was started. On the 23rd hospital day a continuous subcutaneous infusion therapy was begun with a micro-infusion pump. The blood sugar values fluctuated widely throughout the hospital course. The data of hematological and urine examinations during the patient's hospitalization are shown in Table 1. Treatment given and clinical course are diagrammed in Fig. 4.
WEGENER'S GRANULOMATOSIS CASE Table 1.
181
Changes in the laboratory data.
Nov. 15
Dec. 2
Dec. 23
Jan. 4
ESR mg/hr WBC 10 RBC 10 Plate 10
97 14.1 461 43
81 12.1 450 35
10.4 386 96
32 22.7 230 14
Glu mg/dl U.A. mg/dl BUN mg/dl
451 4.0 13
248 4.0 12
675 6.2 41
215 12.5 117
54
63
64
Ur.pa mg/dl CRP RA CH50 IgG JgA IgM JgE
U/ml mg/dl mg/d! mg/dl IU/ml
6+
5+
60.5 2,999 309 195 368
57.5 1,709 366 155
2+ + 38.7 1,559 263 246
4+ 32.2 1,180 313 209
a Ur.P, urine protein.
The diagnosis of Wegener's granulomatosis was confirmed when the histological findings of the various biopsies and further laboratory data became available. Symptomatic therapy with anti-tussive agents, analgesics, and hemostatic agents proved ineffective against cough, pain at the root of the nose and continuous epistaxis. The attempts to control the blood sugar ended in failure, but prednisolone therapy was reinitiated on the 16th hospital day, this time at a daily dose of 60 mg, in combination with 50 mg of cyclophosphamide. On the 29th hospital day prednisolone was discontinued again because of severe hyperglycemia and the cyclophosphamide was continued at a dose of 100 mg per day. Prednisolone and cyclophosphamide had been effective against the cough and the pain at the root of the nose. On the 21st day radiation over the nasal cavities was started to control epistaxis. A total of 10 Gy was administered. On the 26th day a perforation of the nasal septum was found. On the 16th day the patient first noticed discomfort of the right knee when walking. Edema of the anterior crural and peri-orbital regions developed on the 19th hospital day. From the 23rd day onward the urinary output gradually decreased. Peritoneal dialysis was performed but the patient died of acute renal failure on January 7, 1983, the 37th hospital day after admission. An autopsy was performed 6 hr after death. The brain and dura mater had no unusual lesions. An attempt to remove the nasal cavities en bloc through the anterior cranial fossa failed because the osseous framework of the nasal cavities was almost destroyed. Part of the inferior turbinates remained intact, but the
H. KAKOI et
182
at.
No. Nasal bleeding
~
Cough Pain at the root of the nose
Prednisolone
","1(---20 mgjday----?l,1
IE-Novolente Me 22U-
Insulin Nov. 15 First visit
20
I
25
I
I
30 Dec. 1 Admission
5
No.2 Nasal bleeding
~
Cough Pain at the root of the nose Nausea, vomiting
~ ~ ~SS\\S\\\"'\~ ~
Edema
- - - - 5 0 mgjday----"".,
Prednisolone
I<-IE
Cyclophosphamide
1<-1,----50 mgjday----~>I<-, 100 mg/day~
Radiation Insulin
k--2Gyjday~
->*-AR.MC 12U+ AR.MC 4U 3*->tl.-AR.MC 19.2U**~AR.MC 40U"*,,AR.MC 19.2U**
Dec. 15
20
25
30 Jan. 1
5
7 Death
* Add 4U every diet. ** Continuous subcutaneous Fig. 4.
AR.MC: Acto Rapid MC infusion.
Treatment and clinical course.
middle turbinates were lost and most of the nasal septum was lacking. Both maxillary sinuses had thickened mucosa. The medial bony walls of both maxillary sinuses were attenuated and partly eroded. The inferior bony walls of both ethmoid sinuses were partly destroyed. A crusty granulomatous lesion resembling that in the nasal cavities was found in the left ethmoid sinus. Necrotizing granulomatous lesions with multiple cavities were present in the upper lobe of the right lung with friable granulomatous lesions extending from the trachea to the main bronchi (Fig. 5). Numerous yellowish-white nodules, 2 to 5 mm in diameter were seen in the spleen (Fig. 6). There were many petechiae over the cortex of the kidney and hyalinization or sclerosis with crescent formation involving in estimated 85 % of the glomeruli (Fig. 7). Some of blood vessels were thrombotic. Medium-sized arteries had thickening of the endothelium and infiltration with round cells. An immunofluorescence study of the kidney showed the deposition
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183
Fig. 5. Cross section of the right lung. Necrotizing granulomatous lesion (arrow) is revealed in the right upper lobe.
Fig. 6. Cross section of the spleen. lesion.
Multiple small nodular lesions are seen as in the lung
of several immunoglobulins and complement (Fig. 8 and Table 2). IgG, IgA and C3 were found in an irregular linear pattern and IgM and Clq were found in a granular pattern. In the pancreas, there were macroscopically almost normal findings
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H. KAKOI et al.
Fig. 7. Renal microscopic finding. Crescent formation (arrows) is found in 85 % of glomeruli. HE staining. x 200.
Fig. 8. Renal immunofluorescence finding. Deposition of IgG is disclosed along the basement membrane in an irregular pattern (arrows). x 300.
WEGENER'S GRANULOMATOSIS CASE
185
Table 2. The renal immunofluorescence findings. Glomerulus IgG IgA IgM Fib C3 Clq C4 PPD Alb
Vessel
Tubule
1+ 3+
1+ 0 0 1+
1+ 1+ 1+ 0
2+ 2+ 1+ 0 2+
0 1+ 0 0 0
1+ 0 0 1+ 2+
Count
Distribution
Pattern
Density'
30/35 2/38 5/26 27/29 23/23 12/ 9 22/35 4/17 0/22 25/25
GD FL FS GD GD
CL IL G CL
2+~3+
FS~D
GD
IL G
GD
CL
0~1+
• Density was graded into four degrees (0 ~ 3 + ). GD, generalized-diffuse; FL, focallocal; FS, focal-segmental; FS~D, focal-segmental~diffuse; CL, continuous-linear; IL, interrupted-linear; G, granular.
but microscopically a moderate decrease in the number of the islets of Langerhans and the hydropic changes in p-cells. DISCUSSION
The necrotizing granulomatous lesion was described by KLINGER (1931) as a borderline type of periarteritis nodosa. WEGENER (1939) considered this granulomatosis a disease independent of periarteritis nodosa. The concept of Wegener's granulomatosis was established by GODMAN and CHURG (1954) by describing three histological characteristics: (1) Necrotizing granulomas in the respiratory tract, (2) generalized necrotizing vasculitis, and (3) focal or granulomatous glomerulonephritis. On the other hand, CARRINGTON and LIEBOW (1966) and CASSAN, CALES, and HARRISON (1970) reported a limited form of Wegener's granulomatosis which had no renal lesions, but did have other localized lesions. Our case represented a classic form of Wegener's granulomatosis with severe diabetes mellitus. The diagnosis was made by the findings of the nasal cavities, the bronchoscopic examination and the laboratory data. Compared to tother reports about this disease, this presentation was unusual in that the patient had typical symptoms and local findings at the first consultation. In one patient reported elsewhere, the initial diagnosis was serous otitis media and paracenteses were repeated without success. When that patient later had a cough, a chest roentgenogram showed multiple nodules with cavitation which confirmed the diagnosis of Wegener's granulomatosis (CALONIUS and CHRISTENSEN, 1980). Another patient with a solitary coin lesion in the lung was diagnosed as having tuberculosis and was treated with antituberculous agents. Subsequently, the patient developed edema which led a correct diagnosis (CHERRY, JORDAN, LIGHT, and CALIF, 1979). Still another patient had arthralgia and was treated with non-
186
H. KAKOI et af. Table 3.
Ear Paranasal sinus
Nose
Lung
Kidney Joint Skin Nerve Others
Early symptoms and complications in 124 cases of Wegener's granulomatosis.
Otitis media Otalgia Sinusitis Forehead pain Face pain Nasal bleeding Rhinorrhea Nasal obstruction Congestion Cough Bloody sputum Chest pain Edema Arthralgia Arthritis Vasculitis Neuritis Fever Weight loss Fatigue Discomfort
Number
%
32 8 23 5 5 20 13 10 9 23 15 8 7 28 7 6 5 28
25.8 6.5 18.5 4.0 4.0 16.0 10.5 8.1 6.5 18.5 12.1 6.5 5.6 22.6 5.6 4.8 4.0 22.6 13.7 6.5 6.5
17 8
8
steroidal, anti-phlogistic and analgesic drugs. The diagnosis was later changed to Wegener's granulomatosis when the patient had hemoptysis (SCULLY, MARK, and McNEELY, 1981). Wegener's granulomatosis is thought to be caused by a disorder of the immune system because deposition of immune complexes are found in tissues such as the nasal mucosa, skin, lungs and kidneys. The symptoms of this disease are so variable that attention should be directed to the patient's complaints and the general physical findings rather than overemphasis on one or more local findings. Table 3 lists the early symptoms during the first two or three months of the disease in 124 cases gathered from European and American reports published from 1976 to 1984. Laboratory data are important in this disease for diagnosis and as an index of the effect of treatment. As subjective symptoms, such as cough and pain at the root of the nose, improve, the laboratory results change. Serum concentration of complement, IgG and IgA may become normal and CRP decreases. WATANABE and NAGAKI (1975) reported that serum complement concentration increased in the active stage and became normal with effective treatment in Wegener's granulomatosis and diseases similar to it.· They noted a remarkable decrease in serum complement concentration immediately before patients had serious exacerbation of their disease. This phenomenon might be explained as follows: there is an activation of the complement producing system in Wegener's granulomatosis,
WEGENER'S GRANULOMATOSIS CASE
187
unknown factors trigger the deposition of immune complexes in tissues which aggravates the patient's condition, the immune complexes consume the serum complement, by a reboun~ phenomenon of the consumption the complement producing system is activated and the serum complement concentration becomes high. Our patient's clinical condition worsened althogh the serum complement and immunoglobulins showed normalization. Apparently the production and deposition in tissues of the immune complexes caused the serum values to return to normal. It is more important to observe the patient's general condition than to rely on laboratory data. NUNAKA, OKOCHI, WATANABE, SAKAI, TAKAHASHI, and YANAMURA (1978), reported that in Wegener's granulomatosis they found the lymphocyte blast formation was almost normal and the T-B cell sUbpopulation ratio showed no remarkable change. In the present case, the lymphocyte blast forma tion was normal but the ratio of T cells to B cells was decreased. Whether or not this was due to an increase in the number of null cells remains to be explained. The renal lesions in Wegener's granulomatosis usually progress slowly. FAUCI and WOLFF (1975), however, reported acute renal failure due to rapidly progressive glomerulonephritis in 3 out of 24 cases with this disease. JUNCOS, ALEXANDER and MARBURY (1979) and HENSLEY, FELDMAN, LAZARUS, and GALVANEK (1979), reported that crescent formation with fibrin deposition was found in 60 % of glomeruli small thrombi were found in capillary vessels in the renal specimens from patients with rapidly progressive glomerulonephritis. JUNCOS et al. (1979) concluded that since thrombus formation played an important role in the disease, heparin was useful for treatment. Our patient developed renal failure on the 18th hospital day and crescent formation with fibrin deposition was found in 85 % of glomeruli. When Wegener's granulomatosis is suspected, a renal biopsy should be performed. This is useful in establishing the diagnosis and for differentiating the classic form of the disease from the limited form. Renal biopsy may also help in the prognosis. In immunoflorescent studies of renal tissue, IgG, IgA and C3 show a linear deposition pattern and IgM and Clq show a granular pattern. It is important to distinguish between the irregular linear pattern and the smooth linear pattern. The irregular linear pattern is found in Wegener's granulomatosis and other related diseases while smooth linear pattern is found in Goodpasture's syndrome. In instances of acute renal failure with crescent formation, the linear pattern is often seen even without anti-basement membrane antibody. The smooth linear pattern is typically found in Goodpasture's syndrome, one of the autoimmune diseases having antibodies in the anti-basement membrane, and lesions in the lung alveoli and renal glomeruli. Our patient had nodular lesions in the spleen with features identical to those of the necrotizing granuloma in the lung. The inflammatory adhesion of the pericardium was apparently due to granulomatous vasculitis of the pericardial vessels.
H. KAKOI et al.
188
Our patient had bleeding from friable granulomatous lesions throughout the nasal cavities. The patient complained of nausea and anorexia due to blood flowing down into the pharynx. Appetite loss impacte~ seriously on the effort to control his blood sugar by insulin injection. On the assumption that the nasal bleeding was due to the production of fresh granuloma in the nasal cavities, a small amount of localized irradiation over the nasal cavities was carried out. A total of 6 to 10 Gy irradiation seemed to be enough to inhibit production of new granuloma and stop the epistaxis. Irradiation was useful for the inhibition of granuloma production at the subglottic space in a patient with this disease, according to a recent report (SHIMIZU, OHMAE, and ASHIKAWA, 1981). The usual systemic treatment for Wegener's granulomatosis is steroid and immunosuppressent agents. However, it is very difficult to control blood sugar in a diabetes mellitus case under steroid therapy. In our case, its control finally ended in a failure by various modes of insulin therapy. An easy medication of prednisolone possibly made the patient worsened in blood sugar level without checking it at first visit. The pancreas showed microscopically typical features of the primary diabetes mellitus. In the present case, the relationship between diabetes mellitus and Wegener's granulomatosis remained obscure. Wegener's granulomatosis is often diagnosed by otorhinolaryngologists. The symptoms and signs of this disease are so variable that its pathophysiology should be well understood and kept in mind when seeing patients. Findings in the nose and throat should make one suspicious of systemic disease. To make an early diagnosis it is important to ask if there has been any arthralgia, cough, fever, weight loss, refractory sinusitis, hemoptysis or epistaxis. In a patient with refractory secretory otitis media it is necessary to examine the nasal cavities and the epipharynx. Useful laboratory findings include positive CRP and RA, elevated serum IgG, IgA and complement, increase in IgE without allergic disease, eosinophilia, and negative PPD skin test. Nose and chest X-ray films should be taken. The Table 4.
Percentages of the organs involved in Wegener's granulomatosis. WOLFF et al. (1974)
KORNBLUT et al. (1980)
LAWSON et al. (1982)
Organ
21
47
Unknown
Nasopharynx Paranasal sinus Ear Eye Lung Kidney Heart Nerve Skin Joint
91% 95 38 43 100 81 29 24 48 57
Cases
more than 90 % 36 55 100 85 17 15 40 48
75% 90 35 60 95 85
WEGENER'S GRANULOMATOSIS CASE
189
most impofiant diagnostic procedures are biopsies of the nasal mucosa and the lung wheflfver they exhibit any abnormality, as the nose and lung show involvement in a high percent of cases of Wegener's granulomatosis. REFERENCES CALONIUS, I. H., and CHRISTENSEN, C. K.: Hearing impairment and facial palsy as initial signs of Wegener's granulomatosis. J. Laryngol. Otol. 94: 649-657, 1980. CARRINGTON, C. B., and LIEBOW, A. A.: Limited forms of angitis and granulomatosis of Wegener's type. Am. J. Med. 41: 497-527, 1966. CASSAN, S. M., CALES, D. T., and HARRISON, E. G.: The concept of limited forms of Wegener's granulomatosis. Am. J. Med. 49: 366-379, 1970. CHERRY, K. G., JORDAN, J. 0., LIGHT, R. W., and CALIF, L. B.: Wegener's granulomatosis. Arch. Intern. Med. 139: 1319, 1979. FAUCI, A. S., and WOLFF, S. M.: Effect of cytotoxic therapy on the renal lesion of Wegener's granulomatosis. Proceedings of the 6th International Congress of Nephrology, p. 489, 1975. GODMAN, G. H., and CHURG, J.: Wegener's granulomatosis, pathology and review of literature. Arch. Pathol. 58: 533-553, 1954. HENSLEY, M. J., FELDMAN, N. T., LAZARUS, J. M., and GALVANEK, E. G.: Diffuse pulmonary hemorrhage and rapidly progressive renal failure. Am. J. Med. 66: 894-898, 1979. JUNCOS, L. I., ALEXANDER, R. W., and MARBURY, T. c.: Intravascular clotting preceding crescent formation in a patient with Wegener's granulomatosis and rapidly progressive glomerulonephritis. Nephron 24: 17-20, 1979. KLINGER, H.: Grenzformen der Periarteritis nodosa. Frankfurter Zeitschri/t fur Pathologie, 42: 455-480, 1931. KORNBLUT, A. D., WOLFF, S. M., DEFRIES, H. 0., and FAUCI, A. S.: Wegener's granulomatosis. Laryngoscope 90: 1453-1465, 1980. LAWSON, V. G., REID, A. J., CARDELLA, C. J" and DEVEBER, G. A.: Wegener's granulomatosis and the respiratory system. J. Otolaryngol. 11: 60-64, 1982. NUNAKA, T., OKOCHI, T., WATANABE, Y., SAKAI, S., TAKAHASHI, Y., and YANAMURA, Y.: Lymphocyte functions in Wegener's granulomatosis. J. Med. 9: 491-501, 1978. SCULLY, R. E., MARK, E. J., and McNEELY, B. V.: Case records of the Massachusetts General Hospital. New Engl. J. Med. 304: 958-966, 1981. SHIMIZU, S., OHMAE, T., and ASHIKAWA, R.: Limited form Wegener's granulomatosis with subglottic stenosis, Otorhinolaryngology (Tokyo) 47: 425-429, 1981. WATANABE, Y., and NAGAKI, K.: Serum complement measurement relative to Wegener's granulomatosis and other related diseases. Otorhinolaryngology (Tokyo) 47: 49-55,1975. WEGENER, F.: Dber eigenartige rhinogene Granulomatose mit besonderer Beteiligung des Arterien systems und der Nieren. Beitrage zur PatllOlogischen Anatomie und zur Allgemeinen Pathologie, 102: 36-68, 1939. WOLFF, S. M" FAUCI, A. S" HORN, R. G., and DALE, D. C.: Wegener's granulomatosis. Ann. Intern. Med. 81: 512-525, 1974.
Request reprints to:
Dr. H. Kakoi, Department of Otolaryngology, Jichi Medical School, 3311-1, Minami-Kawachi-machi, Tochigi 329-04, Japan
WEGENER'S GRANULOMATOSIS: REPORT OF A CASE WITH RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS AND DIABETES MELLITUS Hiroyuki KAKOI, M. D., Fumihisa HIRAIDE, M. D., Shinji NISHIZAWA, M. D.,* Tetsuzo INOUYE, M. D.,** and Nobuyuki YOSHIZAWA, M. D.*** Department of Otolaryngology, Jichi Medical School, Tochigi, Japan
*Department of Otolaryngology, Social Health Insurance Hospital, Tokyo, Japan ** Department of Otolaryngology, and *** Department of 2nd Intestinal Medicine, National Defense Medical College, Saitama, Japan
A patient with the classic form of Wegener's granulomatosis with severe dabetes mellitus and rapidly progressive glomerulonephritis is described. This 61-year-old male presented with epistaxis and nasal pain and obstruction. The nasal cavities were filled with crusts covering eroded mucosa. The diagnosis was made by biopsy of nasal and bronchial mucosa, and laboratory data. The epistaxis was stopped by 10 Gy irradiation over the nasal cavities. The patient had severe diabetes mellitus. His blood sugar was not controlled by diet and insulin injection. His general condition worsened rapidly as the growth of granuloma in the nose and lung. Accordingly, prednisolone therapy reinitiated to suppress the granuloma although it has a reverse effect on diabetes mellitus. Approximately one month after admission, he died of acute renal failure. Autopsy was carried out. Granulomatous lesions were noted in the nasal cavities, lungs and spleen. Many petechiae were found macroscopically over the cortex of the kidney. Hyalinization or sclerosis with crescent formation was found microscopically in estimated 85 % of the glomeruli. Immunohistologic analysis of the renal tissue demonstrated an irregular linear pattern deposition of IgG, IgA and C3 and a granular pattern deposition of IgM and Clq. Wegener's granulomatosis has been considered a rare disease. In Japan approximately 400 cases have been reported. Recently the concept of a limited form of Wegener's granulomatosis was established. Most patients with this disease Recieved for publication February 20, 1986 177
178
H. KAKOI et at.
first consult otorhinolaryngologists complanining of nasal obstruction and bleeding. This disease is thought to be one of the causes of progressive necrotizing rhinitis. While its etiology is still unknown, it is considered similar to autoimmune disease. The necrotizing vasculitis of Wegener's granulomatosis resembles that of periarteritis nodosa and both diseases have elevation of serum immunoglobulins with deposition of immune complexes in tissues. Treatment with adrenal corticosteroids or immunosuppressants benefits most patients with this disease as is also true with autoimmune disease. We present in this paper our experience of treating a patient with a classic form of Wegener's granulomatosis complicated by severe diabetes mellitus. After about two months' hospitalization he died of acute renal failure. Our report includes the autopsy findings and one review of the appropriate literature. CASE REPORT
A 61-year-old male taxi driver was first seen in the Department of Otolaryngology, National Defense Medical College Hospital, on November 15, 1982, with complaints of nasal obstruction, epistaxis and pain at the root of the nose. Approximately one month earlier, he first noted constant nasal obstruction and bloody discharge after blowing his nose. He had lost 14 kg weight in the preceding two months. On examination abundant crusts which obstructed the nasal cavities were seen. When these crusts were removed the underlying surface was eroded and friable. Necrotizing granulomatous lesions were found on the nasal mucosa. The fundoscopic examination revealed no signs of diabetes mellitus or hypertension. The audiogram showed about 20 dB hearing loss with an A-B gap in both ears. There was no fluid or discharge seen on otoscopy. Roentgenographic findings of the nose and paranasal sinuses revealed diffuse shadows in the right maxillary sinus and in both ethmoid sinuses. The mucous membranes of the inferior turbinates and the nasal septum were thickened. On tomographic films of the nasal cavities, a partial defect of the nasal septal cartilage without bone destruction was observed (Fig. 1). The chest X-ray film showed multiple irregular cavitating nodules, 2 to 3 cm in diameter, in the right upper lobe. Thickening of the bronchial wall around the right B3a branch suggested an inflammation (Fig. 2). The laboratory findings at the first visit were: erythrocyte sedimentation rate, 37 mm per hr; WBC count, 14,100/cu mm, with 71 % neutrophils, 2 % eosinophils, 5 % monocytes, and 22 % lymphocytes; blood sugar, 451 mg/dl; alkaline phosphatase, 125 KAU; urinalysis: sugar 3+, with no white or red cells and no crystals. About 10% of the phenolsulfonphthalein was excreted in 15 min and 70.1 % in 120 min. The glomerular filtration rate (GFR) was normal. The renal blood flow (RBF) was 375.8 ml/min. The immunological study data included the fol-
WEGENER'S GRANULOMATOSIS CASE
179
Fig. 1. Tomographic film of the nose, Diffuse infiltrative shadow is noted in the right maxillary sinus and nasal septal cartilage is partly eroded.
--
Fig. 2. Tomographic film of the chest. Infiltrative shadow with multiple cavities is shown in the right upper lung.
lowing values: CRP; 6+; CH50, 60.5 V/ml; IgG, 2,999 mg/dl; IgM, 195 mg/dl; IgA, 309 mg/dl and IgE, 368IV/ml. The T and B lymphocyte subpopulation was 7.9 to 30.1 %. The lymphocyte blast formation was 28,072 cpm (control 23,000 cpm) with concanavalin A and 28,057 cpm (control 25,000 cpm) with phytohemoagglutinin. The purified protein derivative skin test (PPD) measured 9x8mm. Bronchoscopic examination found a granulomatous lesion, which bled easily, that spread from the trachea to the orifices of the right upper, the right middle,
180
Fig. 3. Bronchoscopic finding,
H. KAKOI et al.
;'-
Easily bleeding granulomatous lesion is revealed.
and the left upper bronchi. The orifices of the B3b and B6 were stenosed. Transbronchial lung biopsy (TBLB) could not be performed because of the friable bronchial wall. Tracheal and bronchial biopsies were done instead of TBLB (Fig. 3). A nasal mucosa biopsied specimen showed non-specific chronic inflammatory changes with infiltration of lymphocytes and plasma cells, and proliferation of capillaries. The tracheal mucosa specimen exhibited mucosal necrosis surrounded with infiltration of lymphocytes, polymorphonuclear neutrophils and multi-nuclear giant cells. Some areas revealed reactive hyperplasia of the bronchial cells and squamous epithelization. Tissue specimens from the nose and trachea showed necrotizing inflammatory changes. No renal biopsy was performed. Wegener's granulomatosis was suspected from the history and the physical findings in the nose. Oral prednisolone was started at a daily dose of 20 mg on November 15, 1982, but this was discontinued on November 27 since the initial blood sugar was elevated to 450 mgjdl. The patient was admitted to our hospital on December 6 to regulate his diabetes mellitus. He was put on a 1,500 cal diet and on the 6th hospital day treatment with Novolente insulin MC 22 Ujday was initiated. The dosage of insulin was regulated by the sliding scale method. On the 13th hospital day the patient's nausea, vomiting and anorexia became more severe and an intravenous drip containing Actorapid insulin MC and glucose, I unit to 4 g, was started. On the 23rd hospital day a continuous subcutaneous infusion therapy was begun with a micro-infusion pump. The blood sugar values fluctuated widely throughout the hospital course. The data of hematological and urine examinations during the patient's hospitalization are shown in Table 1. Treatment given and clinical course are diagrammed in Fig. 4.
WEGENER'S GRANULOMATOSIS CASE Table 1.
181
Changes in the laboratory data.
Nov. 15
Dec. 2
Dec. 23
Jan. 4
ESR mg/hr WBC 10 RBC 10 Plate 10
97 14.1 461 43
81 12.1 450 35
10.4 386 96
32 22.7 230 14
Glu mg/dl U.A. mg/dl BUN mg/dl
451 4.0 13
248 4.0 12
675 6.2 41
215 12.5 117
54
63
64
Ur.pa mg/dl CRP RA CH50 IgG JgA IgM JgE
U/ml mg/dl mg/d! mg/dl IU/ml
6+
5+
60.5 2,999 309 195 368
57.5 1,709 366 155
2+ + 38.7 1,559 263 246
4+ 32.2 1,180 313 209
a Ur.P, urine protein.
The diagnosis of Wegener's granulomatosis was confirmed when the histological findings of the various biopsies and further laboratory data became available. Symptomatic therapy with anti-tussive agents, analgesics, and hemostatic agents proved ineffective against cough, pain at the root of the nose and continuous epistaxis. The attempts to control the blood sugar ended in failure, but prednisolone therapy was reinitiated on the 16th hospital day, this time at a daily dose of 60 mg, in combination with 50 mg of cyclophosphamide. On the 29th hospital day prednisolone was discontinued again because of severe hyperglycemia and the cyclophosphamide was continued at a dose of 100 mg per day. Prednisolone and cyclophosphamide had been effective against the cough and the pain at the root of the nose. On the 21st day radiation over the nasal cavities was started to control epistaxis. A total of 10 Gy was administered. On the 26th day a perforation of the nasal septum was found. On the 16th day the patient first noticed discomfort of the right knee when walking. Edema of the anterior crural and peri-orbital regions developed on the 19th hospital day. From the 23rd day onward the urinary output gradually decreased. Peritoneal dialysis was performed but the patient died of acute renal failure on January 7, 1983, the 37th hospital day after admission. An autopsy was performed 6 hr after death. The brain and dura mater had no unusual lesions. An attempt to remove the nasal cavities en bloc through the anterior cranial fossa failed because the osseous framework of the nasal cavities was almost destroyed. Part of the inferior turbinates remained intact, but the
H. KAKOI et
182
at.
No. Nasal bleeding
~
Cough Pain at the root of the nose
Prednisolone
","1(---20 mgjday----?l,1
IE-Novolente Me 22U-
Insulin Nov. 15 First visit
20
I
25
I
I
30 Dec. 1 Admission
5
No.2 Nasal bleeding
~
Cough Pain at the root of the nose Nausea, vomiting
~ ~ ~SS\\S\\\"'\~ ~
Edema
- - - - 5 0 mgjday----"".,
Prednisolone
I<-IE
Cyclophosphamide
1<-1,----50 mgjday----~>I<-, 100 mg/day~
Radiation Insulin
k--2Gyjday~
->*-AR.MC 12U+ AR.MC 4U 3*->tl.-AR.MC 19.2U**~AR.MC 40U"*,,AR.MC 19.2U**
Dec. 15
20
25
30 Jan. 1
5
7 Death
* Add 4U every diet. ** Continuous subcutaneous Fig. 4.
AR.MC: Acto Rapid MC infusion.
Treatment and clinical course.
middle turbinates were lost and most of the nasal septum was lacking. Both maxillary sinuses had thickened mucosa. The medial bony walls of both maxillary sinuses were attenuated and partly eroded. The inferior bony walls of both ethmoid sinuses were partly destroyed. A crusty granulomatous lesion resembling that in the nasal cavities was found in the left ethmoid sinus. Necrotizing granulomatous lesions with multiple cavities were present in the upper lobe of the right lung with friable granulomatous lesions extending from the trachea to the main bronchi (Fig. 5). Numerous yellowish-white nodules, 2 to 5 mm in diameter were seen in the spleen (Fig. 6). There were many petechiae over the cortex of the kidney and hyalinization or sclerosis with crescent formation involving in estimated 85 % of the glomeruli (Fig. 7). Some of blood vessels were thrombotic. Medium-sized arteries had thickening of the endothelium and infiltration with round cells. An immunofluorescence study of the kidney showed the deposition
WEGENER'S GRANULOMATOSIS CASE
183
Fig. 5. Cross section of the right lung. Necrotizing granulomatous lesion (arrow) is revealed in the right upper lobe.
Fig. 6. Cross section of the spleen. lesion.
Multiple small nodular lesions are seen as in the lung
of several immunoglobulins and complement (Fig. 8 and Table 2). IgG, IgA and C3 were found in an irregular linear pattern and IgM and Clq were found in a granular pattern. In the pancreas, there were macroscopically almost normal findings
184
H. KAKOI et al.
Fig. 7. Renal microscopic finding. Crescent formation (arrows) is found in 85 % of glomeruli. HE staining. x 200.
Fig. 8. Renal immunofluorescence finding. Deposition of IgG is disclosed along the basement membrane in an irregular pattern (arrows). x 300.
WEGENER'S GRANULOMATOSIS CASE
185
Table 2. The renal immunofluorescence findings. Glomerulus IgG IgA IgM Fib C3 Clq C4 PPD Alb
Vessel
Tubule
1+ 3+
1+ 0 0 1+
1+ 1+ 1+ 0
2+ 2+ 1+ 0 2+
0 1+ 0 0 0
1+ 0 0 1+ 2+
Count
Distribution
Pattern
Density'
30/35 2/38 5/26 27/29 23/23 12/ 9 22/35 4/17 0/22 25/25
GD FL FS GD GD
CL IL G CL
2+~3+
FS~D
GD
IL G
GD
CL
0~1+
• Density was graded into four degrees (0 ~ 3 + ). GD, generalized-diffuse; FL, focallocal; FS, focal-segmental; FS~D, focal-segmental~diffuse; CL, continuous-linear; IL, interrupted-linear; G, granular.
but microscopically a moderate decrease in the number of the islets of Langerhans and the hydropic changes in p-cells. DISCUSSION
The necrotizing granulomatous lesion was described by KLINGER (1931) as a borderline type of periarteritis nodosa. WEGENER (1939) considered this granulomatosis a disease independent of periarteritis nodosa. The concept of Wegener's granulomatosis was established by GODMAN and CHURG (1954) by describing three histological characteristics: (1) Necrotizing granulomas in the respiratory tract, (2) generalized necrotizing vasculitis, and (3) focal or granulomatous glomerulonephritis. On the other hand, CARRINGTON and LIEBOW (1966) and CASSAN, CALES, and HARRISON (1970) reported a limited form of Wegener's granulomatosis which had no renal lesions, but did have other localized lesions. Our case represented a classic form of Wegener's granulomatosis with severe diabetes mellitus. The diagnosis was made by the findings of the nasal cavities, the bronchoscopic examination and the laboratory data. Compared to tother reports about this disease, this presentation was unusual in that the patient had typical symptoms and local findings at the first consultation. In one patient reported elsewhere, the initial diagnosis was serous otitis media and paracenteses were repeated without success. When that patient later had a cough, a chest roentgenogram showed multiple nodules with cavitation which confirmed the diagnosis of Wegener's granulomatosis (CALONIUS and CHRISTENSEN, 1980). Another patient with a solitary coin lesion in the lung was diagnosed as having tuberculosis and was treated with antituberculous agents. Subsequently, the patient developed edema which led a correct diagnosis (CHERRY, JORDAN, LIGHT, and CALIF, 1979). Still another patient had arthralgia and was treated with non-
186
H. KAKOI et af. Table 3.
Ear Paranasal sinus
Nose
Lung
Kidney Joint Skin Nerve Others
Early symptoms and complications in 124 cases of Wegener's granulomatosis.
Otitis media Otalgia Sinusitis Forehead pain Face pain Nasal bleeding Rhinorrhea Nasal obstruction Congestion Cough Bloody sputum Chest pain Edema Arthralgia Arthritis Vasculitis Neuritis Fever Weight loss Fatigue Discomfort
Number
%
32 8 23 5 5 20 13 10 9 23 15 8 7 28 7 6 5 28
25.8 6.5 18.5 4.0 4.0 16.0 10.5 8.1 6.5 18.5 12.1 6.5 5.6 22.6 5.6 4.8 4.0 22.6 13.7 6.5 6.5
17 8
8
steroidal, anti-phlogistic and analgesic drugs. The diagnosis was later changed to Wegener's granulomatosis when the patient had hemoptysis (SCULLY, MARK, and McNEELY, 1981). Wegener's granulomatosis is thought to be caused by a disorder of the immune system because deposition of immune complexes are found in tissues such as the nasal mucosa, skin, lungs and kidneys. The symptoms of this disease are so variable that attention should be directed to the patient's complaints and the general physical findings rather than overemphasis on one or more local findings. Table 3 lists the early symptoms during the first two or three months of the disease in 124 cases gathered from European and American reports published from 1976 to 1984. Laboratory data are important in this disease for diagnosis and as an index of the effect of treatment. As subjective symptoms, such as cough and pain at the root of the nose, improve, the laboratory results change. Serum concentration of complement, IgG and IgA may become normal and CRP decreases. WATANABE and NAGAKI (1975) reported that serum complement concentration increased in the active stage and became normal with effective treatment in Wegener's granulomatosis and diseases similar to it.· They noted a remarkable decrease in serum complement concentration immediately before patients had serious exacerbation of their disease. This phenomenon might be explained as follows: there is an activation of the complement producing system in Wegener's granulomatosis,
WEGENER'S GRANULOMATOSIS CASE
187
unknown factors trigger the deposition of immune complexes in tissues which aggravates the patient's condition, the immune complexes consume the serum complement, by a reboun~ phenomenon of the consumption the complement producing system is activated and the serum complement concentration becomes high. Our patient's clinical condition worsened althogh the serum complement and immunoglobulins showed normalization. Apparently the production and deposition in tissues of the immune complexes caused the serum values to return to normal. It is more important to observe the patient's general condition than to rely on laboratory data. NUNAKA, OKOCHI, WATANABE, SAKAI, TAKAHASHI, and YANAMURA (1978), reported that in Wegener's granulomatosis they found the lymphocyte blast formation was almost normal and the T-B cell sUbpopulation ratio showed no remarkable change. In the present case, the lymphocyte blast forma tion was normal but the ratio of T cells to B cells was decreased. Whether or not this was due to an increase in the number of null cells remains to be explained. The renal lesions in Wegener's granulomatosis usually progress slowly. FAUCI and WOLFF (1975), however, reported acute renal failure due to rapidly progressive glomerulonephritis in 3 out of 24 cases with this disease. JUNCOS, ALEXANDER and MARBURY (1979) and HENSLEY, FELDMAN, LAZARUS, and GALVANEK (1979), reported that crescent formation with fibrin deposition was found in 60 % of glomeruli small thrombi were found in capillary vessels in the renal specimens from patients with rapidly progressive glomerulonephritis. JUNCOS et al. (1979) concluded that since thrombus formation played an important role in the disease, heparin was useful for treatment. Our patient developed renal failure on the 18th hospital day and crescent formation with fibrin deposition was found in 85 % of glomeruli. When Wegener's granulomatosis is suspected, a renal biopsy should be performed. This is useful in establishing the diagnosis and for differentiating the classic form of the disease from the limited form. Renal biopsy may also help in the prognosis. In immunoflorescent studies of renal tissue, IgG, IgA and C3 show a linear deposition pattern and IgM and Clq show a granular pattern. It is important to distinguish between the irregular linear pattern and the smooth linear pattern. The irregular linear pattern is found in Wegener's granulomatosis and other related diseases while smooth linear pattern is found in Goodpasture's syndrome. In instances of acute renal failure with crescent formation, the linear pattern is often seen even without anti-basement membrane antibody. The smooth linear pattern is typically found in Goodpasture's syndrome, one of the autoimmune diseases having antibodies in the anti-basement membrane, and lesions in the lung alveoli and renal glomeruli. Our patient had nodular lesions in the spleen with features identical to those of the necrotizing granuloma in the lung. The inflammatory adhesion of the pericardium was apparently due to granulomatous vasculitis of the pericardial vessels.
H. KAKOI et al.
188
Our patient had bleeding from friable granulomatous lesions throughout the nasal cavities. The patient complained of nausea and anorexia due to blood flowing down into the pharynx. Appetite loss impacte~ seriously on the effort to control his blood sugar by insulin injection. On the assumption that the nasal bleeding was due to the production of fresh granuloma in the nasal cavities, a small amount of localized irradiation over the nasal cavities was carried out. A total of 6 to 10 Gy irradiation seemed to be enough to inhibit production of new granuloma and stop the epistaxis. Irradiation was useful for the inhibition of granuloma production at the subglottic space in a patient with this disease, according to a recent report (SHIMIZU, OHMAE, and ASHIKAWA, 1981). The usual systemic treatment for Wegener's granulomatosis is steroid and immunosuppressent agents. However, it is very difficult to control blood sugar in a diabetes mellitus case under steroid therapy. In our case, its control finally ended in a failure by various modes of insulin therapy. An easy medication of prednisolone possibly made the patient worsened in blood sugar level without checking it at first visit. The pancreas showed microscopically typical features of the primary diabetes mellitus. In the present case, the relationship between diabetes mellitus and Wegener's granulomatosis remained obscure. Wegener's granulomatosis is often diagnosed by otorhinolaryngologists. The symptoms and signs of this disease are so variable that its pathophysiology should be well understood and kept in mind when seeing patients. Findings in the nose and throat should make one suspicious of systemic disease. To make an early diagnosis it is important to ask if there has been any arthralgia, cough, fever, weight loss, refractory sinusitis, hemoptysis or epistaxis. In a patient with refractory secretory otitis media it is necessary to examine the nasal cavities and the epipharynx. Useful laboratory findings include positive CRP and RA, elevated serum IgG, IgA and complement, increase in IgE without allergic disease, eosinophilia, and negative PPD skin test. Nose and chest X-ray films should be taken. The Table 4.
Percentages of the organs involved in Wegener's granulomatosis. WOLFF et al. (1974)
KORNBLUT et al. (1980)
LAWSON et al. (1982)
Organ
21
47
Unknown
Nasopharynx Paranasal sinus Ear Eye Lung Kidney Heart Nerve Skin Joint
91% 95 38 43 100 81 29 24 48 57
Cases
more than 90 % 36 55 100 85 17 15 40 48
75% 90 35 60 95 85
WEGENER'S GRANULOMATOSIS CASE
189
most impofiant diagnostic procedures are biopsies of the nasal mucosa and the lung wheflfver they exhibit any abnormality, as the nose and lung show involvement in a high percent of cases of Wegener's granulomatosis. REFERENCES CALONIUS, I. H., and CHRISTENSEN, C. K.: Hearing impairment and facial palsy as initial signs of Wegener's granulomatosis. J. Laryngol. Otol. 94: 649-657, 1980. CARRINGTON, C. B., and LIEBOW, A. A.: Limited forms of angitis and granulomatosis of Wegener's type. Am. J. Med. 41: 497-527, 1966. CASSAN, S. M., CALES, D. T., and HARRISON, E. G.: The concept of limited forms of Wegener's granulomatosis. Am. J. Med. 49: 366-379, 1970. CHERRY, K. G., JORDAN, J. 0., LIGHT, R. W., and CALIF, L. B.: Wegener's granulomatosis. Arch. Intern. Med. 139: 1319, 1979. FAUCI, A. S., and WOLFF, S. M.: Effect of cytotoxic therapy on the renal lesion of Wegener's granulomatosis. Proceedings of the 6th International Congress of Nephrology, p. 489, 1975. GODMAN, G. H., and CHURG, J.: Wegener's granulomatosis, pathology and review of literature. Arch. Pathol. 58: 533-553, 1954. HENSLEY, M. J., FELDMAN, N. T., LAZARUS, J. M., and GALVANEK, E. G.: Diffuse pulmonary hemorrhage and rapidly progressive renal failure. Am. J. Med. 66: 894-898, 1979. JUNCOS, L. I., ALEXANDER, R. W., and MARBURY, T. c.: Intravascular clotting preceding crescent formation in a patient with Wegener's granulomatosis and rapidly progressive glomerulonephritis. Nephron 24: 17-20, 1979. KLINGER, H.: Grenzformen der Periarteritis nodosa. Frankfurter Zeitschri/t fur Pathologie, 42: 455-480, 1931. KORNBLUT, A. D., WOLFF, S. M., DEFRIES, H. 0., and FAUCI, A. S.: Wegener's granulomatosis. Laryngoscope 90: 1453-1465, 1980. LAWSON, V. G., REID, A. J., CARDELLA, C. J" and DEVEBER, G. A.: Wegener's granulomatosis and the respiratory system. J. Otolaryngol. 11: 60-64, 1982. NUNAKA, T., OKOCHI, T., WATANABE, Y., SAKAI, S., TAKAHASHI, Y., and YANAMURA, Y.: Lymphocyte functions in Wegener's granulomatosis. J. Med. 9: 491-501, 1978. SCULLY, R. E., MARK, E. J., and McNEELY, B. V.: Case records of the Massachusetts General Hospital. New Engl. J. Med. 304: 958-966, 1981. SHIMIZU, S., OHMAE, T., and ASHIKAWA, R.: Limited form Wegener's granulomatosis with subglottic stenosis, Otorhinolaryngology (Tokyo) 47: 425-429, 1981. WATANABE, Y., and NAGAKI, K.: Serum complement measurement relative to Wegener's granulomatosis and other related diseases. Otorhinolaryngology (Tokyo) 47: 49-55,1975. WEGENER, F.: Dber eigenartige rhinogene Granulomatose mit besonderer Beteiligung des Arterien systems und der Nieren. Beitrage zur PatllOlogischen Anatomie und zur Allgemeinen Pathologie, 102: 36-68, 1939. WOLFF, S. M" FAUCI, A. S" HORN, R. G., and DALE, D. C.: Wegener's granulomatosis. Ann. Intern. Med. 81: 512-525, 1974.
Request reprints to:
Dr. H. Kakoi, Department of Otolaryngology, Jichi Medical School, 3311-1, Minami-Kawachi-machi, Tochigi 329-04, Japan