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Interstitial Cystitis in Chronic Granulomatous Disease
Vol. 105, April Printed in U.S.A.
THE JouRNAL OF UROLOGY
Copyright © 1971 hy The Williams & Wilkins Co.
INTERSTITIAL CYSTITIS IN CHRONIC GRANULOMATOUS DISEASE STELLA B. KONTRAS, JOANN G. BODENBENDER, CHARLES R. MCCLAVE AND J. P. SMITH From the Departments of Pediatrics ancl Surgery, College of Medicine, Ohio State University ancl Children's Hospital Research Foundation, Columbus, Ohio
Herein we will describe 2 male cousins with chronic cystitis whose laboratory and clinical findings indicated chronic granulomatous disease. In chronic granulomatous disease the basic defect is an inability of leukocytes to kill ingested bacteria in spite of normal immunologic functions. 1 An X-linked mode of inheritance has been postulated, with the defect occurring in male individuals and a partial abnormality occurring in female carriers.2 Manifestations of the disease include suppurative adenitis, hepatic abscesses, pyoderma, osteomyelitis and chronic pneumonitis and have been described often since the report by Berendes and associates. 3 Chronic cystitis has not been reported previously in this syndrome. CASE REPORT
G. F. was 2 years old when admitted to Columbus Children's Hospital for the first of 9 hospitalizations. He had had pain on urination for 6 months. Cystoscopy and exploratory laparotomy resulted in a diagnosis of inflammation of the bladder wall and mesenteric adenitis. He was given steroids (meticorten) * and showed improvement. The patient was hospitalized when he was 8 years old for evaluation of kidney function. He had been taking meticorten for the cystitis for almost 5 years and any attempt at withdrawal resulted in symptoms of dysuria. Accepted for publication September 1, 1970. 1 Quie, P. G., White, J. G., Holmes, B. and Good, R. A.: In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J. Clin. Invest., 46: 668, 1967. 2 Windhorst, D. B., Holmes, B. and Good, R. A.: A newly defined X-linked trait in man with demonstration of Lyon effect in carrier female. Lancet, 1: 737, 1967.
3 Berendes, H., Bridges, R. A. and Good, R. A.: A fatal granulomatosis of childhood: the clinical study of a new syndrome. Minn. Med., 40: 309, 1957. * Schering Corporation, Bloomfield, New Jersey.
When he was 11 years old he was of small stature and had no adenopathy, hepatosplenomegaly or pulmonary problems. Laboratory data were blood urea nitrogen (I3UN), creatinine, 1.0; hemoglobin, 12.6 gm. and white blood count (WBC), 11,350 with 78 per cent neutrophils. Urinalysis showed a pH of 4.5, specific gravity 1.008, albumin 100 mg. per cent and was negative for sugar and acetone. There were O to 2 white and 10 to 12 red blood cells per high power field. Sedimentation rate was 35 mm. per hour. Urine cultures on 26 occasions yielded no An excretory urogram (IVP) showed hydronephrosis and a dilated ureter. Cystogram revealed multiple defects in the bladder. Upper gastrointestinal series showed prominence of the rugal folds. Cystoscopy showed edematous, reddened necrotic tissue on the floor of the bladder. Biopsies were obtained. The patient was 10 mg. prednisonet 3 times daily and continued to take furadantin.t He improved considerably and was discharged from the hospital. On his last hospitalization at the age of 14, he had a histmy of dysuria which improved whenever prednisone dosage was increased. He also had enuresis, daytime dribbling, urgency and frequency. Physical examination showed marked underdevelopment-at the age of 14 he was the size of a 7-year-old boy. Laboratory data were normal. Urethral dilatation, endoscopy, cystoscopy and another bladder biopsy were done. An IVP showed some improvement and it was believed that an operation for the urologic condition was not indicated. The patient was released from the hospital on prednisone medication and was to be followed as an outpatient. Family history is significant in that the mother of the patient is 56 years old and well. The father was in a tuberculosis sanitarium for 10 years during the patient's childhood. The first child of this family died at age 7 of pulmonary infections
t McKesson Laboratories, Bridgeport, Connecticut. t Eaton Laboratories, Norwich, New York. 575
576
KONTRAS AND ASSOCIATES
and large lymph nodes. There is a normal daughter. The patient has a male first cousin on the maternal side who has had chronic cystitis since infancy and was hospitalized for liver abscess and lymphadenitis at the age of 16 years. METHODS
The qualitative nitro-blue tetrazolium (NBT) test was done by the method of Windhorst. 2 Five hundred polymorphonuclear cells were counted from the patient and from a healthy control. The bactericidal tests were done by the method of Quie2 using Staphylococcus aureus strain 502 A. The results are expressed as colony counts after O 1 and 2 hours of incubation of bacteria with l~ukocytes from patients and controls. Laboraiory data on propositus and family
GF, propositus Mother of GF* Father of GF GS, first cousin of propositus Mother of GS* Father of GS Brother of GS A S, mother of both sis-
NBT Dye Test(%)
Leukocyte Bactericidal Capacity
Symp· toms
14.5 37.5 Not done 5.0
Decreased Intermediate Normal Decreased
+
+
Intermediate Not available for study Not done Intermediate Not done Intermediate
RESULTS
The results of leukocyte studies are shown in the table and figure 1. Tests on the propositus (G. F.) and his male cousin (G. S.) revealed gross abnormality of both NBT reduction and bactericidal capacity consistent with the diagnosis of chronic granulomatous disease (see table). Serum immunoglobulins were normal. Figure 1 shows that G. F. has a diminished ability to handle Staphylococcus 502 with increased intraleukocytic survival of bacteria. The mother demonstrates intermediate values consistent with the carrier state in both the NBT dye reduction test and the leukocyte bactericidal studies; the father is normal (see table). The patient's male first cousin (G. S.) shows the same degree of leukocyte dysfunction and has similar clinical symptoms. Another male first cousin (C. S.) has an intermediate function but is asymptomatic. The 83year-old maternal grandmother (A. S.) also shows intermediate leukocyte function and has never had problems with infection. The sister and maternal grandmother of the propositus are asymptomatic carriers (fig. 2).
46. 5
ters
Controls (30 male and female)
68-79
PATHOLOGIC FINDINGB
Two bladder biopsies were availa0le from G. F.
In October 1965 a specimen was obtained which showed bladder mucosa with several areas of epithelial hypertrophy. The submucosal space showed edematous, vascular stroma with diffuse
Normal
* Sisters.
MOTHER Of G.F.
CONTROL
800 -
Total colony count ofter incubation of bacteria
700
with leukocytes •••••• Extro·cellulor colony count
600
·- ......
<(
~~
z'°
500
---Intro-cellular colony count
.,
5~
~ ~ 400
z::)
0
<(
c5 ~
u i5
300
CJ)
200 100
•····· ····· 0
•·········· 2
0
I HOURS
2
0
2
Fm. 1. Abnormal leukocyte bactericidal functions of G. F., his mother who has intermediate functions and a normal control.
57'7
INTERSTITIAL CYSTITIS
0 ct c.s.
GS.
'i'
I
G.F.
NOT AFFECTED NORMAL STUDIES
D
• r
l!ll T J'
NOT AFFECTED, INTERMEDIATE LEUKOCYTE DEFECT NOT AFFECTED NOT STUDIED AFFECTED MALE ABNORMAL LEUKOCYTE FUNCTION DECEASED, OTHER CAUSES DECEASED, AFFECTED, NOT STUDIED PROPOSITUS
Fm. 2. Pedigree of families of G. S. and G. F. Their mothers, a sister and maternal grandmother are carriers.
Fm. 3. G. F.~pathologic findings in most recent bladder biopsy show cystic changes m mucosa, chronic submucosal inflammation and edema. cellular infiltrate of plasma cells, eosinophils and lymphocytes; some foci of histiocytes were present. Repeat bladder biopsy in 1968 showed submucosal edema with chronic inflammation and mild hemosiderosis (fig. 3). The diagnosis was chronic cystitis. The Armed Forces Institute of
Pathology also examined the specimens and reported "bladder biopsy with eosinophilic bullous cystitis with focal granulomatous reaction, etiology undetermined". Special stains for tuberculosis and fungi were negative. Bladder biopsy of the cousin, G. revealed
578
KONTRAS AND ASSOCIATES
Fm. 4. G. S.-lymph node shows necrosis and granulomatous inflammation similar findings. In addition, a lymph node was removed which showed necrosis and granulomatous inflammation (fig. 4). DISCUSSION
An atypical form of chronic granulomatous disease in male first cousins is reported with chronic cystitis as the primary manifestation. The cases illustrate the clinical variability of the disorder and suggest that leukocyte dysfunction may be the basic pathophysiologic mechanism for disease manifesting primarily in any organ or system. One of these cases (G. F.) illustrates the effect of steroids on suppression of the systemic manifestations of this disorder. His cousin, though having bladder problems most of his life, was not undergoing steroid treatment and a hepatic abscess developed when the boy was 15 years old. The etiology of chronic interstitial cystitis has not been established. 4 Chronic inflammation, tissue destruction and fibrosis have suggested an auto-immune pathogenesis. 4 • 5 Deficiencies in immunologic or leukocyte bactericidal ability have not been suspected as a possible etiology. Cystitis has not been reported as an important manifestation of chronic granulomatous disease. 4
Campbell, M. F.: Urology. Philadelphia:
W. B. Saunders Co., vol. 3, 1963.
5 Silk, M. R.: Bladder antibodies in interstitial cystitis. J. Urol., 103: 307, 1970.
Chronic interstitial cystitis with Runner's ulcer is common in women but some pediatric cases have been reported by McDonald 6 and by Chenoweth.7 The clinical and pathologic findings were similar to those seen in our 2 cases. The mechanisms of bladder bactericidal activity are not clear and whether the leukocyte bactericidal function is an essential component of bladder defense mechanisms is unknown.8 The cases herein described suggest that normal leukocyte function may be necessary for bladder bactericidal activity and that this may be determined genetically in some families. SUMMARY
Abnormal leukocyte bactericidal activity and NBT reduction identical to that described in fatal chronic granulomatous disease were found in 2 male first cousins with chronic interstitial cystitis many years in duration. It is suggested that this genetically determined syndrome be considered in the differential diagnosis of chronic cystitis. 6 _McDonald, H. P., Upchurch, W. E. and Art1me, M.: Bladder dysfunction in children caused by interstitial cystitis. J. Urol., 80: 354
19~.
'
Chenoweth, C. V. and Clawater, E.W., Jr.: Interstitial cystitis in children. J. Urol. 83: 150 7
1960.
'
'
Norden, C. W., Green, G. M. and Kass, E. H.: Anti~acterial mechanisms of the urinary bladder. J. Clm. Invest., 47: 2689, 1968. 8
THE JouRNAL OF UROLOGY
Copyright © 1971 hy The Williams & Wilkins Co.
INTERSTITIAL CYSTITIS IN CHRONIC GRANULOMATOUS DISEASE STELLA B. KONTRAS, JOANN G. BODENBENDER, CHARLES R. MCCLAVE AND J. P. SMITH From the Departments of Pediatrics ancl Surgery, College of Medicine, Ohio State University ancl Children's Hospital Research Foundation, Columbus, Ohio
Herein we will describe 2 male cousins with chronic cystitis whose laboratory and clinical findings indicated chronic granulomatous disease. In chronic granulomatous disease the basic defect is an inability of leukocytes to kill ingested bacteria in spite of normal immunologic functions. 1 An X-linked mode of inheritance has been postulated, with the defect occurring in male individuals and a partial abnormality occurring in female carriers.2 Manifestations of the disease include suppurative adenitis, hepatic abscesses, pyoderma, osteomyelitis and chronic pneumonitis and have been described often since the report by Berendes and associates. 3 Chronic cystitis has not been reported previously in this syndrome. CASE REPORT
G. F. was 2 years old when admitted to Columbus Children's Hospital for the first of 9 hospitalizations. He had had pain on urination for 6 months. Cystoscopy and exploratory laparotomy resulted in a diagnosis of inflammation of the bladder wall and mesenteric adenitis. He was given steroids (meticorten) * and showed improvement. The patient was hospitalized when he was 8 years old for evaluation of kidney function. He had been taking meticorten for the cystitis for almost 5 years and any attempt at withdrawal resulted in symptoms of dysuria. Accepted for publication September 1, 1970. 1 Quie, P. G., White, J. G., Holmes, B. and Good, R. A.: In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J. Clin. Invest., 46: 668, 1967. 2 Windhorst, D. B., Holmes, B. and Good, R. A.: A newly defined X-linked trait in man with demonstration of Lyon effect in carrier female. Lancet, 1: 737, 1967.
3 Berendes, H., Bridges, R. A. and Good, R. A.: A fatal granulomatosis of childhood: the clinical study of a new syndrome. Minn. Med., 40: 309, 1957. * Schering Corporation, Bloomfield, New Jersey.
When he was 11 years old he was of small stature and had no adenopathy, hepatosplenomegaly or pulmonary problems. Laboratory data were blood urea nitrogen (I3UN), creatinine, 1.0; hemoglobin, 12.6 gm. and white blood count (WBC), 11,350 with 78 per cent neutrophils. Urinalysis showed a pH of 4.5, specific gravity 1.008, albumin 100 mg. per cent and was negative for sugar and acetone. There were O to 2 white and 10 to 12 red blood cells per high power field. Sedimentation rate was 35 mm. per hour. Urine cultures on 26 occasions yielded no An excretory urogram (IVP) showed hydronephrosis and a dilated ureter. Cystogram revealed multiple defects in the bladder. Upper gastrointestinal series showed prominence of the rugal folds. Cystoscopy showed edematous, reddened necrotic tissue on the floor of the bladder. Biopsies were obtained. The patient was 10 mg. prednisonet 3 times daily and continued to take furadantin.t He improved considerably and was discharged from the hospital. On his last hospitalization at the age of 14, he had a histmy of dysuria which improved whenever prednisone dosage was increased. He also had enuresis, daytime dribbling, urgency and frequency. Physical examination showed marked underdevelopment-at the age of 14 he was the size of a 7-year-old boy. Laboratory data were normal. Urethral dilatation, endoscopy, cystoscopy and another bladder biopsy were done. An IVP showed some improvement and it was believed that an operation for the urologic condition was not indicated. The patient was released from the hospital on prednisone medication and was to be followed as an outpatient. Family history is significant in that the mother of the patient is 56 years old and well. The father was in a tuberculosis sanitarium for 10 years during the patient's childhood. The first child of this family died at age 7 of pulmonary infections
t McKesson Laboratories, Bridgeport, Connecticut. t Eaton Laboratories, Norwich, New York. 575
576
KONTRAS AND ASSOCIATES
and large lymph nodes. There is a normal daughter. The patient has a male first cousin on the maternal side who has had chronic cystitis since infancy and was hospitalized for liver abscess and lymphadenitis at the age of 16 years. METHODS
The qualitative nitro-blue tetrazolium (NBT) test was done by the method of Windhorst. 2 Five hundred polymorphonuclear cells were counted from the patient and from a healthy control. The bactericidal tests were done by the method of Quie2 using Staphylococcus aureus strain 502 A. The results are expressed as colony counts after O 1 and 2 hours of incubation of bacteria with l~ukocytes from patients and controls. Laboraiory data on propositus and family
GF, propositus Mother of GF* Father of GF GS, first cousin of propositus Mother of GS* Father of GS Brother of GS A S, mother of both sis-
NBT Dye Test(%)
Leukocyte Bactericidal Capacity
Symp· toms
14.5 37.5 Not done 5.0
Decreased Intermediate Normal Decreased
+
+
Intermediate Not available for study Not done Intermediate Not done Intermediate
RESULTS
The results of leukocyte studies are shown in the table and figure 1. Tests on the propositus (G. F.) and his male cousin (G. S.) revealed gross abnormality of both NBT reduction and bactericidal capacity consistent with the diagnosis of chronic granulomatous disease (see table). Serum immunoglobulins were normal. Figure 1 shows that G. F. has a diminished ability to handle Staphylococcus 502 with increased intraleukocytic survival of bacteria. The mother demonstrates intermediate values consistent with the carrier state in both the NBT dye reduction test and the leukocyte bactericidal studies; the father is normal (see table). The patient's male first cousin (G. S.) shows the same degree of leukocyte dysfunction and has similar clinical symptoms. Another male first cousin (C. S.) has an intermediate function but is asymptomatic. The 83year-old maternal grandmother (A. S.) also shows intermediate leukocyte function and has never had problems with infection. The sister and maternal grandmother of the propositus are asymptomatic carriers (fig. 2).
46. 5
ters
Controls (30 male and female)
68-79
PATHOLOGIC FINDINGB
Two bladder biopsies were availa0le from G. F.
In October 1965 a specimen was obtained which showed bladder mucosa with several areas of epithelial hypertrophy. The submucosal space showed edematous, vascular stroma with diffuse
Normal
* Sisters.
MOTHER Of G.F.
CONTROL
800 -
Total colony count ofter incubation of bacteria
700
with leukocytes •••••• Extro·cellulor colony count
600
·- ......
<(
~~
z'°
500
---Intro-cellular colony count
.,
5~
~ ~ 400
z::)
0
<(
c5 ~
u i5
300
CJ)
200 100
•····· ····· 0
•·········· 2
0
I HOURS
2
0
2
Fm. 1. Abnormal leukocyte bactericidal functions of G. F., his mother who has intermediate functions and a normal control.
57'7
INTERSTITIAL CYSTITIS
0 ct c.s.
GS.
'i'
I
G.F.
NOT AFFECTED NORMAL STUDIES
D
• r
l!ll T J'
NOT AFFECTED, INTERMEDIATE LEUKOCYTE DEFECT NOT AFFECTED NOT STUDIED AFFECTED MALE ABNORMAL LEUKOCYTE FUNCTION DECEASED, OTHER CAUSES DECEASED, AFFECTED, NOT STUDIED PROPOSITUS
Fm. 2. Pedigree of families of G. S. and G. F. Their mothers, a sister and maternal grandmother are carriers.
Fm. 3. G. F.~pathologic findings in most recent bladder biopsy show cystic changes m mucosa, chronic submucosal inflammation and edema. cellular infiltrate of plasma cells, eosinophils and lymphocytes; some foci of histiocytes were present. Repeat bladder biopsy in 1968 showed submucosal edema with chronic inflammation and mild hemosiderosis (fig. 3). The diagnosis was chronic cystitis. The Armed Forces Institute of
Pathology also examined the specimens and reported "bladder biopsy with eosinophilic bullous cystitis with focal granulomatous reaction, etiology undetermined". Special stains for tuberculosis and fungi were negative. Bladder biopsy of the cousin, G. revealed
578
KONTRAS AND ASSOCIATES
Fm. 4. G. S.-lymph node shows necrosis and granulomatous inflammation similar findings. In addition, a lymph node was removed which showed necrosis and granulomatous inflammation (fig. 4). DISCUSSION
An atypical form of chronic granulomatous disease in male first cousins is reported with chronic cystitis as the primary manifestation. The cases illustrate the clinical variability of the disorder and suggest that leukocyte dysfunction may be the basic pathophysiologic mechanism for disease manifesting primarily in any organ or system. One of these cases (G. F.) illustrates the effect of steroids on suppression of the systemic manifestations of this disorder. His cousin, though having bladder problems most of his life, was not undergoing steroid treatment and a hepatic abscess developed when the boy was 15 years old. The etiology of chronic interstitial cystitis has not been established. 4 Chronic inflammation, tissue destruction and fibrosis have suggested an auto-immune pathogenesis. 4 • 5 Deficiencies in immunologic or leukocyte bactericidal ability have not been suspected as a possible etiology. Cystitis has not been reported as an important manifestation of chronic granulomatous disease. 4
Campbell, M. F.: Urology. Philadelphia:
W. B. Saunders Co., vol. 3, 1963.
5 Silk, M. R.: Bladder antibodies in interstitial cystitis. J. Urol., 103: 307, 1970.
Chronic interstitial cystitis with Runner's ulcer is common in women but some pediatric cases have been reported by McDonald 6 and by Chenoweth.7 The clinical and pathologic findings were similar to those seen in our 2 cases. The mechanisms of bladder bactericidal activity are not clear and whether the leukocyte bactericidal function is an essential component of bladder defense mechanisms is unknown.8 The cases herein described suggest that normal leukocyte function may be necessary for bladder bactericidal activity and that this may be determined genetically in some families. SUMMARY
Abnormal leukocyte bactericidal activity and NBT reduction identical to that described in fatal chronic granulomatous disease were found in 2 male first cousins with chronic interstitial cystitis many years in duration. It is suggested that this genetically determined syndrome be considered in the differential diagnosis of chronic cystitis. 6 _McDonald, H. P., Upchurch, W. E. and Art1me, M.: Bladder dysfunction in children caused by interstitial cystitis. J. Urol., 80: 354
19~.
'
Chenoweth, C. V. and Clawater, E.W., Jr.: Interstitial cystitis in children. J. Urol. 83: 150 7
1960.
'
'
Norden, C. W., Green, G. M. and Kass, E. H.: Anti~acterial mechanisms of the urinary bladder. J. Clm. Invest., 47: 2689, 1968. 8