The Role of Viruses in Feline Lower Urinary Tract Disease John M. Kruger, DVM, PhD, and Carl A. Osborne, DVM, PhD
Viruses have been implicated as causative agents in the etiopathogenesis of some forms of feline lower urinary tract disease (LUTD). This hypothesis was supported by isolation of feline calicivirus, bovine herpesvirus 4 (strain FeCAHV), and feline syncytia-forming virus from cats with naturally occurring LUTD, and by experimental studies of induced viral urinary tract infection. Results of early clinical studies yielded contradictory results concerning the role of viruses in feline LUTD. However, recent detection of bovine herpesvirus 4 antibodies in feline serum samples and discovery of calicivirus-like particles in crystalline/matrix urethral plugs obtained from cats with naturally occurring LUTD, suggests the need to reexamine the etiopathologic role of viruses using contemporary methods of virus identification and localization. (Journal of Veterinary Internal Medicine 1990; 4:71-78)
FELINE urologic syndrome (FUS) has traditionally been viewed as a distinct pathophysiologic entity initiated and perpetuated by multiple (often undefined) factors. However, available clinical and experimental data suggest that the term “FUS” represents a constellation of clinical signs associated with lower urinary tract disease (LUTD) in male and female cats. As with all species, feline LUTD may result from fundamentally different causes that may be single, multiple and interacting, and/or unrelated (Table 1).’.* Despite the fact that many causes of hematuria, dysuria, and/or urethral obstruction have been identified in cats affected with LUTD, our observations and those of others suggest the exact cause is unknown in a large percentage of naturally occurring case^.^.^ In a prospective clinical study performed at the University of Minnesota designed to detect the causes of LUTD in 141 male and female cats with naturally occurring disease, a specific etiology could not be determined in 77 (53%) A cause-and-effect relationship between uroliths,
bacterial urinary tract infections, anatomic abnormalities, neoplasms, and neurogenic diseases, and clinical signs was not identified. However, the subsequent course of clinical signs in these cats was consistent with a viral etiology. Clinical signs of gross hematuria, dysuria, and pollakiuria resolved spontaneously without treatment.
Do Viruses Have a Role in Lower Urinary Tract Disease of Cats?
Overview Several hypotheses have been advanced concerning possible causes of idiopathic hematuria, dysuria, and/or urethral crystalline/matrix plug formation in male and female cats. One attractive hypothesis implicates viruses as causative agents in the etiopathogenesis of some forms of naturally occurring feline LUTD.6 This hypothesis was supported by the isolation of feline cell-associated herpesvirus (FeCAHV), feline calicivirus (FCV), and feline syncytia-forming virus (FeSFV) from urine and tissues obtained from cats affected with naturally occurring LUTD.’-I2 Polyomavirus, adenovirus type 1 1 , and herpes zoster have been incriminated as causes of hemorrhagic cystitis in man.I3-l5
From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota. Supported by a grant from Ralston Purina, St. Louis, Missouri. The authors thank Fern Bates, Patricia Brown, Jerome Fahrmann, Heidi Moran, Ruth Semlak, Jeff Sanna, Lori Theisen, and Lisa Unger for technical assistance, Drs. Helmy Ghobrial and Kem Pomeroy for assistance with electron microscopy, Dr. Cecelia Whetstone for assistance with DNA restriction endonuclease analyses, and Debbie Molls and Lori Schultz for assistance with manuscript preparation. Reprint requests: John M. Kruger, DVM, Veterinary Clinical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
Experimental Studies in Cats
Urine Transmission Studies The first indirect evidence supporting the hypothesis of a viral etiology in FUS was reported in 1969, when investigators at Cornell University produced urethral ob-
71
72
Journal of Veterinary Internal Medicine
KRUGER AND OSBORNE
TABLE1. Examples of Confirmed Causes of Lower Urinary Tract Disease in Cats Metabolic (including nutritional) Uroliths* Struvite Calcium phosphates (calcium apatite: calcium hydrogen phosphate) Calcium oxalate (monohydrate and dihydrate) Ammonium urate Uric acid Cystine Xanthine3' Matrix Urethral plugs' Struvite crystals only Matrix only Inflammatory products Sloughed tissue Blood clots Matrix and struvite crystals Matrix and other crystals (e.g., calcium oxalate, ammonium urate) Inflammatory Infectious agents Viral (experimental)'.' 1.''-22 Ba~terial'.~ Mycotic" Parasitic3' Noninfectious idiopathic'.*
Anatomic abnormalities Congenital Urachal anomalies',* Persistent uterus masculinus' Urethrorectal fistula3' Phimosis4' Acquired urethral strictures4' Neoplastic Benign4* Papilloma (bladder) Cystadenoma (bladder) Leiomyoma (bladder) Malignant42 Transitional cell carcinoma (bladder and urethra) Squamous cell carcinoma (bladder) Adenocarcinoma (bladder) Unclassified carcinoma (bladder) Lymphosarcoma (bladder)* Myxosarcoma (bladder) Prostatic adenocarcinoma (urethra)' Endometrial adenocarcinoma (extraurinary)* Neurogenic4' Reflex dyssynergia Urethral spasm Hypotonic or atonic bladder (primary or secondary) ~atrogenic~'.~~ Traumatic45
* Osborne CA. Unpublished data. University of Minnesota, St. Paul, MN, 1988.
results of various inoculation studies are difficult due to inconsistent methodologies in sample handling and recipient inoculation, and lack of comprehensive postinoculation follow-up studies.
struction in male cats by urinary bladder inoculation with centrifuged bacteriologically sterile urine obtained from male cats with naturally occurring urethral obstruction (Table 2)." Other investigators subsequently have been unsuccessful in consistently inducing LUTD by inoculation of normal cats with urine from affected cats (Table 2).3.9.i6 While the reason for this disparity is unknown, it is of importance that all urine donors were selected solely on the basis of urethral obstruction. Apparently little consideration was given to identifying other possible causes of obstructive uropathy unrelated to viral infectious agents. In addition, comparison of
Feline Calicivirus Studies Isolation of a calicivirus from a Manx cat with spontaneous urethral obstruction and experimental induction of obstructive uropathy in conventionally reared cats by urinary bladder inoculation with this virus supported the concept of a viral etiology for feline LUTD (Tables 3 and 4).' However, inconsistent production of ob'3''
TABLE 2. Summarv of Attempts to Transmit Naturally Occurring Lower Urinary Tract Disease with Urine from Affected to Normal Cats ~~
Urine Donors
Urine Recipients
Urine Culture Results Date 1969'' 197516 19799
Clinical No. Signs
2 4
UO UO 4 NR (LUTD)
Bacteria
0/2* ND 114 (Streptococci and E.~chrrichia
Virus ND 014 014
Method of Bladder Inoculation Catheter Cystocentesis Catheter or cystocentesis
Clinical Signs No. Hem Dys 6
8 9
UO
Urine Culture Results Bacteria
ND ND 119
ND 416 ND 018 119 019
ND
3/13 1/13 1/10
NRt ND 119 (Streptococci)
Virus
Necropsy Results
Urolithf Plug Analysis
ND ND ND
ND ND ND
ND NA NA
019
Crystals in LUT (3113): thickened bladder wall (1113)
ND
coli) 1982'
13
UO
Catheter 1/10 1/13 (Staphylococci) (FHV- I )
13
(Staphylococci)
Hem: gross hematuria: Dys: dysuria: UO: urethral obstruction: NR: not reported: ND: not determined: NA: not applicable; FHV-I: feline herpesvirus type I ; LUT: lower urinary tract: LUTD: lower urinary tract disease. * Numerator indicates number of positive cases: denominator indicates number of cases evaluated. t Bacteria were occasionally cultured from urine of inoculated cats.
UB
UB
Aerosol
Contact
FCVt
FCVt
FCVt
FCVt
UB:IV UB;IV
FeCAHV FeCAHV FCVt
M MC F MC
2
+
ND None None None None
2
0 4 0
0
5
0 6
I
0 0 0
ND
ND ND 611 Ill I7
5
0 6 I
0 0 0
SPF SPF SPF
0
0 0
61 61
0 0
SPF SPF
0
I
I
0
0 0
21 611
Std Std Std SPF
SPF
I
I
ND
I
SPF
I
2
ND ND
ND ND
ND ND
SPF SPF
4
4
None
None
ND ND
ND
ND
ND ND
FeSFV (I)
(1)
ND
ND
Std
FeCAHV (6)
FeCAHV (6)
FeCAHV (I) FeCAHV (2) FeCAHV ( 2 ) FeCAHV (5)
FeCAHV (6)
FeCAHV ( I ) FeCAHV (6)
FeCAHV ( 5 )
FeCAHV (2)
FCV(I): FeSFV (4) FeCAHV ( I ) FeCAHV (2)
FeSFV (4)
FeSFV (I)
4
4
FeSFV (4)
ND
ND
ND ND
FCV (4): FeSFV
FCV(I5)
ND
ND
Std
I
ND
2
4
I
7
ND ND
Tissue
Virus lsolationll Urine
0 3 .
UO
4
ND
ND
0 3
DYS
ND
ND
ND
Std
Std
ND
ND ND
ND ND
Std Std Std
MicroRBC
Gross RBC
Type
Clinical Signs5
Neg
Neg
Neg Neg Neg Neg
Neg
Neg Neg
Neg
ND ND
ND
ND
ND ND
ND ND Neg
ND
ND
ND
ND
ND
ND
ND
ND
ND
,
ND ND
ND ND ND
Mycoplasma
Bacteria
Urine Culture
NA NVL
NA NA NA NA
NA
NA MgAmP (Urolith)
ND
NA
MgAmP (Urolith)
ND ND
ND
ND
ND
ND
ND
NA ND
Urolith/Plug Analysis
Urolith ( I ): cystitis (I) Ureth plug ( I): ureth swelling ( I): cystitis (4): NVL Ureth plug (4): urolith (I): cystitis (6) Cystitis (6): urethritis (4) Cystitis ( I ) Cystitis (I) NVL Cystitis (2): urachal diverticulum (1) NVL
Ureth plug (4): cystitis (4) Ureth plug (4): cystitis (4) ND ND
NVL Ureth plug (3): cystitis ( 3 ) Ureth plug ( 2 ) : cystitis ( 2 ) Ureth plug (I): cystitis (I) Ureth plug (4): cystitis (4)
Necropsy findingsLower Urinary Tract#
FeCAHV: feline cell-associated herpesvirus: Dys: dysuria: F female: FCV: feline calicivirus: FeSFV: feline syncytia-forming virus: Gross RBC: gross hematuria: Inoc: inoculation: IP: intrapentoneally: IV: intravenously: M: male: MC: castrated male: micro RBC: microscopic hematuria: MPA: methylprednisolone acetate: ND: not determined: Std: conventionally reared: S P F specific-pathogen-free: U B urinary bladder: U O urethral obstruction: MgAmP: magnesium ammonium phosphate: NA: not applicable: Neg: negative: NVL: no visible lesions: Ureth: urethra. * Muscle isolate. t Manx isolate. $ Methyl prednisolone acetate ( 10 mg/kg) was administered intramuscularly before FeCAHV exposure. 5 Number indicates number of affected cats. ll Urine samples for analysis collected by cystocentesis. / I Number i n parenthesis indicates number of cats from which the virus was recovered. # Number in parenthesis indicates number of affected cats.
1988’’
2 6
2
F
M
6
6
F M
I 6
UB
M
5
MC
M
6
6
M M
4 4
UB
M
5
FeCAHV MPAS FeCAHV + MPAS
M
5
UB:IP UB:IP UB: IP UB
M
5
FeCAHV FeCAHV FeCAHV FeCAHV
M
15
1988”
M
M M
Sex
8
4 4
No.
FeCAHV
UB:IV
UB
FeCAHV
+
UB: IV
FCVt FeCAHV FCVt FCVt
+
UB
FCVt
UB UB
UB UB
Route oflnoc
FCV* FCVt
Agent
198422
1977‘9
1975‘
1971’’
Date
Animals
TABLE 3. Summary of Results of Experimentally Induced Viral Lower Urinary Tract Disease in Cats
4
w
aP
m
n
z
Viruses have been implicated as causative agents in the etiopathogenesis of some forms of feline lower urinary tract disease (LUTD). This hypothesis was supported by isolation of feline calicivirus, bovine herpesvirus 4 (strain FeCAHV), and feline syncytia-forming virus from cats with naturally occurring LUTD, and by experimental studies of induced viral urinary tract infection. Results of early clinical studies yielded contradictory results concerning the role of viruses in feline LUTD. However, recent detection of bovine herpesvirus 4 antibodies in feline serum samples and discovery of calicivirus-like particles in crystalline/matrix urethral plugs obtained from cats with naturally occurring LUTD, suggests the need to reexamine the etiopathologic role of viruses using contemporary methods of virus identification and localization. (Journal of Veterinary Internal Medicine 1990; 4:71-78)
FELINE urologic syndrome (FUS) has traditionally been viewed as a distinct pathophysiologic entity initiated and perpetuated by multiple (often undefined) factors. However, available clinical and experimental data suggest that the term “FUS” represents a constellation of clinical signs associated with lower urinary tract disease (LUTD) in male and female cats. As with all species, feline LUTD may result from fundamentally different causes that may be single, multiple and interacting, and/or unrelated (Table 1).’.* Despite the fact that many causes of hematuria, dysuria, and/or urethral obstruction have been identified in cats affected with LUTD, our observations and those of others suggest the exact cause is unknown in a large percentage of naturally occurring case^.^.^ In a prospective clinical study performed at the University of Minnesota designed to detect the causes of LUTD in 141 male and female cats with naturally occurring disease, a specific etiology could not be determined in 77 (53%) A cause-and-effect relationship between uroliths,
bacterial urinary tract infections, anatomic abnormalities, neoplasms, and neurogenic diseases, and clinical signs was not identified. However, the subsequent course of clinical signs in these cats was consistent with a viral etiology. Clinical signs of gross hematuria, dysuria, and pollakiuria resolved spontaneously without treatment.
Do Viruses Have a Role in Lower Urinary Tract Disease of Cats?
Overview Several hypotheses have been advanced concerning possible causes of idiopathic hematuria, dysuria, and/or urethral crystalline/matrix plug formation in male and female cats. One attractive hypothesis implicates viruses as causative agents in the etiopathogenesis of some forms of naturally occurring feline LUTD.6 This hypothesis was supported by the isolation of feline cell-associated herpesvirus (FeCAHV), feline calicivirus (FCV), and feline syncytia-forming virus (FeSFV) from urine and tissues obtained from cats affected with naturally occurring LUTD.’-I2 Polyomavirus, adenovirus type 1 1 , and herpes zoster have been incriminated as causes of hemorrhagic cystitis in man.I3-l5
From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota. Supported by a grant from Ralston Purina, St. Louis, Missouri. The authors thank Fern Bates, Patricia Brown, Jerome Fahrmann, Heidi Moran, Ruth Semlak, Jeff Sanna, Lori Theisen, and Lisa Unger for technical assistance, Drs. Helmy Ghobrial and Kem Pomeroy for assistance with electron microscopy, Dr. Cecelia Whetstone for assistance with DNA restriction endonuclease analyses, and Debbie Molls and Lori Schultz for assistance with manuscript preparation. Reprint requests: John M. Kruger, DVM, Veterinary Clinical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
Experimental Studies in Cats
Urine Transmission Studies The first indirect evidence supporting the hypothesis of a viral etiology in FUS was reported in 1969, when investigators at Cornell University produced urethral ob-
71
72
Journal of Veterinary Internal Medicine
KRUGER AND OSBORNE
TABLE1. Examples of Confirmed Causes of Lower Urinary Tract Disease in Cats Metabolic (including nutritional) Uroliths* Struvite Calcium phosphates (calcium apatite: calcium hydrogen phosphate) Calcium oxalate (monohydrate and dihydrate) Ammonium urate Uric acid Cystine Xanthine3' Matrix Urethral plugs' Struvite crystals only Matrix only Inflammatory products Sloughed tissue Blood clots Matrix and struvite crystals Matrix and other crystals (e.g., calcium oxalate, ammonium urate) Inflammatory Infectious agents Viral (experimental)'.' 1.''-22 Ba~terial'.~ Mycotic" Parasitic3' Noninfectious idiopathic'.*
Anatomic abnormalities Congenital Urachal anomalies',* Persistent uterus masculinus' Urethrorectal fistula3' Phimosis4' Acquired urethral strictures4' Neoplastic Benign4* Papilloma (bladder) Cystadenoma (bladder) Leiomyoma (bladder) Malignant42 Transitional cell carcinoma (bladder and urethra) Squamous cell carcinoma (bladder) Adenocarcinoma (bladder) Unclassified carcinoma (bladder) Lymphosarcoma (bladder)* Myxosarcoma (bladder) Prostatic adenocarcinoma (urethra)' Endometrial adenocarcinoma (extraurinary)* Neurogenic4' Reflex dyssynergia Urethral spasm Hypotonic or atonic bladder (primary or secondary) ~atrogenic~'.~~ Traumatic45
* Osborne CA. Unpublished data. University of Minnesota, St. Paul, MN, 1988.
results of various inoculation studies are difficult due to inconsistent methodologies in sample handling and recipient inoculation, and lack of comprehensive postinoculation follow-up studies.
struction in male cats by urinary bladder inoculation with centrifuged bacteriologically sterile urine obtained from male cats with naturally occurring urethral obstruction (Table 2)." Other investigators subsequently have been unsuccessful in consistently inducing LUTD by inoculation of normal cats with urine from affected cats (Table 2).3.9.i6 While the reason for this disparity is unknown, it is of importance that all urine donors were selected solely on the basis of urethral obstruction. Apparently little consideration was given to identifying other possible causes of obstructive uropathy unrelated to viral infectious agents. In addition, comparison of
Feline Calicivirus Studies Isolation of a calicivirus from a Manx cat with spontaneous urethral obstruction and experimental induction of obstructive uropathy in conventionally reared cats by urinary bladder inoculation with this virus supported the concept of a viral etiology for feline LUTD (Tables 3 and 4).' However, inconsistent production of ob'3''
TABLE 2. Summarv of Attempts to Transmit Naturally Occurring Lower Urinary Tract Disease with Urine from Affected to Normal Cats ~~
Urine Donors
Urine Recipients
Urine Culture Results Date 1969'' 197516 19799
Clinical No. Signs
2 4
UO UO 4 NR (LUTD)
Bacteria
0/2* ND 114 (Streptococci and E.~chrrichia
Virus ND 014 014
Method of Bladder Inoculation Catheter Cystocentesis Catheter or cystocentesis
Clinical Signs No. Hem Dys 6
8 9
UO
Urine Culture Results Bacteria
ND ND 119
ND 416 ND 018 119 019
ND
3/13 1/13 1/10
NRt ND 119 (Streptococci)
Virus
Necropsy Results
Urolithf Plug Analysis
ND ND ND
ND ND ND
ND NA NA
019
Crystals in LUT (3113): thickened bladder wall (1113)
ND
coli) 1982'
13
UO
Catheter 1/10 1/13 (Staphylococci) (FHV- I )
13
(Staphylococci)
Hem: gross hematuria: Dys: dysuria: UO: urethral obstruction: NR: not reported: ND: not determined: NA: not applicable; FHV-I: feline herpesvirus type I ; LUT: lower urinary tract: LUTD: lower urinary tract disease. * Numerator indicates number of positive cases: denominator indicates number of cases evaluated. t Bacteria were occasionally cultured from urine of inoculated cats.
UB
UB
Aerosol
Contact
FCVt
FCVt
FCVt
FCVt
UB:IV UB;IV
FeCAHV FeCAHV FCVt
M MC F MC
2
+
ND None None None None
2
0 4 0
0
5
0 6
I
0 0 0
ND
ND ND 611 Ill I7
5
0 6 I
0 0 0
SPF SPF SPF
0
0 0
61 61
0 0
SPF SPF
0
I
I
0
0 0
21 611
Std Std Std SPF
SPF
I
I
ND
I
SPF
I
2
ND ND
ND ND
ND ND
SPF SPF
4
4
None
None
ND ND
ND
ND
ND ND
FeSFV (I)
(1)
ND
ND
Std
FeCAHV (6)
FeCAHV (6)
FeCAHV (I) FeCAHV (2) FeCAHV ( 2 ) FeCAHV (5)
FeCAHV (6)
FeCAHV ( I ) FeCAHV (6)
FeCAHV ( 5 )
FeCAHV (2)
FCV(I): FeSFV (4) FeCAHV ( I ) FeCAHV (2)
FeSFV (4)
FeSFV (I)
4
4
FeSFV (4)
ND
ND
ND ND
FCV (4): FeSFV
FCV(I5)
ND
ND
Std
I
ND
2
4
I
7
ND ND
Tissue
Virus lsolationll Urine
0 3 .
UO
4
ND
ND
0 3
DYS
ND
ND
ND
Std
Std
ND
ND ND
ND ND
Std Std Std
MicroRBC
Gross RBC
Type
Clinical Signs5
Neg
Neg
Neg Neg Neg Neg
Neg
Neg Neg
Neg
ND ND
ND
ND
ND ND
ND ND Neg
ND
ND
ND
ND
ND
ND
ND
ND
ND
,
ND ND
ND ND ND
Mycoplasma
Bacteria
Urine Culture
NA NVL
NA NA NA NA
NA
NA MgAmP (Urolith)
ND
NA
MgAmP (Urolith)
ND ND
ND
ND
ND
ND
ND
NA ND
Urolith/Plug Analysis
Urolith ( I ): cystitis (I) Ureth plug ( I): ureth swelling ( I): cystitis (4): NVL Ureth plug (4): urolith (I): cystitis (6) Cystitis (6): urethritis (4) Cystitis ( I ) Cystitis (I) NVL Cystitis (2): urachal diverticulum (1) NVL
Ureth plug (4): cystitis (4) Ureth plug (4): cystitis (4) ND ND
NVL Ureth plug (3): cystitis ( 3 ) Ureth plug ( 2 ) : cystitis ( 2 ) Ureth plug (I): cystitis (I) Ureth plug (4): cystitis (4)
Necropsy findingsLower Urinary Tract#
FeCAHV: feline cell-associated herpesvirus: Dys: dysuria: F female: FCV: feline calicivirus: FeSFV: feline syncytia-forming virus: Gross RBC: gross hematuria: Inoc: inoculation: IP: intrapentoneally: IV: intravenously: M: male: MC: castrated male: micro RBC: microscopic hematuria: MPA: methylprednisolone acetate: ND: not determined: Std: conventionally reared: S P F specific-pathogen-free: U B urinary bladder: U O urethral obstruction: MgAmP: magnesium ammonium phosphate: NA: not applicable: Neg: negative: NVL: no visible lesions: Ureth: urethra. * Muscle isolate. t Manx isolate. $ Methyl prednisolone acetate ( 10 mg/kg) was administered intramuscularly before FeCAHV exposure. 5 Number indicates number of affected cats. ll Urine samples for analysis collected by cystocentesis. / I Number i n parenthesis indicates number of cats from which the virus was recovered. # Number in parenthesis indicates number of affected cats.
1988’’
2 6
2
F
M
6
6
F M
I 6
UB
M
5
MC
M
6
6
M M
4 4
UB
M
5
FeCAHV MPAS FeCAHV + MPAS
M
5
UB:IP UB:IP UB: IP UB
M
5
FeCAHV FeCAHV FeCAHV FeCAHV
M
15
1988”
M
M M
Sex
8
4 4
No.
FeCAHV
UB:IV
UB
FeCAHV
+
UB: IV
FCVt FeCAHV FCVt FCVt
+
UB
FCVt
UB UB
UB UB
Route oflnoc
FCV* FCVt
Agent
198422
1977‘9
1975‘
1971’’
Date
Animals
TABLE 3. Summary of Results of Experimentally Induced Viral Lower Urinary Tract Disease in Cats
4
w
aP
m
n
z
