Extraperitoneal Lesions in Feline Infectious Peritonitis

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                  Extraperitoneal Lesions in Feline Infectious Peritonitis
                                  R. J. Montali and J. D. Strandberg
                                        Vet Pathol 1972 9: 109
                                 DOI: 10.1177/030098587200900204

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Vet. Path. 9: 109-121 (1972)




      Extraperitoneal Lesions in Feline Infectious Peritonitis

                        R. J. MONTALI J. D. STRANDBERG
                                    and

                  The Johns Hopkins University School of Medicine,
           The Division of Animal Medicine and The Department of Pathology
                                   Baltimore, Md.



    Absrunct. Twelve cats with pathologic diagnoses of feline infectious peritonitis were stu-
died. The lesions were primarily extraserosal. This pathologic syndrome was characterized
by granulomatous inflammation in a variety of organs, but principally affected the kidneys,
visceral lymph nodes, lungs, liver, eyes, and leptomeninges. Histologically, the granulomas
were composed of mixtures of neutrophils, lymphocytes, plasma cells, and large spindle-
shaped histiocytes, and contained areas of necrosis. Inflamed superficial and deep pulmon-
ary and renal cortical veins, the latter often thrornbosed, were consistently detected. Phlebi-
tis was also present in other organs, but to a lesser degree. Cell-free tissue extracts from one
cat produced clinical and pathologic changes compatible with those originally described
for feline infectious peritonitis. Observations of these natural and induced cases show that
this form of the disease with disseminated granulomas and minimal serosal lesions may
progress by vascular routes.

    Since feline infectious peritonitis was first recognized as a specific entity
[ 151, several reports have discussed the characteristic prevalence and clinical
and pathologic findings [3, 6, 8-1 I , 13, 161. Evidence for a viral cause
has also been presented [7, 12, 171. Some reports [ 14-1 61 have mentioned ex-
traperitoneal lesions as part of the pathologic process, but a study has not
been made of naturally occurring cases in which the major lesions are in par-
enchymatous organs and tissues other than the peritoneum. The pathologic
changes i n 12 cats with lesions of this type and the induction of typical feline
infectious peritonitis by material transmitted from one of them to kittens are
discussed.

                                   Materials and Methods

                                         Pathologic Study

    Twelve cats were selected for necropsy from a total of 32 cases diagnosed as feline
infectious peritonitis at the Johns Hopkins University from 1964 to 1971. Cats 1-6 (table I )




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110                                           MONTALI/STRANDBEKG

                             Table I . Distribution of gross lesions incats 1-12

Cat Age                Sex      Breed          Major                  Duration, Major gross lesions
                                               presenting             months
                                               signs

 1       1 year        M/c 1 DSH2              renal masses3              3            renal nodules and
                                                                                       infiltration
 2       3 years       M        DSH                           3
                                        renal n i a ~ s e s , ~                        renal nodules, ocular
                                        ophthalmitis                                   exudates
 3       1 '/z years   M        DSH     ophthalmitis, 3                                renal nodules, focal
                                        weight loss                                    hepatic necrosis
 4       1 year        M/c      Siamese renal masses,:' -                              renal nodules and infiltrates
                                        lethargy
 5       young         F        DSH     renal masses,:' -                              renal nodules, ocular
         adult                          ophthalmitis,                                  exudates
                                        cachexia
 6       I % years     F        DSH     weakness,              1                       renal nodules and infiltrates
                                        emaciation
 7       4months       F        Siamese fever,                        ~                renal nodules, pulmonary
                                        ophthalmitis                                   foci, ocular exudates
 8       9months       F        Siamese URI,"                 3                        renal nodules, hepatic
                                        renal masses?                                  nodules
 9       2 years       F        Angora renal                  -                        renal nodules
                                        polyuria,
                                        polydipsia
10       5months       M                       ~
                                Burmese U R L jaundice I                               hepatic nodules, renal
                                                                                       nodules
1I       2% years      F        DSH            weight loss,                            hepatic nodules,
                                               jaundice                                niesenteric lymphadeno-
                                                                                       pathy
12       1 year        M        DSH            enlarged                                myocardial nodules,
                                               popliteal                               lymphadenopathy
                                               lymph node,
                                               depression

     '   c = castrated.
         DSH = domestic shorthair.
         Determined by palpation or radiography.
         U R I = upper respiratory infection.



were necropsied immediately after death at this institution. Complete gross examinations
were made, and representative sections of all organs were fixed in 10% buffered formalin.
Cats 7-1 2 (table 1) were autopsied by practicing veterinarians, who submitted tissue
specimens in 10% formalin. The fixed tissues from the 12 cats were embedded, sectioned,
and stained with hematoxylin and eosin, Gomori's methenamine silver and Taylor's




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                  Extraperitoneal Lesions in Feline Infectious Peritonitis                   111

bacterial stains. Selected tissues were also stained with acid-fast and azure-eosin stains.
In addition, samples of organs with lesions from cats 1-6 were cultured in thioglycollate
and ‘Mycocel’ media.



                                        Transmission Study

    First Passage
    Grossly normal splenic tissue and pieces of a nodular renal lesion were removed asepti-
cally at necropsy from cat I . The tissues were pooled and made into a 10% suspension in
Hank’s balanced salt solution with a Tenbroeck tissue grinder. The suspension was frozen
and thawed three times using dry ice and alcohol, and a 37°C water bath, and then was cen-
trifuged at 2,000 rpm for 15 min. The bacteriologically sterile supernatant liquid was used as
the inoculum and administered to six 1-day-old littermate kittens (1 A-6A) weighing
100-130 g. Three kittens ( I A , 5A, 6A) were given 0.5 c m 3of t h e inoculuni intraperitoneally
and three kittens (2A, 3A, 4A) 0.5 cm3 intravenously. Inoculated kittens were killed when
they became moribund. Gross, histopathologic and microbiologic examinations were per-
formed as described above. Peritoneal exudate and niesenteric lymph node from kitten 3A
were also examined for feline Mycoplusma species by plate immunofluorescence [ I , 21
(courtesy of Dr. ROGER   WILSNACK,    Huntingdon Research Center).

    Second Passage
    Using the techniques described above, an inoculuni was made from pooled spleen, liver,
and lymph node from kitten 2A and spleen and liver from kitten 3A and administered to
five healthy cats approximately I year of age that were of unknown background. Two cats
(2B and 5B) received 1 cnT3 of the inoculuni, intraperitoneally, and three cats (1 B, 3B, 4B)
received I cm3 of the inoculum intravenously. When clinical signs were advanced, the cats
were killed, and gross, histopathologic, and microbiologic examinations were performed as
previously outlined.



                                                 Results

                                          Natural Cases

   Pathology
   Major lesions were most frequently found i n the kidneys. They consisted
of gray-white raised nodules scattered over the cortical surface (fig. 1). These
nodules were firm, extended deeply into the cortical zones, and measured 0.5-
2.0 cm in diameter. Occasionally, similar lesions were noted in medullary
areas. I n advanced cases, the nodules were confluent and replaced large seg-
ments of the renal parenchyma. Similar, but smaller nodular foci, 1-2 nim in
diameter, were often found in other visceral organs, including liver, pancreas,




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I12                                      MONTALI/STRANDBERG




      Fig. 1. Typical gross appearance of kidney with white, raised nodular foci




spleen, and mesenteric lymph node. The ocular chambers contained yel-
low-white exudates, and the inner ocular structures were granular and thick-
ened. Two cats had approximately 10 cm3 of clear yellow peritoneal fluid;
but fibrinous serosal exudates or visceral fibrous adhesions were absent i n all
animals.
    Histologic lesions consisted of disseminated foci of granulomatous in-
flammation and necrosis mainly i n the kidneys, visceral lymph nodes, lungs,
liver, eyes, and leptonieninges.
    The renal nodules observed grossly were granulomas composed of pleo-
morphic cells that included neutrophils, lymphocytes, plasma cells, and large
spindle-shaped histiocytes. These inflammatory cells surrounded remnants of
degenerate renal parenchyma and often replaced large areas of cortical tissue
(fig. 2, 3). Necrosis within areas of granuloma formation was also evident. In
some foci, prominent regenerating tubular and stromal cells added to the pro-
liferative appearance of the lesions (fig. 4). Similar inflammation involved the
adventitia and inner walls of cortical and stellate veins, many of which con-
tained fibrinous thrombi (fig. 5).
    Livers contained scattered granulomas with necrosis o r multiple discrete
foci of coagulative necrosis, or both, with a mild reaction by inflammatory




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                  Extraperitoneal Lesions in Feline Infectious Peritonitis            1 I3




    Fig. 2. Granuloma with central area of necrosis. Note compression of surrounding renal
tissue.
    Fig. 3. Detail of granuloma in figure 2 with various inflammatory cells. HE.




cells. The granulomatous process also often affected the biliary tree, and in
one cat necrotizing thrombotic vasculitis was noted i n the wall of the gall
bladder.
    Pulmonary changes were characterized by scattered focal and confluent
areas of inflammation principally of small subpleural and parenchymal veins
and surrounding pulmonary tissues. This phlebitis, distinguished by neutro-
phils and mononuclear cells within and around the disrupted vessel walls,
was more evident in the smaller focal lesions. The alveolar walls immediately
surrounding these vessels were distended with similar inflammatory cells
(fig. 6). In the large confluent lesions the vasculitis was obscured by the in-
tense cellular reaction and by the proliferation of large, irregular alveolar-lin-
ing cells (fig. 7).
    Similar inflammatory cellular infiltrates were noted i n the brain. They
were distributed focally i n the leptomeninges and choroid plexus and often




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1 I4                   MONTALI/STR ANDBERG




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                 Extraperitoneal Lesions in Feline Infectious Peritonitis              115

were accompanied by phlebitis but rarely by thrombophlebitis. Occasionally,
cerebral vessels beneath the pia-arachnoid had cuffs of lymphocytes, plasma
cells, and macrophages.
    Ocular lesions included focal o r diffuse granulomatous inflammation of
the uvea, retina, and meninges of the optic nerves. Fibrinocellular exudates
were present in the ocular chambers. The degree of inflammation was most
intense i n the uveal tracts i n which vasculitis and excessive accumulation of
melanin were also evident.
    In cats i n which visceral lymph nodes o r spleen were affected, the lesions
were typical of the patchy, necrotic granulomas described above. Reactive
hyperplasia of lymph nodes with plasmacytosis of medullary cords and
prominent sinusoidal erythrophagocytosis as well as hyperplasia of reticu-
loendothelial cells of the spleen and of myeloid cells of the bone marrow were
cons istent I y found .
    Lesions in remaining organs were mild and included disseminated foci of
granulomatous inflammation and vasculitis of peritoneum, skeletal muscle,
thyroid gland, pancreas, pleura, and urinary bladder. One exception oc-
curred in cat 12 i n which granulomatous myocarditis was themajorpatholog-
ic finding (fig. 8).

    Microbiology
   All cultures for bacterial and fungal organisms were negative. Special
stains of formalin-fixed tissues for bacteria, including acid-fast organisms,
fungi, and protozoa, were also negative.


                                        1 nduced Cases

    Pathology
    Five of the six kittens injected with material from cat 1 became moribund
o r died 1-3 weeks after inoculation. The major gross finding at necropsy of
the five kittens was exudative, fibrinous peritonitis. Principal histologic find-
ings included extensive fibrinonecrotic and pyogranulomatous inflammation
of visceral and parietal peritoneum and omentum with apparent extension



   Fig. 4 . Extensive tubular regeneration within a proliferative inflammatory focus in the
renal cortex. HE.
   Fig. 5. Thrombophlebitis and inflammation spreading to the outer renal cortex. HE.




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I I6                      MONTALl/STRANDBERC




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                 Extraperitoneal Lesions in Feline Infectious Peritonitis             117

into abdominal parenchymatous and reticuloendothelial organs, and less ex-
tensive and variable involvement of pleura, lungs, meninges, eyes, and ves-
sels.
    I n the second-passage study, the young adult cats were killed from 3 t o
14 weeks after inoculation. At necropsy, major gross findings in four of the
jive cats were pleural or peritoneal effusions, or both, scattered, firm greyish
serosal plaques and nodules, and solitary renal granulomas that varied i n dis-
tribution from cat to cat. Microscopically the lesions consisted of serositis
and widely disseminated proliferative granulomas with necrosis. The inflam-
matory process had a predilection for vessels, and phlebitis was noted in
many organs. One cat (5B) that was allowed to survive for 3 months after in-
oculation had very cellular nodules formed mainly of histiocytes with a few
neutrophils, lymphocytes, and plasma cells in the Iivzr and visceral nodes
(fig. 9).

   Miuoliiology
   In both transmission studies, tests performed for the identification of pro-
tozoa, fungi, mycoplasmas, and bacteria were negative except for a hemolytic
Staphylococcus that was recovered from the peritoneal exudate of cat 4A and
was thought to be a secondary invader.


                                           Discussion

     Before the original description of feline infectious peritonitis as a diffuse
fibrinous peritonitis by WOLFE CRIESEMER FELDMANN JORTNER
                                        and               [ I 51,       and
[5] had described a syndrome i n a cat which was characterized by granulo-
matous lesions, necrosis, and phlebitis in many organs including the kidneys,
lungs, eyes, and meninges. This condition, which they named ‘feline systemic
proliferative and exudative vasculitis’, resembles forms of feline infectious
peritonitis subsequently reported by other investigators in which visceral,
men i ngea I, and oc LI I a r gran u I om a to u s inflammation accompanied by vasc u-
litis were major pathologic findings [4, 13, 141. The findings in the 12 cats
presented i n this paper demonstrate that the disease often takes this dis-


    Fig. 6. Inflamed pulmonary vein. Neutrophils and mononuclear cells in lumen and wall.
Extension of inflammatory reaction into the surrounding lung. HE.
    Fig. 7. In an advanced pulmonary granulomatous lesion, remaining alveolar septa are
lined with large irregular epithelial cells. HE.




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1 I8                     MONTALI/STRANDBERG




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                 Extraperitoneal Lesions in Feline Infectious Peritonitis               119

seminated form. The gross and histologic lesions in various organs are
identical to those reported by other investigators whose primary descriptions
center on the serosal lesions and effusions [3, I 1, 151. The production of the
more ‘classical’ disease in neonatal kittens with inoculum obtained from
cat 1 is additional strong evidence that this pathologic syndrome represents
fel i ne i n fect i o us peritonitis .
      The range in distribution and type of inflammatory lesions in this disease
is demonstrated well in our series of both natural and induced cases. Although
overlap of changes does occur from case to case, one can distinguish an
acute fibrinonecrotic form predominantly of serous membranes from a more
disseminated, granulamatous type in which phlebitis is more prominent.
Proliferative lesions were more frequent i n the natural cases, but were also
evident in an induced case (cat 5B). These proliferative lesions superficially
resemble pleomorphic tumors of the reticuloendothelial system.
      111 our limited transmission studies, both intraperitoneal and intravenous
routes of inoculation produced peritoneal or pleural lesions, or both, in most
cats. It is likely that the mesotlielium represents one of the initial target tis-
sues i n this disease. In this study, age at the time of infection and duration of
the disease appeared to be factors in determining the major location and type
of lesion. Kittens inoculated in tlie neonatal period usually developed an ex-
udative serositis within a period of 1-3 weeks; whereas the older, longer sur-
viving, second-passage cats had more proliferative visceral lesions. These ob-
servations, although they are preliminary and d o not consider any possible
effects of passage on the agent, suggest that in some cases the exudative
serosal lesions are either initially very mild or that they resolve as the dis-
ease progresses in other locations. A progressive differentiation of lesions
from the early acute type to a more graiiulomatous form has been proposed
by HARDY O’REILLY Our cases support this proposal, but more con-
                and                 [6].
trolled temporal studies are essential to establish tlie pathogenesis.
      Morphologic evidence suggests that, once established, the lesions may
spread by direct extension through serous membranes and organ capsules
 [ 151. Further dissemination of the disease process is apparently accomplished
by the subsequent invasion of subcapsular vessels, priiicipally the veins. This



    Fig. 8. Granulomatous myocarditis found in cat 12. Many fibers are necrotic and separ-
ated by the cellular infiltrate. HE.
    Fig. 9. Proliferative lesion in mesenteric lymph node of cat 5B. Large histiocytic cells
predominate. HE.




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120                                   MONTALI/~TRANDBERG

sequence is particularly evident in the kidneys of our naturally affected cats.
Subcapsular phlebitis, noted in other descriptions of feline infectious peri-
tonitis [5, l l , 16, IS], was in some instances the only lesion in these organs.
    Further dissemination by a vascular route was most strongly suggested by
lesions in the lungs in which there is extension of the inflammatory process
from isolated foci of phlebitis into the surrounding parenchyma (fig. 6).
These observations, coupled with the finding of lesions i n structures such as
the eyes and meninges, which are distant from affected visceral organs,
indicate the importance of hematogenous routes i n the dissemination of
feline infectious peritonitis. Elucidation of the pathogenesis of this disease
must await the isolation of the causative agent.
    One probable reason for the large number of cats with extensive renal
granulomas seen at this institution is the existence of an animal leukemia
clinic to which some of the cats were referred with a tentative diagnosis of
renal lymphosarcoma. Our collection is composed of cases from the Middle
Atlantic states, New York and New England. The high frequency (12 out of
32) of cases of feline infectious peritonitis represented by these cats with
primarily disseminated granulomatous disease and with mild peritonitis has
not been reported previously.



                                       A ckno wledgenwnts

   This investigation was supported by U.S. Public Health Service research grant F R 00130
and U.S. Public Health Service training grant F R 05010.



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Author’s address: Dr. R.J. MONTALI, Johns Hopkins Hospital, Baltimore, M D 21205
                                 The
(USA)




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