Feline histoplasmosis presenting with bone and joint involvement: clinical and diagnostic findings in 25 cats

Abstract

Objectives

The aim of this study was to describe clinical and diagnostic findings in cats with bone and joint disease associated with histoplasmosis.

Methods

Medical records from between 2011 and 2017 were reviewed. Inclusion criteria required: (1) diagnosis of histoplasmosis by cytology, histology, urine or serum Histoplasma antigen testing, or culture; and (2) lameness or joint effusion as a presenting complaint or physical examination finding.

Results

Twenty-five cases met the inclusion criteria. Four had incomplete records, but available data were included when applicable. Lameness was a presenting complaint in 17/21 cats and was the only complaint in 9/21 cats. Initial diagnosis was made by cytology in 22/25 cats and by culture, urine antigen and necropsy in one case each. Diagnostic cytology samples included synovial fluid (n = 13), lymph node (n = 5), skin (n = 2), lung (n = 1) and bone (n = 1). Two additional cases had synovial fluid examined but no organisms present. Inflammation was present in all synovial fluid samples examined. Biopsy was obtained in two cats and histologic diagnoses included osteomyelitis with no infectious organisms identified and severe lymphoplasmacytic synovitis suggestive of feline periosteal proliferative polyarthritis. Histoplasma urine antigen test was positive in 7/12 cats.

Conclusions and relevance

Inflammatory arthritis is common in cats with histoplasmosis, with lameness a common presenting complaint. Organisms are found in synovial fluid cytology in most cases. If not, appropriate additional diagnostics must be pursued.

Introduction

Histoplasma capsulatum is a soil-borne dimorphic fungus found in temperate and subtropical regions throughout the world including the Central USA. ¹ Histoplasmosis is the second most common fungal infection in domestic cats, with the highest reported incidence in Oklahoma. ²

Diagnosis of histoplasmosis is commonly made by identification of the organism on cytology or histopathology. H capsulatum is a small round yeast with a thin halo and an eccentrically located basophilic nucleus. It is often found within macrophages and neutrophils, but may also be seen throughout the background. ¹ H capsulatum has been identified in a number of cytology samples, including lymph node, spleen, lung, liver, bone marrow, cerebrospinal fluid, gingiva, rectal scraping, pleural and peritoneal fluid, synovial fluid and skin lesions. ³

Most cats display disseminated histoplasmosis with non-specific clinical signs, including weakness, weight loss and anorexia. Respiratory signs are common, and include dyspnea, tachypnea, nasal discharge and a cough. ⁴ Other common findings are fever, lymphadenopathy, splenomegaly, hepatomegaly, signs of ocular disease and skin lesions.^3,4 Musculoskeletal signs are rare but have been reported.^2,4 One report of seven cats with osseous lesions described clinical signs of lameness, bone pain, and soft tissue swelling of the limbs and joints. ⁵ More recent studies have described lameness and joint effusion. A 2016 study described 3/15 (20%) cats with disseminated disease exhibiting lameness and joint effusion and a 2017 retrospective study reported 8.9% (9/101) and 15.8% (16/101) of cats with joint effusion and lameness, respectively.^6,7 Only a single case of inflammatory arthritis associated with histoplasmosis has been reported. ⁸ However, clinical experience in endemic areas suggests that bone and joint disease is common in cats with histoplasmosis.

The objective of this study was to describe the clinical and diagnostic findings in cats with histoplasmosis with bone and joint involvement presented to the Oklahoma State University Boren Veterinary Medical Hospital (OSU-BVMH) or Clinical Pathology Laboratory (OSU-CPL).

Materials and methods

Medical records of all cats at OSU-BVMH between 2011 and 2017 were reviewed. Search terms included ‘histoplasma’, ‘histoplasmosis’, ‘pneumonia-fungal-histoplasmosis’, ‘polyarthropathy’ and ‘feline chronic progressive polyarthritis’. Additionally, medical records obtained from private veterinary clinics for cases diagnosed with histoplasmosis from samples submitted to the OSU-CPL were also reviewed. The inclusion criteria required a diagnosis of histoplasmosis by cytology, histology, urine or serum Histoplasma antigen testing, or culture, and lameness or joint effusion as a presenting complaint or physical examination finding, respectively.

Data extracted from the medical records included signalment (age, sex), clinical signs and physical examination findings. Results from cytology, histopathology, radiographs (orthopedic, thoracic and abdominal), fungal culture, Histoplasma antigen testing and other diagnostic tests were recorded. Follow-up was obtained from medical records and referring veterinarian contact. Remission was defined as resolution of clinical signs, including lameness and joint effusion, resolution or stasis of radiographic changes, absence of organism on cytology, and/or negative serum or urine Histoplasma antigen test.

Results

Records from 109 cats presented to OSU-BVMH were reviewed and 21 met the inclusion criteria. Additionally, four cases from outside clinics for which samples had been submitted to OSU-CPL met the inclusion criteria and were also included (total n = 25). Some had incomplete medical records and information from these cases was included when applicable.

Signalment and presenting complaint

Mean age at diagnosis was 5 years (range 6 months to 17 years). Thirteen cats were female and 12 were male. The presenting complaint was available in 21 cats. Lameness was the most common presenting complaint (17/21; 81%) and the only complaint in 9/21 (43%) cats. Other less common presenting signs included lethargy (n = 5), weight loss (n = 3), fever (n = 1), draining wounds (n = 1), blindness (n = 1), generalized pain (n = 1), weakness (n = 1) and lymphadenopathy (n = 1).

Historical findings and physical examination

Lameness was commonly identified on physical examination (20/21; 95%). Lameness involved multiple limbs in 10/20 (50%), a single limb in 9/20 (45%) and was unknown in 1/20 (5%) cats. Lameness was limited to the forelimbs in 11/19 (58%) and the hindlimbs in 3/19 (16%). All fore- and hindlimbs were affected in 5/19 (26%). Joint effusion was identified in 18/24 (75%). Effusion was found in multiple joints in 9/17 (53%) and a single joint in 8/17 (47%). The most common joint affected was the tarsus (n = 10), followed by the carpus (n = 9), elbow (n = 7) and stifle (n = 2). In 8/21 (38%) cats, clinical signs were confined to the musculoskeletal system at initial presentation. Fever (>39°C) was seen in 18/21 (86%) cats, with 6/21 (29%) cats having marked pyrexia (>40°C). Other abnormal physical examination findings included lymphadenopathy (n = 13), weight loss (n = 11), cutaneous lesions (n = 8) and labored breathing (n = 2).

Diagnostics

Initial diagnosis of histoplasmosis was made by cytology in 22/25 cats (88%); other methods of diagnosis included: fungal culture of lymph node (n = 1), urine Histoplasma antigen test (n = 1) and histology from post-mortem examination (n = 1).

Cytologic samples from which H capsulatum organisms were initially identified included synovial fluid (n = 13), lymph node (n = 5), skin (n = 2) lung (n = 1) and bone (n = 1). Three cats diagnosed by synovial fluid analysis also had H capsulatum organisms found on tissue aspirate cytology of lymph node (n = 2), spleen (n = 1) and a cutaneous lesion (n = 1). Organisms were identified in synovial fluid from the tarsus (n = 6), carpus (n = 5) and elbow (n = 2). In two cats, organisms were in synovial fluid from multiple joints. Inflammation was found in all synovial fluid samples for which full cytology reports were available (n = 11). Inflammation was classified as pyogranulomatous (n = 7), suppurative (n = 3) and lymphocytic histiocytic (n = 1). In three cats inflammation was present, but organisms were not identified on initial cytology of synovial fluid. One cat was tentatively diagnosed with feline periosteal proliferative polyarthritis based on clinical signs, radiographic changes and the presence of suppurative inflammation with no organism on synovial fluid cytology. H capsulatum was identified on repeat synovial fluid cytology 2 months after initiation of immunosuppressant therapy.

In a second cat, diagnosis was made by urine Histoplasma antigen test. In a third cat, urine and serum Histoplasma antigen tests were negative; however, H capsulatum was cultured from an enlarged, inflamed lymph node adjacent to an affected joint.

Urine Histoplasma antigen test was positive in 7/10 (70%) cats. Both urine and serum Histoplasma antigen tests were performed in two cats. Urine Histoplasma antigen test was negative in one cat and serum Histoplasma antigen test was negative in both cats.

Biopsy of the affected joint was obtained in two cats. One cat was diagnosed with osteomyelitis with no infectious organisms identified, including staining with Gomori’s methenamine silver (GMS) to specifically exclude fungal infection. Despite 6 months of antibiotic therapy, lameness progressed to multiple joints with joint effusion noted in the joint previously biopsied. H capsulatum was identified on cytology of synovial fluid from this joint. Treatment with itraconazole resulted in resolution of clinical signs by 5 weeks. A second cat was diagnosed with severe lymphoplasmacytic synovitis and bone proliferation of the hock. Staining with GMS did not reveal H capsulatum organisms and a presumptive diagnosis of feline periosteal progressive arthritis was made. One year of immunosuppressive therapy resulted in only mild transient improvement of clinical signs. Subsequent cytologic evaluation of an enlarged popliteal lymph node adjacent to the previously biopsied joint revealed pyogranulomatous inflammation and H capsulatum organisms. Treatment with itraconazole resulted in resolution of lameness.

Initial orthopedic radiographs were available for 18/25 (72%) cats, for a total of 41 separate orthopedic studies, including the tarsus (n = 17), carpus (n = 16), elbow (n = 5), antebrachium (n = 2) and shoulder (n = 1). Eleven of those cats had two or more joints or long bones imaged at least once and 9/11 (82%) had multiple joints or long bones affected. Of these studies, 5/41 (12%) were described as unremarkable (two tarsi and three elbow studies). Intracapsular and/or extracapsular soft tissue swelling was identified in 26/33 (79%) combined carpal and tarsal studies. Osseous lesions were identified in 29/33 (88%) carpal and tarsal radiographs; 19/29 (66%) had lysis of cuboidal bones, six of which had metaphyseal lysis, and 10/29 (34%) had lysis of the metaphysis of adjacent long bones without adjacent articular surface lysis. Other non-articular or metaphyseal osseous lesions, all described as well-defined punctate lucencies, were identified in 4/25 (16%) cats. Thoracic radiographs were performed in 13/25 (52%) cats and one cat had an abdominal radiograph. Pulmonary abnormalities were identified in 8/13 (62%) and were described as either diffuse interstitial (n = 4), nodular (n = 2) or both (n = 2) pulmonary patterns. The remaining 5/13 (38%) were described as unremarkable. Concurrent hepatomegaly was identified in the cranial abdomen of 3/13 (23%).

Hematologic (n = 20) and biochemical (n = 20) data were evaluated. Anemia was identified in 10/20 (50%) and most (9/10) were classified as non-regenerative, based on blood smear evaluation. A mature neutrophilia was identified in 13/20 (65%) and 5/20 (25%) had a band neutrophilia (Table 1). Platelets were difficult to assess due to platelet clumping in 13/20 (65%). While an accurate platelet count could not be obtained for these samples, all were determined to be adequate based on blood smear review and thrombocytopenia was not identified in any sample. Biochemistry abnormalities included hyperbilirubinemia in 6/17 (35%), hyperglobulinemia in 5/19 (26%), hypoalbuminemia in 4/19 (21%) and hypercalcemia in 2/19 (11%) (Table 2).

Table 1

Hematologic data in cats with bone- and joint-associated histoplasmosis

Variable	n	RI	Mean	SD	Median	Range	Number lower than RI (%)	Number higher than RI (%)
White blood cells (k/µl)	20	3.5–16	15.3	4.7	15.3	5.1–24.1	0 (0)	9 (45)
Segmented neutrophils (k/µl)	20	2.5–8.5	10.4	4.2	10.1	3.8–19.1	0 (0)	13 (65)
Band neutrophils (k/µl)	20	0–0.3	0.3	0.8	0	0–3.1	0 (0)	5 (25)
Lymphocytes (k/µl)	20	1.2–8.0	3.7	2.7	3	4.5–11.3	3 (15)	1 (5)
Monocytes (k/µl)	20	0–0.6	0.6	0.5	0.4	0.1–2.2	4 (20)	0 (0)
Eosinophils (k/µl)	20	0–1.0	0.4	0.4	0.3	0–1.1	0 (0)	2 (10)
HCT (%)	20	29–48	29	6	28	21–40	10 (50)	0 (0)
MCV (fL)	20	37–61	45	6	44	36–61	1 (5)	0 (0)
MCHC (g/dl)	20	30–38	32	2	32	29–35	2 (10)	0 (0)

RI = reference interval; HCT = hematocrit; MCV = mean cell volume; MCHC = mean cell hemoglobin concentration

Table 2

Biochemical data in cats with bone- and joint-associated histoplasmosis

Variable	n	RI	Mean	SD	Median	Range	Number lower than RI (%)	Number higher than RI (%)
TP (g/dl)	19	5.2–8.8	7.7	0.8	7.6	6.6–9.9	0 (0)	1 (5)
Alb (g/dl)	19	2.5–3.9	2.7	0.3	2.7	2.2–3.3	4 (21)	0 (0)
Glob (g/dl)	18	2.3–5.3	4.9	0.9	4.8	3.5–7.1	0 (0)	5 (28)
AST (U/l)	12	10–100	41	20	42	12–79	0 (0)	0 (0)
ALT (U/l)	18	10–100	57	54	45	10–230	0 (0)	2 (11)
ALP (U/l)	18	6–102	24	12	22	10–53	0 (0)	0 (0)
GGT (U/l)	15	1–10	4.2	4.4	2	1–14	0 (0)	2 (13)
T bili (mg/dl)	17	0.1–0.4	0.5	0.7	0.2	0.1–2.2	0 (0)	6 (35)
BUN (mg/dl)	20	14–36	25	23	20	10–121	1 (5)	1 (5)
Creat (mg/dl)	19	0.6–2.4	1.1	0.8	0.8	0.5–4.4	1 (5)	1 (5)
P (mg/dl)	16	2.4–8.2	5.7	1.8	5.2	3.8–10.9	0 (0)	1 (6)
Gluc (mg/dl)	19	64–170	121	32	119	78–197	0 (0)	2 (11)
Ca (mg/dl)	16	8.2–10.8	9.5	0.8	9.4	8–11	1 (6)	2 (13)
Mg (mg/dl)	11	1.5–2.5	1.7	0.3	1.7	1.3–2.5	2 (18)	0 (0)
Na (mg/dl)	17	145–158	151	2.3	152	147–155	0 (0)	0 (0)
K (mg/dl)	17	3.4–5.6	4.1	0.6	4.1	3.5–6.0	0 (0)	1 (6)
Cl (mg/dl)	17	104–128	119	2	119	114–124	0 (0)	0 (0)
Chol (mg/dl)	16	75–220	129	45	129	62–225	2 (13)	1 (6)
Trig (mg/dl)	11	25–160	39	17	40	18–76	3 (27)	0 (0)
Amy (U/l)	15	100–1200	807	332	823	132–1401	0 (0)	1 (7)
CPK (U/l)	16	56–529	458	974	102	39–4093	1 (6)	2 (13)

RI = reference interval; TP = total protein; Alb = albumin; Glob = globulin; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; GGT = gamma-glutamyl transferase; T bili = total bilirubin; BUN = blood urea nitrogen; Creat = creatinine; P = phosphorus; Gluc = glucose; Ca = calcium; Mg = magnesium; Na = sodium; K = potassium; Cl = chloride; Chol = cholesterol; Trig = triglycerides; Amy = amylase; CPK = creatine phosphokinase

Outcome

Initial follow-up data were available for 21 cats and 18/21 (86%) survived to hospital discharge. Follow-up until resolution of clinical signs was available for eight cats and mean time to resolution of lameness in those cats was 16 weeks (range 4–36 weeks). Resolution of joint effusion was noted concurrently with resolution of lameness in all but two cats in which joint effusion persisted for an additional 4 and 16 weeks. Synovial fluid cytology was repeated in only one cat. In this cat, five samples were examined over a period of 9 months after initial diagnosis and suppurative inflammation was identified in all, although H capsulatum was not present in any sample after the start of antifungal therapy.

Seven cats had at least one set of follow-up orthopedic radiographs, with a total of 15 separate joints having at least one follow-up. One cat that initially presented with carpal or tarsal soft tissue swelling only had articular lysis on a subsequent examination. Animals with metaphyseal lysis tended to have slowly improving remodeling of these regions, while animals with joint disease were generally described as having unchanged amounts of cuboidal bone lysis, improved long bone diaphyseal/metaphyseal lysis with remodeling, increased amounts of periosteal or periarticular new bone, sclerosis and joint space collapse. One cat with follow-up thoracic radiographs showed improvement of pulmonary nodules.

Discussion

Inflammatory arthritis is a common, but potentially under-reported, manifestation of histoplasmosis in cats in endemic areas. A recent retrospective study of cats with histoplasmosis reported 15.8% of cats with lameness and 8.9% with joint effusion. ⁷ We report here 25 cases of feline histoplasmosis in which lameness or joint effusion was either the presenting complaint or a prominent physical examination finding. Inflammatory arthritis was identified in all cases in which sampling of synovial fluid was pursued. Similar clinical signs have been described in cats with disseminated histoplasmosis, but synovial fluid was not evaluated in those cases.^5,9–11 Only a single case report (which is included in the present retrospective study) of inflammatory arthritis was identified in the literature. ⁸

Lameness was the most common presenting complaint in the present study and was the only presenting complaint in nearly half of the cats. These findings are similar to articular histoplasmosis cases in humans in which the only presenting signs were painful and/or swollen joints.^12–16 Lameness has been reported as a less common clinical sign in other studies of histoplasmosis in cats, but it was not further characterized in those studies and there was no mention of synovial fluid findings.^2,4,6,7 Smaller joints (ie, tarsus, carpus) were most commonly affected in our study and this is consistent with previously reported findings in cats.^5,9,10

Monoarthritis and polyarthritis were identified in equal numbers based on physical examination in the cats in this study. This is in contrast to human studies where monoarthritis is considered rare. ¹² It is likely that many of our cases that were identified as monoarticular based on physical examination actually had polyarticular disease that was not clinically evident. This is supported by the fact that approximately 82% of the radiographic studies identified soft tissue and bony changes in more than one joint, when these were performed. This suggests that radiographic studies of multiple joints may be informative even in patients for which clinical presentation appears monoarticular.

Joint effusion was identified in most cats in this study and inflammatory arthritis was diagnosed in all synovial fluid samples that were evaluated cytologically. The inflammatory response was most commonly classified as pyogranulomatous. Inflammatory arthropathy is more common in dogs than in cats. In dogs, most inflammatory arthropathies result from either immune-mediated or bacterial joint disease and typically produce a suppurative (purulent) inflammation. ¹⁷ Thus, a pyogranulomatous inflammatory response should arouse suspicion, especially in cats from Histoplasma species-endemic areas or travel history to endemic areas.

Cytology of synovial fluid was often diagnostic not just of inflammation, but Histoplasma organisms were identified in 13/15 patients for which synovial fluid was evaluated. Organisms were often present in very low numbers, and were found only after prolonged examination. In cases where synovial fluid was not diagnostic for histoplasmosis, multiple joints were sampled and significant inflammation, either suppurative or pyogranulomatous, was present. Diagnosis was attained by urine Histoplasma antigen test in one cat. In the second cat, multiple urine and serum Histoplasma antigen tests were negative and a diagnosis was reached when H capsulatum was cultured from an adjacent enlarged, inflamed lymph node aspirate.

These findings demonstrate that synovial fluid cytology is often diagnostic if there is sufficient clinical index of suspicion to warrant a prolonged search for the organisms. However, even with this some cases require additional testing such as Histoplasma antigen testing. Fungal culture of adjacent enlarged lymph nodes or joint fluid may also be helpful, but should be interpreted in conjunction with other evidence of disease. In the few cases where organisms were not identified, it should be considered that the inflammation in these cats may represent a secondary immune-mediated polyarthritis rather than an infectious arthritis. However, H capsulatum was eventually confirmed in these cases and is likely the cause of the inflammation seen in these cats by either mechanism.

Anemia was a common finding in these cats and was typically non-regenerative. This is consistent with previous reports of cats with disseminated histoplasmosis and is thought to be multifactorial, although anemia of chronic inflammation is the most likely cause. In contrast to previous reports of neutropenia in cats with disseminated histoplasmosis, more than half of the cats in this study had a neutrophilia; however, the left shift seen with many of these cats is consistent with previous findings. As reported in other studies, lymphopenia was identified in some of the cats in this study. Thrombocytopenia is reported as a common finding in cats with disseminated histoplasmosis, but thrombocytopenia was not identified in this study.

Hyperbilirubinemia was the most common biochemical abnormality found in this group of cats and has been previously described in cats with disseminated histoplasmosis. This may be due to liver disease secondary to hepatic involvement in disseminated disease or hepatic lipidosis associated with anorexia. Hypoalbuminemia and hyperglobulinemia are likely associated with inflammation and have been previously reported in cats with disseminated histoplasmosis.

The urine Histoplasma antigen test from Mira Vista Diagnostics has been shown to be a sensitive test (89.7%) for the diagnosis of disseminated histoplasmosis in cats.^18,19 This test was negative in 3/10 (30%) cats reported in the current study. Disease was isolated to the bone and joints in these three cats and diagnosis was delayed in all with a presumptive diagnosis of feline periosteal proliferative arthritis in two cats. This suggests that the sensitivity of this test in cats with disease confined to the joint might be lower than that for cats with disease in other organ systems. Localized disease likely leads to lower antigen loads and ultimately decreased performance of urine antigen testing. A positive urine Histoplasma antigen test suggests histoplasmosis, but a negative test does not rule out histoplasmosis involving bone and joint.

Inherent in most retrospective studies, there were several limitations including a lack of standardization of history and clinical findings, as well as cytologic, histopathologic and radiographic descriptions. Also, many of the medical records were incomplete and four of the cases had minimal data beyond history and cytologic findings. The authors felt that these data were still informative and included findings where applicable. Follow-up data were not available for most of the cases and, when available, it included little clinical information or repeat diagnostics. This precluded further conclusions about remission rate and clinical outcome.

Conclusions

To our knowledge, synovial fluid findings associated with histoplasmosis involving the bone and joint have not been previously described in cats. In many cases musculoskeletal signs may be the primary or only clinical finding. Cytologic evaluation of synovial fluid was often diagnostic, but some cases required additional testing, such as testing urine or serum for Histoplasma antigen or culture of affected tissues. In endemic areas, histoplasmosis should be suspected in cats presenting with musculoskeletal signs.