- Cryptococcosis in Cats
- Agent properties
- Clinical signs
- Nasal form
- CNS form
- Cutaneous form
- Systemic form
- Antigen detection
- Polymerase chain reaction
- Antibody detection
- Diagnostic imaging
- Disease management
Cryptococcosis in Cats
Edited November, 2016
The Cryptococcosis in cats guidelines were first published in the J Feline Med Surg 2013, 15: 611-618 by Maria Grazia Pennisi et al. The present guidelines were updated by Maria Grazia Pennisi.
Cryptococcosis is worldwide the most common systemic fungal disease in cats; it is caused by the C. neoformans-C.gattii species complex, which includes eight genotypes and some subtypes (strains) with different geographical distribution, pathogenicity and antimicrobial susceptibility. Cryptococcosis is a non-contagious, rare or sporadic disease; cats acquire the infection from a contaminated environment.
Prognosis is favourable in most cases, provided diagnosis is obtained sufficiently early (before dissemination or before the development of irreversible lesions) and patients and owners are co-operative to provide a long course treatment (months) and follow-up (years).
Basidiospores are the infectious propagules of Cryptococcus as they penetrate the respiratory system and induce the primary infection. Asymptomatic colonization of the respiratory tract is more common than clinical disease. Avian guanos, particularly pigeon droppings, offer favourable conditions for the reproduction of C. neoformans, but both Cryptococcus species are associated with decaying vegetation such as Eucalyptus leaves.
Cryptococcosis caused by C. neoformans or C. gattii is indistinguishable clinically. The disease can present in several different clinical forms, including the nasal form, CNS form (which can derive from the nasal form or occur independently), the cutaneous form and the systemic form. Geographical differences in the prevalence of some clinical presentations are postulated as a consequence of the distribution of genotypes with different virulence.
An easy and reliable test for cryptococcosis diagnosis is antigen detection in body fluids. Alternatively, biopsy samples can be collected from lesions and be submitted for cytology, culture, histopathology and PCR. Only isolation and PCR give the opportunity to identify the species and the genotype involved.
Treatment guidelines have not been established and the choice of the appropriate antifungal drug depends on many factors, including the owner compliance. Amphotericin B, ketoconazole, fluconazole and itraconazole have all been used to treat cats. Surgical excision of any nodules located in the skin, nasal or oral mucosa is a valuable aid in cats under medical therapy. In general, treatment is recommended until the antigen test is negative.
The presence of avian guanos, particularly pigeon droppings and some decaying vegetation substrates such as Eucalyptus leaves may be considered a risk factor but efficient preventative measures have not been demonstrated. Vaccines are not available.
Feline cryptococcosis (FC), discovered over a century ago, is a non-contagious systemic fungal disease acquired from contaminated environment. For this reason it is not considered a zoonotic disease; animals may serve as sentinel hosts.
FC is caused by basidiomycetous yeasts of the genus Cryptococcus belonging to the C. neoformans-C. gattii complex. A previous classification distinguished five serotypes (A, B, C, D, AD) according to antigenic characteristics of the capsular polysaccharide (Sykes and Malik, 2012). The updated nomenclature based also on genotyping differentiates two main species affecting cats: C. neoformans – including the varieties C. n.var. grubii (former serotype A) and C. n. var. neoformans (former serotype D) – and C. gattii (former serotypes B and C). According to molecular characterization, isolates from the C. neoformans-C. gattii complex includes eight genotypes and some subtypes (strains) with different geographical distribution, pathogenicity and antimicrobial susceptibility (Lester et al., 2011).
Small size infectious propagules such as basidiospores (<2 μm) and desiccated yeast cells (<3 μm) are easily dispersed by air flow and can penetrate the respiratory system where the primary infection takes place. The fungus can differentiate into several morphological forms including yeast, chlamydospores, pseudohyphae and hyphae under certain conditions but it is typically present in the yeast form in mammalian hosts, reproducing by mitosis in animal tissues (Alspaugh et al., 2000; Lin and Heitman, 2006).
Other species were rarely reported: C. albidus that may affect immunocompromised cats and C. magnus isolated in cats affected by otitis (Kano et al., 2004, 2008).
Cryptococcosis affects humans, cats, dogs, ferrets, horses, goats, sheep, cattle, dolphins, birds, koalas, and other marsupials (Sykes and Malik, 2012). It has a worldwide distribution and is observed more commonly in cats than in dogs (McGill et al., 2009).
Unfortunately, Cryptococcus is not usually identified to the species and molecular level with routine diagnostic sampling, and data regarding the feline disease in Europe are from single case reports or small case series, since the disease usually occurs sporadically (Castella et al., 2008). Larger retrospective studies are available only from Canada, Australia and California (Craig et al., 2002; O’Brien et al., 2004; Duncan et al., 2005, 2006; McGill et al., 2009; Sykes et al., 2010).
The disease is usually rare or sporadic. However, in 1999, a large-scale outbreak of cryptococcosis caused by C. gattii for the first time involved humans, terrestrial (dogs, cats, ferrets, llamas, horses, birds) and marine (porpoises Phocoenoides dalli) animals; it occurred on southern Vancouver Island, British Columbia, Canada in a region characterized by wet, mild winters and dry, warm summers. It is now well known that C. gattii has a worldwide distribution with a high prevalence along the Pacific coast of North America. In Europe, it was reported from Austria, Denmark, France, Germany, Greece, Italy, the Netherlands, Portugal, Spain, Sweden and the United Kingdom (Lester et al., 2011). Also C. n. var. grubii has a worldwide distribution and is commonly isolated from affected individuals in various animal species. C. neoformans is considered a cosmopolitan opportunistic pathogen in human urban populations, whereas C. gattii is a true pathogen, more prevalent in rural areas (Sykes and Malik, 2012).
Environmental exposure and asymptomatic colonization of the respiratory tract are more common than the clinical disease (Malik et al., 1997b; Connolly et al., 1999). Asymptomatic carriage of C. gattii has been recognized in 4.3% of cats, 1.1% of dogs and in 2% of wild animals (squirrel) trapped in British Columbia (Bartlett et al., 2003; Duncan et al., 2005).
- neoformansecology is usually related to the presence of avian guanos, particularly pigeon droppings, which offer favourable conditions for the mitotic amplification and reproduction of the fungus, but both Cryptococcusspecies have been associated with decaying vegetation such as Eucalyptus leaves (Fortes et al., 2001). Pigeons serve as C. neoformans carriers that likely contribute to the world-wide distribution, as they carry Cryptococcus on their beaks, feathers, and legs (Pal, 1989). Animals, plants, soils and waterways are the sources from where the potential pathogen may be contracted.
Cats are five to six times more likely to be affected by the disease than dogs, and three times more than horses (McGill et al., 2009). Retrospective studies of feline cases tended to show a preponderance in males, although this finding was not confirmed in other studies (Malik et al., 1992; Flatland et al., 1996; Jacobs et al., 1997; Gerds-Grogan and Dayrell-Hart, 1997; Lester et al., 2004; McGill et al., 2009; Sykes et al., 2010). Pedigree breeds such as Ragdoll, Birman, Siamese and Himalayan were considered more often affected than domestic cats but again, this finding has not been confirmed in more recent studies (Malik et al., 1992; O’Brien et al., 2004; McGill et al., 2009; Sykes et al., 2010; Trivedi et al., 2011). In contrast with other animal species where usually young adults contract the infection, cats of all ages may be affected (Malik et al., 1992; McGill et al., 2009). No seasonal trend in the diagnosis of infection has been observed (McGill et al., 2009). Also lifestyle does not seem to be a risk factor – the disease has been reported in indoor cats, too.
Cryptococcus is primarily an airborne pathogen, and the nasal cavity is usually the primary site of infection in cats and dogs. In most cases there is only a subclinical colonization without the invasion of the epithelium (Duncan et al., 2005). When invasion of mucosal tissues occurs, progression to disease occurs locally and/or systemically. In both people and cats, the infection may follow ingestion of desiccated yeast cells or, more rarely, cutaneous inoculation of fungal forms. The incubation period varies from months to years, and the source of infection often remains unknown. The virulence (genotype) and burden of the inhaled organisms influence the outcome of infection.
From the upper respiratory tract the infection may spread locally to the CNS through the ethmoid bone, and rarely also to the lower respiratory tract or systemically (Martins et al., 2011).
There are temperature-sensitive strains which are unable to grow at temperatures > 37.0°C and may cause infections only at body sites where the temperature is lower (skin, nose, scrotum) (Bemis et al., 2000; Lin, 2009).
Antibodies produced against capsular antigens are not protective. Persistent infections can occur because the capsule of Cryptococcus yeast forms inhibits phagocytosis, and other virulence factors such as melanin production protects the yeast cells from oxidative damage. It is therefore able to survive inside phagocytic cells such as macrophages and neutrophils and can be disseminated with these cells (Urban et al., 2006; Lester et al., 2011; Trivedi et al., 2011).
Some studies suggested that cryptococcosis has a higher prevalence or a less favourable outcome in FeLV- or FIV-infected cats (Gerds-Grogan and Dayrell-Hart, 1997; Jacobs et al., 1997), but this conclusion has not been shared by others (Malik et al., 1992; O’Brien et al., 2004, 2006; Norris et al., 2007; Sykes et al., 2010). The disease has been reported in cats under chemotherapy or with a concurrent opportunistic infection so that a role for immunocompetence cannot be excluded in the pathogenesis of FC (Trivedi et al., 2011; Graham et al., 2011).
Cryptococcosis caused by C. neoformans or C. gattii is clinically indistinguishable.
This disease can present in several different clinical forms, including the nasal form, CNS form (which can derive from the nasal form or occur independently), the cutaneous form and the systemic form. Geographical differences in the prevalence of some clinical presentations are postulated as a consequence of the distribution of genotypes with different virulence. Abnormalities in blood tests are non-specific, if present, showing an inflammatory process.
The nasal form is the most common in cats, presenting as a chronic sino-nasal disease, either alone or together with local spread to the skin, subcutis, bones and regional (sub-mandibular) lymph nodes (Malik et al., 1992; O’Brien et al., 2004; McGill et al., 2009). It induces naso-facial swelling followed by deep nonhealing ulceration draining gelatinous exudate, chronic nasal discharge (monolateral or bilateral) with serous, mucopurulent or bloody aspect, stertor and inspiratory dyspnoea, sneezing and snuffling and submandibular lymphadenopathy (Figs. 1-3). Anorexia and subsequent weight loss may also be a result of anosmia affecting cats with chronic nasal disease. Cryptococcus is an important differential in cats with chronic nasal discharge, regardless whether or not facial swelling and/or skin ulceration is present.
In some cases, a protruding fleshy mass from one or both nostrils may occur. Nasopharyngeal granulomas (resembling polyps or cancer) presenting with stertor, inspiratory dyspnoea and open mouth-breathing have also been described (Malik et al., 1997a). Proliferative or ulcerated lesions in the oral cavity or pharynx may also develop. Otitis media/interna with vestibular signs may occur (Beatty et al., 2000, Paulin et al., 2013). Lower respiratory tract disease may follow and its manifestation may be evident radiologically as only pulmonary or mediastinal nodules.
CNS involvement most likely arises following local dissemination through the cribriform plate; in such cases, sudden blindness due to optical neuritis appears together with seizure or behavioural changes. In other cases it follows dissemination and induces granulomatous encephalomyelitis with solitary or multiple lesions (Belluco et al., 2008; Sykes et al., 2010). Many cats show head or spine pain but other signs of meningeal involvement (hyperesthesia, nuchal rigidity) are not common (Sykes et al., 2010).
Cutaneous forms are characterized by solitary or multiple dermal to subcutaneous nodules in the skin: the former are suggestive of direct inoculation, the latter of haematogenous spread from the primary site of infection (Sykes and Malik, 2012). The nodules are usually non pruritic and not painful, and commonly accompanied by regional lymphadenopathy.
Systemic forms may occur through haematogenous dissemination and manifest with signs of meningo-encephalomyelitis (see CNS form), uveitis, chorioretinitis, osteomyelitis and polyarthritis, systemic lymphadenitis or multi-organ involvement, including the kidneys (Figs. 4 and 5). Cranial venal caval syndrome with severe edema of the head and neck was recently reported in a cat affected by the developmet of a cryptococcal mediastinal mass compressing the vein, but also the oesophagus and trachea (Letendre and Boysen, 2015).
Apathy and cachexia appear in cats with severe dissemination during the prolonged chronic course of the disease. Systemic form arising from dissemination may or may not follow classical nasal disease (Tisdall et al., 2007; Martins et al., 2011).
An easy and reliable test for cryptococcosis diagnosis is antigen detection in body fluids. Alternatively, samples can be collected from lesions and be submitted for cytology, culture, histopathology and PCR. These include (i) pleural or peritoneal effusions, (ii) cerebrospinal fluid (CSF), (iii) specimens collected from broncho-alveolar lavage, (iv) fine needle aspirates from nodules or enlarged lymph nodes, (v) biopsies taken from any affected tissues. An increased risk of cerebellar herniation after CSF collection is suspected and this invasive procedure should be considered only when a CNS disease compatible with FC was not confirmed by using other suitable biological samples (Sykes et al., 2010).
Isolation and PCR give the opportunity to identify the species and the genotype (PCR only) involved.
Antigen detection in blood is the test of choice if available because it is fast, reliable and minimally invasive. Cryptococcal capsular antigen may be detected by latex cryptococcal antigen agglutination test (LCAT) on serum, CSF or urine. The sensitivity and specificity of the test is improved by pre-treating samples with heat and a proteinase (pronase, often included in commercial diagnostic kits) and it is considered good in cats (Sykes and Malik, 2012). In some cases, false negative results may occur (Belluco et al., 2008). If the antigen test is negative, and cryptococcosis is still a possibility, tissue samples should be submitted for cytology, histology and culture. On the other hand in case of titres <200 a confirmatory cytology, culture or PCR is suggested.
LCAT titre is also an efficient way of monitoring the efficacy of therapy. Treatment is usually continued until a negative LCAT is obtained, but it has been reported that the titre continues to decrease after stopping therapy in cats with clinical resolution with a still positive LCAT (O’Brien et al., 2006).
Cytology can be an easy tool to diagnose cryptococcosis because the appearance of the organisms is characteristic and the number of yeasts in the lesions is usually high, but a negative result does not exclude the diagnosis. Appropriate cytological samples can be obtained through impression smears from ulcerated skin lesions, fine needle aspirates of nodules, impression smears of biopsy samples or broncho-alveolar lavage or CSF taps. In case of renal involvement yeast may be seen in the urinary sediment (Brandt and Blauvelt, 2010).
Smears stained with Romanowsky-type stain (Wright, Diff-Quick, Giemsa) may show pink to violet, round or budding extracellular yeasts that vary in size (4-15 μm) and shape and are typically surrounded by a clear more or less thick halo corresponding to the unstained capsule (Figs. 6, 7). If Gram stain is used, the organism appears Gram+ with a Gram-(pink) capsule. A pyogranulomatous inflammatory pattern is usually seen. Although filamentous forms are not commonly observed in tissues, those atypical morphologic forms of C. neoformans may be present in cats (Bemis et al., 2000; Lin, 2009).
Biopsy samples of nasal mucosa, lymph nodes or skin nodules may be obtained for histology, but they may also provide impression smears for cytology and material for culture and PCR. Haematoxylin-eosin stained sections show eosinophilic bodies surrounded by a clear halo and a pyogranulomatous reaction (Fig. 8). Mayer’s mucicarmine method specifically stains the capsule of Cryptococcus. Immunohistochemistry on tissue sections is used for species differentiation, using monoclonal antibodies (Fig. 9) (Krockenberger et al., 2001).
Culture should be performed if the antigen test is negative, when titres are low or absent. Only samples from nasal biopsies should be submitted for culture, because presence of cryptococcus in nasal discharge cultures is not considered evidence of disease. Positive culture of biopsy samples and histological changes consistent with infection are considered diagnostic and may be used for test the sensitivity towards antifungal drugs.
Culture of biopsy samples is more sensitive than cytology in confirming infection. Cryptococcus is easily isolated in Sabouraud’s dextrose agar after incubation at 25°C and 37°C for 10 days but also on bacterial standard media. It is now possible to differentiate C. neoformans from C. gattii by a specific agar test (Lester et al., 2011).
When samples are contaminated by bacteria as it occurs in nasal secretions, media containing antibiotics are useful (Sykes and Malik, 2012).
Polymerase chain reaction
Polymerase chain reaction (PCR) has been developed for genetic identification in CSF, urine, serum and biopsy samples but is not used routinely in practice (Kano et al., 2001; Meyer et al., 2003; Okabayashi et al., 2006).
Antibody detection is not a diagnostic tool because it cannot distinguish subclinical infection from disease.
Advanced diagnostic imaging techniques (CT and MRI) are frequently used in the diagnostic process of chronic nasal and CNS signs. Abnormal findings in feline cryptococcosis are the presence of chronic rhinitis, frontal sinusitis ad/or intranasal or intracranial focal solitary or multifocal masses or fluid-filled lesions (Sykes et al., 2010). Confirmation of diagnosis is not possible by imaging alone, but resolution of a mass lesion can be followed up by MRI in cats under medical therapy (Karnik et al., 2009; Hammond et al., 2011). MRI findings may also include meningeal enhancement, optic nerve and cribriform plate involvement (Sykes et al., 2010).
Prognosis is favourable in most cases, provided diagnosis is obtained sufficiently early (before dissemination or before the development of irreversible lesions) and patients and owners are co-operative to provide a long course treatment (months) and follow-up (years).
Although information on outcomes is quite limited, it seems that cats have a more favourable prognosis than dogs or horses which develop more frequently lower respiratory, disseminated and neurological disease associated with higher mortality (Duncan et al., 2006; O’Brien et al., 2006; McGill et al., 2009; Sykes et al., 2010).
In one retrospective study, disease severity did not influence outcome, although the presence of CNS involvement had a significantly adverse impact on the outcome of therapy (O’Brien et al., 2006). On the other hand, alteration of the mental status was the only negative prognostic factor in a retrospective study on cats with CNS form of FC and complete recovery was documented also in cats with a CNS form (Sykes et al., 2010; Hammond et al., 2011).
No prospective controlled studies exist on the treatment of feline cryptococcosis and all data are based on retrospective studies and case reports. Treatment guidelines have not been established and the choice of the appropriate antifungal drug depends on many factors. Owner compliance is crucial, because of the high costs in terms of both money and long time required for treatment.
Some retrospective studies on treatment outcomes of feline cryptococcosis have been reported with heterogeneous criteria for evaluating the success of therapy (Medleau et al., 1995; Davies and Troy, 1996; Jacobs et al., 1997). In the largest retrospective study performed on 59 cats 68% had a successful outcome (O’Brien et al., 2006). Most of them needed one single course of therapy of several months (1 to 24) duration and few cats received a second course of therapy because of clinical recurrence or raised LCAT titre. According to a more recent retrospective study, the clinical outcome may be favourable in approximately 2/3 of treated cats (McGill et al., 2009). Most recovered cats were presented with sino-nasal or single lesions at skin, subcutis or intestinal and the ones that did not recover had CNS or disseminated disease.
Amphotericin B, ketoconazole, fluconazole and itraconazole have all been used to treat cats. Concerning the effect of different therapeutic protocols, there was no significant difference in outcome between cats treated with amphotericin B-containing protocols and those treated with azole monotherapy using fluconazole or itraconazole (O’Brien et al., 2006).
The median cumulative dose of AMB for cats cured at the first attempt was 16 mg/kg (range 7 to 23 mg/kg). This was higher than the previously recommended cumulative dose of 4 to 8 mg/kg. The median duration of treatment for fluconazole-treated cats was significantly shorter (4 months; range 1 to 8 months) than the median for the itraconazole group (9 months; range 3 to 24 months). Liposomal formulations of AMB may be better tolerated but are very expensive and not easily available. Recommendations for treatment based on case studies are that fluconazole or itraconazole are good choices.
In CNS or systemic cases amphotericine B alone or in combination with flucytosine maybe the first choice followed by a long treatment with fluconazole or itraconazole (O’Brien et al., 2006). Cats with pre-existing renal disease should be treated with itraconazole or fluconazole only. Fluconazole seems to be more effective than itraconazole for infections in CNS, eye and urinary tract and is also better tolerated (Trivedi et al., 2011; Hammond et al., 2011; Sykes and Malik, 2012). Resistance to fluconazole was reported with some isolates that however were susceptible to other azoles (Lester et al., 2011; Kano et al., 2015).
The clinical condition of cats with cerebral cryptococcosis may worsen soon after starting amphotericin B therapy, presumably due to an inflammatory response and increased intracranial pressure. Short-acting corticosteroid (dexamethasone or prednisolone sodium succinate) therapy is reported of immediate benefit in such cases and associated with more chances of survival in the short term (O’Brien et al., 2006; Sykes et al., 2010).
Surgical excision of any nodules located in the skin, nasal or oral mucosa must be considered as a valuable aid in cats under medical therapy (Hunt et al., 2002).
In general, treatment is recommended until the antigen test is negative. If the antigen test is negative at the time of diagnosis and the disease was confirmed by other methods or if the antigen test is not available, treatment should be continued at least until 2 to 4 months after resolution of clinical signs.
Table 1 lists the treatment options for this infection.
Treatment of cryptococcosis
|Drug/therapy||Dose and duration||Comments|
|IV = intravenous, |
PO = oral,
CNS = central nervous system
|Itraconazole||50-100mg/cat q24h||good absorption without food. Oral solution better than capsules. Hepatotoxicity possible; monitor liver enzymes periodically / monthly|
|Amphotericin B||0.25 mg/kg q48h IV to a total dose of 4-16 mg/kg||treatment of choice for CNS infection and/or systemic disease. Significant nephrotoxicity; monitor renal function frequently / weekly|
|Flucytosine||25-50 mg/kg PO q6h||Synergistic with amphotericin B; do not use as single treatment|
|Fluconazole||50 mg/cat q12h||Suggested treatment of choice, especially for CNS infection. Good absorption without food. Monitor liver enzymes|
|Terbinafine||10 mg/kg q24h||Use if resistance to azoles|
|Surgical excision||Skin, oropharyngeal and nostril granulomas|
Free-roaming cats in rural areas are potentially more exposed to Cryptococcus, even though urban cats can be contaminated through pigeon guano. According to ecology, the presence of avian guanos, particularly pigeon droppings and some decaying vegetation substrates such as Eucalyptus leaves may be considered a risk factor (Fortes et al., 2001). A knowledge of local fungal habitats that carry the largest risks of exposure and about seasonal variations in the production of infectious propagules would be useful to develop preventive measures for both the human and animal infection.
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Tisdall PL, Martin P, Malik R (2007): Cryptic disease in a cat with painful and swollen hocks: an exercise in diagnostic reasoning and clinical decision-making. J Feline Med Surg 9, 418-423.
Trivedi SR, Sykes JE, Cannon MS, Wisner ER, Meyer W, Sturgess BK et al (2011): Clinical features and epidemiology of cryptococcosis in cats and dogs in California: 93 cases (1988-2010). J Am Vet Med Assoc 239, 357-369.
Urban CF, Lourido S, Zychlinsky A (2006): How do microbes evade neutrophil killing? Cell Microbiol 8,1687-1696.
For further reading:
Cardoso PH, Baroni FdeA, Silva EG, Nascimento DC, Martins Mdos A, Szezs W, et al (2013): Feline nasal granuloma due to Cryptococcus gattii type GII. Mycopathologia 176, 303-307.
Castrodale LJ, Gerlach RF, Preziosi DE, Frederickson P and Lockhart SR (2014): Prolonged incubation period for Cyptococcus gattii infection in cat, Alaska, USA. Emerg Infect Dis 19, 1034-1035.
Espino L, Barreiro JD, Gonzalez A, Santamarina G, Mino N and Vazquez S (2014): Intracranial epidural empyema due to Cryptococcus neoformans in a 5-year-old neutered male European short hair cat. Vet Q 28, 1-16.
Pennisi MG, Hartmann K, Lloret A, Ferrer L, Addie D, Bélak S, et al (2013): Cryptococcosis in cats. ABCD guidelines on prevention and management. J Feline Med Surg 15, 611-618.