Cryptococcosis

Edited October 28, 2015

 

 

The Cryptococcosis in cats guidelines that the present article is updating were published in J Feline Med Surg 2013; 15: 611-618; this update has been compiled by Maria Grazia Pennisi.

 

 

Cryptococcosis occurs rarely or sporadically, but Cryptococcus (C) gattii has a worldwide distribution with a high prevalence along the Pacific coast of North America. It was reported also from Brazil,47 and in Europe from Austria, Denmark, France, Germany, Greece, Italy, the Netherlands, Portugal, Spain, Sweden and the United Kingdom.2 Also C neoformans 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.1

 

Cryptococcosis caused by C neoformans or C gattii is clinically indistinguishable.

 

This disease can manifest after a long incubation period48 and presents in 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.49 CNS involvement most likely arises following local dissemination through the cribriform plate.50 Recently, otitis interna following systemic spread of the fungus was reported.34 

 

 

 

Synopsis

 

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.

 

 

Agent properties

 

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.1 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.2

 

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.3,4

 

Other species were rarely reported: C. albidus that may affect immunocompromised cats and C. magnus isolated in cats affected by otitis.5,6 

 

 

Epidemiology

 

Cryptococcosis affects humans, cats, dogs, ferrets, horses, goats, sheep, cattle, dolphins, birds, koalas, and other marsupials.1 It has a worldwide distribution and is observed more commonly in cats than in dogs.7

 

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.8 Larger retrospective studies are available from Canada, Australia and California. 7,9-13

 

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.2 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.1

 

Environmental exposure and asymptomatic colonization of the respiratory tract are more common than the clinical disease.14,15 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.10,16

 

C. neoformans ecology 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 Cryptococcus species have been associated with decaying vegetation such as Eucalyptus leaves.17 Pigeons serve as C. neoformans carriers that likely contribute to the world-wide distribution, as they carry Cryptococcus on their beaks, feathers, and legs.18 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.7 Retrospective studies of feline cases tended to show a preponderance in males, although this finding was not confirmed in other studies.7,13,19-23 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.7,12,13,20,24 In contrast with other animal species where usually young adults contract the infection, cats of all ages may be affected.7,20 No seasonal trend in the diagnosis of infection has been observed.7 Also lifestyle does not seem to be a risk factor – the disease has been reported in indoor cats, too.

 

 

Pathogenesis

 

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.10 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.25

 

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).26,27

 

 

Immunity

 

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.2,24,28

 

Some studies suggested that cryptococcosis has a higher prevalence or a less favourable outcome in FeLV- or FIV-infected cats,19,21 but this conclusion has not been shared by others.12,13,20,29,30 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.24,31 

 

 

Clinical signs

 

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.

 

Fig.1 Nasal cryptococcosis - chronic monolateral nasal discharge and mild nasal deformity. Courtesy of Maria Grazia Pennisi

Fig.1 Nasal cryptococcosis – chronic monolateral nasal discharge and mild nasal deformity. Courtesy of Maria Grazia Pennisi

 

Nasal form

 

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.7,12,20 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.

 

Fig. 2. Cryptococcal disease - severe naso-facial swelling and deformity. Courtesy of Maria Grazia Pennisi

Fig. 2. Cryptococcal disease – severe naso-facial swelling and deformity. Courtesy of Maria Grazia Pennisi

 

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.32 Proliferative or ulcerated lesions in the oral cavity or pharynx may also develop. Otitis media/interna with vestibular signs may occur.33,34 Lower respiratory tract disease may follow and its manifestation may be evident radiologically as only pulmonary or mediastinal nodules.

 

 

Fig. 3. Cryptococcal disease - ulcerated skin nodules on the face. Courtesy of Maria Grazia Pennisi

Fig. 3. Cryptococcal disease – ulcerated skin nodules on the face. Courtesy of Maria Grazia Pennisi

 

CNS form

 

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.13,35 Many cats show head or spine pain but other signs of meningeal involvement (hyperesthesia, nuchal rigidity) are not common.13 

 

 

Cutaneous form

 

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.1 The nodules are usually non pruritic and not painful, and commonly accompanied by regional lymphadenopathy.

 

Fig. 4. Cryptococcal disease - kerato-uveitis and cryptococcoma in the anterior chamber. Courtesy of Maria Grazia Pennisi

Fig. 4. Cryptococcal disease – kerato-uveitis and cryptococcoma in the anterior chamber. Courtesy of Maria Grazia Pennisi

 

Systemic form

 

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). 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.25,36 

 

Fig. 5. Thoracic radiography, ventro-dorsal view: diffuse, multiple, poorly defined nodules with blurred margins in the lung of a cat with systemic cryptococcosis. Courtesy of Maria Grazia Pennisi

Fig. 5. Thoracic radiography, ventro-dorsal view: diffuse, multiple, poorly defined nodules with blurred margins in the lung of a cat with systemic cryptococcosis. Courtesy of Maria Grazia Pennisi

 

Diagnosis

 

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.13

 

Isolation and PCR give the opportunity to identify the species and the genotype (PCR only) involved.

 

 

Antigen detection

 

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.1 In some cases, false negative results may occur.35 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.29

 

 

Cytology

 

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.37

 

Fig. 6. Diff Quick stained smear of nasal exudate from a cat with C. neoformans infection. Note the prominent capsule (clear halo) and narrow-necked budding (arrow). Photomicrograph courtesy of Richard Malik.

Fig. 6. Diff Quick stained smear of nasal exudate from a cat with C. neoformans infection. Note the prominent capsule (clear halo) and narrow-necked budding (arrow). Photomicrograph courtesy of Richard Malik.

 

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.26,27  

 

Fig. 7. Diff Quick stained smear of fine needle aspirate from a cryptococcal lesion. Note the enormous capsule surrounding the yeast cells. Photomicrograph courtesy of Mark Krockenberger

Fig. 7. Diff Quick stained smear of fine needle aspirate from a cryptococcal lesion. Note the enormous capsule surrounding the yeast cells. Photomicrograph courtesy of Mark Krockenberger

 

Histology

 

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).38 

 

Fig. 8. Early invasion of Cryptococcus gattii into the respiratory epithelium of a koala. Note the eosinophilic body surrounded by a clear halo. Photomicrograph courtesy of Mark Krockenberger.

Fig. 8. Early invasion of Cryptococcus gattii into the respiratory epithelium of a koala. Note the eosinophilic body surrounded by a clear halo. Photomicrograph courtesy of Mark Krockenberger.

27 Cryptoccosis Fig. 9

Fig. 9 Immunohistology to demonstrate Cryptococcus gattii in tissue. The agent can be conclusively identified in paraffin-embedded formalin-fixed sections using monoclonal antibodies directed against different epitopes of the capsule. Brown precipitates highlight both the yeast cell body and its capsule. Note also the narrow neck budding. Photomicrograph courtesy of Mark Krockenberger.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Culture

 

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.2

 

When samples are contaminated by bacteria as it occurs in nasal secretions, media containing antibiotics are useful.

 

 

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.39-41 

 

 

Antibody detection

 

Antibody detection is not a diagnostic tool because it cannot distinguish subclinical infection from disease.

 

 

Diagnostic imaging

 

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.13 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.42,43 MRI findings may also include meningeal enhancement, optic nerve and cribriform plate involvement.13 

 

 

Prognosis

 

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.7,11,13,29

 

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.29 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.13,43 

 

 

Disease management

 

Therapy

 

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.21,44,45 In the largest retrospective study performed on 59 cats the 68% had a successful outcome.29 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.7 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.29

 

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.29 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.1,24,43 Resistance to fluconazole was reported with some isolates that however were susceptible to other azoles.2

 

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.13,29

 

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.46

 

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.

 

 

Prevention

 

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.17 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.

 

 

References

 

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21. Jacobs GJ, Medleau L, Calvert C, Brown J (1997). Cryptococcal infection in cats: factors influencing treatment outcome, and results of sequential serum antigen titers in 35 cats. J Vet Intern Med 1997; 11:1–4.
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36. Tisdall PL, Martin P, Malik R. Cryptic disease in a cat with painful and swollen hocks: an exercise in diagnostic reasoning and clinical decision-making. J Feline Med Surg 2007; 9:418-23.
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