Cryptococcus gattii infection: Clinical features and diagnosis

INTRODUCTION — 

Cryptococcus gattii has emerged as an important fungal pathogen. Infection manifests most often as potentially fatal meningoencephalitis and/or pulmonary disease. The emergence of clusters of cryptococcosis due to C. gattii in British Columbia, Canada, in 1999, with subsequent spread to the United States Pacific Northwest, challenged our understanding of this disease. It evolved from being a disease localized predominantly in tropical and subtropical climates (eg, Australia and Papua New Guinea) to one with a more widespread geographic distribution [1,2] (see "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis"). With robust microbial testing, we now appreciate its presence as an important pathogen, especially in western states of North America and in South America. It is also clear that local (non-imported) cases occur in many regions around the world.

The clinical manifestations, complications, and diagnosis of C. gattii infection will be reviewed here. The microbiology, epidemiology, pathogenesis, and treatment of C. gattii infection are discussed separately; Cryptococcus neoformans infection is also reviewed elsewhere. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Treatment" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV" and "Cryptococcus neoformans: Pulmonary and other infections outside the central nervous system" and "Cryptococcus neoformans: Treatment and prevention of meningoencephalitis and disseminated infection in patients without HIV".)

CLINICAL MANIFESTATIONS

Incubation period — The incubation period of C. gattii infection in humans is uncertain. A study of seven travelers to Vancouver Island, British Columbia, revealed a median time to clinical presentation of six to seven months (range 2 to 11 months) [3]. A subsequent report of a traveler to British Columbia suggested a shorter incubation of six weeks [4], whereas other reports have described patients who developed infection 13 months and 36 months after exposure, respectively [5,6]. The proportion of C. gattii disease representing acute infection versus reactivation of latent infection remains unknown; however, most reported cases of C. gattii infection are likely to be primary infections.

Clinical features — C. gattii infection often presents as an indolent illness and most commonly involves the central nervous system (CNS), the lungs, or both. Neurologic infection is more common in cases of C. gattii infection that occur in endemic areas (eg, Australia), compared with the Vancouver outbreak setting, where pulmonary manifestations were more frequent. Documented outbreaks of infection since the Vancouver outbreak have been rare. As with C. neoformans, patients with HIV and C. gattii infection overwhelmingly present with meningoencephalitis (up to 97 percent of cases) [7,8].

Systemic — Systemic features of C. gattii infection including fever, chills, and weight loss were reported in 17 to 47 percent of all patients (those with and without HIV) in the North American Pacific Northwest outbreak [9,10]. Elsewhere, estimates have varied from a low of 10 percent in an Australian study published in 2012 [11] to 37 percent in Colombia (2014) [12] and 41 percent in China (2022) [13]. Notably, in an Australian study published in 2023, the proportion of patients with fever had risen to 32 percent [11].

Neurologic — Headache and neck stiffness are common neurologic symptoms at diagnosis. Other neurologic deficits that may be present, or evolve during the course of illness, include seizures, cranial nerve deficits, cerebellar abnormalities, focal limb weakness, and abnormal mentation (eg, confusion and personality change) [12-19].

Among 47 patients with culture-confirmed C. gattii infection in Australia and New Zealand in the 1990s, meningitis and/or brain involvement occurred in 30 patients (64 percent) [20]. With wider availability of cerebral computed tomography (CT) and magnetic resonance imaging (MRI), additional data revealed CNS involvement in 73 of 86 C. gattii-infected patients (85 percent: 76 percent with meningoencephalitis and 52 percent with brain infection, including cryptococcomas) [14,21] . In another analysis of 82 cases occurring from 2015 to 2019, 64 (78 percent) had CNS disease, of which 28 (34 percent) had cryptococcomas. However, in another study of 17 C. gattii-infected patients, none of the patients demonstrated cerebral cryptococcomas on MRI [13]. In Colombian patients with C. gattii infection, more than 80 percent had neurological disease [12]. By contrast, among patients affected by the outbreak in British Columbia, Canada, and the United States Pacific Northwest, CNS disease was estimated to occur in approximately 31 to 49 percent of cases [9,10,22,23]. In a large study of 257 patients from the United States and Australia, CNS infection was present in 50 percent of cases [18].

Papilledema — When papilledema is present, most commonly, optic disc swelling is seen with loss of definition of the disc margins [17]. Hemorrhagic changes around the disc accompanied by loss of visual acuity occur in severe cases. (See 'Complications' below.)

Papilledema was observed in 15 to 53 percent of cases of C. gattii infection in Australia and Papua New Guinea [14,17]. In the United States Pacific Northwest outbreak, seizures and papilledema occurred in only 8 and 6 percent of cases, respectively [9]. The frequency of papilledema was not stated in other nationwide surveys of C. gattii infection [11,13,19].

Pulmonary — Cough, dyspnea, and chest pain are the most common symptoms of lung infection, [22] although pulmonary nodules or cryptococcomas also present as asymptomatic (incidental) findings on chest radiographs. Very large lesions are typical of disease due to C. gattii [21,24]; in at least one case, involvement of the right upper lobe caused Pancoast syndrome, mimicking lung malignancy [25]. (See 'Chest imaging' below and "Superior pulmonary sulcus (Pancoast) tumors", section on 'Clinical manifestations'.)

Lung disease predominated in the outbreak of C. gattii infection in British Columbia, Canada, and the United States Pacific Northwest [9,10,22,23]. Of 218 patients with C. gattii infection in the outbreak in British Columbia, 189 (87 percent) presented with a respiratory syndrome and 22 (10 percent) also had CNS disease [22]. Isolated lung infection was present in 69 percent of patients [10]. Of patients with C. gattii infection in the United States Pacific Northwest outbreak, 31 of 57 (54 percent) presented with pneumonia, and 20 of 61 (33 percent) had lung cryptococcomas [9].

Lung infection is also common in areas outside of North America. In Australia 63 to 67 percent of cases presented with lung involvement, but occurs mostly in conjunction with CNS disease (82 percent of cases) [11,14,20]. In a study conducted in Colombia, of the 45 patients with C. gattii infection, only 6.7 percent had pulmonary cryptococcosis [12]. In a study from China, of 17 patients, 77 percent had abnormal chest imaging with 6 having lung cryptococcomas on CT scan [13].

Other features — In addition to the brain, eyes, and lungs, C. gattii can also involve the skin, soft tissues (image 1), bones, joints, bone marrow, larynx, and lymph nodes, and can be found in blood [2,14,15,18,26,27]. Intra-abdominal cryptococcosis is rare [27].

Such sites are more often culture positive in immunocompromised hosts and hence only occasionally involved in patients with C. gattii disease, most of whom are immunocompetent [15]. However, in one study, the likelihood of the involvement of blood, CNS, lungs, and other body sites was independent of host immune status [14].

Cutaneous infections can occur either in conjunction with lung and CNS infection or as primary skin disease [26,28]. Lesions typically affect the face and neck as papules, pustules, ulcers, subcutaneous masses, or cellulitis.

Comparison of C. gattii and C. neoformans infection — Certain clinical features of C. gattii infection are different from those noted with C. neoformans infection. As an example, pulmonary infection (but not CNS involvement) is much more likely to occur in disease caused by C. gattii than C. neoformans [18]. C. gattii is also significantly more likely than C. neoformans to cause large mass lesions (cryptococcomas) of the lungs and/or the brain [11,20,29,30]. Such large mass lesions, especially when occurring as single lesions, can mimic neoplastic disease or pyogenic abscesses (image 2). Although some studies have identified that focal neurological signs are more common with C. gattii infection [11,13], this may not always be the case [18]. Compared with C. neoformans infection, papilledema, seizures, focal neurologic deficits, and severe neurologic sequelae have been reported more frequently in C. gattii infections [16].

In addition to differences in clinical manifestations between C. gattii and C. neoformans infection, there are also differences in host factors. In countries endemic for this fungus, C. gattii infection largely affects immunocompetent patients rather than immunocompromised patients; the opposite is true for C. neoformans infection. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis", section on 'Hosts'.)

Complications

Elevated ICP — Elevated intracranial pressure (ICP), defined as cerebrospinal fluid (CSF) pressure >20 cm H₂0, is a common complication of meningitis due to C. gattii (occurring in 23 to 88 percent of cases [10-13]), as it is for C. neoformans (occurring in 30 to 75 percent of cases) [14,17,31,32]. Early raised ICP was a poor prognostic indicator in studies of C. gattii in Papua New Guinea [17,33]. In a study from Australia, elevated ICP was associated with abnormal neurologic findings at presentation and neurologic sequelae and/or death at 12 months [34]. These findings have been supported by clinical experience and by an illustrative case report from the United States, where adverse outcomes were seen in a patient who had severe C. gattii CNS disease with an initial CSF pressure >60 cm H₂O [35].

Manifestations of increased ICP include severe headache, morning headaches, nausea, vomiting, double vision or visual loss, hearing loss, decreasing levels of consciousness, seizures, coma, papilledema, other neurologic deficits, and death, presumably from brain ischemia. Some patients with raised ICP may be asymptomatic [17,32,34,35]. In one study, 25 percent of patients with C. gattii infection and hydrocephalus had "silent" meningitis, presenting with features of obstructive hydrocephalus with dilated ventricles on brain CT scan, and unexpected findings of meningitis on CSF examination [16]. (See 'Brain imaging' below.) Cryptococcomas due to C. gattii can cause or contribute to raised ICP or obstructive hydrocephalus via a mass effect [16,36].

Symptomatic hydrocephalus, ataxia, and deteriorating mental status in association with meningitis generally respond well to relief of pressure by insertion of a CSF shunt [16,36,37]. Factors that predispose patients with C. gattii meningitis to develop hydrocephalus remain unclear [35].

Ocular complications — Ocular complications of C. gattii infection include papilledema, visual field defects, extraocular muscle paresis, impaired pupillary and accommodative function, multifocal choroiditis, endophthalmitis, and optic atrophy [16,17]. Blindness is a debilitating sequel, thought to result from invasion of the optic nerve by cryptococci, effects of raised ICP, or from local arachnoiditis, leading to nerve infarction and cryptococcal infiltration of the choroid [32,38]. High rates (>50 percent) of visual loss have been noted in Papua New Guinea [33], but lower rates have been observed in other endemic areas [14,18,34]. In a survey from China, visual impairment was observed in 17 percent of patients [11,13]. An immune reconstitution inflammatory syndrome (IRIS)-like syndrome, which may affect visual function, is discussed below. (See 'IRIS-like syndrome' below.)

IRIS-like syndrome — Immune reconstitution inflammatory syndrome (IRIS)-like disease has been described uncommonly during treatment of C. gattii infection in immunocompetent patients [13,14,18,32,39-41]. The mechanism is thought to be due to a switch following initiation of antifungal therapy from a predominantly Th2 immune response (anti-inflammatory) to a Th1 or proinflammatory response [42,43].

Patients develop clinical deterioration, including neurologic deficits, such as visual impairment, associated with one or more inflammatory mass lesions, meningeal enhancement, hydrocephalus, new onset or enlarging CNS lesions, and/or increased inflammation in the CSF during the course of successful antifungal therapy. Appearance (or reappearance) of disease elsewhere (eg, lymph node enlargement) may be present. IRIS-like changes may occur late in disease and account for symptomatic relapse after an apparently successful antifungal induction course [39,40,44].

In an observational study that evaluated the therapy and long-term outcomes of 86 patients with C. gattii infection in Australia, an IRIS-like syndrome developed 6 weeks to 12 months after starting antifungal therapy in eight patients who presented with new or enlarging brain lesions; two of these patients were immunocompromised and one was pregnant [34]. In another retrospective multicenter study, the estimated frequency of IRIS was 7.1 percent [18]. Risk factors for the development of an IRIS-like syndrome included female sex, brain involvement at presentation, and higher median CD4 count; glucocorticoids reduced cryptococcoma-associated edema.

The management of the IRIS-like syndrome is discussed separately. (See "Cryptococcus gattii infection: Treatment", section on 'IRIS-like syndrome'.)

IMAGING

Chest imaging — Chest imaging may provide the first clues to disease, including the finding of incidental disease. In endemic areas such as Australia, the predominant pulmonary manifestations have been circumscribed cryptococcomas (image 2), both in patients with lung infection only (83 percent) and in those with combined lung and central nervous system disease (77 percent) [14,20,21]. In the British Columbia, Canada outbreak, an initial report found that 75 percent of patients had pulmonary nodules [22]. In subsequent publications of the same outbreak, pulmonary cryptococcomas, either single or multiple, were present in 66 percent of patients [10]. In one study from China, pulmonary nodules/masses were present in 65 percent of cases [45]; in another study from China, 50 percent of patients had a lung cryptococcoma [13].

Cryptococcomas range from 1 to 7 cm diameter with smooth or ill-defined edges and have no particular lobar predilection (image 2 and image 3) [21,29]. Alveolar and interstitial pulmonary infiltrates account for 14 to 17 percent of chest abnormalities [13,18]; these findings have occurred more frequently (26 to 70 percent) in immunocompromised hosts [18,20,22,46], but can also be seen in immunocompetent patients with lung cryptococcosis [47]. Pleural effusions, cavitary lesions, and lymphadenopathy are less common [11,47].

Computed tomography (CT) scans are more sensitive than chest radiographs for detecting abnormalities. Following treatment, radiographic lesions can persist for a prolonged period of time.

It is worthy of mention that lung lesions, such as large cryptococcomas, can commonly masquerade as neoplastic lesions, and may be associated with distant "metastases" [25,48]. In the Vancouver outbreak, more than 42 percent of patients had a provisional diagnosis of malignancy until the diagnosis of C. gattii infection was made [10].

Brain imaging — The global guidelines for the diagnosis and management of cryptococcosis prefer magnetic resonance imaging (MRI) as the diagnostic brain imaging modality [32]. Intracranial disease manifests on CT or MRI as single or multiple cryptococcomas, with or without contrast enhancement and edema, and hydrocephalus (image 4). The most common sites of involvement included the basal ganglia, thalamus, and cerebellum [20]. MRI is more sensitive than CT for detecting small mass lesions and showing basilar meningeal enhancement after injection of gadolinium [49]. MRI provides the most information on potential intracranial abnormalities, such as cryptococcomas, hydrocephalus (ventriculomegaly), sulcal effacement, and lacunar and cortical infarcts. Meningeal enhancement is a common abnormality and was documented in 24 and 82 percent of patients in Australian and Chinese studies, respectively [11,13].

Cryptococcomas are characteristic of C. gattii brain infection and have been observed on cranial CT scans in 33 to 58 percent of cases [11,20], and obstructive hydrocephalus has been reported in 17 to 36 percent of cases [16,18,20], but the frequency of these findings varies [10]. In addition, some patients with symptoms of raised intracranial pressure (ICP) may have imaging findings on CT that do not show dilated ventricles ("frozen brain") [35,50]. It is important to note that both CT scans and MRI may be normal [18].

DIAGNOSIS — 

Laboratory diagnosis of C. gattii infection is usually straightforward, although many microbiology laboratories in nonendemic areas do not identify Cryptococcus isolates to the species level. With the increasing awareness of the differences in clinical manifestations of C. gattii infection compared with C. neoformans, clinicians should be aware that some laboratories will report "C. neoformans" to indicate the species complex, even when the causative organism is C. gattii.

Approach to diagnosis — The approach to diagnosis of C. gattii infection is generally similar to that for C. neoformans infection. Brain and chest imaging to look for cryptococcomas is more of a priority with C. gattii than C. neoformans given the propensity of C. gattii to cause cryptococcomas (which may be asymptomatic early in the course of infection). A variety of tests are indicated for evaluating patients with possible C. gattii infection, as outlined below.

Although C. gattii commonly affects people without apparent immunocompromise, evaluation for HIV infection (by HIV antibody testing) and other general causes of immunocompromise (eg, CD4 cell count for idiopathic CD4 lymphopenia, quantitative immunoglobulin subsets) is recommended since up to 50 percent of patients in studies from the outbreak in the Pacific Northwest of North America were immunosuppressed [9,51]. In addition, there is some evidence that such infections may serve as sentinels for underlying immunodeficiency [52-54]. In particular, anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies have been detected in the plasma of immunocompetent patients with C. gattii infection [55] and in a Colombian study, 9 of 13 (69 percent) C. gattii patients had autoantibodies to GM-CSF [55,56]. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis", section on 'Hosts'.)

The following tests should be performed in patients suspected of having C. gattii meningoencephalitis (eg, patients residing or travellers to in an endemic area or an area affected by an outbreak presenting with a headache with or without neck stiffness and/or fever), pneumonia, or infection of other sites. Even in patients who are found to have infection of a site other than the central nervous system (CNS) and who do not have clinical manifestations suggestive of CNS infection, a lumbar puncture and cerebral imaging are necessary because the presence or absence of CNS disease will affect the choice of therapy.

●Funduscopic examination – All patients should undergo a funduscopic examination to evaluate for papilledema prior to undergoing lumbar puncture. (See 'Clinical features' above and "Overview and differential diagnosis of papilledema".)

●Cerebral imaging – Some patients will require cerebral imaging with a cranial computed tomography (CT) scan or magnetic resonance imaging (MRI), which is more sensitive, depending on availability and practicality prior to undergoing lumbar puncture [32]. Patients who do not require cranial imaging prior to lumbar puncture but who are found to have C. gattii infection should subsequently have either a CT with contrast or MRI to look for evidence of cryptococcomas. The indications for imaging prior to lumbar puncture are discussed in detail separately. For patients who present with altered consciousness and/or focal neurologic signs, we suggest brain MRI if possible. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Indications for CT scan before LP'.)

●CSF examination – In patients in whom meningoencephalitis is suspected, testing for the possible causes of meningitis and/or encephalitis should be undertaken. Cerebrospinal fluid (CSF) cell counts, white blood cell differential, protein, and glucose should be performed in all patients. The choice of specific tests to evaluate possible etiologies will depend upon various factors, such as host immune status, clinical presentation, geographic location, and season. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Cerebrospinal fluid examination' and "Approach to the patient with chronic meningitis" and "Approach to the patient with chronic meningitis", section on 'Diagnosis' and "Aseptic meningitis in adults" and "Viral encephalitis in adults", section on 'Diagnosis'.)

●Since a critical determinant of the outcome of cryptococcal meningoencephalitis is control of intracranial pressure (ICP) pressure, CSF opening pressure should always be measured as part of the lumbar puncture procedure, where such a procedure can be performed safely [31,32,50]. The management of raised ICP is discussed separately. (See "Cryptococcus gattii infection: Treatment", section on 'Monitoring during therapy'.)

●If C. gattii is suspected, in addition to routine CSF analysis to evaluate for other possible causes of meningoencephalitis, CSF should also be sent for cryptococcal antigen testing, India ink stain, and fungal culture as a minimum. Among these, the cryptococcal antigen test is the most sensitive, but culture provides a definitive diagnosis and differentiates between C. gattii and C. neoformans (unlike the other diagnostic tests). In patients who have no signs or symptoms of meningoencephalitis but are undergoing lumbar puncture because they have C. gattii infection of the lungs or another non-CNS site, it is appropriate to focus the CSF studies on those used to evaluate for C. gattii infection (CSF cell counts and white blood cell differential, protein, glucose, cryptococcal antigen testing, India ink stain, and fungal culture).

●Serum cryptococcal antigen – In addition to the CSF studies discussed above, we also suggest sending serum for cryptococcal antigen testing. In many cases, this test will have been sent prior to CSF analysis. In patients who are found to have a positive serum cryptococcal antigen prior to lumbar puncture, lumbar puncture is still required to determine whether CNS infection is present, to measure opening pressure, and to attempt to culture C. gattii. (See "Cryptococcus gattii infection: Treatment", section on 'Monitoring during therapy'.)

●Lung imaging – In patients suspected of having C. gattii infection, we recommend a chest radiograph and, if there is any suspicion of pulmonary involvement, a noncontrast chest CT. In those with evidence of lung involvement, we suggest fungal stain and culture of appropriate specimens (eg, bronchoalveolar lavage [BAL] fluid, sputum).

Diagnostic tests

Culture and histopathology — Almost all cases of C. gattii infection can be diagnosed by visualizing or culturing the organism and/or by a positive serum or CSF cryptococcal antigen test [2]. Since cryptococcal antigen detection does not allow identification of the species of Cryptococcus, culture is essential for definitive diagnosis. BAL fluid, fine needle aspirates, or lung biopsy sections are the preferred specimens to diagnose lung infection, but sputum may also yield C. gattii. Positive sputum cultures are indicative of invasive disease with few exceptions.

Since CNS disease is common and may present in an indolent fashion, CSF should always be examined unless there is a contraindication to lumbar puncture. Brain biopsy is sometimes performed when cryptococcomas are present, because of suspected brain abscesses or tumors. In patients with focal lesions (pulmonary cryptococcomas, mass lesions in soft tissues), aspirates and/or tissue biopsy specimens should be obtained. Blood cultures, when positive, are useful, but the yield of obtaining a positive culture from blood is not known.

Either mucicarmine or alcian blue combined with the Fontana-Masson stain is superior to any of these stains alone for visualizing cryptococci in tissue sections [2,57]. This approach is more specific than methenamine silver and calcofluor white, since it highlights both the cell wall (Fontana-Masson stain) and mucin-positive capsule (mucicarmine/alcian blue). Since the Fontana-Masson stain detects melanin, dual staining has the added advantage of being able to distinguish rare capsule-deficient strains.

India ink staining of CSF is valuable for rapid (<5 minutes) detection of encapsulated cryptococci (5-to-7-micron diameter) as a halo against a black background. CSF India ink was positive in 70 percent of patients with C. gattii meningitis in Papua New Guinea [17], in almost 95 percent of cases in Australia [14] and almost 83 percent in China [13]. Although the diagnostic sensitivity of India ink staining for C. neoformans is reportedly lower in patients without HIV than in those with AIDS [58], this has not been observed for C. gattii.

Clinical specimens may be plated onto selective media for Cryptococcus as well as on standard bacteriology agar (on which Cryptococcus spp will also grow). Methods are variable in different centers, and some laboratories (even those in areas which were affected by the original outbreak in the Pacific Northwest of North America) do not identify the organisms to the species level. Use of canavanine glycine-bromothymol blue (CGB) agar is recommended and is sufficient for distinguishing between C. gattii and C. neoformans; C. gattii colonies will turn CGB agar blue, whereas C. neoformans colonies will not change the color of the agar from its original yellow-green [57,58].

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is increasingly used to identify and distinguish between C. neoformans and C. gattii. Commercial spectral databases, when used alone, may not be able to distinguish between the two species. However, when supplemented with in-house-generated spectra of both species or with access to a validated research database, identification of species and genotypes of C. gattii is possible with careful post analytic evaluation, using both the Bruker Biotyper (Bruker Daltonics, Germany) and Vitek MS (BioMerieux, Marcy L'Etoile, France) systems [59-61].

Cryptococcal antigen

Latex agglutination or enzyme-linked immunosorbent methods — Detection of cryptococcal polysaccharide antigen in body fluids by latex agglutination or enzyme-linked immunosorbent assay (ELISA) methods has high sensitivity and specificity for the diagnosis of C. gattii infection. The sensitivity of serum cryptococcal antigen testing is 94 to 100 percent for CNS disease and 90 percent for lung disease; the sensitivity of CSF cryptococcal antigen testing is 87 to 100 percent, and specificity is 100 percent [7,14,58]. False-negative results are uncommon but may be due to a prozone effect (in which the amount of antigen in the sample is in excess of the amount of antibody in the assay; this can be overcome by sample dilution) or occasionally from low organism burden or rare capsule-deficient strains. False-positive tests are also uncommon [57]. Agreement between the two most commonly used commercial test formats, latex agglutination and enzyme-linked immunoassays (EIAs), is excellent (92 to 98 percent) [58].

Test utility for detection of cryptococcal antigen in BAL fluid is uncertain, although these specimen types have yielded positive results in C. neoformans infection.

In contrast with its diagnostic value, the utility of serum or CSF cryptococcal antigen testing in monitoring response to therapy is uncertain. Concordance between changes in titers and clinical or mycologic outcomes is often poor. Titers remain elevated for prolonged periods (months to >2 years) [10,14,32]. Cryptococcal antigen results should therefore be interpreted in conjunction with the clinical assessment.

Cryptococcal antigen testing is discussed in greater detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Cryptococcal antigen (CrAg)' and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV", section on 'Cryptococcal antigen' and "Cryptococcus neoformans: Pulmonary and other infections outside the central nervous system", section on 'Evaluation and diagnosis'.)

Lateral flow assay — A number of lateral flow assays (LFAs) for cryptococcal antigen detection have been developed as a rapid test to screen patients for cryptococcosis. The simple dipstick format of these assays uses monoclonal antibodies directed at glucuronoxylomannan to capture cryptococcal antigen of both C. neoformans and C. gattii. Data from the manufacturers and from two studies examining the performance of the first LFA (IMMY, Immuno-Mycologics, Norman, Oklahoma) on samples from patients with HIV and C. neoformans infection indicate sensitivities of 90 to 99.8 percent for serum, 96 to 100 percent for CSF, and 70 to 98 percent for urine [62,63]. LFA results showed good agreement with EIA results [62,63]. As of June 2019, the IMMY LFA test has been US Food and Drug Administration (FDA) cleared in the United States and is European Conformity (CE) marked in Europe; other LFA formats have had only limited validation with varying sensitivity and specificity [64].

The LFA is only semiquantitative. Titers obtained by this method have not yet been systematically correlated with those obtained by latex agglutination and are not comparable. Sensitivity and specificity of the LFA in the diagnosis of C. gattii infection are likely to be similar to that for C. neoformans, as indicated by two small studies in which 4 and 10 patients, respectively, with confirmed C. gattii infection, had positive LFA results [65,66]. However, although the IMMY LFA reliably detects C. gattii infection, not all commercial LFAs are able to detect disease caused by all C. gattii genotypes [67,68]. Large studies to evaluate the ability of the assay to detect different C. gattii VG types have not yet been performed.

The LFA has potential as a point-of-care test to screen patients for C. gattii infection, especially in resource-limited regions because it is simple, rapid (10 to 15 minutes), and does not require refrigeration or substantive laboratory infrastructure; costs are $1.25 to $2.50 (USD) per test. Prospective studies are needed to determine the position of the LFA as a screening tool for asymptomatic cryptococcemia.

Molecular tests — Molecular tests, such as the polymerase chain reaction test, can distinguish between C. neoformans and C. gattii but are seldom required for diagnosis [69]. However, in the uncommon event that the isolate does not grow or is seen only in histologic sections, molecular methods may be used.

Molecular techniques demonstrate good overall sensitivity in identifying C. gattii in clinical specimens [58,69-71]. Many assays, however, do not distinguish between C. gattii and C. neoformans. In one study, a real-time cyt-b gene directed assay was shown to accurately detect and reliably distinguish all C. neoformans and C. gattii genotypes in clinical specimens including from fresh frozen paraffin embedded material [72].

For patients with meningoencephalitis, a combined C. neoformans/C. gattii target has been incorporated into the commercial FilmArray meningitis/encephalitis panel (BioFire Diagnostics, Salt Lake City, Utah) for use on CSF specimens. In one study, the correlation between the results of this test and cryptococcal antigen testing was 52 percent; however, the correlation between this test and fungal smear or culture was 92 percent [73]. Other studies reported false-negative results for cryptococcal meningitis using this platform [74,75]. More extensive evaluation is required to better determine the performance of this test for cryptococcosis.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of C. gattii infection includes cryptococcal infection caused by C. neoformans as well as other infectious and noninfectious etiologies. The differential diagnosis varies depending upon the clinical manifestations and host immune status.

●Meningitis or meningoencephalitis – For patients presenting with meningitis or meningoencephalitis, the differential diagnosis is broad and includes C. neoformans, bacteria, and viruses (eg, herpes simplex, arboviruses). (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Aseptic meningitis in adults" and "Viral encephalitis in adults".)

●Mass lesions in the brain – For patients with mass lesions in the brain, the differential diagnosis includes cryptococcomas due to C. neoformans; abscesses caused by Aspergillus spp, Nocardia spp, bacteria, or Toxoplasma gondii; and brain tumors. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess" and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis" and "Epidemiology and clinical manifestations of invasive aspergillosis" and "Toxoplasmosis in patients with HIV" and "Overview of the clinical features and diagnosis of brain tumors in adults".)

●Pneumonia and/or pulmonary nodules or masses – In patients with pneumonia and/or pulmonary nodules or masses, the differential diagnosis includes other fungal pathogens (eg, C. neoformans, Aspergillus spp, Histoplasma capsulatum), bacterial causes of pneumonia (eg, Nocardia spp), and, in some cases, septic emboli, malignancy, or granulomatosis with polyangiitis [6]. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Primary pulmonary coccidioidal infection" and "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "Diagnostic evaluation of the incidental pulmonary nodule".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cryptococcosis".)

SUMMARY

●General – Cryptococcus gattii is an important fungal pathogen that is endemic in certain regions including Australia, Papua New Guinea, and South America. In the late 1990s, it caused an outbreak in British Columbia, Canada, and the United States Pacific Northwest and has since become an endemic pathogen there. Sporadic cases have been reported in many regions around the world. Infection manifests most often as potentially fatal meningoencephalitis and/or pulmonary disease. (See 'Introduction' above.)

●Clinical features – Neurologic infection is more common in cases of C. gattii infection that occur in endemic areas (eg, Australia), compared with the Vancouver outbreak setting, where pulmonary manifestations were more frequent. (See 'Clinical manifestations' above.)

●C. gattii compared with C. neoformans – Compared with Cryptococcus neoformans, C. gattii is significantly more likely to affect the lungs and to cause large mass lesions (cryptococcomas) in the lungs and/or brain. (See 'Comparison of C. gattii and C. neoformans infection' above.)

●Diagnosis – The approach to diagnosis of C. gattii infection is generally similar to that for C. neoformans infection, although imaging to look for cryptococcomas is more of a priority with C. gattii than C. neoformans given the propensity of C. gattii to cause large cryptococcomas. (See 'Diagnosis' above.)

•Approach to diagnosis – Patients suspected of having C. gattii infection (eg, patients residing in an endemic area or an area affected by an outbreak [Pacific Northwest region of North America] presenting with evidence of meningoencephalitis [a headache with or without neck stiffness and/or fever] or pneumonia) should undergo studies for C. gattii meningoencephalitis, pneumonia, and cryptococcomas of the brain and lungs. Appropriate studies include funduscopic examination, cerebral imaging, chest imaging, serum cryptococcal antigen testing, and cerebrospinal fluid examination for routine studies as well as opening pressure, cryptococcal antigen, India ink staining, and fungal culture. (See 'Approach to diagnosis' above.)

•Diagnostic tests – Special culture medium is required to identify the organism to the species level and is frequently not performed even in endemic areas. However, identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) can also provide species identification, provided species-specific reference spectra are adequately represented in the spectral database. Laboratories that do not distinguish to the species level report all isolates as C. neoformans. (See 'Diagnostic tests' above.)

•Post-diagnostic evaluation – We favor testing for underlying HIV infection and for other causes of immunodeficiency (eg, CD4 subsets and immunoglobulin subsets). (See 'Approach to diagnosis' above.)