Clinica Chimica Acta 524 (2022) 78–83

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Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/cca

Comparison of laboratory diagnosis, clinical manifestation, and

management of pulmonary cryptococcosis: Report of the clinical scenario
and literature review
Po-Jen Hsiao a, b, c, 1, 2, *, Han Cheng d, 1, Yung-Hsi Kao c, 2, Yuan-Hung Wang d, e,
Chih-Chiun Chiu f, g, Wen-Fang Chiang a, b, Chih-Chun Kuo h, Chih-Pin Chuu i, j, 2, Kuo-An Wu k, 2
a
Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
b
Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
c
Department of Life Sciences, National Central University, Taoyuan, Taiwan
d
Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
e
Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
f
Division of Infectious Disease, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
g
Division of Infectious Disease and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
h
Division of Metabolism and Endocrinology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
i
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan
j
Graduate Program for Aging, China Medical University, Taichung, Taiwan
k
Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan

A R T I C L E I N F O A B S T R A C T

Keywords Background: Pulmonary cryptococcosis is an opportunistic aggressive mycosis in immunocompromised patients,

Cryptococcus neoformans but it can be increasingly seen in immunocompetent patients. It is still challenging to make a rapid and accurate
Pulmonary cryptococcosis diagnosis due to the various clinical manifestations and limitations in the diagnostic tools.
Cryptococcal infection
Method: A 54-year-old man presented with intermittent productive cough and fever for 1 week. A chest X-ray
Cryptococcal antigen
demonstrated multiple consolidations in both lungs. Blood biochemistry indicated elevated immunoglobulin G
Hypersensitivity pneumonitis
Immunoglobulin G levels. Including sputum cultures, polymerase chain reaction (PCR) tests for severe acute respiratory syndrome
coronavirus 2, influenza A and B virus were all negative. Computed tomography of the chest showed ground-
glass opacities with a nodular pattern. The serum cryptococcal antigen test was positive; however, the cere­
bral spinal fluid was negative. The diagnosis of pulmonary cryptococcal infection was made. An initial bron­
choscopy was performed unsuccessfully and the patient received intravenous fluconazole therapy for 2 weeks.
Due to poor improvement of clinical condition, he then underwent a surgical lung biopsy. The pathology
revealed several encapsulated yeast cells, diffuse pulmonary interstitial fibrosis, noncaseating granulomas sur­
rounded by T lymphocytes and multinucleated giant cells with intracellular inclusions, confirming pulmonary
yeast infection associated with hypersensitivity pneumonitis. Ultimately, fungal cultures of the pathology sam­
ples revealed Cryptococcus neoformans. Subsequently antifungal therapy combined with oral steroid treatment,
his general condition improved. After a total of 6 months of antifungal therapy, the patient recovered completely.
Conclusions: Applicable laboratory diagnosis can help facilitate the accurate and rapid diagnosis of pulmonary
cryptococcosis. This report elected to provide an update on the topic of laboratory diagnosis, clinical manifes­
tation, and management of pulmonary cryptococcosis.

* Corresponding author at: Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taiwan, No.168, Zhongxing Rd.,
Longtan Dist., Taoyuan City 325, Taiwan, R.O.C.
E-mail addresses: [email protected], [email protected] (P.-J. Hsiao).
1
These authors contributed equally to this work (co-first author).
2
These authors also contributed equally to this work (co-corresponding author).

https://doi.org/10.1016/j.cca.2021.11.017
Received 11 July 2021; Received in revised form 4 October 2021; Accepted 17 November 2021
Available online 27 November 2021
0009-8981/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
P.-J. Hsiao et al. Clinica Chimica Acta 524 (2022) 78–83

1. Introduction Table 1
Blood biochemistry data.
The incidence and severity of fungal infections have increased Parameters Normal value
because of the human immunodeficiency virus (HIV)/acquired immu­ 3
White blood cell (10 /ul) 8.96 4.8–10.8
nodeficiency syndrome epidemic, as well as the recent increase in the Hemoglobin (g/dL) 11.8 12–16
use of immunosuppressive therapy. In addition to widespread bacterial Platelet (103/mm) 298 130–400
or viral microorganisms, there are far more pathogens with clinical BUN (mg/dL) 20.5 6–20
relevance implicated in these diseases, but their role is not yet fully Creatinine (mg/dL) 1.22 0.5–0.9
Sodium (mmol/L) 136 136–145
elucidated. Actually, pulmonary fungal infections have been reported to Potassium (mmol/L) 3.6 3.5–5.1
be accompanied with coronavirus disease 2019 (COVID-19) infections, GPT (IU/L) 12.4 0–41
indicating a fungus may be the next cause of a pandemic after corona­ Total calcium (mg/dL) 8.8 8.5–10.3
virus COVID-19 [1–3]. Cryptococcal infection is common in immuno­ Albumin (g/dL) 3.25 3.5–5.2
BNP (pg/mL) 92
suppressed individuals and relatively rare in the immunocompetent <100
IgA (mg/dL) 367 70–400
population [2–4]. There are over 30 species of Cryptococcus but just two IgE (IU/mL) 65 <85
organisms – Cryptococcus neoformans (C. neoformans) and Cryptococcus IgG (mg/dL) 1904 700–1600
gattii (C. gattii) commonly affect animals and humans. As a result, both IgM (mg/dL) 158 40–230
species are accountable for most clinical cases. C. neoformans is an C3 (mg/dL) 127 80–170
C4 (mg/dL) 33.7 13–44
opportunistic pathogen and primarily affects immunosuppressed peo­ Anti-ds DNA (IU/ml) 1 <4 (negative)
ple; however, this does not appear to be the case for C. gattii in humans, ANCA 20 X <20 X (negative)
or for either organism in animals [4]. Pulmonary cryptococcal infection ANA 40 X <40 X (negative)
is acquired via inhalation of spores and occurs predominantly in Abbreviation: BUN: blood urea nitrogen, BNP: brain-type natriuretic peptide,
immunosuppressed individuals. Cryptococcal antigen (CrAg) levels and GPT: glutamate pyruvate transaminase, IgA: Immunoglobulin A, IgE: Immuno­
fungal cultures are important for the diagnosis of fungal infection [5,6]. globulin E, IgG: Immunoglobulin G, IgM: Immunoglobulin M, C3: complement 3,
However, as diagnostic methods, fungal culture and microscopy have C4: complement 4, Anti-ds DNA: Anti-double stranded DNA, ANCA: Anti-
long turnaround times, which can delay the timely implementation of neutrophil cytoplasmic antibody, ANA: Antinuclear antibody.
antifungal therapy and cause poor outcomes; therefore, it is challenging
to make a rapid diagnosis of pulmonary cryptococcosis due to the We attempted to perform bronchoscopy with bronchoalveolar lavage
various clinical manifestations [2–7]. Pulmonary cryptococcosis may (BAL), but this procedure was unsuccessful due to the shortness of
disseminate and further cause life-threatening complications. In breath in this patient. Video-assisted thoracic surgery with lung biopsy
immunocompetent patients, pulmonary cryptococcosis can spread from was then performed, and pathology revealed several encapsulated yeasts
the lung to the central nervous system (CNS) causing cryptococcal (Fig. 1b, arrowhead), multinucleated giant phagocytic cells containing
meningitis [2–7]. Schaumann bodies (Fig. 1b, red arrows), diffuse pulmonary interstitial
There is accumulating evidence that bacterial, viral, or fungal fibrosis and multiple noncaseating granulomas surrounded by mature T
microbiota in the lungs may predict the susceptibility of further airway lymphocytes, indicating a yeast infection complicated hypersensitivity
infections, such as pneumonia, and contribute to the severity of various pneumonitis [3,7,8]. Supplementary oral prednisone (20 mg, daily) was
types of respiratory diseases including chronic obstructive asthma and prescribed, and a resolution of the chest X-ray appearance was noted at
chronic obstructive pulmonary diseases. Hypersensitivity pneumonitis the one-week follow-up. The fungal culture grew C. neoformans, and the
usually occurs after the inhalation of certain allergens, such as animal or diagnosis of pulmonary C. neoformans infection complicated by hyper­
plant proteins, microbes, certain chemicals, and haptens. Hypersensi­ sensitivity pneumonitis was finally made. After a total of 6 months of
tivity pneumonitis is generally induced by an immunopathologic reac­ antifungal therapy, the patient recovered completely. No recurrence was
tion to inhaled antigens, producing interstitial lung disease with an noted at the one-year follow-up.
unclear pathogenesis. Antigen exposure results in the early formation of
type III immune complexes, followed by type IV delayed hypersensi­ 3. Discussion
tivity [4,8,9]. We presented a case of pulmonary cryptococcosis
concomitant hypersensitivity pneumonitis and intended to review the Fungi are ubiquitous in the environment and occur as commensals in
topic focused on laboratory diagnosis and management in these patients. the flora of mucosal surfaces of mammalian tissues. Fungal infections,
nevertheless, can cause severe morbidity and mortality, particularly in
2. A clinical scenario critically ill patients and immunocompromised patients. Cryptococcosis
is an infectious disease caused by pathogenic encapsulated yeast, and it
A 54-year-old man presented with intermittent productive cough and has a global distribution with various clinical presentations. Cryptococci
fever for 1 week without the use of immunosuppressants. His family are ubiquitous free-living encapsulated saprophytic yeast. There are two
history was unremarkable, and he had no history of contact with pigeon species that are pathogenic to humans: C. neoformans and C. gattii.
excrement or travel. Physical examinations revealed a febrile status and C. neoformans is naturally found in soil contaminated with bird drop­
diffuse rhonchi in the lungs. The polymerase chain reaction (PCR) test pings, heartwood and in the homes of HIV-infected persons; it causes the
for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was majority of opportunistic infections in the CNS of immunocompromised
negative. Blood laboratory analysis showed elevated C-reactive protein patients. C. gattii infection predominantly occurs in immunocompetent
and immunoglobulin G levels, whereas other markers were within patients [9–11].
normal limits (Table 1). A chest X-ray demonstrated multiple consoli­
dations in both lungs and multiple nodular patterns. High-resolution
computed tomography (HRCT) of the chest revealed ground-glass 3.1. Identification and epidemiology of Cryptococcus
opacities with a nodular pattern (Fig. 1a). Sputum cultures, screening
for influenza A and B virus, serum autoimmune antibody, and HIV tests Cryptococcal infection has been described in many species of mar­
were all negative. His serum CrAg test was positive, with a titre of supials and mammals. Clinical cases have also been reported in most
1:1024, but the cerebral spinal fluid (CSF) was negative. Antifungal other species of domesticated animals, including ferrets, dogs, horses,
therapy with 400 mg of intravenous fluconazole was administered daily guinea pigs, donkeys, sheep, cattle, pigs, water buffalo, goats and South
for 2 weeks, but his clinical condition showed little improvement. American camelids (llamas, alpacas and vicunas). The variety of affected

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Fig. 1. (a) HRCT revealed multiple patchy consolidations containing air-bronchograms. (b) Several encapsulated yeasts (arrow head) and multinucleated giant cells
processing phagocytosis (arrow) in Hematoxylin & Eosin stain, 400X.

species suggests that most marsupials and mammals might be suscep­ NaCl at 4 ◦ C, 15–20% NaCl at room temperature or distilled water at
tible. Asymptomatic colonization of the nares has been described in 4 ◦ C. Both C. gattii and C. neoformans have been associated infrequently
dogs, cats, horses, koalas and wild squirrels, but whether this was caused with insects (e.g., insect frass and a wasp nest). Fomites and environ­
by environmental exposure or colonization is still unknown. mental contamination from infected people or animals might be
C. neoformans can temporarily colonize the intestinal tract of some avian responsible for disseminating infections from endemic foci (e.g., the area
species [3,4,12]. It can also be found in the guano of asymptomatic affected by C. gattii in the Pacific Northwest). Cryptococcus spp. that are
birds, either because it was shed from the bird or because the droppings uncommon pathogens, such as C. laurentii or C. albidus, can be found in
provided the nutrients for organisms to proliferate. C. gattii has also been various environments, including in plants, food, soil, and avian guano.
isolated occasionally from cloacal swabs or bird droppings. Cryptococcal C. albidus is a prevalent saprophyte in the soil [4,14].
infection seems to be very unusual in pigeons and poultry, despite the
exposure of pigeons to massive quantities of C. neoformans. A few cases
3.2. Diagnosis of pulmonary cryptococcosis
of cryptococcosis have been described in reptiles, including snakes and
lizards [3,4,12].
Given the complexities surrounding the identification of pulmonary
Humans can be infected by both C. gattii and C. neoformans. These
cryptococcosis, the accurate diagnosis of pulmonary cryptococcosis is
organisms are thought to be acquired from the environment rather than
generally based on the combination of clinical and radiological suspi­
from affected hosts. C. neoformans infections are occasionally associated
cion and laboratory confirmation. The laboratory diagnostic tests used
with exposure to guano, especially that of pigeons. Cases have rarely
to confirm the cryptococcal infection include fungal culture, direct
been linked to contact with droppings from pet birds. Many people with
microscopic examination, histopathology, serology, and molecular
C. neoformans infection have no history of contact with birds [3,4,12].
detection [10]. The conventional laboratory diagnosis is usually made
Both C. gattii and C. neoformans are abundant in decaying material
via the isolation of Cryptococcus from a clinical specimen or direct
within hollows of various tree species, although C. gattii has been sug­
microscopic examination of the fungus by means of India ink staining of
gested to favour trees with waxier cuticles (such as the Douglas fir
body fluids [4]. The turnaround time using conventional culture me­
Pseudotsuga menziesii) [13]. C. gattii was initially thought to be limited
dium (Mycosel agar or Sabouraud Dextrose Agar; BD Diagnostic Sys­
to tropical and subtropical areas, however, it has also been identified in
tems) is usually more than 1 week. India ink staining is not a suitable
temperate regions. C. neoformans occurs worldwide. In Europe, C. gattii
tool for the diagnosis of invasive cryptococcal disease due to its low
is common in the Mediterranean region, but a few clinical cases have
(86%) sensitivity and the high fungal burden in CSF or deep-tissue bi­
been described in colder areas. C. gattii and C. neoformans appear to
opsies. However, direct microscopic examination of clinical samples,
occupy different environmental niches. C. neoformans is strongly asso­
histopathology, and culture may rely on the experience of personnel,
ciated with droppings from birds. This organism can be found in cloacal
and their widespread use in resource-limited settings is limited [4,7]. A
or faecal samples from a variety of avian species, but pigeon guano is
new fungal culture medium was developed from birdseed (Guizotia
thought to be the most important niche. Pigeon guano allows
abyssinica) agar for the detection and rapid identification of
C. neoformans to proliferate extensively, especially when droppings are
C. neoformans, and this medium decreases the detection time of most
protected from sunlight in roosts or lofts. Pigeon guano also seems to
strains from approximately several days to 72 h [7]. Isolating a positive
support the mating of both C. neoformans var. neoformans and
culture of Cryptococcus from BAL or pleural fluid, accompanied by the
C. neoformans var. grubii. C. neoformans can remain viable for 2 years or
clinical symptoms and/or radiology findings are the key diagnostic
more in desiccated or fresh pigeon faeces. Droppings from other birds,
approaches.
including canaries and parrots, can support the growth of cryptococcal
The capsular polysaccharides of Cryptococcus can be detected and
yeasts, but whether they can support mating is still unclear [4,13,14].
quantified from body fluids such as serum, CSF, BAL fluid, and urine.
C. gattii and C. neoformans can also be found in other environments,
Both the latex agglutination test (LAT) and the lateral flow immunoassay
where they may survive for long periods. C. neoformans has been
(LFA) are commonly used in clinical practice [6]. Serum CrAg tests and
recovered from a wide range of contaminated objects. For instance,
blood cultures are rarely positive only if there is associated with
C. neoformans has been isolated from peach juice. C. gattii has been
disseminated cryptococcal infection. Use of the lysis centrifugation of
detected in saltwater and freshwater samples, which may become
buffy coat from blood may increase the detection. Once the diagnosis of
contaminated from soil runoff. Additionally, C. gattii has been reported
pulmonary cryptococcosis is made or with high clinical suspicion, the
to survive in ocean water or distilled water at room temperature for
procedure of lumbar puncture and CSF examination (including CrAg
more than 12 months. No viable cells were found after 12 weeks in 10%
tests) should be performed in these patients.

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Serum CrAg tests can facilitate the early detection of cryptococcosis. differentiation of Cryptococcus species. Previous studies demonstrated
The evolution of CrAg testing in the development of inexpensive and that CGB test is inferior to PCR in distinguishing species of Cryptococcus
highly sensitive methods to detect cryptococcal antigens is significant. in 4.58% of samples. Furthermore, CGB may provide a rapid identifi­
Consequently, there has been an increased emphasis on methods for cation and identify mating-type profiles via amplification of the STE
antigen detection for the diagnosis of cryptococcosis, especially those gene sequences [10]. In patients with pulmonary cryptococcal infection,
that do not require a complex laboratory setup and have the potential to respiratory samples processed with multiplex real-time PCR revealed
detect disease early, reducing the time to diagnosis [7]. The serum CrAg 90.7% sensitivity and 100% specificity to detect C. neoformans. PCR may
test has high sensitivity and specificity for cryptococcal CNS infections, also help to separate the diverse species of Cryptococcus spp. by means of
and false-negative results are usually associated with pulmonary cryp­ the target genes of STR1F and STR1R [10]. Matrix-assisted laser
tococcosis, likely because of the low fungal burden outside the lung or desorption/ionization time-of-flight mass spectrometry (MALDI-
the presence of a capsule-deficient strain of Cryptococcus. Nonetheless, TOFMS) is another and new tool for pathogen identification. It can
false-positive results can occur under various conditions, such as in the distinguish the obtained Cryptococcus into varieties rapidly and pre­
presence of rheumatoid factors or infections by Trichosporon beigelii, cisely, such as C. neoformans var. grubii [17,18]. However, the applica­
Klebsiella pneumonia, Capnocytophaga canimorsus or Stomatococcus tion of MALDI-TOFMS is not widely available in the clinical practice
mucilaginosus. The median titer of serum CrAg produced by pulmonary because of its cost, especially at the area of high prevalence of crypto­
cryptococcal infections is 1:16 in immunocompetent patients and 1:32 coccosis, as well as of low social-economic state.
in patients in an immunocompromised state [11]. After 1 year follow-
up, the serum CrAg titers were found to decrease slowly from greater
than 1:32 to negative during the maintenance period of antifungal 3.3. Clinical characteristics and complications of pulmonary
therapy in most (76%) immunocompetent patients with pulmonary cryptococcosis
cryptococcosis. Although positive results are often found in immuno­
compromised hosts with C. neoformans pneumonia, antigen detection is The symptoms of pulmonary cryptococcosis vary from a nonspecific
not a sensitive test for the diagnosis of pulmonary infection in immu­ cough alone to more significant symptoms that can include pleuritic
nocompetent patients [10,11]. Moreover, a decrease in serum CrAg ti­ chest pain, haemoptysis or dyspnoea. Other signs and symptoms may
ters has been found in untreated patients, even though CrAg rarely include weight loss, malaise and anorexia [10,11]. Pleural effusions can
becomes negative. Indeed, serum CrAg may persist for several months occur but are rare, and acute respiratory distress syndrome has been
after successful treatment. Consequently, the serum CrAg titer cannot be reported. Progressive pulmonary disease and serious respiratory syn­
considered a prognostic tool or useful for assessing the response to dromes are more likely to occur in immunocompromised patients. Many
treatment for pulmonary cryptococcal infection [10]. CSF examination infections in healthy patients may be self-limited [10,11]. Most exposed
(including CrAg titers) is recommended for patients with pulmonary individuals develop immune tolerance, and antigen inhalation may
cryptococcosis [10,11,15]. A comparison of the sensitivity/specificity result in a mild increase in local lymphocytes, without clinical conse­
with respect to laboratory diagnostic tools for CSF in patients with CNS quences. Although a potent immune response to Cryptococcus spp. is
cryptococcal infections is shown in Fig. 2 [11,15,16]. essential for fungal clearance, too strong a response can also be harmful.
The molecular diagnosis of cryptococcal infection is required under An immunologic reaction to an inhaled agent, particularly an organic
specific conditions where other diagnostic tests fail to produce a diag­ antigen, occurs within the pulmonary parenchyma [13,19]. The devel­
nosis of cryptococcosis. One such situation is a positive histological opment of an exaggerated immune reaction results in marked lung
examination but negative culture. Molecular tests for detection of inflammation with immune complex formation and an influx of neu­
Cryptococcus include multiplex PCR, deoxyribonucleic acid (DNA) trophils [19,20].
sequencing for identification, pan-fungal PCR, probe-based microarrays, The consequences of infection with C. gattii or C. neoformans range
and isothermal amplification methods [10]. Canavanine-glycine- from asymptomatic colonization of the airways to respiratory signs of
bromothymol blue (CGB) test is a conventional method for variable severity or disseminated infections that may involve the eye,
skin, CNS and other organs. While there appear to be some differences

Fig. 2. The comparison of sensitivity and specificity of cryptococcal diagnostic assays in patients with suspected meningitis. CrAg: cryptococcal antigen; CSF: ce­
rebrospinal fluid; LFA: lateral flow immunochromatographic assay. †Two quantitative CSF culture procedures were used in 10 μl input volume of CSF and 100 μl
input volume of CSF. ‡ Immy, Inc., Norman, OK, USA.

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between the syndromes caused by C. gattii and C. neoformans, both optic neuritis and chorioretinitis. Ocular signs, including vision loss, can
species can affect any organ. In immunosuppressed hosts, C. neoformans also be triggered by intracranial hypertension from CNS disease
may cause little inflammation, and the symptoms can be mild even with [2,10,11]. The spread of organisms to the skin can result in a variety of
widespread disease [10,11]. Only a small percentage of the people lesions, which may mimic other diseases. Papules, which may ulcerate
exposed to either organism become ill. In most patients, Cryptococcus or develop to other forms, are often seen at first. Other reported lesions
spp. enter the body via the respiratory tract and replicate first in the include vesicles, pustules, ulcers, bullae, superficial granulomas,
lungs. Many pulmonary infections are asymptomatic in both immuno­ palpable purpura, plaques, tumour-like masses, abscesses, cellulitis or
suppressed and immunocompetent hosts, although lesions may be sinus tracts, and even rare cases of necrotizing fasciitis [9–11]. Cuta­
obvious on X-ray [21–23]. Pulmonary cryptococcosis exhibits a variety neous involvement often occurs concurrently with cryptococcosis in the
of imaging manifestations ranging from nodules to mass-like lesions, brain or other organs. Less frequent syndromes include septic arthritis,
including single or multiple pulmonary nodules, a reticulonodular osteomyelitis, lymphadenitis, myocarditis, peritonitis, hepatitis,
pattern of opacities or segmental consolidation, lymphadenopathy, gastrointestinal involvement, abdominal cryptococcomas, prostatitis,
cavitation and pleural effusion. Pulmonary cryptococcosis can occur in renal abscesses, endocarditis, myositis and septic shock [2,6,9–11].
patients with other lung diseases. Thus, it is sometimes difficult to
establish an accurate and rapid diagnosis of fungal infection based on 3.4. Genetic analysis and functional analysis of cryptococcosis
these radiographic findings [21–23].
Hypersensitivity pneumonitis, also known as extrinsic allergic Cryptococcosis, a mycosis presenting commonly as meningoen­
alveolitis, is a complex syndrome caused by repeated inhalation and cephalitis, affecting mainly patients with HIV, is mainly caused
sensitization to a wide variety of aerosolized antigens. Hypersensitivity by C. neoformans. The mating type of the isolates can be assessed by PCR,
pneumonitis usually overlaps with other lung diseases, which are and the serotype by agglutination and CAP59-restriction fragment
characterized by a variety of clinical manifestations. Therefore, clini­ length polymorphism (RFLP). Genetic diversity can also be determined
cians need a high degree of clinical suspicion to diagnose hypersensi­ by URA5-RFLP, PCR-fingerprinting, amplified fragment length poly­
tivity pneumonitis accurately. The pathophysiology of hypersensitivity morphism (AFLP), and multilocus sequence typing (MLST) [27]. A
pneumonitis may be associated with malfunction of regulatory T cells recent epidemiologic study in Lima demonstrated that the cryptococcal
[24]. The histopathologic process usually involves peribronchiolar population from the HIV-positive patients showed a low degree of ge­
change, interstitial cellular infiltration, poorly formed non-necrotizing netic diversity. In most patients with persistent cryptococcal infection,
granulomas or interstitial giant cells and Schaumann bodies [25]. Pul­ the same genotype was recovered during the follow-up [27]. The
monary parenchyma inflammation appears to be mainly mediated by a capsule of C. neoformans includes of mannoproteins, glucuronox­
type 3 response in acute hypersensitivity pneumonitis, as suggested by ylomannogalactan, and glucuronoxylomannan. Mannoproteins are a
the high titers of serum IgG and accumulation of neutrophils in the lung. kind of glycoproteins with low content but high immunogenicity,
Subacute or chronic hypersensitivity pneumonitis is characterized by further stimulating the immune protection of the host [28]. To the best
the development of characteristic T lymphocytic alveolitis and a T cell- of our knowledge, it is still not well-known about the role of man­
mediated immune response with increased T cell migration. The sensi­ noproteins in virulence of the human fungal pathogen C. neoformans. A
tivity and specificity of serum IgG antibodies vary based on the duration recent genetic study recommended that the identification and functional
and frequency of exposure, the particular antigen, the stage of the dis­ analysis of a predicted mannoprotein Cmp1 could regulate fungal
ease, and cigarette smoking. Previous human studies have confirmed virulence in C. neoformans [28].
that IgG concentrations in BAL fluid are significantly higher in hyper­
sensitivity pneumonitis patients than in healthy subjects. Overall, BAL is 3.5. Treatment of pulmonary cryptococcosis
a sensitive tool for detecting alveolitis and should be performed in pa­
tients suspected of having hypersensitivity pneumonitis [24–26]. For Completely preventing exposure is probably impossible. In some
example in our patient, the definitive diagnosis of pulmonary crypto­ situations, it might be possible to reduce the level of exposure from some
coccosis complicated by hypersensitivity pneumonitis can be made environmental sources, including pigeon droppings, trees during log­
based on serology, fungal cultures, and histopathological findings. Hy­ ging and cutting, soil disturbances, and eucalyptus trees in blooms. The
persensitivity pneumonitis may be induced by many allergens, including removal of guano should be preceded by chemical decontamination or
pulmonary cryptococcal infection. Experienced clinicians should sus­ moistening with water or oil to reduce aerosolization [12–14].
pect pulmonary fungal infections with hypersensitivity pneumonitis. The successful management of pulmonary cryptococcal infection
In HIV patients, pulmonary cryptococcosis may cause more CNS based on the host’s immunological status, along with the severity of the
involvements. CNS disease is the most common form of disseminated disease and whether it has spread to the CNS, is present as a localized
cryptococcosis. The typical syndromes are subacute or chronic menin­ condition in the lung, or is generally disseminated to the other organs.
goencephalitis and meningitis or cryptococcomas in the brain. The Including the blood cultures, CSF inspections via lumbar puncture in­
development of the illness is often insidious, with early signs such as vestigations, and serum CrAg tests should be carried out for both
fatigue, headache, and changes in behavior or drowsiness. [2,4,10,18]. immunocompetent and immunocompromised patients with pulmonary
Persistent headache is a common presentation, and neck stiffness is often cryptococcal infection [10,11,15]. Fluconazole is the treatment of
minimal or absent. Body temperature can be normal or only slightly choice for pulmonary cryptococcosis without involvement of the CNS,
elevated. Other signs, including vomiting, seizures, abnormalities in especially in immunocompetent hosts [10]. It is recommended that
vision, paralysis and impaired consciousness, can develop with disease immunocompetent patients in either an asymptomatic or a symptomatic
progression. Cranial nerve paralysis is not rare. Cryptococcomas may state take 400 mg/day of fluconazole orally for 6 to 12 months. Oral
cause focal signs such as cerebellar syndrome, paresis and aphasia, voriconazole or itraconazole (200 mg) twice daily may be used as re­
especially in immunocompetent patients. Increased CSF pressure from placements if fluconazole is not available or contraindicated [15]. A
chronic meningoencephalitis or cryptococcomas can cause hydroceph­ recent study demonstrated a mean fluconazole resistance of 10.6% in
alus and further neurological signs, including dementia. Other syn­ HIV-infected patients [29]. Accordingly, there is an urgent need for new
dromes, including ischaemic stroke or spinal cord lesions, have also been antifungals to counter cryptococcal resistance. Thioridazine and amio­
observed. Untreated infections in the brain are eventually lethal. These darone appear to actively kill phagocytosed C. neoformans in the lungs,
infections may be rapidly lethal in some immunocompromised in­ which is known as a site that is inaccessible to amphotericin B and flu­
dividuals [2,4,10,11]. The eye is also a common site of dissemination of conazole [10]. Increasing evidence suggests the effectiveness of corti­
cryptococcal infection, resulting in lesions such as endophthalmitis, costeroids in acute hypersensitivity pneumonitis. To date, there are no

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invasive candidiasis, aspergillosis, cryptococcosis, and Pneumocystis pneumonia,
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