ABSTRACT
Background: With the advances in medical care, invasive fungal
infections possess a significant health problem especially in
immunocompromised patients. These infections have varied aetiological
agents which are commonly found in soil, water, plant debris and organic
substrates. Aim: The overview of different fungal aetiological agents,
newer and rapid diagnostic modalities and overall treatment and
prevention options available is presented in this article. Methods:
Literature search was performed in PubMed by using MeSH terms
‘mycoses’ and ‘immunocompromised host’. Only relevant review articles
published within the last five years were considered. Google Scholar
search engine was also used. Results: Common invasive fungi include
Candida spp., Cryptococcus spp., Aspergillus spp., Trichosporon spp.,
Rhodotorula spp., Fusarium spp., Mucormycotina, Pheohyphomycosis
spp., Pneumocystis jirovecii, Scedosporium spp., and endemic mycoses
such as Penicillium, Histoplasma and Blastomyces. A high degree of
suspicion is required for early diagnosis and optimal management of these
infections. Conclusion: Early and rapid diagnosis of causative fungal
agents is required so that appropriate treatment can be initiated. Adequate
preventive measures must be applied in an immunocompromised host that
can prevent development of drug resistant super-infections.
2. Dash et al.: Invasive fungal infections in immuno-compromised hosts
newer immunosuppressive agents. Other
risk factors are malnutrition, severe burns,
prolonged stays in intensive care units
(ICUs), invasive medical procedures,
major surgery, advanced age, and
premature birth.[1,2]
Well known opportunists like Candida
albicans, Cryptococcus neoformans, and
Aspergillusfumigatus are being reported
for causing life threatening systemic
infections in IC hosts. New and emerging
fungal pathogens that include species of
non-albicans Candida, non-neoformans
Cryptococcus, Aspergillus other than A.
fumigatus, opportunistic yeast-like fungi
such as Trichosporon Spp., Rhodotorula
Spp., Geotrichum capitatum
(Blastoschizomyces capitatus), the
zygomycetes such as Fusarium Spp.,
Acremonium Spp., Scedosporium Spp.,
Paecilomyces Spp., Trichoderma Spp.,
and a wide variety of dematiaceous
fungi.[3,4,5]
Due to complexity of the patients at-risk
for infections and the diverse and ever
increasing array of fungal pathogens,
opportunistic mycoses pose considerable
diagnostic and therapeutic challenges.[6]
Diagnosis depends upon clinical
suspicion and the collection of
appropriate material for microscopy,
culture, histopathology, antigen detection,
molecular tests and imaging. Detection of
the infecting fungi is extremely important
for proper management of infection due to
the less common opportunistic fungi.
Some of these fungi are inherently non-susceptible
to standard azole or polyene
therapy and may require the use of
alternative anti-fungal agents.In addition,
it may also require surgical management
and reversal of underlying impairment of
host defences.[7] The overview of different
fungal etiological agents, newer and rapid
diagnostic modalities and overall
treatment and prevention options
available is presented in this article.
METHODOLOGY
Literature search was performed in
PubMed by using MeSH terms ‘mycoses’
and ‘immunocompromised host’. Only the
relevant review articles published within
last five years were considered. Also the
Google Scholar search engine was used
for the collection of articles.
Int J Infect Trop Dis 2014;1(2):87-95
88
REVIEW
Organisms
Candida spp.
Candida Spp. is currently one of the five
principal causes of nosocomial blood
stream infections, especially among
patients taking broad spectrum antibiotics
for a prolonged period, under
immunosuppressive therapy, total
parenteral nutrition, patients exposed to
multiple invasive procedures, and
prolonged hospitalization (> 30
days).[8,9]Although C. albicans is the most
common cause of invasive fungal
infections, the growing number of new
and emerging yeast infections from non-albicansCandida
species is increasingly
recognised.[5,10] These are C. tropicalis, C.
glabrata, C. parapsilosis, and rarer
isolates such as C. gullermondii, C.
pelliculosa, C. krusei, C. kefyr, C. rugosa,
C. lusitaniae, C. famata, C. norvegensis
and C. dubliniensis.[11]Candida is isolated
from 84 to 88 percent of mucocutaneous
surfaces in hospitalized patients.
Colonization and adhesion leading to
biofilm production to the mucosal surface
is the most important step in the process
of systemic candidiasis. From colonizing
Candida Spp. extracellular enzymes such
as phospholipases, proteinases and
hydrolytic enzymes contribute to host
tissue invasion.[12] Candida hyphal forms
are also able to release hydrolytic
enzymes and can specially invade
epithelial and endothelial cells.[13] Clinical
diagnosis of invasive Candida infection is
difficult, positive blood and sterile fluid
can be delayed and yield positive results
only in 50 to per cent cases of
disseminated infection.
Cryptococcus spp.
Genus Cryptococcus belongs to
basidiomycetes, which contain more than
500 species; only C. neoformans and C.
gatti are considered as principal
pathogens in IC patients. Primary
infection due to C. neoformans that
usually acquired by inhalation is common
and most of these cases are
asymptomatic in the lung. C. neoformans
can cause severe form of meningitis and
meningo-encephalitis in patients with
AIDS and corticosteroid use.[14]
Disseminated Cryptococcal infection can
cause clinical manifestations in the skin,
ocular, soft tissue and bone and joints.
3. Dash et al.: Invasive fungal infections in immuno-compromised hosts
Saprophytic non-neoformans Cryptococci
are occasionally reported especially those
with advanced stage of HIV infection
patients with cancer who are undergoing
transplant surgery.[15] These are C.
laurentii, C. albidus, C. curvadus, C.
humiculus, and C. uniguttulatus.[15] In
Cryptococcus Spp. the polysaccharide
capsule protects the organism against the
host immune system. Other pathogenic
factors include melanin production,
mannitol secretion, superoxide
dismutase, proteases and
phospholipases.[16]
Aspergillus spp.
Aspergillus is ubiquitous, thermophilic
filamentous fungi that are transmitted by
inhalation of air borne conidia. A.
fumigatus, A. flavus, A. niger and A.
terreus are commonly associated with
human infection. Risk factors to invasive
aspergillosis are neutropenia, advanced
AIDS, stem cell and organ transplant
recipients.[17] Conidial size and high
conidia count are factors that affect
virulence in Aspergillus Spp. For example
A. fumigatus, with small conidia, is the
main agent in invasive pulmonary
aspergillosis.[18] Other pathogenic factors
detected in patients with invasive
aspergillosis are sensory deprivation
(environmental pH), mutational restriction
of nutrient acquisition, siderophore, and
amino acid biosynthesis, extracellular
elastolytic proteases, gliotoxin and
hyaronic acid.[19] Clinical manifestation
can range from colonization in allergic
bronco-pulmonary aspergillosis (ABPA) to
active disseminated infection including
invasive pulmonary aspergillosis,
cutaneous and wound infection, keratitis
and aspergillus sinusitis.
Trichosporon spp.
Trichosporon genus is one of the
basidiomycetous yeast producing septate
hyphae, arthroconidia, yeasts and
pseudo-hyphae. Trichosporon Spp. can
be found in soil, fresh water, and are part
of normal flora of the human skin, and
gastrointestinal tract.[5] The risk-factors
associated with infection are malignant
haematological disease, severe burns,
AIDS, chronic corticosteroid use, and
heart valve surgery.[21]It is second most
common cause of yeast fungemia (after
Candida Spp.) in patients with malignant
haematological disease.[5] The important
species causing invasive fungal infections
Int J Infect Trop Dis 2014;1(2):87-95
89
are T. asahii, T. asteroids, T. cutaneum,
T. inkin, T. mucoides, and T. ovoides.[21]
Rhodotorula spp.
Genus Rhodotorula, a basidiomycetes
yeast which produces carotenoid
pigments (yellow to red), multilateral
budding cells, rudimentary pseudohyphae
and occasionally a faint capsule.[5]
Rhodotorula species are environmental
fungi that can be found in soil, fresh
water, fruit juice, milk, shower curtains
and tooth brushes. R. mucilaginosa is the
most common cause of fungemia,
followed by R. glutinis, and R. minuta.[21]
Patient who is undergoing bone marrow
transplant, AIDS, previous abdominal
surgery, cirrhosis, burns, and
autoimmune diseases are at-risk.[22]
Other uncommon yeasts
Geotrichum is very similar to
Trichosporon yeast.[5] It is rarely present
as bloodstream infection or disseminated
infection in immunocompromised hosts.
Presence of blastoconidia with hyphae
differentiates Trichosporon from
Geotrichum.[23]
Hansenula anomala (Pichia anomala)
yeast has been reported neonatal,
paediatric and surgical ICUs, and in IC
patients. It can cause a wide range of
invasive infections, but fungemia
especially associated with a central
venous catheter is most common.[24]
Lipophilic Malassazia furfur causes
fungemia which is related to lipid infusion
in IC patients, but the organism is less
virulent than other fungal pathogens.[25]
Fungemia in ICUs and in patients with
central venous catheter has been linked
to use of live yeast capsules
Saccharomyces cerevisiae (S. boulardii)
which are taken for prevention of
diarrhoea.[26]
Fusarium spp.
One of the most frequent septate mould
causing IFIs reported in
immunocompromised patients is due to
Fusarium Spp. Three important species
clinically identified are F. solani, F.
oxysporum, and F. verticillioidis. In IC
patients fusarium causes fungemia with
or without endocarditis, skin lesions,
sinusitis and lung disease.[27]Risk factors
for invasive fusariosis include prolonged
4. Dash et al.: Invasive fungal infections in immuno-compromised hosts
neutropenia, and T cell immunodeficiency
particularly in stem cell recipients with
severe graft versus host disease.[28]
Mucormycotina
The subphylum Mucormycotina (formerly
Zygomycetes) contains most frequently
isolated species such as Mucor,
Rhizopus, Rhizomucor, Lichtheimia
(previously known as Absidia),
Cunninghamella, Berthotella, and
Apophysomyceselegans.[29]These
opportunistic fungi produce acute rhino-cerebral
and pulmonary diseases with
thrombosis, infarction and blood vessel
invasion. Risk factors include profound
and prolonged neutropenia, chronic high
dose corticosteroid use, uncontrolled
diabetes mellitus, hypertriglyceridemia,
voriconazole prophylaxis in stem cell
transplant, tissue iron excess, and
previous skin and soft tissue trauma.[30]
Rapid growth and affinity to the blood
stream, heat tolerance, the production of
efficient proteolytic enzymes such as
lipases, proteases, glycosidic and lipolytic
extracellular enzymes, siderophore
production and an efficient iron transport
system are pathogenic factors in
members of the Zygomycetes family.[1]
Pheohyphomycosis spp.
Pheohyphomycosis consists of a group of
mycotic infections characterized by the
presence of dematiaceous (dark walled)
septate hyphae, and sometimes yeast or
a combination of both in tissue.[31] They
are responsible for subcutaneous and
systemic (especially cerebral and
pulmonary) infection in IC hosts. Agents
associated are Cladophialophora
bantiana, Bipolaris hawaiiensis,
Exserohilum rostatum, Phialophora Spp.,
Cladosporium cladosporioides, Exophiala
spinifera, and Fonsecea pedrosoi.[32,33]
Pneumocystis jirovecii
Pneumocystis is a genus of unicellular
fungi found in respiratory tract of many
mammals and humans.[34] It is most
common opportunistic infection in
persons with HIV, followed by cancer
patients receiving chemotherapy and
solid organ transplant recipients receiving
immunosuppressant.[35] Clinical
manifestations are pneumonia as well as
systemic infection involving lymph nodes,
spleen, bone marrow and liver.
Int J Infect Trop Dis 2014;1(2):87-95
90
Scedosporium spp.
Scedosporium Spp. is recently emerging
as resistant life threatening opportunistic
infection in IC hosts. The commonest
sites of infections are lungs, sinuses,
bones, joints, eyes and brain. S.
apiospermum and S. prolificans are two
medically significant species of this
genus.[36]
Endemic mycoses in
immunocompromised patients
Among endemic mycoses, genus
Penicillium, Histoplasma and
Blastomyces are common in IC patients.
Only dimorphic Penicillium species,
P.marneffei appears late in the course of
HIV infection, usually at CD4 lymphocyte
count < 100cells/cumm.[37]
Histoplsmosis caused by Histoplasma
capsulatum usually produces acute and
chronic pulmonary infections. The other
common features like fever with
hepatospleenomegaly may be
misdiagnosed as visceral leishmaniasis in
endemic areas of histoplsmosis.
Diagnosis of fungal infections in
immunocompromised hosts
As clinical manifestations of fungal
infections are non-specific, high degree of
suspicion is required for early diagnosis
and optimal management of these
infections. Conventional mycological
detection methods include direct
microscopic examination, culture of
samples, use of chromogenic agar,
biochemical analyses, germ tube
examination, histopathological
examinations using special stains.
Although conventional methods are
efficient approaches, but these routine
methods can require 48 to 72 hours or
longer arriving at definitive identification,
thus can cause considerable delay in
correct patient diagnosis and
management.
Antigen detection
Commercially available ELISA kits for
detection of fungal cell wall markers in
serum has been reported for
galactomannan (GM), mannan and 1,3-
beta-D-glucan (BDG). Galactomannan is
relatively specific for Aspergillus Spp. and
it can also be detected in urine,
bronchoalveolar lavage (BAL) fluid,
cerebrospinal fluid (CSF), and other
sterile specimens.[19] For diagnosis of
5. Dash et al.: Invasive fungal infections in immuno-compromised hosts
invasive aspergillosis it has variable
sensitivity rates ranging from 30 to 100
per cent and specificity from 38 to 98 per
cent.[38,39] Factors the sensitivity and
specificity are false positive results in
patients treated with beta-lactam
antibiotics such as piperacillin-tazobactam,
dietary GM in pasta, cereals,
and milk and cross reactivity with moulds
such as Penicillium Spp. and
Paecillomyces Spp.[40] Thus serial testing
of patient’s sample is required to achieve
acceptable sensitivity and specificity.
Mannan is found as a characteristic cell
wall component in yeasts especially
Candida Spp. The detection of circulating
Candida mannan and anti-mannan
antibodies has been used as diagnostic
marker for invasive candidiasis or
candidemia in adult IC patients with
neutropenia.[41,42] The overall sensitivity of
mannan antigen detection in patients with
candidemia has been reported to be
between 69 and 90.9 per cent and
specificity between 46.2 and 89 per cent
when compared to culture as gold
standard.[43,44]
1,3-beta-D-glucan (BDG) is present as
cell wall polysaccharide in most
pathogenic fungi including Candida Spp.,
Aspergillus Spp., Fusarium Spp.,
Trichosporon Spp., SaccharomycesSpp.,
and Acremonium Spp. and it is not
species or genus specific for each
organism. However, Mucorales,
Cryptococcus Spp. and
Blastomycesdermatidis which either lack
the glucan or produce it at minimal
levels.[45] The sensitivity has been
reported to be 50 to 100 per cent and
specificity 71 to 93 per cent.[,45,46]False
positive BDG findings occur in the
patients with fungal colonization or
mucositis who have received empirical
antifungal therapy.[47] The combined use
of BDG assay (FungitellTMAssociates of
Cape Code Inc., East Falmouth, MA,
USA) and GM enzyme immunoassay
(PlateliaAspergillusTM EIA; Bio-Rad
Laboratories, Hemel Hempstead, UK)
improves the specificity of diagnosis.
Molecular tests
Polymerase chain reaction (PCR) assay
constitutes one of the recent progresses
in identification of fungal genomics in
high-risk immunocompromised patients.
Both qualitative and quantitative PCR
Int J Infect Trop Dis 2014;1(2):87-95
91
methods are available for the detection of
fungal DNA. The nested PCR and pan-fungal
PCR have sensitivities of 92.8 and
80 per cent and specificities of 94 and
95.6 per cent respectively.[48,49] The
quantitative real-time PCR has shown the
sensitivity of 100 per cent and the
specificity of 97 per cent.[50]
Pyrosequencing is another rapid DNA
sequencing method that requires novel
chemistry to sequence pre-selected
regions of the genome to short
sequences (> 70 bp).[51] Molecular
methods are rapid (within 6 hours) that
enable diagnosis during the incubation
period, very early stage of infection and
prior to bone marrow transplantation.
Since opportunistic fungi can cause high
morbidity and mortality in IC patients, thus
serial tests and more than one method
should be employed for early diagnosis.
Radiological imaging
The radiographic patterns obtained from
X-rays, high-resolution computed
tomography (HRCT) and magnetic
resonance imaging (MRI) can be useful
for detection of both pulmonary and extra-pulmonary
IFIs with some degree of
certainty. These tests are often non-specific
and require the existence of
macroscopic lesions which are usually
occur late in the course of disease and
are markers of poor prognosis. HRCT of
chest can detect classic halo sign and
macronodules are considered as early
indicators of invasive disease.[52,53]
Treatment with antifungal drugs based on
these non-specific early CT findings have
been associated with improved
survival.[54]Serial HRCT in neutropenic
patients has shown to be more sensitive
than single test in non-neutropenic
patients.[54]
Treatment and prevention
The early and prompt initiation of
antifungal treatment is most crucial in the
outcome for the patient. It has been
reported that in Candidemia infections a
20 per cent increase in mortality if there
was more than 12 hour have elapsed in
antifungal treatment after positive blood
culture result and the mortality rate
increases significantly on each of the
following three days.[55]
The treatment of fungal infections
depends on the type of infection and its
6. Dash et al.: Invasive fungal infections in immuno-compromised hosts
etiologic agent. Also the antifungal agents
have varying spectrums of activity,
dosing, safety profiles and costs. Broadly,
the systemic antifungal agents have
grouped into azoles (i.e., fluconazole,
voriconazole), polyenes (i.e.,
amphotericin B deoxycholate,
amphotericin lipid formulations and
liposomal amphotericin B) and
echinocandins (i.e., caspofungin,
micafungin and anidulafungin).[56] The
echinocandins exhibit potent in vitro and
in vivo fungicidal activity against Candida
species, including azole-resistant
pathogens and are approved for the
treatment of oesophageal candidiasis,
Candidemia and other select forms of
invasive candidiasis.[57]
To improve outcomes for patients with
invasive fungal infections, complimenting
strategies such as immunomodulators
and combination therapies can be
used.[28] Adjunctive interferon gamma
could be suggested for refractory
cryptococcosis.[28] Combination therapy is
highly recommended for candida
endocarditis, cryptococcal meningitis and
other difficult to treat cases.[5]
To prevent infection in IC patients,
exposure to fungal spores must be limited
with high-efficiency particulate air filters
and positive pressure ventilation in the
patient’s room. Also high-risk patients
should avoid contact with soil, tap water
and shower facilities.[58] Decreasing the
duration of neutropenia or discontinuing
immunosuppressive agents should be
considered in efforts to prevent infection.
Adequate information about susceptibility
pattern of current fungi that are prevalent
in a particular area should be available.
Routine monitoring of serum
concentrations of antifungal agents are
required to know the efficacy and toxicity
of antifungals by using high performance
liquid chromatography and bioassay
methods. This may also prevent the
development of drug resistance.
Antifungal prophylaxis is recommended
for high-risk patients undergoing
pancreas, liver, and small bowel
transplantations, for chemotherapy
induced neutropenic patients,
haemopoitic stem cell transplantation
recipients with neutropenia and adults
admitted in ICUs who are at risk for
developing candidiasis.[5]
Int J Infect Trop Dis 2014;1(2):87-95
92
CONCLUSION
The best approach to optimal
management of fungal infection in IC
patients is early detection and
identification of causative fungus, so that
appropriate treatment can be initiated as
soon as possible. Regular surveillance
testing combined with clinical and
radiological information is required to
arrive at early diagnosis. The message to
both clinicians and clinical microbiologists
is that there are no uniformly non-pathogenic
fungi.[6] Any fungus can cause
a lethal infection in an IC host,[6] and
should never be rejected as a
contaminant provided they are detected
from sterile specimen in sterile condition.
Broad and injudicious use of any anti-infective
agent in a severely IC host may
result in superinfections due to organisms
that are both unusual and drug
resistant.[7,59]
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doi: http://dx.doi.org/10.14194/ijitd.1.2.6
How to cite this article: Dash M,
Chayani N, Sarangi G. An overview of
invasive fungal infections in immuno-compromised
hosts. Int J Infect Trop
Dis 2014;1(2):87-95.
Conflict of Interest: None declared
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