Brown Fungal Infections Killers

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Hidden Killers: Human Fungal Infections
Gordon D. Brown et al.
Sci Transl Med 4, 165rv13 (2012);
DOI: 10.1126/scitranslmed.3004404

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Science Translational Medicine (print ISSN
1946-6234; online ISSN 1946-6242) is
published weekly, except the last week in
December, by the American Association for the
Advancement of Science, 1200 New York
Avenue NW, Washington, DC 20005. Copyright
2012 by the American Association for the
Advancement of Science; all rights reserved.
The title Science Translational Medicine is a
registered trademark of AAAS.

REVIEW
M E D I C ALM Y C O LO G Y

Hidden Killers: Human Fungal Infections
1

2

1

3

Gordon D. Brown, * David W. Denning, * Neil A. R. Gow, * Stuart M. Levitz, *
4
5
Mihai G. Netea, * Theodore C. White *
Although fungal infections contribute substantially to human morbidity and mortality, the impact of these diseases on human health is not widely appreciated. Moreover, despite the urgent need for efficient diagnostic
tests and safe and effective new drugs and vaccines, research into the pathophysiology of human fungal
infections lags behind that of diseases caused by other pathogens. In this Review, we highlight the
importance of fungi as human pathogens and discuss the challenges we face in combating the devastating
invasive infections caused by these microorganisms, in particular in immunocompromised individuals.
Aberdeen, Aberdeen AB25 2ZD, UK.
population worldwide (2). c
2
National Aspergillosis Centre Education
These infections are caused a
and Research Centre, University Hospital
INTRODUCTION
of South Manchester, Manchester M23
primarily by dermatophytes, u
It is widely accepted that fungal pathogens have an 9LT, UK. 3Department of Medicine,
which give rise to well- s
enormous in-fluence on plant and animal life. University of Massachusetts Medical
known conditions such as e
School, Worcester, MA 01605, USA.
Indeed, a recent report detailed the extraordinary and 4Department of Internal Medicine and the
athlete’s foot (occurs in 1 in 5 d
frightening impact of these pathogens on species Nijmegen Institute for Infection,
adults), ringworm of the scalp
and Immunity, Radboud
extinctions, food security, and ecosystem Inflammation,
University Nijmegen, Nijmegen 6500HB,
(common in young children m
disturbances (1). In contrast, the effect fungal Netherlands. 5School of Biological
and thought to affect 200 o
Sciences,
University
of
Missouri-Kansas
infections have on human health is not widely recogmillion
individuals s
City, Kansas City, MO 64110, USA.
nized (Table 1), and deaths resulting from these *To whom correspondence should be
worldwide), and infection of t
E-mail:
infections are often overlooked. For example, the addressed.
the nails (affects ~10% of the o
(G.D.B.);
World Health Organization has no program on fungal [email protected]
general
population f
[email protected] (D.W.D.);
infection, and most public health agencies—with the
worldwide, although this [email protected]
(N.A.R.G.);
singular exception of the U.S. Centers for Disease m.netea@
aig.umcn.nl
(M.G.N.);
incidence increases with age t
Control and Pre-vention (CDC)—conduct little or [email protected] (S.M.L.);
to ~50% in individuals 70 e
mycological surveillance. Most people in their [email protected] (T.C.W.)
years and older) (2, 3). The n
lifetimes will suffer from superficial fungal
incidence of each particular
infections that are generally easy to cure, but
infection also varies with b
millions of individuals worldwide will contract lifesocioeconomic
conditions, y
threatening invasive infections that are much harder
geo-graphic
region,
and
to diagnose and treat (Fig. 1).
cultural habits.
Mucosal s
Of particular concern is the high rate of mortality
infections of the oral and e
associated with invasive fungal infections, which often
genital tracts are also v
exceeds 50% despite the availa-bility of several
common,
especially e
antifungal drugs (Table 1). The purpose of this Review
vulvovaginal candidiasis (or r
is to estimate, from available scattered data, the disease
thrush). In fact, 50 to 75% of a
burden caused by these pathogens; describe the types
women in their childbearing l
and impact of fungal infections worldwide; and
years suffer from at least one s
illustrate the pressing need for more research in this
episode of vulvovaginitis, and p
field to facilitate the development of better diagnostic
5 to 8% (~75 mil-lion e
tests and therapies and of as yet unrealized preventative
women) have at least four c
vaccines. Indeed, funding for med-ical mycology is
episodes annually (4). In i
greatly underrepresented when compared to other inworld regions with limited e
fectious diseases, although this may also reflect the
health
care
provision, s
number of applications for funding in the area. For
HIV/AIDS adds nearly 10 o
example, from the total spent over the last 5 years on
million cases of oral thrush f
immunology and infectious disease research by the
and 2 million cases of C
Wellcome Trust (a U.K. charitable body), the U.K.
esophageal fungal infections a
Medical Re-search Council, and the U.S. National
annually (5). Oral infections n
Institutes of Health (NIH), only 1.4 to 2.5% was
are also common in babies d
allocated specifically to medical mycology.
and denture wearers, in i
individuals who use inhaled d
FUNGI AND HUMAN DISEASE
steroids for asthma, in a
leukemia
and
transplant ,
Superficial infections of the skin and nails are the most
patients, and in people who w
common fun-gal diseases in humans and affect ~25%
have had radiotherapy for h
(or ~1.7 billion) of the general
head and neck cancers. These i
superficial infections are c
1
Aberdeen Fungal Group, Institute of Medical Sciences, University of

h are the second most numerous agents of fungal
infection worldwide.
Invasive fungal infections have an incidence that
is much lower than superficial infections, yet
invasive diseases are of greater concern because they
are associated with unacceptably high mortality
rates. Many species of fungi are responsible for these
invasive infections, which kill about one and a half
million people every year. In fact, at least as many, if
not more, people die from the top 10 invasive fungal
diseases (Table 1) than from tuberculosis (6) or
malaria (7). More than 90% of all reported fungalrelated deaths result from species that be-long to one
of four genera: Cryptococcus, Candida, Aspergillus,
and
Pneumocystis. However, epidemiological data for
fungal infections are notoriously poor because fungal
infections
are
often
misdiag-nosed
and
coccidioidomycosis (also sometimes called “valley
fever”) is the only fungal disease that must be
reported to the CDC. The sta-tistics presented in
Table 1 have been largely extrapolated from the few
(mostly geographically localized) studies that have
been performed (also see Supplementary Materials)
and are undermined by the lack of accurate incidence
data from many parts of the developing world. Consequently, our calculations may significantly
underestimate the true burden of invasive fungal
diseases.
The immune system of healthy individuals has
effective mecha-nisms for preventing fungal
infections, and the current incidence of invasive
diseases is largely a result of substantial escalations
over the last few decades in immunosuppressive
infections, such as HIV/AIDS,

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www.ScienceTranslation
alMedicine.org 19

December 2012 Vol 4

I
sue 165 165rv13
s

1

REVIEW

ssi
ve
aand
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ve
mme
odic
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m
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rat
ive

Fig. 1. Remarkable fungal infections. (Top, left to right) Chronic mucocutaneous candidiasis, chromoblastomycosis, and mucicarmine-stained histological section of the cerebellum of an AIDS patient
who died from cryptococcal meningoencephalitis (demonstrating an abundance of pink-stained fungi).
(Bottom) Computed tomography (CT) scan of the lungs of a patient showing a large fungal ball
(aspergilloma, black box), which was surgically removed (right). Three smaller cavities are also visible
in the CT scan (red arrows), which is typical of chronic pulmonary aspergillosis.

rty
eof

ly
str

1a
(8).
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oin
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nnt
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es a
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cry
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Cr
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soi
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ptro
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al
s
eand
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mthe
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epeo
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-

(pro
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ver
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sin
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19
90,
hu
ma
n
an
d
vet
eri
nar
y
cas
es
of
C.
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tii

ind
uc
ed
cry
pto
co
cc
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s
ha
ve
be
en
rep
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h
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g
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qu
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o
u

patric C. gattii lineages
(12).
Perhaps
climate
change is promoting a
more hospitable hab-itat
for C. gattii.
Some fungi normally live,
in manage-able numbers, on
the host epithelial surfaces of
most healthy humans, but can
initiate
life-threatening
systemic in-fections in those
who
are
immunocompromised.
Candida
species are the most common
fungal etiological agent of
life-threatening
invasive
infections in patients who (i)
are
severely
immunocompromised, (ii) have
endured invasive clinical
procedures, or (iii) have
experienced major trauma,
and
treatment
requires
extended stays in intensive
care units. Indeed, Candida
species are the fourth most
common cause of nosoco-mial
(hospital-acquired)
bloodstream in-fections (13),
and
advanced
medical
procedures—such as the use
of
catheters,
neonatal
intensive care, major gut surgery, or liver transplantation—
are predis-posing factors to
disseminated
Candida
infections. More than a dozen
Candida species can cause
disease, but in almost all
patient groups and disease
manifesta-tions,
Candida
albicans dominates in terms of
incidence
(14).
The
occurrence of disseminated
Candida infections has been
surveyed frequently in the
United States and in many
European
countries,
and
variable reported incidences
ranging from 2.4 (Norway) to
29 cases (Iowa, United States)
per 100,000 inhabitants have
been published (14–23). A
median value of 5.9 per
100,000 inhabitants

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Fig. 3. Diagnostic dilemma. A representative clinical scenario that demonstrates the magnitude of problems
associated with the diagnosis of fungal infections with current diagnostic tools. The figure shows the diagnostic
considerations, starting with the organ that may be involved (inner circle), the most likely diagnoses (middle
circle), and the testing required to rule in or out each of these diagnoses (outer circle). Certain features of the
illness make some diagnoses much more or less likely, in particular, the patient’s travel history and skin
papule, whereas other abnormalities are nonspecific. The patient is a 53-year-old man (photograph displayed
unaltered, with permission from patient) admitted after having been increasingly unwell for 10 days despite
administration of oral antibiotics. He has a previous history of pneumonia (2 years earlier), is a 30–pack per
year smoker, and takes 15 mg of prednisolone (a cor-ticosteroid) and 50 mg of azathioprine (an
immunosuppressive agent) for interstitial lung disease. He has traveled extensively in the United States,
southern Europe, and the Middle East. On admission, he had a fever of 38.3°C, was slightly confused but fully
conscious, had oxygen saturations of 94%, had a blood pressure of 95/60 (low), had a new nonulcerated dark
papule on his right lower arm 1 cm across, and had nonspecific general wheezing in his chest. He had a
slightly raised white blood cell count with neutro-philia, a raised serum creatinine indicative of significantly
impaired renal function, and negative blood cultures. Nine months earlier, an HIV antibody test had been
performed for employment purposes and was negative. His chest radiograph showed slightly increased
haziness bilaterally and showed no improve-ment after 36 hours of treatment with broad-spectrum antibiotics.
PHOTO CREDIT: G. WHITEHURST

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Sat
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REVIEW

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Ack
nowl
edg
men
ts:
We
than
k J.
Koll
s, A.
Kalo
ti, J.
Day,
T.
Harr
ison
,

F.

Odd
s, V.
Cali
ch,
H.
Phill
ips,
and
D.
Mart
in
for
inpu
t; J.
Will
men
t
and
H.
Carr
uthe
rs
for
prep
arati
on
of
figur
es;
and
T.
Smit
h
(Uni
vers
ity
of
Mas

w
w
.
S
ci
e
n
c
e
wT
r
a
n
s
l
a
ti
o
n
a
Vol
4
Issu
e
165
165

rv13

9

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