Seminars in Diagnostic Pathology 36 (2019) 177–181

Contents lists available at ScienceDirect

Seminars in Diagnostic Pathology

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

Review article

Emerging and reemerging fungal infections T

a,⁎ b
Shawn R. Lockhart , Jeannette Guarner
a
Mycotic Diseases Branch, Centers for Disease Control and Prevention 1600 Clifton Rd. Mailstop G-11, Atlanta, GA 30333, United States
b
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Fungal infections throughout the world appear to be increasing. This may in part be due to the increase in the
Fungi population of patients that are susceptible to otherwise rare fungal infections resulting from the use of immune
Histoplasma modulating procedures such as hematopoietic stem cell transplants and drugs like tissue necrosis factor an-
Fusarium tagonists. Histoplasma capsulatum, an endemic fungus throughout North and South America, is reemerging
Candida auris
among HIV+ patients in Central and South America and among patients taking tissue necrosis factor antagonists
and other biologics in North America. Fusarium species, a relatively rare fungal infection, is reemerging
worldwide in the immunocompromised populations, especially those who are neutropenic like hematopoietic
stem cell transplant recipients. A new yeast species is currently emerging worldwide: Candida auris, unknown
just a decade ago. It is causing large healthcare-associated outbreaks on four continents and is spreading
throughout the world through patient travel. In this review the epidemiology, pathology, detection and treat-
ment of these three emerging and reemerging fungi will be discussed.

Introduction population. In addition, we will review characteristics of Candida auris,

The worldwide incidence of fungal infections appears to be in-
creasing.1 Although there are multiple reasons for this increase, one
leading risk factor for invasive fungal infection is immune modulation
of the host, including receipt of solid organ and hematopoietic stem cell
transplants (HSCT), and the use of immune modifiers such as tissue
necrosis factor (TNF) antagonists to treat several chronic inflammatory
diseases. The number of patients receiving HSCT has dramatically in-
creased in the last decade, leading to marked increase in the number of
patients experiencing at least transient neutropenia.2 TNF inhibitors are
some of the top selling drugs in clinical practice; as their number and
applications multiply, their use will keep increasing.3 However, the
increase in HSCT and the widespread use of immune modifying drugs,
among other factors, has created an entirely new population of patients
at risk for fungal infections. The number of different fungi causing in-
fections may be increasing as well. Endemic fungal infections caused by
Histoplasma capsulatum, Blastomyces dermatitidis and Coccidioides im-
mitis/posadasii appear to be on the rise. So have environmentally ac-
quired infections such as aspergillosis, fusariosis and mucormycosis,
and healthcare-associated infections like candidiasis. This review will
discuss two fungi, H. capsulatum and Fusarium, which are not as fre-
quently diagnosed as Candida, Aspergillus and the Mucorales, but which
are reemerging, as they have found a niche among this new patient
a yeast with substantial public health and hospital infection control
implications which has suddenly appeared in the last decade.
Histoplasmosis
The causative agent of histoplasmosis is H. capsulatum, a thermally
dimorphic fungus found in the environment and specifically associated
with bird and bat guano.4 Although isolated cases occur in Africa, Asia,
Australia and Europe, histoplasmosis is predominantly endemic to the
United States and certain parts of Central and South America.5 Cases of
histoplasmosis are increasing in the United States and this has caused
an increased number of histoplasmosis-associated hospitalizations.6
While HIV has been the primary comorbidity associated with histo-
plasmosis hospitalization over the last several decades, histoplasmosis
hospitalization is increasingly associated with diabetes, transplant, and
the use of TNF blockers. It remains one of the more common AIDS
defining illnesses in Central and South America, and because the
symptoms of histoplasmosis mimic those of tuberculosis, it can be dif-
ficult to differentiate between these two syndromes without definitive
laboratory testing.7,8
The majority of Histoplasma infections in normal hosts are subacute,
with only about 5% of patients having an influenza-like illness.9 In
patients with impaired cellular immunity or those who have been

⁎
Corresponding author.
E-mail address: gyi2@cdc.gov (S.R. Lockhart).

https://doi.org/10.1053/j.semdp.2019.04.010

0740-2570/ Published by Elsevier Inc.

S.R. Lockhart and J. Guarner
exposed to an overwhelming inoculum of conidia, infection normally
begins as an acute pulmonary infection which can subsequently pro-
gress to a chronic cavitary infection. Histoplasmosis can also dis-
seminate, especially to the reticuloendothelial system, liver, spleen,
bone marrow, central nervous system, gastrointestinal tract, en-
docardium, and the skin.10
Symptoms of acute pulmonary pneumonia with Histoplasma include
fever, headache, dyspnea and a dry cough.9 Radiographic findings in-
clude patchy infiltrates in one or more lobes, pulmonary nodules and
enlarged hilar and mediastinal lymph nodes.11 In chronic pulmonary
histoplasmosis a productive cough, night sweats, low-grade fever and
weight loss are typical, and cavitation and fibrosis in the lungs can
occur. Dissemination can manifest in immunocompromised patients or
patients who have been exposed to an overwhelming inoculum. Non-
specific symptoms in patients with disseminated histoplasmosis include
fever, fatigue, weight loss and general malaise. Respiratory symptoms
are common, as are splenomegaly and hepatomegaly.4,9
Histoplasma reproduces in tissue as round to oval, 2–4 µm, narrow-
based budding yeast cells. These cells are typically found inside mac-
rophages, hence their usual arrangement in clusters (Fig. 1), especially
in lung tissue, but they can also be seen as free yeast cells. Histoplasma
cells are best visualized in tissue using a methenamine silver or periodic
acid-Schiff (PAS) stain. Giemsa staining is effective for visualizing
Histoplasma cells in bronchoalveolar lavages (BAL). In culture at room
temperature, Histoplasma is a slow-growing hyaline mold with club-
shaped microconidia as well as tuberculate macroconidia. While vi-
sualization of hyphae in tissue can usually be used to rule out Histo-
plasma, in cardiac tissue Histoplasma can grow as short hyphae.12 Pa-
thologists need to recognize that other small yeast can be confused with
Histoplasma, thus it is best to describe the yeasts observed, budding
pattern and arrangement as the diagnosis. They should state that the
yeasts seen are likely Histoplasma and suggest the use of alternative tests
such as the urine antigen test.
Culture is the gold standard for diagnosis of histoplasmosis. Both the
yeast phase at 37 °C and the mold phase at 25 °C grow slowly and it can
178
Seminars in Diagnostic Pathology 36 (2019) 177–181
Fig. 1. Case of disseminated histoplasmosis in skin and
bone marrow. A: Skin with mononuclear inflammatory
infiltrate in the upper dermis (hematoxylin and eosin
stain, original magnification 100×). B: Higher magni-
fication (250×) of hematoxylin and eosin stain
showing macrophages filled up with Histoplasma. C:
Grocott methenamine silver stain highlighting the
Histoplasma inside the macrophages from the bone
marrow biopsy (original magnification 250×). D:
Macrophage with multiple Histoplasma from the bone
marrow aspirate (Giemsa stain, original magnification
250×).
take up to four weeks to rule out Histoplasma by culture. The best
specimens for culture are sputum or BAL for acute pulmonary infec-
tions, and blood culture, tissue biopsy, or bone marrow for dis-
seminated infections. Under the best conditions culture is only positive
in up to 75% of cases.13 Detection of Histoplasma urine antigen may be
the most rapid and sensitive test for an acute infection.14–16 A serum
antigen test is available but may not contribute to further detection
when the urine antigen assay is used.17 Immunodiffusion and comple-
ment fixation tests for the detection of anti-Histoplasma antibodies are
not commercially available but are available in some public health and
commercial laboratories. Alone, they may not be ideal for detection of
acute infection as antibodies can take 4–8 weeks to develop.18 Com-
bining antigen and antibody testing can increase the sensitivity of de-
tection of acute pulmonary histoplasmosis to 96%.19 There are many
laboratory-developed molecular tests for Histoplasma, but none are
commercially available.20,21 A commercially available chemilumines-
cent probe kit (Gen-Probe®) is useful for definitive identification of
Histoplasma from an isolate.22
In otherwise healthy individuals mild histoplasmosis generally re-
solves without treatment. In cases of acute and chronic pulmonary or
disseminated histoplasmosis treatment is generally amphotericin B
followed by itraconazole for severe cases or intraconazole alone for less
severe cases. The dose and duration of therapy depend both on the
severity of the disease and the underlying immune status of the patient.
Treatment guidelines are available.23
Fusariosis
Fusarium species are plant pathogens that are widely distributed
across the world, thriving in both tropical and temperate regions and
causing serious economic damage to commercial crops. The first case of
human disease reported in the literature, a keratitis case, was not re-
ported until 1958.24 Although keratitis is still the predominant mani-
festation of infection, Fusarium also causes localized infections of the
respiratory tract and sinuses. In immunocompromised patients,
S.R. Lockhart and J. Guarner
especially those with profound neutropenia, dissemination to the gas-
trointestinal tract, lungs, kidneys, heart, liver, central nervous system
and skin is common.25,26 Fusarium caused 22% of non-Aspergillus mold
infections in the TRANSNET study of solid organ and stem cell trans-
plant patients in the US, making it the most common mold in that pa-
tient population after Aspergillus and molds in the order Mucorales.27
The most common route of infection in the immunocompetent host is
traumatic inoculation, especially in the presence of organic material.
Airborne conidia, both inside and outside of the hospital setting, are
likely the source of infection in immunocompromised patients, and
conidia can become aerosolized through water systems such as sinks,
showers and drains.28–30
The clinical manifestations of Fusarium infection cannot be dis-
tinguished from other common fungal infections such as Aspergillus.
Sinusitis and pneumonia typically manifest the same as other fungal
infections but are more likely to become invasive. However, unlike
most other fungal infections, fusariosis often disseminates to the skin as
painful red nodules that may ulcerate and develop into eschars, most
commonly on the extremities. In a recent review of Fusarium infection,
dissemination to the skin was present in 70% of the patients.31 There is
no typical radiological pattern for fusariosis although the halo sign
tends to be absent.32
In tissue, Fusarium is seen as a hyaline, septated mold with acute to
right angle branching similar to Aspergillus (Fig. 2). Thus, when pa-
thologists see hyaline septated molds they should refrain from using the
name of a species (Aspergillus, Fusarium or other) and rather describe
the hyphae observed. In a comment they can name species that can
produce similar morphologies: Aspergillus, Fusarium even Candida. Si-
milar to the mucormycosis, Fusarium are angioinvasive and will cause
thrombosis and necrosis of tissues. In vitro, but also sometimes in sinus
or cavitary lesions, Fusarium reproduces asexually by producing 1–3
celled pyriform or fusiform microconidia as well as macroconidia with
>2 cells that are banana-shaped or canoe-shaped. On most fungal
media without cycloheximide it grows as a velvety to cottony colony
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Seminars in Diagnostic Pathology 36 (2019) 177–181
that can be white, gray, lavender, purple, pink or salmon in color de-
pending on the species. The most common species seen in clinical
practice are members of the F. solani and F. oxysporum species com-
plexes, but over 70 species have been isolated from human infections,
some of which have not been named yet and are identified only by their
DNA barcode.33–35
Definitive diagnosis generally relies on culture. Unlike most other
filamentous fungi, Fusarium commonly grows in fungal blood culture.26
Culture can be derived from blood, BAL, sinus, or tissue. Skin biopsy is a
very good source for culture.31 β-D-glucan is positive in cases of dis-
seminated fusariosis but because this test is not specific for any parti-
cular fungus it is not useful for diagnosis.36 The galactomannan test,
generally used to diagnose aspergillosis, cross-reacts with Fusarium.37 It
is extremely difficult to identify Fusarium to species without the use of
molecular tools. DNA sequencing is the best method for identification
although MALDI-TOF may become an alternative in the future.38,39
Most isolates of Fusarium are placed in species complexes which is ac-
ceptable in clinical practice.33,40
Fusarium can be highly antifungal resistant and the resistance pat-
tern varies from species to species, even within a species complex.41
Posaconazole and/or amphotericin B are the usual treatment although
some isolates may respond to voriconazole.26 Surgical debridement is
essential for the prevention of progression. Due to the underlying im-
mune status of the susceptible population, even with antifungal treat-
ment mortality is high.26
Candida auris
The previous two fungi, Histoplasma and Fusarium, are described as
reemerging because both have been recognized by clinicians for a long
time and may be increasing in prevalence due to a change in the sus-
ceptible population. However, there is one fungus that was previously
unknown to clinical practice just a decade ago and is truly emerging; C.
auris. This yeast was first described in 2009 from a single isolate
Fig. 2. Case of disseminated fusariosis. A: Gram stain of blood
culture showing abundant hyphae (original magnification
250×). B: Skin with petechial hemorrhages in the upper
dermis (hematoxylin and eosin stain, original magnification
25×). C: Higher magnification (250×) of hematoxylin and
eosin stain showing single hyaline hyphae with one septum
inside a blood vessel in the upper dermis. D. Grocott methe-
namine silver stain highlighting abundant septated hyphae in
the sinus debridement specimen from the same patient.
S.R. Lockhart and J. Guarner
recovered from the ear discharge of a patient in Japan.42 Since that time
it has been identified around the world as a pathogen causing primarily
bloodstream infections, but also, wound, urinary tract, and other in-
fections.43 A recent look-back at multiple international culture collec-
tions confirmed that the emergence of C. auris is recent with only a
couple isolates identified before 2011.44
The most common manifestation of C. auris infection is candidemia.
There have also been infections of the central nervous system, re-
spiratory tract, urogenital tract, abdomen, bone, and skin and soft
tissue.45 In a review of 31 candidemia cases from New York the 30 day
mortality was 39% and the 90 day mortality was 58%.46 Patients can
also become colonized with C. auris in the axilla, groin, nares, ear and
rectum. While colonization does not pose an immediate threat to the
patient, colonized patients can subsequently become infected and they
also pose a serious risk for colonization of other patients if infection
control practices are not initiated in the hospital. At this time there is no
known protocol for decolonization.46-48
It has also been shown through whole genome sequencing that four
distinct clonal populations (clades) emerged simultaneously on three
continents, South America, Asia and Africa, and these four clades have
been responsible for further spread around the world. Despite being
unknown only a decade ago, C. auris is now causing large healthcare-
associated outbreaks all over the world, which is unusual for any
Candida species.44,46,47,49,50 One of the unique aspects of C. auris epi-
demiology is that when it is introduced into a healthcare setting it has
the ability to spread clonally from patient to patient as both a pathogen
and a colonizer.46,48,51
C. auris is an ellipsoid to elongate ascomycete budding yeast that is
2–5 µm in size. It can grow at temperatures up to 42 °C and can survive
in high salt environments (up to 10% NaCl).52 It generally grows singly
or in pairs but it is able to form aggregates in liquid culture and there is
evidence that it can form hyphae following passage through an animal
host.53,54 Based on its own growth pattern and that of other Candida
spp., it is likely that C. auris will appear in tissue sections as yeasts with
rare hyaline hyphae.
Diagnosis of C. auris is the same as for other Candida species. It
grows well in blood culture and from other specimens such as urine or
wound exudates. There are extenuating factors that make identification
difficult. Because it is a newly identified species, C. auris is not in the
database of many conventional yeast identification systems, and bio-
chemically it is very closely related to two other Candida species, C.
haemulonii and C. duobushaemulonii which hinders distinguishing be-
tween the three species. C. auris can be accurately identified by DNA
sequencing or by MALDI-TOF, provided it is in the database being
used.55
Unlike most other Candida species, C. auris can acquire resistance to
the three commonly used classes of antifungals; azoles, echinocandins
and polyenes.44,56 Antifungal resistance is dependent upon the parti-
cular clone but approximately 70% of over 900 isolates in the CDC
collection are resistant to at least one antifungal, 25% are resistant to at
least two antifungals and 1% are resistant to all three available classes
of antifungal, making those isolates essentially untreatable (CDC, un-
published data). Resistance to fluconazole is most common (almost
100% in isolates from South Asia), followed by resistance to ampho-
tericin B (25% of isolates from South Asia), and resistance to echino-
candins (5% of all isolates with no clonal association).44,46,56
The recommended treatment for C. auris is an echinocandin, which
follows the Infectious Disease Society of America's recommendations
for the treatment of candidemia.57 Susceptibility testing should be
performed on all isolates and therapy can be stepped down to an azole
or up to amphotericin B if the isolate tests susceptible. Because of the
high proportion of antifungal resistance for C. auris isolates, patients
should be monitored closely for treatment failure no matter which
antifungal is given.
When an isolate of C. auris is identified, the CDC recommends that
strict infection control guidelines be followed (https://www.cdc.gov/
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Seminars in Diagnostic Pathology 36 (2019) 177–181
fungal/candida-auris/c-auris-infection-control.html). This includes pa-
tient isolation and contact precautions. Cleaning and disinfecting the
patient care environment is important as C. auris has been shown to
contaminate patient rooms.46,47,58 Chlorine-based products are the
most effective but other products are also effective. Products from List K
published by the US Environmental Protection Agency are re-
commended (https://www.epa.gov/pesticide-registration/list-k-epas-
registered-antimicrobial-products-effective-against-clostridium).
Conclusion
Although they may cause significant morbidity and mortality in
susceptible populations, fungi can be overlooked as a cause of emerging
infection. Surgeons may remove tissue or perform a biopsy on what is
thought to be a malignant mass only to find out after it has been placed
in formalin that it is a fungal mass.59,60 While only three specific fungi
were discussed above, the overall number of fungal infections is in-
creasing as the susceptible population expands. It is prudent for pa-
thologists to keep fungi in mind as a cause of masses, swellings, and
infiltrates as they receive frozen sections so that material is sent for
microbiological culture. Pathologists should also be cognizant of the
pitfalls of diagnosing fungal structures (hyphae or yeasts) in different
specimens by species. With the increased armamentarium of antifungal
agents, pathologists need to be aware that their descriptive diagnosis of
yeast and hyphae will have significant impact to patient care.
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