Diagnostic Imaging and Invasive Fungal Diseases in

Children
Aspasia Katragkou,1 Brian T. Fisher,2,3 Andreas H. Groll,4 Emmanuel Roilides,5 and
Thomas J. Walsh6

Invasive fungal disease (IFD) is a life-threatening condition, especially in immunocompromised

children. The role of diagnostic imaging in children at risk for an IFD is multifactorial, including
initially detecting it, evaluating for dissemination of infection beyond the primary site of disease,
monitoring the response to antifungal therapy, and assessing for potential relapse. The objective
of this review was to synthesize the published literature relevant to the use of various imaging
modalities for the diagnosis and management of IFD in children.

Keywords. Aspergillus; blastomycosis; Candida; histoplasmosis; mucormycosis. Invasive fungal

diseases (IFDs) are associated with significant morbidity and death in immune-compromised
children.
Other populations at risk for IFD include those who live in areas where mycoses such as
coccidioidomycosis, blastomycosis, and histoplasmosis are persistently endemic. Other
vulnerable pediatric populations are premature neonates and those who are critically ill or bear
medically placed catheters or prostheses. The early detection of IFD is critical, because
therapeutic outcome strongly depends on the prompt initiation of appropriate interventions.
Despite the importance of early detection, diagnosing IFD in children can be quite challenging
for multiple reasons. Clinical signs and symptoms are not specific to IFD, data on novel
biomarkers measured in samples obtained noninvasively from children are limited, and there is
often resistance to perform invasive diagnostic procedures. Therefore, diagnostic imaging can be
critical in assessing for IFD or establishing the diagnosis. Although conventional radiography
can serve as an initial imaging evaluation for
IFD, ultrasonography, computed tomography (CT), magnetic
resonance imaging (MRI), and other imaging modalities have
proven more beneficial in delineating the number, type, and
extent of mycotic lesions.
Beyond initially identifying lesions that raise suspicion for
IFD, radiographic imaging in children can help to define the
extent of dissemination of infection beyond the primary site
of disease and monitor the response to antifungal therapy or
examine for potential relapse. Imaging findings also can provide
the data necessary to justify an invasive diagnostic procedure
and serve as a map for sampling of the affected tissue (eg, bronchoalveolar
lavage or CT-guided biopsy).
With this review we provide an overview of the utility of
imaging studies for the diagnosis and management of IFD in
pediatric patients. Radiographic findings are detailed relative to
the organ involved and imaging modality used. We focus particularly
on radiographic findings associated with invasive candidiasis
and aspergillosis, because they are the leading causes of
IFD in immunocompromised children. Because of the paucity
of pediatric-specific studies, much of the review was informed
by publications related to adult patients. Important to note is
that the radiographic appearance of IFD in children can differ
significantly from that in adults. For example, the radiographic
appearance of pulmonary aspergillosis in children is associated
less commonly with the hallmark findings described in adults
[4]. Such known radiographic differences between children and
adults are highlighted; however, additional studies are needed
to define more comprehensively pediatric-specific radiographic
findings of IFD.

INVASIVE CANDIDIASIS
Invasive candidiasis can present clinically in a variety of ways,
including candidemia, disseminated candidiasis, and single-organ
infection [5]. Specific imaging details of manifestations
related to organs commonly affected by hematogenous and
nonhematogenous spread are discussed below.
Pulmonary Candidiasis
Candida involvement of the lung is typically secondary to
hematogenous dissemination. Although limited published
descriptions of the radiographic appearance of this entity in
pediatric patients are available, reports from radiographic chest
imaging studies in adults with disseminated candidiasis often
reveal numerous small nodules in a miliary nodular pattern [6].
A report of 17 adult hematopoietic stem cell transplant recipients
with histologically proven pulmonary candidiasis revealed
multiple nodules as the most common radiographic finding [7].
Patients were described less commonly as having ground-glass
opacities, consolidations, halo signs, and cavitation, which are
nonspecific and can be seen in patients with other infections,
including invasive aspergillosis [7].
Primary Candida pneumonia is a rare condition that occurs
after aspiration of oropharyngeal material [8, 9]; however, proving
the link between Candida species and a pneumonic infiltrate
is challenging, given that they are frequent colonizers of the
respiratory tract, especially in intensive care unit patients [10].
Nonetheless, the radiologic appearance of primary Candida
pneumonia has been described as an air-space process or as diffusely
micronodular disease [11].
Imaging findings in infants with pulmonary involvement
can differ from those in older children and adults. A review
of autopsy records from a 12-year period (1968–1979) that
included 14 infants with invasive candidiasis involving the
pulmonary parenchyma revealed that 3 characteristic histologic
patterns of pulmonary candidiasis can be found:
embolic (arterial invasive), disseminated (capillary invasive),
and bronchopulmonary (air-space invasive) [12]. The
typical radiographic appearance of pulmonary candidiasis
in these neonates was progressive air-space consolidation,
whereas focal cavitation was observed in 2 infants with the
hematogenous form of pulmonary candidiasis. The authors
concluded that the radiographic findings in these neonates
with invasive candidiasis were nonspecific and might have
actually represented pathology from coexisting diseases [12].
For example, some patients had pleural-based homogeneous
consolidation such as that seen with pulmonary infarctions,
massive areas of homogeneous consolidation such as those
that occur with bacterial lobar pneumonia, or the presence
of mass-like rounded images with or without central necrosis
such as those that occur with angioinvasive fungus-like
Aspergillus [13].
Osteoarticular Candidiasis
Candida osteoarticular infections develop most often as a
complication of candidemia. Infection can occur also after
exogenous inoculation after trauma or at the time of intraarticular
injection or prosthesis implantation. Imaging is critical
for defining the location and extent of the infection; however,
there are no radiologic findings specific to Candida infection
[14]. A review of 207 pediatric and adult cases of Candida
osteomyelitis (1970–2011) revealed that the most common
radiologic findings were bone destruction (54%), extension into
soft tissues (27%), increase in radionuclide scan uptake (23%),
decreased intervertebral space (21%), and epidural abscess
(12%). Decreased signal intensity on T1-weighted images and
increased signal intensity on T2-weighted images were commonly
observed with MRI [15].
Among the pediatric patients (≤18 years old), the most common
infected bone sites were femur, humerus, and vertebra or
ribs. Most patients had 2 or more bones infected, which underscores
the importance of searching for other sites. In neonates,
Candida osteomyelitis is usually multifocal and associated with
arthritis [15]. The most common radiologic abnormalities in
patients with Candida arthritis are bone destruction (42%)
and joint effusion (31%), followed by extension into soft tissue
(21%), decrease of articular space, osteoarthritis, periosteal
reaction, and/or synovitis. The joint sites most commonly
infected were the knee (77%) and hip (25%) [16].
Hematogenous Candida Meningoencephalitis
Hematogenous Candida meningoencephalitis (HCME) occurs
as a result of candidemia with blood-borne dissemination to
the brain. In the pediatric population, central nervous system
(CNS) candidiasis in neonates and children with serious
underlying disease or a cerebrospinal fluid (CSF) shunt has
been described. Compared to its occurrence in adults, HCME is
disproportionately frequent in neonates and immunocompromised
children. The syndrome has been associated with high
rates of death and neurodevelopmental abnormalities [17–19].
Historically, in these cases, the diagnostic interval was long, the
CSF findings nonspecific, the fungus difficult to culture, and
the clinical course insidious. Imaging studies often provided
the only evidence that CNS candidiasis was present [20–24].
Imaging can also facilitate assessment for the need for and
approach to surgical intervention and provide a measure for
assessing the response to therapy.
Although some authors describe the condition as Candida
meningitis, HCME manifests both clinically and radiologically
as meningoencephalitis. Furthermore, radiographic
findings can reveal involvement of the brain parenchyma
or ventricular system. Cranial sonography can inform on
midline supratentorial, ventricular, intraventricular, and
periventricular morphology. Intraventricular “fungus balls,”
calcifications, hydrocephalus, and encephalitic changes also

can be seen. Abscesses might be seen as hypoechoic areas

with echogenic rims. The presence of intraventricular septations,
strands, and/or debris suggest ventriculitis [21–23].
The most common CT or MRI findings are multiple abscesses
with ring enhancement or nodular enhancing lesions that are
indistinguishable from other inflammatory process.
Chronic Disseminated Candidiasis or Hepatosplenic Candidiasis
Chronic disseminated candidiasis (CDC) is a persistent infection
of the liver, spleen, and other tissues that can present in
neutropenic patients and after recovery from neutropenia [25,
26]. When isolated to the liver and spleen, this entity is often
referred to as hepatosplenic candidiasis (HSC). This infection is
characterized by a chronic debilitating course that can be refractory
to conventional therapy or require an extensive course of
antifungal therapy [27–31]. Imaging is important in diagnosing
probable CDC and monitoring treatment response [5, 32].
Ultrasonography remains a useful tool for detecting and
monitoring CDC [32]. The advantages of its use include the
absence of nephrotoxicity and radiation exposure and the feasibility
of a bedside examination. However, ultrasonography
and other imaging modalities might not detect lesions, because
CDC is not usually radiologically apparent before neutrophil
count recovery. In addition, its sensitivity depends largely on
the experience of the sonographer [32]. In a series of 731 autopsies
of hematopoietic stem cell transplant recipients performed
between 1980 and 1989, imaging studies were not sensitive in
identifying liver IFD (23% of IFDs were identified with CT,
and 13% were identified with ultrasonography), but they were
highly specific [33]. In 26 leukemic patients with CDC, during
the first 3 weeks after their recovery from neutropenia, focal
changes in the liver, spleen, or kidneys were detected in >90%
of the patients by CT and in fewer than half of the patients by
ultrasonography [34]. Contrast-enhanced ultrasonography
(CEUS) might improve the yield of ultrasonography for detecting
these lesions. CEUS is a real-time imaging technique that
has few adverse effects and can be performed even in patients
with impaired renal function. An inherent advantage of CEUS
is the opportunity it provides to assess contrast-enhancement
patterns in real time with a much higher temporal resolution
than is possible with other imaging modalities [35, 36].
The most frequent ultrasound pattern of CDC is disseminated
hypoechogenic small lesions that, unfortunately, are
difficult to differentiate from lymphoma of the liver, leukemic
infiltrates, and metastases. A typical ultrasound finding of CDC
lesions in the liver is the “bull’s eye” or target pattern with a
peripheral hypoechogenic halo encircling a central hyperechogenic
core. Shawker et al [37] described 4 distinct ultrasound
patterns of HSC, one of which was described as a “wheels-within-
wheels” pattern.
CT and MRI scans seem to be superior to ultrasound for the
identification of lesions associated with CDC. However, both
CT and MRI rarely detect lesions before bone marrow reconstitution
and neutrophil count recovery [38, 39]. The enhancement
patterns of the lesions in patients with CDC differ depending on
the acute, subacute, or chronic stage of the disease. The most
sensitive CT phase for liver involvement in the acute stage is the
arterial-dominant phase (ie, 25–35 seconds after contrast injection),
in which a hyperattenuating rim surrounding a hypoattenuating
center bull’s eye or a hyperattenuating lesion can be
seen [40]. In the portal-venous phase (ie, 60–80 seconds after
injection), microabscesses very often show as hypoattenuating
lesions ≤1 cm in size. Both phases in enhanced images are more
sensitive than nonenhanced images.
MRI seems to be superior to CT in identifying liver lesions
associated with CDC; its sensitivity is 100% and specificity is
96% when the appropriate techniques are used [39, 41, 42].
In a patient with acute HSC, lesions on MRI are round, measure
<1 cm in diameter, and are markedly hyperintense on
T2-weighted images. Subsequent MRI scans during or after
treatment usually reveal a dark ring surrounding the initial
lesions and a nonenhancing center on gadolinium-enhanced
images. This central area corresponds to the necrotic core seen
on histologic examination [39, 43, 44]. After successful antifungal
treatment, lesions appear with irregular margins and measure
1 to 3 cm in diameter with the disappearance of the central
area. In MRI, healed fungal lesions appear in a time period that
has ranged from 3 months to >1 year [39, 44, 45]. The major
drawback of MRI use is cost and availability. In this regard, contrast-
enhanced biphasic CT or ultrasonography remain credible
imaging modalities for patients with suspected CDC [44].
The role of fluorine-18 fluorodeoxyglucose positron emission
tomography ([18F]FDG PET)/CT in diagnosing CDC has not
been well defined. [18F]FDG accumulates in metabolically active
cells, including neoplastic and inflammatory cells, and produces
a distinct image during PET scanning. Case reports have shown
that [18F]FDG PET/CT is useful in detecting CDC, guiding subsequent
patient management, and helping determine the best
lesion for biopsy [46–48]. In a small pilot prospective study, the
contribution of [18F]FDG PET/CT was assessed in the diagnosis
and staging of proven IFD in a cohort of 30 patients. Among the
10 patients with HSC, 6 had lesions detected only by [18F]FDG
PET/CT and not by CT [49]. However, it is not clear that this
modality offers any benefit over MRI, and [18F]FDG PET/CT
results in significant radiation exposure to the patient, which
makes it less attractive for diagnostic and monitoring purposes.
INVASIVE ASPERGILLOSIS
The sinopulmonary tract is the most common portal of entry
for aerosolized Aspergillus conidia [50]. In the absence of an
effective host immune response, conidia germinate into hyphae
and can invade pulmonary arteries and cause pulmonary
arterial thrombosis, hemorrhage, lung necrosis, and systemic dissemination [50, 51]. Lungs are
the most frequently infected
site, followed by the CNS [52]. Diagnosing invasive aspergillosis
is difficult [50]. However, there are key imaging features
that can alert clinicians to the possible diagnosis of invasive
aspergillosis.
Invasive Pulmonary Aspergillosis
The manifestations of invasive pulmonary aspergillosis (IPA)
can be classified according to the underlying pathologic process;
however, on many occasions, more than 1 Aspergillusrelated
pathologic feature can coexist in the same patient [53].
Acute angioinvasive aspergillosis is characterized histologically
by invasion and occlusion of small-to-medium pulmonary
arteries by fungal hyphae, which leads to the formation of
necrotic hemorrhagic nodules or pleura-based wedge-shaped
hemorrhagic infarcts [54]. In pediatric patients, invasive pulmonary
aspergillosis occurs predominantly in patients with a
hematologic malignancy or aplastic anemia or in those who are
undergoing corticosteroid or other immunosuppressive therapy
[55]. The characteristic CT findings of acute angioinvasive
aspergillosis consist of a nodule or nodules surrounded by a
halo of ground-glass attenuation (“halo sign”) or pleura-based
wedge-shaped areas of consolidation (Figure 1) [56]. Although
the halo sign is often linked with IPA, it is actually nonspecific
and has been described with other angioinvasive mycoses,
including mucormycosis, fusariosis, and scedosporiosis, and
with other nonfungal pathogens (eg, Pseudomonas aeruginosa
or Mycobacterium tuberculosis) or processes (eg, herpes simplex
virus, cytomegalovirus pneumonia, Wegener granulomatosis,
Kaposi sarcoma, or hemorrhagic metastasis) [51, 54].
Nonetheless, in the appropriate clinical setting, a halo sign seen
with CT is highly suggestive of angioinvasive aspergillosis.
The “air-crescent sign” can also be seen on CT imaging and
represents the separation of necrotic lung tissue from the neighboring
pulmonary parenchyma (Figure 1) [56]. The air-crescent
sign usually occurs 2 to 3 weeks after the onset of treatment and
granulocyte recovery and is considered by some investigators to
be an indicator of favorable recovery [54].
Individual lesions in patients with IPA can increase in
diameter within the first 2 weeks of antifungal therapy. In an
analysis of the kinetics of CT imaging in neutropenic adults,
Caillot et al [57] found that the halo sign is an early manifestation
that regresses during the course of antifungal therapy.
They also elucidated, through volumetric analysis, that nodular
Aspergillus lesions increased a median of 4-fold from baseline
to day 7. The median volume then remained stable from days 7
to 14. However, when the lesions do not decrease in either size
or number or there is no air-crescent sign or cavitation after 2
to 3 weeks, the patient should be evaluated for possibly refractory
infection. It should be noted that within the first month of
treatment initiation and during hematopoietic recovery, nodule
volume can be increased as a result of the infiltration of neutrophils
and monocytes, which makes the interpretation of imaging
results challenging [57–59].
Many of the aforementioned CT signs associated with IPA
were delineated from adult studies. Although the halo and
air-crescent signs in children have been described, the radiologic
findings in pediatric patients with IPA have been more
variable and mostly nonspecific [60–63] (Table 1). Cavitation
and air-crescent formation might occur more frequently in
older children and adults than in younger children [55], which
could be attributed to either differences in the host immune
response [64] or the late-stage performance of CT [61, 65].
Allergic Bronchopulmonary Aspergillosis, Aspergilloma, and Chronic
Invasive Aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity
reaction to Aspergillus and a recognized complication
of asthma and of cystic fibrosis. Patients with ABPA have
markedly elevated total serum immunoglobulin E levels and
increased levels of specific immunoglobulin E antibodies to
Aspergillus fumigatus [55, 66]. Imaging findings seen in patients with ABPA usually involve the
middle or upper lobes and can be
transient or permanent. Chest radiographs can depict pulmonary
air-space shadows, tubular densities representing mucoid
impaction, parallel and ring shadows representing bronchiectasis,
and pseudohilar adenopathy caused by mucous plugging
central bronchi [53, 67]. High-resolution CT is more sensitive
than radiography in detecting bronchial thickening, central
bronchiectasis, and parenchymal consolidations [68].
The typical radiologic finding for aspergilloma is a rounded
mobile mass within a cavity with a rim of air (air-crescent sign).
Any cavity within the lung can facilitate the development of an
aspergilloma.
Chronic pulmonary aspergillosis is a rare form of Aspergillus
infection that usually occurs in children with ABPA, patients
who suffer from an atypical mycobacterial infection, or in the
setting of a primary immunodeficiency. Initial radiologic findings
constitute foci of consolidations usually in the upper lobes
that progress to cavitation and aspergilloma formation with
pleural thickening [67].
CNS Aspergillosis
CNS aspergillosis occurs almost exclusively in immunocompromised
patients [69]. In the pediatric population, the predominant
underlying conditions that predispose a child to CNS
aspergillosis are prematurity and leukemia [70]. Aspergillus
usually reaches the CNS via hematogenous dissemination to
the brain parenchyma, seeding of CSF, or direct extension from
the sinuses, which results in a clinical presentation that includes
cerebritis, abscess, meningitis, and ventriculitis (Figures 2 and
3) [69, 71, 72]. Aspergillus infection can result in a variety of histopathologic findings, including
microhemorrhages, mycotic
aneurysms, subarachnoid hemorrhage, thrombosis, and infarction
with hemorrhagic transformation. Aspergillus spp. have a
characteristic predilection for perforating arteries of the basal
ganglia, thalamus, and corpus callosum.
Patterns of CNS aspergillosis identified in neuroimaging
in immunocompromised patients include (1) multiple areas
of hypodensity (CT) or hyperintensity (T2-weighted MRI) in
the cortex and/or subcortical white matter corresponding to
thromboembolic infarction with or without hemorrhage, (2)
multiple intracerebral ring-enhancing lesions consistent with
abscesses with a low signal (T2-weighted MRI), and (3) dural
enhancement associated with enhancing lesions in the adjacent
paranasal sinus structure or calvaria or dural enhancement of
the optic sheath with associated optic nerve and intraorbital fat
enhancement [73].
Aspergillus Sinusitis
Aspergillus is a common cause of fungal sinusitis, which can
extend into the CNS [74]. Dural enhancement in association
with enhancement of the adjacent sinus is a common finding
of contiguous Aspergillus invasion from the paranasal sinuses, especially when the frontal and
sphenoid sinuses are involved.
Aspergillus infection of the mastoid airspace can be associated
with venous thrombosis of the adjacent sigmoid sinus.
Acute Aspergillus infection of the paranasal sinuses appears
in CT images as nonspecific dense opacification of the airspaces.
Bony erosion is often absent and should not be considered a
necessary finding for acute Aspergillus sinusitis. Ethmoidal
sinusitis with involvement of an orbit can occur in the absence
of bony erosion of the lamina papyracea. Also consistent with
this observation is that ethmoidal sinus aspergillosis can involve
the medial rectus muscle of the orbit while the lamina papyracea
remains intact. Increased diameter on a CT scan and elevated
signal intensity on T2-weighted imaging will delineate
the medial rectus infection. Similarly, aspergillosis of the frontal
sinuses can be associated with infection of the frontal lobes
without erosion of the walls of the frontal bone. Maxillary sinus
aspergillosis can invade the palatine vessels and result in necrosis
of the hard palate.
Chronic Aspergillus sinusitis appears on CT images as a
hypodense mass lesion separated from the sinus walls. The
adjacent bony structures might show erosion or sclerosis [75].
The mass lesion can have concentric or parallel internal layers,
which reflect eposes of inflammation.
Aspergillus Osteoarticular Infections
Osteoarticular aspergillosis can develop in both immunocompromised
and immunocompetent patients [76].
Immunocompetent patients with osteoarticular infection
often have an important anatomic barrier compromised, such
as after thoracic and abdominal surgery or after sustaining an
open fracture. Vertebral and costal Aspergillus osteomyelitis can
develop from contiguous pulmonary aspergillosis, by hematogenous
dissemination, or by traumatic inoculation. Cranial
aspergillosis develops most commonly from a contiguous focus.
In a recent review of 180 patients with Aspergillus osteomyelitis,
21% were children. Of those children, 73% had chronic granulomatous
disease (CGD) as their underlying predisposing factor.
Infection of the ribs and sternum is a relatively common
presentation in children with CGD; it accounted for 36% of the
Aspergillus osteomyelitis cases in this patient group. In addition,
contiguous involvement of the vertebrae, ribs, and sternum is a
relatively frequent complication of recurrent pulmonary aspergillosis
[76–78].
Osteolysis, bone destruction, and erosion were the most
common radiologic patterns of Aspergillus osteomyelitis (65%),
followed by extension of the infection into soft tissue (26%).
Less common changes included periosteal reaction, abscess,
and sequestrum. Spinal cord compression, decreased intervertebral
space, paraspinal abscess, epidural abscess, subdural
abscess, and spondylolisthesis each can be seen with radiographic
imaging in the setting of spinal aspergillosis. The most
common features of MRI included decreased signal intensity on T1-weighted images, increased
signal intensity on T2-weighted
images, and increased gadolinium contrast enhancement on
T1-weighted images [76].
A comprehensive review of 31 reported cases of Aspergillus
arthritis included 2 children with underlying acute lymphoblastic
leukemia and 1 with CGD. Two of these children had polyarthritis
(1 at multiple intervertebral sites and 1 at the knee, ankle,
and carpal joints), and 1 had a monoarticular hip infection. The
child with CGD had intervertebral osteomyelitis with an epidural
abscess [77, 79] (Figure 4).
MUCORMYCOSIS
Mucormycosis is an aggressive angioinvasive infection that can
cross tissue planes and invade adjacent organs and structures [80,
81]. Similar to aspergillosis, CNS mucormycosis can develop via
hematogenous dissemination of pulmonary mucormycosis or
via direct extension from a sino-orbital infection [82].
Pulmonary Mucormycosis
The radiologic manifestations of pulmonary mucormycosis
include consolidation, cavitation, abscess formation, nodules,
and masses. Pulmonary lesions are usually unifocal and affect
the upper lobe. As with other angioinvasive fungal infections,
the air-crescent or halo sign can be seen. The “reverse-halo”
sign has been associated with pulmonary mucormycosis. This
finding represents a focal rounded area of ground-glass opacity
surrounded by a crescent or complete ring of consolidation.
Although the reverse-halo sign has been found in patients with
a spectrum of diseases (infectious and noninfectious), it has
been described as an indicator of pulmonary mucormycosis
in patients with a hematologic malignancy [83]. Although the
probability for mucormycosis is high in patients with a hematologic
malignancy and the reverse-halo sign, there is a wider
differential diagnosis to consider. The reverse-halo sign also
can be observed in patients with tuberculosis, histoplasmosis,
sarcoidosis, and pulmonary vasculitis. In comparison to invasive
aspergillosis, pulmonary mucormycosis is associated with
more pulmonary nodules (>10), a higher frequency of sinusitis,
and more frequently occurring pleural effusions [84]. Although
these findings are biologically instructive, they do not help in
the assessment of a patient who might present with any variation
of sinopulmonary mucormycosis and aspergillosis.
Sino-orbital Mucormycosis
Sinus opacification, bony erosions, and obliteration of deep fascia
planes can be detected with the use of CT and MRI [69].
Bony erosion is neither a sensitive marker for fungal sinusitis
nor an indicator of extension into the CNS. Because venous
drainage of the ethmoid sinuses extends into the cavernous
sinuses, ethmoidal mucormycosis carries a high risk of cavernous
sinus thrombosis that can be seen with MRI. It should be
noted that cavernous sinus thrombosis seen with diagnostic
imaging is a late finding associated with potentially irreversible
neurological deficiency. By comparison, a neuro-ophthalmologic
examination showing dysconjugate gaze is a sensitive finding
that usually precedes imaging findings of overt cavernous
sinus infection.
OTHER INVASIVE FUNGAL INFECTIONS
Pneumocystis Pneumonia
Pneumocystis pneumonia is a common fungal pneumonia
among immunocompromised patients and is the most common
acquired immunodeficiency syndrome–defining opportunistic
infection. The characteristic chest radiographic findings
are symmetrical perihilar interstitial infiltrates, although normal
findings, unilateral infiltrates, consolidations, nodules, and
cavities can be observed also. Pneumothorax and pneumomediastinum
can appear as an occasional complication. CT is the imaging modality of choice to show diffuse
patchy ground-glass
opacity and thickening of the interlobular septa [67].
Histoplasmosis
Histoplasmosis is caused by Histoplasma capsulatum, a fungal
species usually transmitted through the respiratory tract [85].
Histoplasma infection occurs most commonly in specific regions
of North America. Children have a high rate of asymptomatic
or mild infection, whereas clinically overt histoplasmosis affects
mainly young adults who are infected in an outbreak or immunosuppressed
patients with T-cell immune impairment. Infants are at
high risk of developing disseminated disease. Infantile histoplasmosis
is a distinctive syndrome characterized by fever, pancytopenia,
and hepatosplenomegaly that can resemble acute leukemia or
severe aplastic anemia. Although the tissue burden in infantile histoplasmosis
is high, a chest radiograph can be devoid of nodules.
The radiologic manifestations of histoplasmosis are similar
to those of tuberculosis. In patients with acute pulmonary histoplasmosis,
enlarged hilar or mediastinal lymph nodes and
lobar infiltrates are found. Mediastinal granuloma, mediastinal
fibrosis, and pericarditis are late sequelae of mediastinal
histoplasmosis. Many of the findings on radiographs represent
the immune response to infection. As such, radiographic findings
can be absent in immunocompromised hosts. As much
as 40% to 50% of immunocompromised patients with disseminated
histoplasmosis can have normal chest radiograph
results [85, 86].
Blastomycosis
Infection caused by Blastomyces dermatitidis occurs in North
America in several geographically distinct areas, including
the north-central United States, the Mid-Atlantic, and the
Southeast and south-central Canada. Blastomycosis is characterized
by dense pulmonary infiltrates or spiculated nodules
associated with lytic bone infection and cutaneous lesions [87].
CNS infection in children with blastomycosis can present as a
solitary mass lesion on either a brain CT scan or MRI simulating
a brain tumor [88].
Coccidioidomycosis
Infection caused by Coccidioides spp. can present with pulmonary,
CNS, and osteoarticular involvement. Unlike the lesions
of histoplasmosis, the cavities of pulmonary coccidioidomycosis
tend to be thin walled, and the nodules do not usually calcify.
CNS coccidioidomycosis can cause basilar meningitis with
hypopituitarism and basilar granulomatous vasculitis leading to
stroke. The bony lesions are osteolytic.
Rammaert et al [89] compared the patterns of osteomyelitis
caused by the major endemic dimorphic mycoses. When only
1 osteoarticular site was involved, Sporothrix schenckii most
commonly infected joints. By comparison, the most common
cause of single bone infection was B dermatitidis. When B dermatitidis, Coccidioides immitis,
and H capsulatum infected
vertebrae, they most commonly did so as a single site. By comparison,
when S. schenckii and Talaromyces (Penicillium) marneffei
caused vertebral osteomyelitis, the infection was virtually
always associated with disseminated polyosseous disease.
FUTURE DIRECTIONS
Diagnostic imaging in children at risk for an IFD plays a critical
role in the diagnostic evaluation and therapeutic monitoring.
Diagnostic imaging has undergone a revolution in technology
within the past 25 years. Future studies of pediatric mycoses are
necessary to continue to elucidate the utility of these technologies
of early detection and the implication of using modality-
specific findings to narrow the differential diagnosis of these
devastating diseases.
Notes
Financial support. Dr Walsh was supported in part for this work as a
scholar in mucormycosis of the Henry Schueler Foundation.
Supplement sponsorship. This article appears as part of the supplement
“State of the Art Diagnosis of Pediatric Invasive Fungal Disease:
Recommendations From the Joint European Organization for the Treatment
of Cancer/Mycoses Study Group (EORTC/MSG) Pediatric Committee,”
sponsored by Astellas.
Potential conflicts of interest. Dr Fisher’s institution receives research
funding on his behalf from Pfizer, Merck, and Ansun Biopharma. All other
authors report no potential conflicts. All authors have submitted the ICMJE
Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors
consider relevant to the content of the manuscript have been disclosed.