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E D I T O R I A L C O M M E N TA R Y
Earlier Diagnosis of Angioinvasive Pulmonary Mold Disease: Is
Computed Tomography Pulmonary Angiography a New Step?
Raoul Herbrecht1 and Marie-Noëlle Roedlich2
1Department
of Oncology and Hematology, 2Department of Radiology, Hôpital de Hautepierre, Strasbourg, France
(See the Major Article by Stanzani et al, on pages 610–6.)
Molds are a frequent cause of morbidity and
mortality in allogeneic hematopoietic stem
cell transplant recipients and in patients
with hematological malignancies. The most
frequent molds involved in this setting
are Aspergillus spp. and Zygomycetes [1].
Aspergillus and Zygomycetes infect the
lower or upper respiratory tract after inhalation of spores. When host defenses are
failing, the spores germinate and the hyphae invade the tissue. Because they also
invade the vessels (Figure 1) and occlude
them, thrombosis results in infarction of
the tissues, and necrosis is a hallmark of
the disease whatever the localization. Most
of the clinical and radiological signs are
explained by tissue infarction.
High-resolution computed tomography
(CT) scan allows earlier detection of pulmonary lesions in high-risk febrile patients.
The typical CT scan aspects of invasive aspergillosis are presence of nodules. The lesions can be modified by presence of a halo
sign (early phase), an air crescent sign
(usually after recovery from neutropenia),
or a cavity. The halo sign indicates a rim of
Received 23 October 2011; accepted 28 October 2011;
electronically published 14 December 2011.
Correspondence: Raoul Herbrecht, MD, Department of
Oncology and Hematology, Hôpital de Hautepierre, 67098
Strasbourg, France ([email protected]).
Clinical Infectious Diseases 2012;54(5):617–20
Ó The Author 2011. Published by Oxford University Press on
behalf of the Infectious Diseases Society of America. All rights
reserved. For Permissions, please e-mail: journals.permissions@
oup.com.
DOI: 10.1093/cid/cir894
ground glass opacity around a nodule
with a progressive attenuation. At pathologic examination, the nodules represent foci of infarction, and the halo of
ground glass opacity results from alveolar hemorrhage [2]. Presence of a halo
sign around nodules was first described
in invasive pulmonary aspergillosis [3].
It has also been reported in non-Aspergillus
fungal infections, nonfungal infections,
primary or metastatic neoplasms, inflammatory or systemic diseases, and iatrogenic injury such as transbronchial lung
biopsy [4].
Based on data from a large clinical
trial [5], Greene et al showed that nodules
were present at baseline in 94% of the
cases of invasive aspergillosis and that at
least one macronodule (.1 cm) was surrounded by a halo sign in 64% of the cases
with nodular lesions [6]. These results
supported the decision by the European
Organisation for Research and Treatment
of Cancer/Mycosis Study Group (EORTC/
MSG) consensus group to consider a nodule with a halo sign a strong radiological
signal in favor of invasive aspergillosis in
a patient with host factors predisposing to
this infection [7]. However, a limitation of
the analysis by Greene et al is that the
presence of a nodule with a halo sign was
a criterion for inclusion in the clinical trial,
and therefore there might have been an
overestimation of the rates of nodular lesion as well as of halo sign. In our local
series of 208 consecutive cases of invasive pulmonary aspergillosis [8], 155
(75%) patients had at least one nodule
on the first CT scan, and only 51% of
them had a halo sign around the nodule.
The consensus definitions for invasive
fungal diseases have appropriately been
updated in 2008 and have accepted that
patients with a dense well-circumscribed
lesion may qualify for invasive pulmonary fungal disease [7, 9]. Although not
clearly stated, dense well-circumscribed
lesions include nodules, non-nodular
infarcts, and consolidations. Whether alveolar infiltrates are also included remains
a debate, and clarification is expected from
the next update.
Despite recent improvements in diagnosis and treatment of invasive aspergillosis, the mortality rate remains high, in
the range of 30%–40% [5]. Because earlier
onset of treatment has been associated
with better outcome, any new diagnostic
method can help to further improve the
outcome. In 2005, Sonnet et al suggested
that high-resolution multidetector CT
angiography allows direct detection of
angioinvasion in aspergillosis or mucormycosis by showing the vascular occlusion at a peripheral level [10]. Vascular
occlusion has been defined as an interruption of a pulmonary artery at the
border of a focal lesion without depiction
of the vessel inside the lesion or peripheral to the lesion. Vascular occlusion was
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Figure 1. Disseminated Cunninghamella bertholettiae infection. Lung histopathology shows hyphae (arrows) penetrating into an arteriole (A) to form
a fungal thrombosis. The left side shows a section of a bronchiole (B). Gomori methenamine silver staining.
detected on CT angiography in 4 of the 5
lesions with histologically proven fungal
angioinvasion. Only 2 of the lesions had
a halo sign on the CT scan, suggesting
a superiority of the vascular occlusion
sign in detecting invasive mold infections.
In all 9 lesions in which angioinvasive
infection was excluded, CT angiography
showed patent vessels. Final diagnoses in
these 9 cases were scar tissue, hematoma,
lymphoma, atypical mycobacterium infection, or diffuse alveolar damages. The
authors concluded that high-resolution
multidetector CT angiography can directly depict vessel occlusion in the setting
of suspected fungal infections.
In this issue, Stanzani et al report their
experience with CT pulmonary angiography in diagnosis of pulmonary mold
diseases in patients with hematological
malignancies [11]. Thirty patients with
a suspicion of invasive mold disease were
enrolled. The CT angiography was performed after the basal high-resolution CT
scan had shown a nodule ($10 mm).
Interestingly, results have been correlated
with final diagnosis using the EORTC/
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MSG criteria [9]. Twenty-one patients
had proven, probable, or possible invasive molds disease. Nineteen (90%) had
a positive vascular occlusion sign. Fifteen
patients had no invasive mold disease,
and only one had a positive vascular occlusion sign. The sensitivity of the sign to
detect an invasive mold disease is 83%, and
the specifity is 93%. These performances
are similar to those observed by Sonnet
(80% and 100%, respectively) [10]. These
results place the occlusion sign at the
same level of performance for the diagnosis of invasive disease as the serum
galactomannan detection test for invasive
aspergillosis [12]. The vascular occlusion
sign probably deserves a place among the
criteria defining invasive mold disease.
We must also highlight the limitations
with routine angiography in patients suspected of invasive mold disease. Contrastinduced acute kidney injury, usually
defined by an increase of serum creatinine
of $0.5 mg/dL or by .25% increase over
baseline creatinine value within 48 hours
following contrast exposure, is the third
most common cause of hospital acquired
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acute renal failure [13, 14]. Incidence of
contrast-induced acute kidney injury has
been estimated to be 3% in patients
without risk factors but can rise to 30%
among patients aged .70 years or with
chronic renal disease, diabetes mellitus,
congestive heart failure, or hypotension.
Occurrence of a contrast-induced acute
renal failure has major consequences for
patients, including need for dialysis and
increased mortality [14, 15]. Patients at
risk of invasive mold disease certainly are
at increased risk of contrast-induced acute
kidney injury because of prior or concomitant exposure to nephrotoxic agents
such as aminoglycosides, glycopeptides,
cytotoxic agents, or immunosuppressants.
They also often have diabetes mellitus,
a significant risk factor for zygomycosis.
In addition to nephrotoxicity, others
adverse events are also possible after contrast media injection. In a recent review of
the tolerance of iodinated contrast media
administration in 1514 patients, Lapi et al
reported immediate (within 1 hour after
injection) or delayed (.1 hour and up to
1 week) adverse events in 172 (11.3%)
patients [16]. Thirty-four (2.2%) patients
experienced immediate events that included nausea, vomiting, headache, hypotension, bronchospasm, glottal obstruction,
local or generalized urticaria, palpebral
edema, rash, and itching. Most immediate
events occurred in patients who received
monomeric low-osmolar contrast media
(iopromide, iomeprol, iobitridol), while
only three immediate events were recorded
in patients receiving dimeric iso-osmolar
media (iodixanol). Delayed events occurred in 144 (9.5%) patients, with a higher
incidence in patients receiving dimeric isoosmolar media. Delayed events included
skin events similar to the immediate skin
events, diarrhea, fever, myalgia, arthralgia,
and abdominal pain. However, despite the
overall high incidence of adverse events, all
but one were mild or moderate.
Increased irradiation dose can also be
a concern. Before deciding for angiography,
Stanzani et al first realized a high-resolution
CT scan without contrast. Angiography
was only performed if a dense nodule
($10 mm) was present on a basal CT scan.
This double CT scan is mandatory to avoid
exposure to contrast media if there is no
dense lesion on the basal CT scan. It leads,
however, to a double radiation exposure.
Because response assessment of invasive
pulmonary mold diseases is mainly based
on radiology [17], patients may be exposed to cumulative high radiation dose.
Options to limit total radiation dose are to
reduce the number of follow-up CT scans
and to use low-dose follow-up CT scans.
Low-dose CT scans may be associated
with a slight decrease in image accuracy
that is unlikely to affect the response assessment of lesions previously identified
by standard-dose CT scans [18].
A technical limit of the approach proposed by Sonnet et al and Stanzani et al is
the size of the lesion [10, 11]. Small
(,10 mm) or very peripheral nodules are
not exhaustively assessable by angiography. In both studies, the CT scan was
a 16-multidetector scan. Currently CT
scanners often have 32, 64, or even 128
detectors. This technical improvement
should result in an improvement in detection of smaller lesions.
Angioinvasive aspergillosis is the most
common pattern of invasive aspergillosis in
neutropenic patients, stem cell transplant
recipients, and patients receiving steroids
[19]. A second pattern of the disease, more
frequent in non-neutropenic patients, is
airway invasive aspergillosis. CT scan aspects of airway invasive disease are airspace consolidations, also called Aspergillus
bronchopneumonia, and a ‘‘bud in tree’’
pattern [20]. No vascular occlusion is
expected at the early stage of an airway
invasive aspergillosis, and therefore CT
pulmonary angiography is useless.
In conclusion, the vascular occlusion
sign is a sensitive and specific sign of
angioinvasive pulmonary mold disease.
The diagnostic performance of this sign
seems better than that of the halo sign
and close to the performance of the serum galactomannan test for invasive
aspergillosis. The need for iodinated
contrast media administration requires
excluding from this approach patients
with a higher risk of contrast-induced
acute kidney injury.
Note
Potential conflicts of interest. All authors: No
reported conflicts.
Both 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.
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