the diagnostic value of halo and reversed halo signs … · signs for invasive mold infections in...

I M M U N O C O M P R O M I S E D H O S T S I N V I T E D A R T I C L EDavid R. Snydman, Section Editor

The Diagnostic Value of Halo and Reversed HaloSigns for Invasive Mold Infections inCompromised Hosts

Sarah P. Georgiadou,1 Nikolaos V. Sipsas,1 Edith M. Marom,2 and Dimitrios P. Kontoyiannis3

1Infectious Diseases Unit, Pathophysiology Department, Laikon General Hospital and Medical School, National and Kapodistrian University of Athens,Athens, Greece; and Departments of 2Diagnostic Radiology, and 3Infectious Diseases, Infection Control, and Employee Health, The University of TexasMD Anderson Cancer Center, Houston, Texas

The halo sign is a CT finding of ground-glass opacity surrounding a pulmonary nodule or mass. The reversed

halo sign is a focal rounded area of ground-glass opacity surrounded by a crescent or complete ring of

consolidation. In severely immunocompromised patients, these signs are highly suggestive of early infection by

an angioinvasive fungus. The halo sign and reversed halo sign are most commonly associated with invasive

pulmonary aspergillosis and pulmonary mucormycosis, respectively. Many other infections and noninfectious

conditions, such as neoplastic and inflammatory processes, may also manifest with pulmonary nodules

associated with either sign. Although nonspecific, both signs can be useful for preemptive initiation of

antifungal therapy in the appropriate clinical setting. This review aims to evaluate the diagnostic value of the

halo sign and reversed halo sign in immunocompromised hosts and describes the wide spectrum of diseases

associated with them.

Opportunistic invasive fungal infection (IFI), particu-

larly fungal pneumonia, continues to be a diagnostic

and therapeutic challenge. Early detection of IFI is im-

perative, because the outcome depends strongly on

prompt use of appropriate antifungals [1]. CT is an

important tool in early diagnosis of pulmonary infection

in immunocompromised hosts [2]. With the in-

troduction of multidetector CT scanners, thin-section

scans (<3 mm) are routinely used to image the lungs.

Thin-section CT may identify the halo sign (HS) and

reversed HS (RHS), which in immunocompromised

patients, are presumed to indicate pulmonary IFI [3, 4].

However, the following 2 questions are arising: whether

these radiological signs are pathognomonic for pulmo-

nary mycoses and whether their absence can rule out

pulmonary IFI. In this review, we describe and evaluate

the diagnostic value of the HS and RHS in the immu-

nocompromised host and summarize the wide spectrum

of diseases associated with these radiological signs.

THE HS

The HS was initially described by Kuhlman et al [5] in

patients with acute leukemia and IPA. The definition

of the HS was published in 1996 and agreed on by ra-

diologists: HS corresponds to ground glass opacity

surrounding the circumference of a nodule or mass

(Figure 1A) [6]. Histopathologically, it represents

a focus of pulmonary infarction surrounded by alveolar

hemorrhage (Figure 1B). In neutropenic patients,

Aspergillus invades small and medium-sized pulmonary

vessels, causing thrombosis and subsequent ischemic

necrosis of the lung parenchyma [7]. The central area of

necrosis corresponds to the nodule, whereas surround-

ing hemorrhage corresponds to the halo of ground-glass

attenuation.

Received 5 October 2010; accepted 27 January 2011.Correspondence: Dimitrios P. Kontoyiannis, MD, Dept of Infectious Diseases,

Infection Control and Employee Health, Unit 402, The University of Texas MDAnderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 ([email protected]).

Clinical Infectious Diseases 2011;52(9):1144–1155� The Author 2011. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]/2011/529-0001$37.00DOI: 10.1093/cid/cir122

1144 d CID 2011:52 (1 May) d IMMUNOCOMPROMISED HOSTS

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Since its first report, HS has also been associated with a variety

of pulmonary diseases, both infectious and noninfectious, such

as neoplastic and inflammatory conditions (Table 1) [8–11]. In

these cases, the HS is caused by neoplastic or inflammatory

infiltration of the surrounding lung parenchyma or, rarely,

hemorrhage around a metastasis.

MEDICAL CONDITIONS ASSOCIATED WITH

THE HS

Fungal InfectionsAspergillosis. The most common pulmonary infection in im-

munocompromised patients indicated by HS is IPA [12–16].

Patients with the other, more chronic forms of pulmonary as-

pergillosis typically do not exhibit HS [17, 18]. The incidence of

HS among patients with IPA is particularly high during its early

stages; over time, HS tends to disappear [19]. In a seminal report,

Caillot et al [20] systematically studied the evolution of lung le-

sions in 25 patients with neutropenia, hematological malignan-

cies, and IPA with use of serial CT. The incidence of HS on days 0,

3, 7, and 14 of IPA was 96%, 68%, 22%, and 19%, respectively.

One of the main conclusions of that study was that HS is the

earliest radiological manifestation of IPA but is transitory, because

its incidence decreased rapidly during the first 3 days after the

onset of infection. A recent study further underlined the transient

nature of HS. In that study, the researchers evaluated 40 patients

with hematological malignancies and IPA [21]. The exact in-

cidence of HS was 88%, 63%, 37%, and 18% on days 1, 4, 8, and

16, respectively. Thus, this narrow window of opportunity for

early detection of IPA according to HS presence underscores the

importance of early, systematic CT in patients at high risk.

Not surprisingly, initiation of systemic antifungal therapy

for early-stage IPA, as indicated by HS, influences outcome. In

fact, studies since the 1980s have shown that the mortality

associated with IPA among patients with acute leukemia and

IPA reached 90% when treatment was initiated at least 10 days

after the first clinical or radiological signs of disease, com-

pared with 40% when treatment was instigated early [1, 22,

23]. In another recent study of a cohort of 235 patients with

hematological malignancies and IPA enrolled in a pivotal

randomized trial, Greene et al [3] reported that the HS was

present on 61% of baseline CT scans. Initiation of treatment with

antifungals based on the identification of HS on a chest CT was

associated with significantly improved responses to treatment

and survival, reflecting the beneficial effect of early initiation of

treatment [3, 24].

Although still a subject of contention, initiation of aspergil-

losis treatment driven by early CT findings may be more reliable

than that driven by Aspergillus galactomannan (GM), because

detection of biomarkers may not precede detection of lesions by

chest CT. [25]. In addition, the treatment response is higher in

patients with IPA diagnosed according to HS presence than in

patients with microbiologically confirmed IPA [26–28], high-

lighting that early treatment based on probable IPA, compared

with proven IPA, contributes to improved outcomes [27]. A

recent retrospective study demonstrated that GM–supported

IPA, without prespecified radiologic criteria (eg, dense, well-

circumscribed lesions with or without HS, air crescent sign, or

cavity) on the basis of European Organization for Research and

Treatment of Cancer/Mycoses Study Group definitions [29],

likely represents an earlier stage of IPA and should, therefore, be

considered as probable IPA [30]. Nevertheless, the lack of

Figure 1. Radiological and histopathological appearance of HS. A, A 41-year-old neutropenic man who received treatment for acute myeloid leukemiapresented with a temperature of 39.5�C. This thin-section (3 mm) contrast-enhanced chest CT scan of the patient at the level of the main bronchi (B)shows pulmonary nodules (N) surrounded by ground-glass opacities (white arrows), the HS. Of note, the normal lung vessels can be seen through theincreased opacity surrounding the nodules, thus the term ground-glass opacities. The result of the Aspergillus antigen assay was positive on the day thatCT was performed, and Aspergillus terreus grew in bronchoalveolar lavage (BAL) cultures. B, Histopathological correlates of the HS in IPA. Left,Macroscopic lung section (autopsy specimen) with discrete, sharply demarcated nodules (arrows) surrounded by a rim of hemorrhaging. Right, Acutehemorrhagic necrosis in the periphery of the nodule (arrow) without an inflammatory response (hematoxylin and eosin stain). Figure 1B is published withpermission from Shibuya K, et al J Infect Chemother 2004; 10: 138–45. � Japanese Society of Chemotherapy and The Japanese Association forInfectious Diseases, 2004.

IMMUNOCOMPROMISED HOSTS d CID 2011:52 (1 May) d 1145

specificity of GM test may lead to more patients without IPA

enrolled in clinical trials [31].

Whereas it is widely acknowledged that the HS is seen fre-

quently in patients with early-stage IPA, not all authors have

reported the same high frequency. In fact, the incidence of HS

among neutropenic patients with hematological malignancies

has varied widely, ranging from 25% to 95% [5, 12, 13, 15, 20,

21, 32–37]. Whether these discrepancies reflect differences in HS

definition or differences in the timing of CT is unclear. Although

data on interobserver agreement regarding the HS are limited,

a recent study found that the rate of interradiologist agreement

was 72% [3]. In studies evaluating patients with IPA after allo-

geneic hematopoietic stem cell transplantation (HSCT), HS was

observed in 47%–75% of patients [14, 38, 39]. Of interest, the HS

was a relatively common indicator of late IPA in allogeneic HSCT

recipients who developed graft-versus-host disease (GVHD) [40].

In comparison, the incidence of the HS among other im-

munosuppressed but not myelosuppressed patients with IPA

appears to be lower than that among neutropenic patients with

hematological cancer. A recent study showed that only 2.5% of

patients with IPA in an intensive care unit had HS on CT scans

[41] (Table 2). Moreover, only a few series have evaluated the

radiological spectrum of IPA in the pediatric age group [47–49].

In general, the frequency of HS and cavitation among pediatric

patients seems to be lower than that among adults. This phe-

nomenon could be possibly attributed either to differences in

host immune response or to the late-stage performance of CT.

Although the frequency of HS in early stage IPA may vary

according to the host’s state of myelosuppression, most [12–16]

but not all [35, 37, 50] investigators have demonstrated the high

specificity of the HS in diagnosis of IPA in immunocompro-

mised hosts (Table 3). Likewise, the specificity of HS in di-

agnosis of IPA seems to be higher among patients with

hematological malignancies who have profound neutropenia

and persistent fever not responding to broad-spectrum anti-

biotics than among patients with pulmonary infection who are

immunosuppressed but not myelosuppressed. Yeghen et al [51]

and Bernard et al [52] demonstrated that the presence of HS

had a high positive predictive value (.90%) for presumptive

diagnosis of IPA in neutropenic patients with hematological

Table 1. Spectrum of Pulmonary Diseases Associated with theHalo Sign

Fungal infections

Invasive aspergillosis

Mucormycosis

Pulmonary candidiasis

Cryptococcosis

Coccidioidomycosis

Phaeohyphomycosis

Viral infections

Herpes simplex virus

Varicella-zoster virus

Respiratory syncytial virus

Cytomegalovirus

Myxovirus (including Influenza A)

Bacterial infections

Coxiella burnetii

Chlamydia psittaci

Actinomyces species

Bacterial pneumonia

Slow-resolving pneumonia

Septic emboli

Mycobacterial infections

Mycobacterium tuberculosis

Mycobacterium avium-intracellulare

Parasitic infections

Schistosoma (haematobium, mansoni)

Paragonimus westermani

Hydatid disease

Toxocara canis

Ascaris suum

Systemic diseases

Wegener granulomatosis

Sarcoidosis

Amyloidosis

Neoplastic diseases

Primary

Bronchoalveolar carcinoma

Squamous cell carcinoma

Adenocarcinoma

Mucinous cystadenocarcinoma

Kaposi sarcoma

Angiosarcoma

Lymphoma

Metastatic lesions

Angiosarcoma

Choriocarcinoma

Osteosarcoma

Melanoma

Gastrointestinal tract/pancreatic cancer

Renal cell carcinoma

Lymphoma

Various pulmonary diseases

Cryptogenic organizing pneumonia

Table 1. (Continued)

Eosinophilic pneumonia

Idiopathic hypereosinophilic syndrome

Hypersensitivity pneumonia

Iatrogenic injuries: pulmonary artery catheterization ortransbronchial biopsy (especially in lung transplants)

Other

Endometriosis

Drug toxicity (amiodarone)


Table 2. Prevalence of the Halo Sign (HS) among Immunocompromised Patients with Invasive Fungal Infection (IIFI)

Study Sample size Timing of CT scan after the

onset of clinical symptoms

Validation of IFI Presence of the HS

Greene et al [3] 235 patients with IPA (203 with a hematologicalmalignancy, 12 with high-dose corticosteroid use,11 with AIDS, 8 with solid organ transplantation,and 1 with a solid tumor)

NA Criteria of the EuropeanOrganisation for Researchand Treatment ofCancer/Mycoses StudyGroup [42]

143/235 (61%) (135 with ahematological malignancyand 8 with a nonhematological malignancy)

Kuhlman et al [5] 9 patients with acute leukemia, neutropenia, andIPA

NA Sputum culture or histologically viatransthoracic needlebiopsy aspiration or surgicallobectomy

2/9 (22%)

Blum et al [12] 38 patients with neutropenia (31 with ahematological malignancy, 6 with solid tumors,and 1 with human immunodeficiency virus) andsuspected IPA

<10 days (group A)and .10 days(group B)

Antemortem microscopically,BAL culture, or histologicallyusing surgery/percutaneousneedle biopsy/postmortemautopsy

16/22 (72%) with provenIPA in group A and 3/13(23%) with proven IPA ingroup B

Bruno et al [13] 68 patients with IPA and 56 patients with bacterialpneumonia and prolonged neutropenia inducedby bone marrow transplantation and/or high-dosechemotherapy for hematological malignancies

Within 24 hours Histologically using lung biopsyor BAL culture

17/68 (25%) in the IPA groupand 2/56 (4%) in thebacterial pneumonia group

Escuissato et al [14] 111 patients with proven pulmonary infection afterHSCT for hematological conditions

Within 24 hours Histologically or using cultureof BAL, sputum, or bloodspecimens

10/21 (48%) patients withIFI (17 with IPA, 3 withpulmonary candidiasis, and1 with both)

Kami et al [15] 48 patients with neutropenia, a hematologicalmalignancy, and suspected IPA who underwentautopsy

NA Culture or microscopically inlung specimens

13/17 (76%) with proven IPA

Caillot et al [20] 25 patients with a hematological malignancy,neutropenia, and IPA

Days 0, 3, 7,and 14

Histologically using surgicaltissue excision

24/25 (96%) on day 0, 8/13(62%) on day 3, 4/18 (22%)on day 7, and 3/16 (19%)on day 14

Brodoefel et al [21] 40 patients with a hematological malignancy andIPA (65% with neutropenia)

Days 1, 4, 8,and 16

Histologically using lung biopsy,positivity for galactomannanantigen, positive BAL culture,or PCR BAL positive

88% on day 1, 63% on day 4,37% on day 8, and 18% onday 16

Hauggaard et al [32] 21 patients with a hematological malignancy,neutropenia, and IPA

Mean, 9 days(range,1-10 days)

Criteria of the EuropeanOrganisation for Research andTreatment of Cancer/MycosesStudy Group [42]

20/21 (95%),

Horger et al [33] 45 patients with IPA (42 with a hematologicalmalignancy, 2 with renal transplantation, and 1with long-term corticosteroid use), 24 of whomhad neutropenia

Day 1 Histologically using lung biopsy,positivity for galactomannanantigen, BAL culture, or PCRBAL positivity

38/45 (84%)

Horger et al [34] 43 patients with IPA who were either neutropenicor severely immunocompromised because ofhematological disease following high-dosechemotherapy (n 5 13) or HSCT (n 5 30)

NA Histologically using lung biopsy,BAL culture, positivity forgalactomannan antigen, or apositive PCR in the BAL specimen

31/43 (72%)

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Table 2. (Continued)Study Sample size Timing of CT scan after the

onset of clinical symptoms

Validation of IFI Presence of the HS

Kim et al [35] 31 patients with a hematological malignancy(22 with severe neutropenia) and suspectedIPA who underwent lung biopsy

Median duration,12 days(range, NA)

Histologically using open lungbiopsy

11/17 (65%) with provenIFI (13 with IPA, 2 withaspergilloma, and 2 withPM)

Kuhlman et al [36] 10 patients with acute leukemia, neutropenia,and IPA

NA Microscopically or histologically,via surgical lobectomy/lungbiopsy/autopsy, or positivecultures from sputum and/orextrapulmonary sites

8/10 (80%)

Won et al [37] 11 patients with neutropenia, a hematologicalmalignancy, and suspected IPA who underwentlung biopsy

NA Histologically using lungbiopsy

2/5 (40%) with proven IPAand 1/2 (50%) with PM

Ribaud et al [38] 27 patients with HSCT and IPA (5 with neutropenia,20 with acute GVHD, and 5 with chronic GVHD)

NA Microscopically or usingculture of BAL or sputumspecimens

15/27 (56%)

Gasparetto et al [39] 12 patients with IPA after HSCT for hematologicalconditions (3 cases [25%] in the neutropenicphase, 5 [42%] in the early phase, and 4 [33%] inthe late phase after HSCT)

NA Culture of sputum or BALspecimens, histologicallyusing lung biopsy, ormicroscopically after autopsy

9/12 (75%)

Kojima et al [40] 27 patients with late IPA after allo-SCT for hematological conditions without neutropenia (24 withGVHD)

NA Histologically or cultureafter autopsy

12/27 (44%)

Vandewoude et al [41] 83 patients in the ICU with IPA (60% without riskfactors such as neutropenia, a hematologicalmalignancy, HSCT, or allo-SCT)

NA Histologically or using cultureof lung tissue obtained vialung biopsy, autopsy, or BALculture

2/83 (2%)

Jamadar et al [43] 8 patients with PM (6 patients with a hematologicalmalignancy and 2 with solid organ transplantation)

NA Histologically using lungbiopsy, BAL culture, bloodculture, or sputum culture

3/8 (38%)

Chamilos et al [44] 16 patients with PM (15 with a hematological malignancy) and 29 with IPA (27 with a hematological malignancy)

5 days in the PMgroup and 2 in the IPA group

Criteria of the EuropeanOrganisation for Researchand Treatment of Cancer/Mycosis Study Group [42]

4/16 (25%) in the PMgroup and 5/24 (21%)in the IPA group

Althoff Souza et al [45] 32 patients with IPA and 22 with pulmonary candidiasis (in total, 48 with a hematological malignancy, 3 with solid organ transplantation, 1 witha solid tumor, 1 with high-dose corticosteroiduse, and 1 with leptomeningeal granulomatosis)

NA Histologically using lungbiopsy/autopsy or sputumculture, or BAL culture

12/32 (38%) in the IPAgroup and 7/22 (32%) inthe candidiasis group

Franquet et al [46] 17 patients with allo-SCT and proven pulmonarycandidiasis

3 days Histologically usingtransbronchial biopsy,open lung biopsy, or autopsy

5/17 (29%)

NOTE. NA, not available; PCR, polymerase chain reaction; HSCT, hematopoietic stem cell transplantation; ICU, intensive care unit; CT, computed tomography; IFI, invasive fungal infection; HS, halo sign; IPA,

invasive pulmonary aspergillosis; BAL, broncho-alveolar lavage; PM, pulmonary mucormycosis; GVHD, graft-versus-host-disease.

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malignancies. Whether this specificity is decreased in the era of

frequent use of Aspergillus-active agents as prophylaxis is of

concern. In fact, recent studies at health care centers with high

incidences of PM indicated that CT-guided lung biopsy was

superior to CT imaging for reliable diagnosis of IFI caused by

septate versus nonseptate hyphae [35, 53].

Investigators have placed great emphasis on the HS for di-

agnosis of IPA, but in reality, any pulmonary nodule .1 cm in

diameter in a severely immunocompromised host is more likely

to indicate IPA than other nonfungal infections with or without

a halo surrounding it [14, 54]. At different stages of IPA, in

severely immunocompromised hosts, cavitation of the nodule

or mass and appearance of the air crescent sign are seen [3, 20,

21]. The air crescent sign, in particular, is a rather late sign of

IPA. This sign is caused by retraction of necrotic lung from the

adjacent parenchyma after neutrophil infiltration and resolution

of neutropenia [5, 20, 21, 55, 56]. In the study by Caillot et al

[20], the air crescent sign was observed in 8%, 28%, and 63% of

the cases and nonspecific airspace consolidation in 31%, 50%,

and 18% of the cases on days 3, 7, and 14, respectively, after the

onset of infection. Thus, the air crescent sign is diagnostically

useful for IPA but has little impact on management, because

patients are already beyond the neutropenic phase.

The majority of patients with IPA present with at least 1

macronodule on a chest CT, defined as a nodule at least 1 cm in

diameter [3, 54]. Other common but less-specific CT findings

that can occur with IPA include segmental or peribronchial

consolidation with or without tree-in-bud opacities, cavitary le-

sions with or without air crescent sign, pleural effusions, non-

specific ground-glass opacities, atelectasis [3, 15, 16, 32, 33, 39],

and, rarely, mycotic aneurysms of the pulmonary artery [57].

Bilateral, asymmetric distribution of pulmonary lesions is the

dominant pattern. Of importance, the volume of aspergillosis

lesions evaluated by sequential thoracic CT may increase during

the first days after antifungal treatment [20, 21]. In a recent

prospective study, authors showed that the sequential analysis of

CT in neutropenic patients with IPA depicts more precisely the

evolution of lesion volumes, compared with baseline images [58].

Although other imaging modalitites, such as positron emis-

sion tomography (PET) and MRI, can detect IPA, thin-section

CT remains the most sensitive and validated radiological

method of early detection of IPA, because its spatial resolution is

Table 3. Prevalence of IFIs in Immunocompromised Hosts with the HS and Specificity of the HS for IFIs

Study Sample size with the HS

Timing of CT scan

after the onset of

clinical symptoms Prevalence of IFIs Specificity (%)

Blum et al [12] 16 patients with neutropenia andpulmonary infection

<10 days 16/16 (100%) with IPAand none withbacterial pneumonia

100.0

Bruno et al [13] 19 patients with prolongedneutropenia induced by HSCTand/or high-dose chemotherapyfor hematologic malignancies

Within 24 hours 17/19 (89%) with IPAand 2/19 (11%) withbacterial pneumonia

96.4

Escuissato et al [14] 16 patients with a proven pulmonaryinfection after HSCT for hematologicalconditions

Within 24 hours 10/16 (63%) with IFIs(mostly IPA), 3/16 withRSV pneumonia, 2/16 withbacterial pneumonia, and1/16 with CMV pneumonia

92.3

Kami et al [15] 13 patients with neutropenia and ahematological malignancy

NA 13/13 (100%) IPA 100.0

Kami et al [16] 17 patients with a hematologicalmalignancy, HSCT, and a pulmonaryinfection

NA 15/17 (88%) with IPA and2/17 (12%) with non-IPA

97.4

Kim et al [35] 23 patients with a hematologicalmalignancy (most with severe neutropenia)and suspected IPA who underwent lungbiopsy

Median, 12 days 11/23 (48%) with provenIFIs (mostly IPA) and 12/23(52.2%) with non-IFIs

20.0

Won et al [37] 5 patients with neutropenia, a hematologicalmalignancy, and suspected IPA whounderwent lung biopsy

NA 2/5 (40%) with IPA, 1/5 withPM, and 2/5 with cryptogenicorganizing pneumonia

60

Franquet et al [50] 22 immunocompromised patients (HSCT,solid organ transplantation, hematologicalmalignancy, HIV infection, or corticosteroidtherapy) with pulmonary infections

NA 4/22 (18%) with IFIs, 7/22(32%) with viral infections,6/22 (27%) withmycobacterial infections, and5/22 (23%) withbacterial infections

67.8

Abbreviations. CMV, cytomegalovirus; HIV, human immunodeficiency virus; HSCT, hematopoietic stem cell transplantation; IPA, invasive pulmonary

aspergillosis; NA, not available; PCR, polymerase chain reaction; PM, pulmonary mucormycosis; RSV, respiratory syncytial virus.


much higher than that of PET and MRI. In brief, fluorodeox-

yglucose (FDG)-PET can detect foci of invasive mold infections

[59], but it is nonspecific, because both infection and malig-

nancy show increased FDG uptake. FDG - PET could be con-

sidered for immunosuppressed patients with suspected

infections and an infection-negative diagnostic examination and

in those with a recently treated fungal pneumonia but persistent

radiological findings to determine the activity of infection [59,

60]. Furthermore, nuclear medicine agents are constantly

evolving. For example, in a recent study, 68Ga-siderophores

accumulated selectively in Aspergillus fumigatus in mice both

in vitro and in vivo [61]. Finally, MRI has yet to be studied

extensively in IPA. Researchers found that the typical pattern of

an isointense nodular pulmonary lesion on a T1-weighted MRI

and a hyperintense center on a T2-weighted image (reverse target

sign) with a gadolinium-enhanced rim margin was a strong in-

dicator of fungal pneumonia in immunocompromised patients

[62]. Nevertheless, diagnosis of IPA with use of MRI may be

rather problematic, because MRI findings are not as character-

istic as the CT HS during the early course of IPA [12, 63].

Mucormycosis. Over the past 10 years, PM has emerged in

patients with hematological malignancies and in transplant re-

cipients [64, 65]. The radiographic manifestations of PM are

nonspecific and include consolidation, cavitation or abscess

formation, the air crescent sign, and nodules and masses [43, 44,

66, 67]. In most cases, PM lesions are unifocal and affect the

upper lobes. Not surprisingly, the HS is also seen in patients with

PM [35, 37, 43, 44], because Zygomycetes are highly angioinva-

sive molds. For example, Jamadar et al [43] reported the ap-

pearance of the HS in 3 of 8 patients with PM. A study at MD

Anderson Cancer Center that compared patients with IPA and

PM showed no statistically significant differences in the in-

cidence of the HS between the 2 groups (21% and 25%, re-

spectively) [44]. Therefore, the HS should not be used to

distinguish IPA from PM. Nevertheless, a point of emphasis is

that PM is not as common as IPA.

Other Fungal Infections. In view of the wide spectrum of

opportunistic fungi that can afflict immunocompromised hosts,

authors have sporadically described the HS in a variety of

pulmonary mycoses, including candidiasis, cryptococcosis, en-

demic mycoses, and phaeohyphomycosis [46, 68–70], but not in

fusariosis [71]. The incidences of the HS in contemporary co-

horts of patients with cancer and pulmonary mold infections at

MD Anderson are shown in Table 4 [44, 68, 71].

Nonfungal InfectionsSeveral different infectious diseases are occasionally associated

with the presence of the HS, such as viral infections [14, 50, 69, 72,

73]; mycobacterial infections [50, 72, 74]; bacterial pneumonias

caused by Staphylococcus, Pseudomonas, and Nocardia [13, 14,

50]; parasitic and other infections; infections caused by Coxiella

burnetii, Chlamydia psittaci, and Actinomyces species; and slowly

resolving bacterial pneumoniae and septic emboli [10, 75–81].

Because the HS was documented only in case reports and small

series for most of these reports, developing a sense of its frequency

and diagnostic value at various stages of the natural history of

these infections is impossible. Furthermore, the possibility of

undetected coinfection due to an Aspergillus species, especially in

patients at high risk of IPA, cannot be ruled out.

HS in Noninfectious Pulmonary Entities: Neoplastic, Vasculitic,and Other Inflammatory DiseasesGround-glass attenuation surrounding a nodule may indicate

tumor infiltration in several neoplastic diseases [69, 72, 82–89].

Of note, adenocarcinoma with bronchoalveolar features, which

commonly manifests as a solitary peripheral nodule associated

with ground-glass attenuation, is probably the most common

cause of the HS in relatively immunocompetent patients [72].

Moreover, various systemic diseases, such as Wegener gran-

ulomatosis, sarcoidosis, amyloidosis [69, 72, 90, 91], and

a number of diverse conditions [9, 72, 92–94] may cause pul-

monary nodules occasionally surrounded by an HS.

THE RHS

The RHS is a distinct radiological sign representing a focal

rounded area of ground-glass opacity surrounded by a crescent

or complete ring of consolidation (Figure 2). In 1996, Voloudaki

et al [95] reported 2 cases of cryptogenic organizing pneumonia

Table 4. Prevalence of the Halo Sign (HS) in Contemporary Cohorts of Patients with Cancer and Invasive Pulmonary Mold Infection atthe MD Anderson Cancer Center, Houston, Texas

Study Fungus

Time to CT

(median number of days)

Sample size/number

of neutropenic patients (%)

Incidence of

the HSa

Chamilos et al [44] Aspergillosis 2 29 (52) 5/24 (21%)

Chamilos et al [44] Mucormycosis 5 16 (19) 4/16 (25%)

Ben-Ami et al [68] Phaeohyphomycosis NA 39 (64) 3/15 (20%)

Marom et al [71] Fusariosis 9 20 (95) 0

Abbreviation. NA, not available.a Among patients with pulmonary involvement.


that manifested on high-resolution CT scans as central ground-

glass opacity surrounded by denser airspace consolidation of

crescent and ring shapes. Kim et al [96] were the first to describe

this particular CT feature as the RHS and to consider it to be

a relatively specific sign of cryptogenic organizing pneumonia.

Later, studies demonstrated the presence of this sign in patients

with a spectrum of diseases (Table 5).

Fungal Infections Associated with the RHS inImmunocompromised HostsIn a previous study at our institution [4], 4% of immunocom-

promised patients with pulmonary IFIs, particularly those with

PM, exhibited the RHS early in their disease courses. Specifically,

the RHS appeared in 19% of patients with PM, in ,1% of

patients with IPA, and in no patients with fusariosis (P, .001).

In histopathological analysis, the RHS was associated with in-

farcted lung tissue, with a greater amount of hemorrhaging at

the periphery than at the center (Figure 2). Although the evo-

lution of the RHS is unclear, in our experience, we observed

subsequent cavitation in 5 (71%) of 7 cases. The clinical im-

portance of these findings is that having an imaging tool, such as

the RHS, that can indicate the possibility of PM in a patient

rather than the more common IPA would allow physicians to

preemptively initiate Zygomycetes-active antifungal treatment.

In fact, other radiological findings have favored PM over IPA in

patients with hematological malignancies, such as the presence

of multiple (.10) pulmonary nodules, concomitant sinusitis,

and pleural effusion [44]. Authors have also described the RHS

in �10% of patients with paracoccidioidomycosis [97].

Nonfungal Infections and Noninfectious Conditions Associatedwith RHSCase reports described the RHS in patients with infectious

and noninfectious conditions, such as systemic inflammatory

and neoplastic diseases (Table 5) [95, 96, 98–111]. Again, its

frequency is unknown.

CONCLUSIONS

The potential of HS and RHS for early diagnosis of pulmonary

IFI, especially IPA (HS) and PM (RHS), is a reflection of the

particular clinical context. Future studies should incorporate

protocols for standardization of imaging and interpretation of

its findings as diagnosis of IFI shifts to heavy reliance on early

use of CT and biomarkers. Combining CT and biomarkers for

early diagnosis of IFI is another area of interest, because available

Table 5. Spectrum of Diseases with the Reversed HaloSign (RHS)

Fungal infections

Mucormycosisa

Invasive aspergillosis

Paracoccidioidomycosis

Bacterial infections

Slow-resolving pneumonococcal pneumonia

Chlamydia psittaci

Legionella pneumophila

Mycobacterial infections

Mycobacterium tuberculosis

Systemic diseases

Wegener granulomatosis

Sarcoidosis

Churg–Strauss syndrome

Dermatomyositis

Neoplastic diseases

Lymphomatoid granulomatosis

Various pulmonary diseases

Cryptogenic organizing pneumoniab

Acute fibrinous and organizing pneumonia

Lipoid pneumonia

a The most common condition with the RHS in immunocompromised

patients.b The most common condition with the RHS in immunocompetent

patients.

Figure 2. A 49-year-old neutropenic woman who received treatment for acute myeloid leukemia presented with fever. A, Thin-section (2.5 mm)contrast-enhanced chest CT scan of the patient demonstrated a ring of consolidation (black arrow) surrounding a center of ground-glass opacities, theRHS. B, Photomicrograph of a lobectomy specimen obtained from the patient (hematoxylin and eosin stain), showing that peripheral consolidation of thenodule and the ground-glass opacities were caused by an infarcted lung with more hemorrhaging at the periphery (P) than at the center (C). C, Gomorimethenamine silver stain showing fungal hyphae with 90� branching, which is consistent with the presence of Zygomycetes hyphae.


data from prospective studies comparing the temporal re-

lationship between CT findings and serum GM are rather con-

flicting and are based on small numbers of patients [16, 25, 112].

Furthermore, comparative studies of CT and new imaging

modalities regarding their sensitivity, specificity, and positive

and negative predictive values have yet to be performed but

would be of interest. The improvement in patient survival with

early IFI recognition outweighs the drawbacks of CT, which are

radiation and cost. Although chest CT typically delivers .100

times the radiation dose of a chest radiograph, such a dose rarely

produces radiation induced cancer in asymptomatic young

patients [113]. The risk benefit ratio of this radiation is less

important for the immunecompromised patient with sus-

pected IFI, a disease with high mortality, and patient pop-

ulation with a shorter life expectancy. Similarly, the cost of

a chest CT (average $1800) is justified because of its impact on

treatment and survival [114]. Finally, incorporating objective

criteria for consistent measurement of the size of fungal le-

sions in consecutive CTs would be important in future clinical

studies of pulmonary mycoses. Studies from malignant lung

lesions have shown that interobserver variability of meas-

urements is significant and could lead to an incorrect in-

terpretation of treatment response [115]. Therefore, an

improved methodology for measuring fungal lung lesions

sequentially—and ideally by the same radiologist—would

improve the accuracy and reproducibility of CT for assessing

the evolution of lung mycoses.

Acknowledgments

Financial Support. This work was supported by the Amphiarion

Foundation of Chemotherapeutic Studies (to S.P.G.), the Special Ac-

count for Research Funds (E.L.K.E.) of the National and Kapodistrian

University of Athens (to N.V.S. and S.P.G.), and the National Institutes

of Health through an MD Anderson Cancer Center Support Grant

(CA016672).

Potential conflicts of interest. D.P.K. is a consultant and board

member and received payment for lectures from Schering-Plough, Pfizer,

and Astellas Pharma US; and has received grant support from Astellas

Pharma US and Merck; and has received honorarium from Enzon Phar-

maceuticals. All other authors: no conflicts.

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the diagnostic value of halo and reversed halo signs … · signs for invasive mold infections in...

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