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Clin Infect Dis. May 1, 2011; 52(9): 1144–1155.
PMCID: PMC3106265

The Diagnostic Value of Halo and Reversed Halo Signs for Invasive Mold Infections in Compromised Hosts

David R. Snydman, Section Editor

Abstract

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), particularly fungal pneumonia, continues to be a diagnostic and therapeutic challenge. Early detection of IFI is imperative, 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 introduction 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 pulmonary 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 immunocompromised 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 radiologists: 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 surrounding hemorrhage corresponds to the halo of ground-glass attenuation.

Figure 1.
Radiological and histopathological appearance of HS. A, A 41-year-old neutropenic man who received treatment for acute myeloid leukemia presented with a temperature of 39.5°C. This thin-section (3 mm) contrast-enhanced chest CT scan of the patient ...

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) [811]. In these cases, the HS is caused by neoplastic or inflammatory infiltration of the surrounding lung parenchyma or, rarely, hemorrhage around a metastasis.

Table 1.
Spectrum of Pulmonary Diseases Associated with the Halo Sign

MEDICAL CONDITIONS ASSOCIATED WITH THE HS

Fungal Infections

Aspergillosis.

The most common pulmonary infection in immunocompromised patients indicated by HS is IPA [1216]. Patients with the other, more chronic forms of pulmonary aspergillosis 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 lesions in 25 patients with neutropenia, hematological malignancies, 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 incidence 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, compared 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 aspergillosis 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 [2628], highlighting 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 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 frequently 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, 3237]. 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 allogeneic 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 immunosuppressed 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 [4749]. In general, the frequency of HS and cavitation among pediatric patients seems to be lower than that among adults. This phenomenon could be possibly attributed either to differences in host immune response or to the late-stage performance of CT.

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

Although the frequency of HS in early stage IPA may vary according to the host's state of myelosuppression, most [1216] but not all [35, 37, 50] investigators have demonstrated the high specificity of the HS in diagnosis of IPA in immunocompromised hosts (Table 3). Likewise, the specificity of HS in diagnosis of IPA seems to be higher among patients with hematological malignancies who have profound neutropenia and persistent fever not responding to broad-spectrum antibiotics 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 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].

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

Investigators have placed great emphasis on the HS for diagnosis 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 lesions with or without air crescent sign, pleural effusions, nonspecific 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 emission 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 much higher than that of PET and MRI. In brief, fluorodeoxyglucose (FDG)-PET can detect foci of invasive mold infections [59], but it is nonspecific, because both infection and malignancy show increased FDG uptake. FDG - PET could be considered 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 indicator 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 characteristic 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 recipients [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 angioinvasive molds. For example, Jamadar et al [43] reported the appearance 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 incidence of the HS between the 2 groups (21% and 25%, respectively) [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, endemic mycoses, and phaeohyphomycosis [46, 6870], but not in fusariosis [71]. The incidences of the HS in contemporary cohorts of patients with cancer and pulmonary mold infections at MD Anderson are shown in Table 4 [44, 68, 71].

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

Nonfungal Infections

Several 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, 7581]. 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 Diseases

Ground-glass attenuation surrounding a nodule may indicate tumor infiltration in several neoplastic diseases [69, 72, 8289]. 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 granulomatosis, sarcoidosis, amyloidosis [69, 72, 90, 91], and a number of diverse conditions [9, 72, 9294] may cause pulmonary 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 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).

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

Fungal Infections Associated with the RHS in Immunocompromised Hosts

In a previous study at our institution [4], 4% of immunocompromised 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 infarcted lung tissue, with a greater amount of hemorrhaging at the periphery than at the center (Figure 2). Although the evolution of the RHS is unclear, in our experience, we observed subsequent cavitation in 5 (71%) of 7 cases. The clinical importance 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 Associated with RHS

Case reports described the RHS in patients with infectious and noninfectious conditions, such as systemic inflammatory and neoplastic diseases (Table 5) [95, 96, 98111]. 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 data from prospective studies comparing the temporal relationship between CT findings and serum GM are rather conflicting 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 suspected IFI, a disease with high mortality, and patient population 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 lesions in consecutive CTs would be important in future clinical studies of pulmonary mycoses. Studies from malignant lung lesions have shown that interobserver variability of measurements is significant and could lead to an incorrect interpretation 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 Account 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 Pharmaceuticals. All other authors: no conflicts.

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