Reversed Halo Sign

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Reversed Halo Sign High-Resolution CT Scan Findings in 79 Patients Edson Marchiori, MD, PhD; Gláucia Zanetti, MD, PhD; Dante Luiz Escuissato, MD, PhD; Arthur Soares Souza Jr, MD, PhD; Gustavo de Souza Portes Meirelles, MD, PhD; Joana Fagundes, MD; Carolina Althoff Souza, MD, PhD; Bruno Hochhegger, MD, PhD; Edith M. Marom, MD; and Myrna C. B. Godoy, MD

Background: The purpose of this study was to evaluate the high-resolution CT (HRCT) scan findings of patients with the reversed halo sign (RHS) and to identify distinguishing features among the various causes. Methods: Two chest radiologists reviewed the HRCT scans of 79 patients with RHS and determined the CT scan findings by consensus. We studied the morphologic characteristics, number of lesions, and presence of features associated with RHS. Results: Forty-one patients presented with infectious diseases (paracoccidioidomycosis, TB, zygomycosis, invasive pulmonary aspergillosis, Pneumocystis jiroveci pneumonia, histoplasmosis, cryptococcosis), and 38 presented with noninfectious diseases (cryptogenic organizing pneumonia, pulmonary embolism, sarcoidosis, edema, lepidic predominant adenocarcinoma [formerly bronchiolo-alveolar carcinoma], granulomatosis with polyangiitis [Wegener]). The RHS walls were smooth in 58 patients (73.4%) and nodular in 21 patients (26.6%). Lesions were multiple in 40 patients (50.6%) and single in 39 patients (49.4%). Conclusion: The presence of nodular walls or nodules inside the halo of the RHS is highly suggestive of granulomatous diseases. CHEST 2012; 141(5):1260–1266 Abbreviations: A(H1N1) 5 2009 influenza A(H1N1); COP 5 cryptogenic organizing pneumonia; HRCT 5 high-resolution CT; IPA 5 invasive pulmonary aspergillosis; OP 5 organizing pneumonia; PCP 5 Pneumocystis jiroveci pneumonia; PE 5 pulmonary embolism; RHS 5 reversed halo sign

reversed halo sign (RHS) is defined as a focal, Therounded area of ground-glass opacity surrounded

by a complete or nearly complete ring of consolidation, as demonstrated on high-resolution CT (HRCT) scan of the chest.1 The RHS was initially considered to be specific to cryptogenic organizing pneumonia (COP).2,3 However, the RHS has since been reported in association with a wide variety of clinical entities, including infectious and noninfectious diseases.4-6 These reports have been limited to sporadic cases or

Manuscript received April 26, 2011; revision accepted October 1, 2011. Affiliations: From the Federal University of Rio de Janeiro (Drs Marchiori, Zanetti, Fagundes, and Hochhegger), Rio de Janeiro; the Federal University of Parana (Dr Escuissato), Curitiba; the Faculty of Medicine of São José do Rio Preto (Dr A. S. Souza Jr), São José do Rio Preto; and the São Paulo Federal University (Dr Meirelles), São Paulo, Brazil; the Ottawa Hospital (Dr C. A. Souza), Ottawa, ON, Canada; and the University of Texas MD Anderson Cancer Center (Drs Marom and Godoy), Houston, Texas.

small series of patients with specific conditions. The aim of this study was to determine the spectrum of diseases that may cause patients to present with the RHS on HRCT scan of the chest and to identify imaging features that may facilitate distinction among various causes. Materials and Methods We retrospectively reviewed the HRCT scans and medical records of 79 consecutive patients who presented with the RHS Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Edson Marchiori, MD, PhD, Rua Thomaz Cameron, 438, Valparaiso, CEP 25685.120, Petrópolis, Rio de Janeiro, Brazil; e-mail: [email protected]. © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.11-1050

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on CT scan examinations and whose pulmonary-disease diagnoses were confirmed using established laboratory, microbiologic, and/or histopathologic criteria. These patients were examined between 2000 and 2010 in nine tertiary hospitals in Brazil, the United States, and Canada. All participating institutions provided institutional review board approval for this study. The patients were divided into two groups: Group A included patients with infectious diseases, and Group B included patients with noninfectious diseases. Group A contained 41 patients (24 men, 17 women) ranging in age from 21 to 63 years (mean, 41.6 years). Group B contained 38 patients (20 men, 18 women) ranging in age from 25 to 77 years (mean, 45.8 years). HRCT scans of the chest were obtained using a variety of scanners in the participating hospitals. In the initial studies, HRCT images were obtained at full inspiration with 1-mm to 2.5-mm slice thickness at 5-mm to 10-mm intervals and reconstructed using a high-spatialfrequency reconstruction algorithm. The most recent CT scans were performed using helical acquisition and reconstructed with 1-mm to 2.5-mm slice thickness and 1-mm to 2.5-mm intervals using a high-spatial-frequency reconstruction algorithm. The acquisition time was 0.5 to 1 s per rotation, peak voltage was 120 kVp, modulated tube current was 100 to 400 mA, pitch was 1, and matrix was 512 3 512 pixels. The images were reviewed using mediastinal (width, 350–450 HU; level, 10–20 HU) and lung (width, 1,200–1,600 HU; level, 2500 to 2700 HU) window settings. Two chest radiologists with . 15 years of experience reviewed the images independently, and decisions on the findings were reached by consensus. The observers were blinded to patient demographics, clinical findings, and final diagnoses. The HRCT scans were assessed for morphologic characteristics and the number of lesions exhibiting the RHS, defined initially as a central ground-glass opacity surrounded by a denser consolidation of crescentic (forming . three-fourths of a circle) or ring (forming a complete circle) shape of ⱖ 2 mm in thickness,2 and later as a rounded area of ground-glass attenuation surrounded by a complete or nearly complete ring of consolidation.1 The presence of associated parenchymal findings, such as air-space consolidation, ground-glass attenuation, linear opacities, nodules, lymph-node enlargement, pleural effusion, and other significant thoracic abnormalities, was also recorded. The definition of these patterns followed the Glossary of Terms for Thoracic Imaging proposed by the Fleischner Society.1

Results Group A (infectious diseases) comprised 41 patients; 29 had fungal infections (paracoccidioidomycosis [Fig 1], zygomycosis, invasive pulmonary aspergillosis [IPA] [Fig 2], Pneumocystis jiroveci pneumonia [PCP], histoplasmosis, cryptococcosis), and 12 had TB (Fig 3). Group B (noninfectious diseases) was composed of 38 patients; 18 had organizing pneumonia (OP) (11 secondary, seven primary) (Fig 4), seven had a pulmonary embolism (PE), five had sarcoidosis, three exhibited pulmonary edema, three had lepidic predominant adenocarcinoma (formerly bronchioloalveolar carcinoma), and two had granulomatosis with polyangiitis (Wegener) (Fig 5) (Table 1). The causes of secondary OP among patients in this study included 2009 influenza A(H1N1) (A[H1N1]) infection (three patients), radiation therapy (three patients), drug reaction (two patients), collagen vascular disease (two patients), and pneumococcal pneumonia (one patients). www.chestpubs.org

Figure 1. High-resolution CT (HRCT) image of a 48-year-old man with pulmonary paracoccidioidomycosis. In the lower lung zone, the scan shows multiple, bilateral rounded and oval lesions containing central ground-glass opacities and a ring of consolidation, forming the reversed halo sign (RHS) (arrows).

HRCT imaging showed smooth RHS walls in 58 patients (73.4%) and nodular walls in 21 patients (26.6%). All patients with TB (n 5 12) and sarcoidosis (n 5 5) presented with nodular RHS walls. Nodular walls were also observed in three of the 14 patients with paracoccidioidomycosis (21.4%) and in the one patient with cryptococcosis (Table 1). Small nodules within the central ground-glass region of the RHS were observed in 10 of the 12 patients with TB, in three of the five patients with sarcoidosis, in one of the 14 patients with paracoccidioidomycosis, and in the one patient with cryptococcosis. Among those with noninfectious diseases, nodular RHS walls were seen only in patients with sarcoidosis. Multiple lesions with the RHS were observed in 40 patients (50.6%), and single lesions were observed in 39 patients (49.4%). All patients with paracoccidioidomycosis presented with multiple lesions. In contrast, all lesions in patients with IPA, PE, and lepidic predominant adenocarcinoma were single lesions. Both single and multiple RHS lesions were seen in the groups of patients with the remaining conditions. In 16 patients (20.3%), the RHS was the only pulmonary abnormality present on HRCT scan examination. These included five patients with OP, six patients with TB, two patients with PE, two with lepidic predominant adenocarcinoma, and one with IPA. Associated parenchymal abnormalities were present in the remaining 63 patients (79.7%) and included consolidation, ground-glass opacities, nodules, and/or linear opacities. Pleural effusion was seen in 13 patients (16.5%); it was present in all patients with zygomycosis, four of seven patients with PE, and three of six patients with IPA. None of the patients in this study exhibited lymphadenopathy. CHEST / 141 / 5 / MAY, 2012

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Figure 2. Images from a 51-year-old woman with invasive pulmonary aspergillosis (IPA). A, Axial HRCT scan. B, Coronal reformatted. C, Sagittal reformatted. Images show two lesions with the RHS in the right upper lobe. These lesions exhibit irregular and thickened walls. See Figure 1 legend for expansion of the other abbreviations.

Figure 3. Images from a 59-year-old woman with active pulmonary TB. A, Axial HRCT scan. B, Coronal reformatted. Images show numerous small, bilateral, random nodules and lesions with the RHS; the largest of these is visible in the superior segment of the right lower lobe (arrows). Note that the lesion walls are nodular and small nodules are also present within the lesions. C, Photomicrograph of right lower lobe lingular segment obtained from open lung biopsy shows scattered granulomas (asterisks) (hematoxylin-eosin, original magnification 3 40). See Figure 1 legend for expansion of the other abbreviations.

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Sarcoidosis was the only noninfectious disease in which nodular RHS walls were observed. Small nodules within the central ground-glass region of the RHS were also distinctive features seen only in granulomatous diseases. Most diseases exhibited both solitary and multiple RHS lesions, frequently in association with other parenchymal abnormalities. All patients with paracoccidioidomycosis in our series showed multiple RHS lesions; on the other hand, single RHS lesions were seen in the majority of patients with zygomycosis and in all patients with IPA, PE, and lepidic predominant adenocarcinoma. However, it should be emphasized that, given the small number of cases of these diseases in our series, these causes should not be excluded in the differential diagnosis of diseases

Figure 4. A, HRCT image of a 39-year-old woman with cryptogenic organizing pneumonia (COP). A focal area of ground-glass attenuation (white arrow) is surrounded by an incomplete ring of consolidation (black arrowheads) in the right lower lobe, forming the RHS. Note the absence of small nodules on the walls or inside the area defined by the halo. B, Photomicrograph of right lower lobe specimen obtained at open lung biopsy shows typical elongated fibroblast plugs filling airspaces (asterisks) (hematoxylineosin, original magnification 3 40). See Figure 1 legend for expansion of the other abbreviations.

Discussion The RHS was described initially in patients with COP and was considered to be an HRCT scan finding characteristic of this disease.2,3 Subsequently, several authors demonstrated the occurrence of this sign in a variety of conditions, including infectious diseases such as paracoccidioidomycosis,7,8 TB,9,10 zygomycosis,11,12 IPA,11 and PCP,13 and noninfectious diseases such as secondary OP,14 granulomatosis with polyangiitis (Wegener),15 lymphomatoid granulomatosis,16 and sarcoidosis.17,18 In our study, the RHS ring of consolidation appeared nodular only in granulomatous diseases, including sarcoidosis and granulomatous infections (eg, TB, cryptococcosis, paracoccidioidomycosis). This appearance is caused by the presence of multiple granulomas19 and has been described as an important finding for use in making a differential diagnosis.19 www.chestpubs.org

Figure 5. Images of a 52-year-old man with granulomatosis with polyangiitis (Wegener). A, Axial HRCT scan. B, Coronal reformatted. Images show multiple smooth-walled RHSs in both lungs. Note the presence of cavitated nodules (arrows), a common finding in this disease. See Figure 1 legend for expansion of the abbreviations. CHEST / 141 / 5 / MAY, 2012

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Table 1—Tomographic Findings of the 79 Patients With RHS Contours Cause OP Primary Secondary Total Paracoccidioidomycosis TB PE IPA Zygomycosis Sarcoidosis Lepidic predominant adenocarcinoma (formerly bronchiolo-alveolar carcinoma) Pulmonary edema Granulomatosis with polyangiitis (Wegener) Histoplasmosis Cryptococcosis PCP Total

Other Lesions

Lesions

Patients

Smooth

Nodular

Single

Multiple

Yes

No

Pleural Effusion

7 11 18 14 12 7 6 6 5 3

7 11 18 11 0 7 6 6 0 3

0 0 0 3 12 0 0 0 5 0

4 4 8 0 6 7 6 5 1 3

3 7 10 14 6 0 0 1 4 0

4 9 13 14 6 5 5 6 5 1

3 2 5 0 6 2 1 0 0 2

0 0 0 0 0 4 3 6 0 0

3 2 1 1 1 79

3 2 1 0 1 58

0 0 0 1 0 21

2 1 0 0 0 39

1 1 1 1 1 40

3 2 1 1 1 63

0 0 0 0 0 16

0 0 0 0 0 13

IPA 5 invasive pulmonary aspergillosis; OP 5 organizing pneumonia; PCP 5 Pneumocystis jiroveci pneumonia; PE 5 pulmonary embolism; RHS 5 reversed halo sign.

for patients with multiple RHS lesions. Although lymphadenopathy has been described in association with one patient with sarcoidosis who exhibited the RHS,14 none of the patients exhibited this feature. Pleural effusion was seen only in patients with zygomycosis, pulmonary edema, and PE. We identified no other distinctive morphologic feature that would facilitate the differential diagnosis of diseases for patients presenting with the RHS. The RHS should thus be considered a relatively nonspecific finding. Although the presence of the RHS may help to narrow the range of diseases considered in making differential diagnoses, final diagnoses should be based on the clinical scenario and the presence of additional disease-specific CT scan findings (Tables 1, 2). When the RHS is the sole abnormality on CT scan studies, as seen in approximately 20% of the patients, correlation with clinical findings is crucial for the final diagnosis. Given the retrospective nature of this study and the diversity of the medical institutions involved in the collection of the cases, it was not possible to establish the percentage of infectious vs noninfectious causes of the RHS. Allowing for possible selection bias, in our series the RHS represented infectious diseases in approximately half of the cases. The patient’s immune status is the most relevant clinical information in making differential diagnoses of infectious diseases. Patients who are immunocompromised and present with the RHS on CT scan examination should be considered to have an infection until further analyses prove otherwise. Zygomycosis

and IPA are typically seen in patients with severe immunosuppression, most commonly secondary to hematologic malignancies. PCP is more prevalent in patients with AIDS. Epidemiologic history is also very important in making differential diagnoses. For example, residence in or recent travel to South America should lead the physician to suspect paracoccidioidomycosis. Patients from endemic areas or who have had contact with soil contaminated with bird or bat guano are at increased risk for histoplasmosis. In our series, the RHS was also present in association with other infectious diseases, including A(H1N1) and pneumococcal pneumonia. However, the RHS appeared late in the course of these diseases, presumably representing secondary OP. The emergence of secondary OP in the evolution of A(H1N1) infection and pneumococcal pneumonia has been reported previously.20,21 In our study, the RHS was associated most frequently with OP; as previously suggested, this disease should be considered first in making a differential diagnosis of patients who are immunocompetent. OP can be idiopathic (COP) or secondary to various causes, including connective-tissue disease, infection, malignancy, drug toxicity, radiation injury, pulmonary hemorrhage, and aspiration.22 Thus, most cases of RHS appearance later in the course of a disease are likely a manifestation of secondary OP. Our study has some limitations. It was an observational retrospective study, and some disease categories included a small number of cases. Although HRCT scan techniques varied widely as a result of the long period

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Table 2—Criteria for the Differential Diagnosis of the RHSa Clinical, Epidemiologic, and Laboratory Findings

Cause

Additional CT Scan Findings

COP

Bilateral peribronchovascular and peripheral consolidation; perilobular consolidation Various patterns of abnormalities (large nodules, cavitated nodules, centrilobular nodules, ground-glass opacities, peribronchovascular interstitial thickening, bronchial wall thickening, traction bronchiectasis, paracicatricial emphysema) in the same examination Centrilobular nodules and tree-in-bud opacities; cavitary lesions in the upper lobes or superior segments of the lower lobes Filling defects in the pulmonary arteries; pleural effusion; peripheral consolidation (pulmonary infarcts)

Subacute constitutional symptoms (fever, unproductive cough, malaise, anorexia, weight loss) Residents, immigrants, or travelers from South American countries; nonspecific respiratory symptoms for several months

Typical pathologic findings for OP

Subacute constitutional symptoms (fever, night sweats, productive cough, malaise, anorexia, weight loss) Risk factors for acute PE; acute onset of dyspnea and chest pain

Positive acid-fast bacilli or culture of respiratory secretions and sputum

Pulmonary nodules; consolidation; halo sign. Later in disease course: cavitary lesions (air-crescent sign) and cavitation of the RHS; pleural effusion Pulmonary nodules; consolidation; halo sign. Later in disease course: cavitary lesions (air-crescent sign) and cavitation of the RHS; pleural effusion Perilymphatic nodules; mediastinal and hilar lymph node enlargement

Severe immunosuppression, particularly leukemia; neutropenia and persistent fever Severe immunosuppression, particularly leukemia; neutropenia and persistent fever Young adults with enlarged lymph nodes, pulmonary infiltrates, and often ocular and skin lesions Chronic cough; slow progression over time. Abundant mucoid expectoration is uncommon but very suggestive of lepidic predominant adenocarcinoma Congestive heart failure; dyspnea

Paracoccidioidomycosis

TB

PE

IPA

Zygomycosis

Sarcoidosis

Lepidic predominant adenocarcinoma (formerly bronchiolo-alveolar carcinoma)

Air-space consolidation; masses; ground-glass opacities; partially solid or solid nodules

Pulmonary edema

Granulomatosis with polyangiitis (Wegener)

Cardiomegaly; pleural effusion; interlobular septal thickening; ground-glass opacities Nodules and masses, often with cavitation

Cryptococcosis

Pulmonary nodules

Histoplasmosis

Lymph node enlargement; nodules

History of contact with soil contaminated with bird or bat guano

PCP

Bilateral perihilar ground-glass opacities; pneumatoceles

AIDS; cough and dyspnea; hypoxemia; increased lactate dehydrogenase

Final Diagnoses

Renal involvement; less commonly, large airway involvement (circumferential thickening, stenosis) Contact with pigeon droppings; immunodeficiency; CNS involvement (meningitis)

Identification of fungi on direct exam of culture or histopathologic specimens; immunologic test results

Positive pulmonary CT scan angiography, high-probability ventilation/perfusion scans; positive MRI or conventional angiography Identification of fungi on direct exam of culture or histopathologic specimens; immunologic test results Identification of fungi on direct exam of culture or histopathologic specimens; immunologic test results Pathologic findings of noncaseating granulomas Positive cytologic or histopathologic study results

History of congestive heart failure/fluid overload; echocardiogram Positive c-ANCA; thrombocytosis; abnormal renal function examination results Direct examination; culture; immunohistochemistry; histopathologic study results; identification of fungi in CNS fluid or tissue specimens Identification of fungi on direct examination of culture or histopathologic specimens; immunologic test results Identification of fungi in respiratory secretions or histopathologic specimens

c-ANCA 5 cytoplasmic antineutrophil cytoplasmic antibody; COP 5 cryptogenic organizing pneumonia. See Table 1 legend for expansion of the other abbreviations. aAccepted criteria in the current literature.

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(10 years) covered by the study and the differences in participating institutions’ equipment, we do not believe that this variation impacted our results. Despite these limitations, this is the largest reported series of patients presenting with the RHS due to a variety of diseases, with a novel approach attempting to establish criteria for the differential diagnosis of diseases in patients presenting with the RHS. In conclusion, the RHS is seen in a wide variety of diseases with inflammatory, infectious, and malignant causes. The presence of small nodules in the wall or within the lesion usually indicates an active granulomatous disease, either granulomatous infection or sarcoidosis. We found no other morphologic feature to facilitate differential diagnosis, and we conclude that the RHS should be considered a relatively nonspecific sign. The radiologic interpretation of the RHS should be based on associated disease-specific imaging findings and strict correlation with clinical manifestations.

4.

5.

6.

7. 8.

9. 10.

Acknowledgments Authors contributions: Dr Marchiori was the principal investigator. Dr Marchiori: contributed to the coordination and design of the study, data interpretation, and preparation and revision of the manuscript. Dr Zanetti: contributed to data interpretation, statistics, and revision of the manuscript. Dr Escuissato: contributed to HRCT scan evaluation, literature review, and revision of the manuscript. Dr A. S. Souza Jr: contributed to HRCT scan evaluation and final review of the manuscript. Dr Meirelles: contributed to HRCT scan evaluation and final review of the manuscript. Dr Fagundes: contributed to the collection of the data and preparation of the manuscript. Dr C. A. Souza: contributed to HRCT scan evaluation and preparation of the manuscript. Dr Hochhegger: contributed to the collection of the data and preparation of the manuscript. Dr Marom: contributed to HRCT scan evaluation, literature review, and revision of the manuscript. Dr Godoy: contributed to the design of study, HRCT scan evaluation, and final review of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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