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Nodular reverse halo sign in active pulmonary tuberculosis: A rare CT feature?
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Diagnostic and Interventional Imaging (2020) xxx, xxx—xxx
ORIGINAL ARTICLE /Thoracic imaging
Nodular reverse halo sign in active pulmonary tuberculosis: A rare CT feature? K. Martini a,b, A. Loubet a, A. Bankier c, S. Bouam d, P. Morand e, L. Cassagnes f, M.-P. Revel a,g,∗, G. Chassagnon a,g a
Department of Radiology, Cochin Hospital, 75014 Paris, France Diagnostic and Interventional Radiology, University Hospital Zurich, 8091 Zürich, Switzerland c Department of Radiology, Beth Israel Deaconess Medical Center, MA 02215, USA d Department of Medical informatics, Cochin Hospital, 75014 Paris, France e Microbiology Department, Cochin Hospital, 75014 Paris, France f Department of Radiology, CHU Gabriel-Montpied, Institut Pascal, UMR6602 CNRS SIGMA, 63000 Clermont-Ferrand, France g Université de Paris, 75006 Paris, France b
KEYWORDS Reverse halo sign; Tuberculosis; Pulmonary; Computed tomography (CT); Pulmonary manifestations; Prevalence
Abstract Purpose: The purpose of this study was to investigate the prevalence of the nodular reverse halo sign (NRHS) in chest computed tomography (CT) in patients with active pulmonary tuberculosis. Materials and methods: From March 2018 to March 2019, 29 consecutive patients with a cultureconfirmed active pulmonary tuberculosis and who underwent chest CT examination during hospital-admission were retrospectively included in the study. There were 24 men and 5 women with a mean age of 40.9 ± 16.7 (SD) years (range: 18—80 years). Chest CT examinations of included patients were evaluated for the presence of NRHS and other tuberculosis-related CT signs. Results: CT revealed the NRHS in 5 patients (5/29; 17%). The other CT signs of tuberculosis included consolidations in 18 patients (18/29; 62%), tree-in-bud pattern in 14 patients (14/29; 48%), cavitation in 12 patients (12/29; 41%), sparse nodules in 10 patients (10/29; 34%), and pleural effusion in 8 patients (8/29; 28%). Conclusion: CT shows NRHS in 17% of patients with active pulmonary tuberculosis, indicating that the sign is not as rare as previously thought in patients with this condition. © 2020 Published by Elsevier Masson SAS on behalf of Soci´ et´ e franc ¸aise de radiologie.
∗
Corresponding author at: Department of Radiology, Hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France. E-mail address: [email protected] (M.-P. Revel).
https://doi.org/10.1016/j.diii.2020.01.013 2211-5684/© 2020 Published by Elsevier Masson SAS on behalf of Soci´ et´ e franc ¸aise de radiologie.
Please cite this article in press as: Martini K, et al. Nodular reverse halo sign in active pulmonary tuberculosis: A rare CT feature? Diagnostic and Interventional Imaging (2020), https://doi.org/10.1016/j.diii.2020.01.013
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The epidemiology of tuberculosis has changed over time, with a halt in prevalence decline in Western countries, attributed to increased immigration from endemic areas. Whereas the proportion for tuberculosis between native and foreign-born is different among the different European countries, molecular studies have shown that active tuberculosis in immigrants is mostly due to reactivation of remote latent infections, with a low rate of disease transmission within the host country [1—3]. Imaging, especially computed tomography (CT), plays an important role for diagnosing tuberculosis and other chest diseases [4,5]. Indeed, pulmonary involvement is most common at initial presentation and radiologists should be aware of the entire spectrum of imaging presentations of the disease [6]. Awareness of imaging findings suggestive of active tuberculosis is not only important for individual patient management, but also of utmost importance with respect to transmission control in public health. In primary pulmonary tuberculosis, the focus of infection has a non-specific appearance and can be located anywhere in the lungs [6]. The appearance ranges from small patchy consolidations to lobar consolidation, whereas in some patients lung involvement cannot be detected on CT. Cavitations are reported in 10—30% of patients with primary tuberculosis. In general, the infection forms a caseating granuloma, which is prone to calcification [6]. Post-primary pulmonary tuberculosis, or also referred to as reactivation/secondary tuberculosis, occurs years later, most often in the setting of a decreased immune status. Mostly, post-primary tuberculosis develops in the posterior segments of the upper lobes or the superior segments of the lower lobes [6]. The typical appearance of post-primary tuberculosis is that of patchy consolidations, poorly defined linear or nodular opacities and cavitations, seen in 20—45% of patients. Another relatively common findings, are welldefined 2—4 mm nodules or branching lesions (tree-in-bud sign), representing endobronchial spread of the infection [6]. Among atypical presentations of lung involvement on CT, the nodular reverse halo sign (NRHS) is a specific presentation, which strongly suggests the diagnosis of an active granulomatous disease, particularly tuberculosis [7]. As opposed to the reverse halo sign seen in cryptogenic organizing pneumonia, which is characterized by areas of ground-glass surrounded by peripheral consolidation, the NRHS is characterized by the presence of micronodules within the wall and inside the reversed halo. These micronodules histologically correspond to granulomas [7]. So far, the NRHS has only been reported in 14 patients with active tuberculosis [7—9] and the sign is therefore thought to be a rare, but rather specific sign for nonbacillary active tuberculosis in immunocompetent patients. The exact prevalence of NRHS on CT, however, remains unclear. The purpose of this study was to investigate the prevalence of NRHS in patients with active pulmonary tuberculosis on CT examinations.
Materials and methods Patients This retrospective study was approved by our local ethics committee and the need for patients’ informed consent was waived. The hospital information system was queried to identify patients admitted during March 2018 to March 2019 with a diagnosis of active pulmonary tuberculosis, proven by positive culture for Mycobacterium tuberculosis (MT). A total of 72 patients were initially identified. From these patients, individuals who underwent unenhanced or contrast-enhanced chest CT during the time of their hospital stay were selected. Forty-three patients were excluded because CT examinations had been performed in outside institutions and were not available for review or had not been performed at all. The study population included 29 patients. There were 24 men and 5 women with a mean age of 40.9 ± 16.7 (standard deviation [SD] years) (range: 18—80 years). Fig. 1 shows patients inclusion and exclusion into the study. Demographic patient characteristics are reported in Table 1.
CT protocol CT examinations were performed using 64-slice CT units (Somatom® Definition AS+ and Edge® , Siemens Healthineers; Revolution HD® and EVO® , GE Healthcare), with 100 or 120 kV depending on the patient weight and automated mA exposure. Images were reconstructed with a slice thickness of 0.625 or 1.25 mm, using both standard and high frequency reconstruction algorithm and iterative reconstruction of various strength. Intravenous iodinated contrast medium had been administered in 10 out of 29 patients.
Image analysis A radiology resident (A.L.) and a board-certified radiologist (K.M.) with six years of experience in thoracic imaging evaluated chest CT examinations for the presence of NRHS. According to Marchiori et al., NRHS was present if the following imaging criteria were met: confluence of small-size micronodules, showing different level of attenuation but a constant distribution, with a central zone of confluence of low attenuation and an area of denser micronodules, organized in a complete or incomplete rim around the central zone [10]. CT examinations where rated as either ‘‘positive’’ when NRHS was present, and ‘‘negative’’ otherwise. CT examinations were additionally evaluated for the presence of consolidation, ‘‘tree-in-bud’’ pattern, cavitations, randomly distributed nodules and pleural effusion. When discordant opinions among the two readers were obtained regarding the presence of one of the lung CT findings, a consensus reading was performed to reach a consensus opinion. Follow-up CT examinations, when available, were analyzed to look for changes of the NRHS over time.
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Nodular reverse halo sign
Figure 1.
Table 1
3
Flow-chart of the study population. Computed tomography (CT), number of patients (n), nodular reverse halo sign (NRHS).
CT findings in patients with proven tuberculosis.
Patient demographics Age (year) Male CT findings Nodular reversed halo sign Pulmonary consolidation Tree-in-bud pattern Cavitation Sparse nodules Pleural effusion
Overall
Positive for NRHS
Negative for NRHS
P-value
40.9 ± 16.7[18—80] 24 (24/29; 83%)
41.2 ± 19.6[27—80] 5 (5/5; 100%)
36.5 ± 16.4[18—76] 19 (19/24; 79%)
0.991 0.553
5 (5/29; 17%) 18 (18/29; 62%) 14 (14/29; 48%) 12 (12/29; 41%) 10 (10/29; 34%) 8 (8/29; 23%)
5 2 2 1 2 0
0 (0/24; 0%) 16 (16/24; 67%) 12 (12/24; 50%) 11 11/24; (46%) 8 (8/24; 33%) 8 (8/24; 33%)
< 0.001 0.339 > 0.999 0.370 > 0.999 < 0.001
(5/5; (2/5; (2/5; (1/5; (2/5; (0/5;
100%) 40%) 40%) 20%) 40%) 0%)
CT: computed tomography; NRHS: nodular reverse halo sign. Quantitative variables are expressed as means ± standard deviations; numbers in brackets are ranges. Qualitative variables are expressed as raw numbers; numbers in parentheses are proportions followed by percentages.
Statistical analysis Continuous variables were expressed as mean ± SD and ranges. Categorical variables were expressed as raw numbers, proportions and percentages. In order to estimate the prevalence of the NRHS in patients with tuberculosis, the proportion of patients presenting with NRHS
among our cohort was calculated. Students t test and Fisher’s exact test were used to investigate for statistically significant differences among groups as appropriate. All statistical analyses were conducted using ‘R’ software (version 3.6.2, R Foundation, Vienna, Austria). A two-tailed P-value ≤ 0.05 was considered to indicate statistical significance.
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Results CT Findings Evaluation of the NRHS On CT examinations the NRHS was present in 5 patients (5/29; 17%). Clinical characteristics of patients with NRHS on CT are given in Table 2. On CT, the common feature in the 5 patients with the NRHS was a confluence of small-size micronodules showing different levels of attenuation. In all 5 patients, the distribution consisted in a central zone of confluence of low attenuation and a peripheral area of denser micronodules, organized in a complete or incomplete rim around the central zone. The mean size of the micronodular rim was 6.7 ± 2.4 (SD) cm (range: 3—11 cm). There was a single NRHS in two patients (patients 1 and 3) whereas the remaining patients presented with multiple areas of NRHS (up to 5 foci in patient 2) (Fig. 2), resulting in an overall number of 13 NRHS foci in the 5 patients. The NRHS foci extended at a supra-lobular scale with the peripheral zone more often in the direction of the pulmonary cortex, in a centrifuge way (Fig. 3). The NRHS foci did not cross the fissures. Six of the 13 NRHS foci were located in the right upper lobe, the remainder being mainly located in the left upper lobe, the middle lobe, or the apical segment of the right or left lower lobes. A small size cavitation was seen in only one patient. The micronodular local concentration and density were also different among the five patients, according to the delay between symptoms onset and date of diagnosis. Marked density was observed in one patient (patient 2) (Fig. 2) with confluent micronodules resulting in a rim of peripheral consolidation, contrasting with low attenuation micronodules in two patients (patients 1 and 4) (Figs. 3 and 4), with only 1- to 3-month duration of symptoms. For two out of the five patients showing the NRHS, follow-up CT examinations were available. For patient 1 no substantial change was seen within a three-month interval (Fig. 3), whereas in another patient (patient 3), repeat CT examination ten months after the first one showed an increased density of the peripheral micronodular zone, with mild signs of retraction (Fig. 5). No increase of the overall size was observed.
Other parenchymal abnormalities Besides the NRHS pattern, CT showed other parenchymal abnormalities in all patients. They consisted in consolidations in 18 patients (18/29; 62%), tree-in-bud pattern in 14 patients (14/29; 48%), cavitation in 12 patients (12/29; 45%), sparse nodules in 10 patients (10/29; 34%), and pleural effusion in 8 patients (8/29; 28%). There were no significant differences among groups with the exception of pleural effusion, which was only present in patients without NRHS (P < 0.001).
Discussion The NRHS is a recently described finding in non-bacillary active tuberculosis. So far, only a few cases have been
reported in the literature and the overall prevalence is supposed to be rare. However, the exact prevalence of this tuberculosis pattern remains unclear. Our retrospective study suggests that the prevalence of NRHS in patients with active tuberculosis reaches 17%, indicating that this rather specific CT sign for active tuberculosis might be far more prevalent than previously thought. The micronodular distribution seen in NRHS is different from the three usual well-known distributions of micronodules, namely centrilobular, perilymphatic and random distributions [11]. It is also different from the micronodular confluence, referred as cluster sign or galaxy sign, that can be found in tuberculosis [12] but more often in pulmonary sarcoidosis [14]. The appearance of NRHS is also different from the ‘‘reverse halo sign’’ or ‘‘atoll sign’’ described in cryptogenic organizing pneumonia, characterized by a central zone of ground-glass opacity surrounded by linear consolidation [14]. The difference between the nodular reverse halo sign (NRHS) and reverse halo sign is the presence of micronodularity in the former. Marchiori et al. were the first to describe the NRHS as a sign suggesting active tuberculosis rather than cryptogenic organizing pneumonia in a series of twelve immunocompetent patients with a mean age of approximately 40 years [7]. In this series, patients had approximately the same age than in our cohort. In the series by Marchiori et al. however, a female predominance of patients was observed (10/12; 83%) [7], whereas in our cohort all patients with NRHS were males. These findings together, may suggest an equal gender distribution of NRHS. Half of the patients in Marchiori et al. series and two of our five patients had a single lesion, with the other patients having from to two to five areas of NRHS [7]. From a physiopathological point of view, the nodular appearance of NRHS could be interpreted as a specific granulomatous reaction in post-primary tuberculosis, with a similar clearance mechanism at the level of the secondary lobule, but on a larger scale. It could reflect the fractal structure of the lungs, and the associated phenomenon of self-similarity, with identical structures or changes occurring at different levels of magnitude [15]. Even though, we did not have histopathologic confirmation in our patients, these findings were observed in one patient of the series by Marchiori et al. who noted the presence of granulomas in the ring component of NRHS [7]. In our study, two out of five patients had followup CT examinations available. No significant changes were observed on CT within a 3-month interval, whereas follow-up at 10 months demonstrated an increased rim of consolidation with a part of retraction. This slow progressive evolution is in line with the hypothesis that the NRHS is due to organizing pneumonia in reaction to tuberculosis, and could represent a form of healing or at least being a sign of a contained process, explaining also the rarity of cavitation. Interestingly, direct sputum microscopy was negative for acid-fast bacilli in all of our patients, and in at least six patients in Marchiori et al. series, with no information regarding the other six patients [7]. Active tuberculosis diagnosis in these patients was based on lavage, sputum or biopsy specimen culture positivity. Sputum examination was also negative in the case of NRHS reported in a 15-year-old boy from India [8]. Lung biopsy via video-assisted thoracoscopy showed multiple caseating granulomas, which were culture
Please cite this article in press as: Martini K, et al. Nodular reverse halo sign in active pulmonary tuberculosis: A rare CT feature? Diagnostic and Interventional Imaging (2020), https://doi.org/10.1016/j.diii.2020.01.013
Age (year)
Ethnicity/place Contact of birth
Revealing symptoms
Delay between symptoms onset and diagnosis (month)
Smoking status
CRP (mg/L)
Number of NRHS foci
Location of NRHS foci
Delay for culture positivity (day)
1
Male
36
Immigrant from Africa
Not found
3
Smoker
<5
1
RUL
17
2
Male
26
Born in France, Caucasian
Not found
GSD Dyspnea Chest pain GSD
6
Never smoker
100
5
15
3
Male
80
Not found
GSD Dyspnea
10
Never smoker
26
1
4
Male
30
Born in France, Caucasian Born in France, Asian descent
RUL, LUL, apical segment of RLL, RLL RUL
Yes
GSD Chest pain
1
Never smoker
<5
4
5
Male
30
Born in Bulgaria, Caucasian descent
Not found
GSD Fatigue Chest pain
2
Smoker
<5
2
RUL, LUL, apical segment of RLL RUL, LUL
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Clinical information regarding the 5 patients with nodular reversed halo sign (NRHS).
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Table 2
14
15
14
NRHS: nodular reverse halo sign; CRP: C-reactive protein; GSD: general status deterioration; LUL: left upper lobe; RLL: right lower lobe; RUL: right upper lobe.
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Figure 2. 26-year-old man with general status deterioration for 6 months. CT images in the axial (A) and sagittal (B) planes, show multiple foci of nodular reverse halo sign. High density of the peripheral rim (white arrow) is denoted (A). A small cavitation (black arrow) was visible in the right upper lobe (C).
Figure 3. 36-year-old man, immigrant from Africa, with general status deterioration, dyspnea and chest pain for 3 months. CT images in the axial (A) and coronal (B) plane show a single focus of nodular reverse halo sign in the right upper lobe, with low density of the peripheral rim of micronodules (arrows), oriented towards the lung periphery (A). No significant changes were observed at 3 months (not shown).
Figure 4. 30-year-old man of Asian descent with general status deterioration and chest pain for 1 month. Axial (A) and sagittal CT images of the right (B) and left (C) lung, show multiple foci of nodular reverse halo sign (arrows), with low density of the micronodules.
Figure 5. 80-year-old man, with general status deterioration and dyspnea. (A, B) CT images in the axial plane obtained at 10-month interval show a single area of nodular reverse halo sign of the right upper lobe (arrow). On the second CT scan (B), the density of the peripheral rim (arrow) has increased.
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Nodular reverse halo sign positive for M. tuberculosis. Negativity of direct sputum microscopy can also be explained by the rarity of cavitation associated with NRHS in our series and the series of Marchiori et al. since only one patient in both series was reported to show concomitant cavitation [7]. Of note, NRHS is not an exclusive tuberculosis finding. Zhan et al. evaluated the incidence of NRHS in different pulmonary diseases and found that the sign is relatively nonspecific and can be found in tuberculosis, but as well in cryptogenic organizing pneumonia, lung cancer, sarcoidosis, cryptococcosis, and granulomatosis with polyangiitis [17]. Further, these researchers showed that among granulomatous diseases RRHS is most common in tuberculosis, while in patients with non-granulomatous disease it is mostly found in those with cryptogenic organizing pneumonia [16,17]. Herráez Ortega et al. evaluated the NRHS in patients with sarcoidosis, referring to it as ‘‘sarcoid cluster sign’’. These researchers found this pattern in 9 out of 91 patients, having therefore in their cohort a prevalence of 10% [13]. The main limitation of our study is the lack of histopathological correlation, allowing confirming that the NRHS was due to the presence of tuberculous granulomas but surgical biopsy is not part of the usual clinical care in patients with a confirmed diagnosis of tuberculosis. A second limitation is that the study only gives insights in how frequent NRHS is in a group of patients with tuberculosis, but does not evaluate how often the sign can be encountered in a different etiology. In conclusion, 17% of patients with active tuberculosis exhibit NRHS on CT, indicating that this sign is not as rare as previously thought. Our observations underline the importance for radiologists to be aware of this sign, and to distinguish it from other similar but etiologically different signs of other lung conditions. If encountered, radiologists should suggest the diagnosis of tuberculosis and active search for tuberculosis, even if direct examinations of bronchial samples are negative, should be initiated. It also imposes that other precautions such as air isolation should be undertaken, since non-bacillary tuberculosis remains contagious, and patients with this condition must be investigated in a specialized environment. Timely confirmation of active tuberculosis will avoid delayed diagnosis and risk of contamination.
Authors’ contributions Katharina Martini: investigation, data curation, writing — original draft. Antoine Loubet, Samir Bouam and Philippe Morand: investigation, resources. Alexander Bankier: conceptualization, methodology, writing — original draft, writing — review & editing. Lucie Cassagnes: writing — review & editing. Marie-Pierre Revel: conceptualization, methodology, writing — original draft, writing — review & editing, supervision. Guillaume Chassagnon: methodology, data curation, formal analysis, writing — review & editing.
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Disclosure of interest The authors declare that they have no competing interest.
References [1] Heldal E, Dahle UR, Sandven P, Caugant DA, Brattaas N, Waaler HT, et al. Risk factors for recent transmission of Mycobacterium tuberculosis. Eur Respir J 2003;22:637—42. [2] Borrell S, Espa˜ nol M, Orcau A, Tudó G, March F, Caylà JA, et al. Tuberculosis transmission patterns among Spanish-born and foreign-born populations in the city of Barcelona. Clin Microbiol Infect 2010;16:568—74. [3] Garzelli C, Rindi L. Molecular epidemiological approaches to study the epidemiology of tuberculosis in low-incidence settings receiving immigrants. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis 2012;12:610—8. [4] Fitton I, Revel M-P, Burgel P-R, Hernigou A, Boussaud V, Guillemain R, et al. Cumulative radiation dose after lung transplantation in patients with cystic fibrosis. Diagn Interv Imaging 2019;100:287—94. [5] Ludes C, Labani A, Severac F, Jeung MY, Leyendecker P, Roy C, et al. Ultra-low-dose unenhanced chest CT: prospective comparison of high kV/low mA versus low kV/high mA protocols. Diagn Interv Imaging 2019;100:85—93. [6] Jeong YJ, Lee KS. Pulmonary tuberculosis: up-to-date imaging and management. AJR Am J Roentgenol 2008;19:834—44. [7] Marchiori E, Zanetti G, Irion KL, Nobre LF, Hochhegger B, Manc ¸ano AD, et al. Reversed halo sign in active pulmonary tuberculosis: criteria for differentiation from cryptogenic organizing pneumonia. AJR Am J Roentgenol 2011;197: 1324—7. [8] Ahuja A, Gothi D, Joshi JM. A 15-year-old boy with ‘‘reversed halo’’. Indian J Chest Dis Allied Sci 2007;49:99. [9] Nattusamy L, Madan K, Bhalla AS, Guleria R. Reversed halo sign in active pulmonary tuberculosis. BMJ Case Rep 2014 [bcr2013202981]. [10] Marchiori E, Hochhegger B, Zanetti G. Nodular reversed halo sign. J Bras Pneumol 2019;45:e20180335. [11] Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology 2008;246:697—722. [12] Heo JN, Choi YW, Jeon SC, Park CK. Pulmonary tuberculosis: another disease showing clusters of small nodules. AJR Am J Roentgenol 2005;184:639—42. [13] Herráez Ortega I, Alonso Orcajo N, López González L. The ‘‘sarcoid cluster sign’’. A new sign in high resolution chest CT. Radiologia 2009;51:495—9. [14] Baque-Juston M, Pellegrin A, Leroy S, Marquette CH, Padovani B. Organizing pneumonia: what is it? A conceptual approach and pictorial review. Diagn Interv Imaging 2014;95: 771—7. [15] Ionescu C, Oustaloup A, Levron F, Melchior P, Sabatier J, De Keyser R. A model of the lungs based on fractal geometrical and structural properties. IFAC Proc Vol 2009;42:994—9. [16] Marchiori E, Zanetti G, Hochhegger B, Irion KL. Re: reversed halo sign: nodular wall as criterion for differentiation between cryptogenic organizing pneumonia and active granulomatous diseases. Clin Radiol 2010;65:770—1. [17] Zhan X, Zhang L, Wang Z, Jin M, Liu M, Tong Z. Reversed halo sign: presents in different pulmonary diseases. PloS One 2015;10:e0128153.
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Diagnostic and Interventional Imaging (2020) xxx, xxx—xxx
ORIGINAL ARTICLE /Thoracic imaging
Nodular reverse halo sign in active pulmonary tuberculosis: A rare CT feature? K. Martini a,b, A. Loubet a, A. Bankier c, S. Bouam d, P. Morand e, L. Cassagnes f, M.-P. Revel a,g,∗, G. Chassagnon a,g a
Department of Radiology, Cochin Hospital, 75014 Paris, France Diagnostic and Interventional Radiology, University Hospital Zurich, 8091 Zürich, Switzerland c Department of Radiology, Beth Israel Deaconess Medical Center, MA 02215, USA d Department of Medical informatics, Cochin Hospital, 75014 Paris, France e Microbiology Department, Cochin Hospital, 75014 Paris, France f Department of Radiology, CHU Gabriel-Montpied, Institut Pascal, UMR6602 CNRS SIGMA, 63000 Clermont-Ferrand, France g Université de Paris, 75006 Paris, France b
KEYWORDS Reverse halo sign; Tuberculosis; Pulmonary; Computed tomography (CT); Pulmonary manifestations; Prevalence
Abstract Purpose: The purpose of this study was to investigate the prevalence of the nodular reverse halo sign (NRHS) in chest computed tomography (CT) in patients with active pulmonary tuberculosis. Materials and methods: From March 2018 to March 2019, 29 consecutive patients with a cultureconfirmed active pulmonary tuberculosis and who underwent chest CT examination during hospital-admission were retrospectively included in the study. There were 24 men and 5 women with a mean age of 40.9 ± 16.7 (SD) years (range: 18—80 years). Chest CT examinations of included patients were evaluated for the presence of NRHS and other tuberculosis-related CT signs. Results: CT revealed the NRHS in 5 patients (5/29; 17%). The other CT signs of tuberculosis included consolidations in 18 patients (18/29; 62%), tree-in-bud pattern in 14 patients (14/29; 48%), cavitation in 12 patients (12/29; 41%), sparse nodules in 10 patients (10/29; 34%), and pleural effusion in 8 patients (8/29; 28%). Conclusion: CT shows NRHS in 17% of patients with active pulmonary tuberculosis, indicating that the sign is not as rare as previously thought in patients with this condition. © 2020 Published by Elsevier Masson SAS on behalf of Soci´ et´ e franc ¸aise de radiologie.
∗
Corresponding author at: Department of Radiology, Hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France. E-mail address: [email protected] (M.-P. Revel).
https://doi.org/10.1016/j.diii.2020.01.013 2211-5684/© 2020 Published by Elsevier Masson SAS on behalf of Soci´ et´ e franc ¸aise de radiologie.
Please cite this article in press as: Martini K, et al. Nodular reverse halo sign in active pulmonary tuberculosis: A rare CT feature? Diagnostic and Interventional Imaging (2020), https://doi.org/10.1016/j.diii.2020.01.013
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The epidemiology of tuberculosis has changed over time, with a halt in prevalence decline in Western countries, attributed to increased immigration from endemic areas. Whereas the proportion for tuberculosis between native and foreign-born is different among the different European countries, molecular studies have shown that active tuberculosis in immigrants is mostly due to reactivation of remote latent infections, with a low rate of disease transmission within the host country [1—3]. Imaging, especially computed tomography (CT), plays an important role for diagnosing tuberculosis and other chest diseases [4,5]. Indeed, pulmonary involvement is most common at initial presentation and radiologists should be aware of the entire spectrum of imaging presentations of the disease [6]. Awareness of imaging findings suggestive of active tuberculosis is not only important for individual patient management, but also of utmost importance with respect to transmission control in public health. In primary pulmonary tuberculosis, the focus of infection has a non-specific appearance and can be located anywhere in the lungs [6]. The appearance ranges from small patchy consolidations to lobar consolidation, whereas in some patients lung involvement cannot be detected on CT. Cavitations are reported in 10—30% of patients with primary tuberculosis. In general, the infection forms a caseating granuloma, which is prone to calcification [6]. Post-primary pulmonary tuberculosis, or also referred to as reactivation/secondary tuberculosis, occurs years later, most often in the setting of a decreased immune status. Mostly, post-primary tuberculosis develops in the posterior segments of the upper lobes or the superior segments of the lower lobes [6]. The typical appearance of post-primary tuberculosis is that of patchy consolidations, poorly defined linear or nodular opacities and cavitations, seen in 20—45% of patients. Another relatively common findings, are welldefined 2—4 mm nodules or branching lesions (tree-in-bud sign), representing endobronchial spread of the infection [6]. Among atypical presentations of lung involvement on CT, the nodular reverse halo sign (NRHS) is a specific presentation, which strongly suggests the diagnosis of an active granulomatous disease, particularly tuberculosis [7]. As opposed to the reverse halo sign seen in cryptogenic organizing pneumonia, which is characterized by areas of ground-glass surrounded by peripheral consolidation, the NRHS is characterized by the presence of micronodules within the wall and inside the reversed halo. These micronodules histologically correspond to granulomas [7]. So far, the NRHS has only been reported in 14 patients with active tuberculosis [7—9] and the sign is therefore thought to be a rare, but rather specific sign for nonbacillary active tuberculosis in immunocompetent patients. The exact prevalence of NRHS on CT, however, remains unclear. The purpose of this study was to investigate the prevalence of NRHS in patients with active pulmonary tuberculosis on CT examinations.
Materials and methods Patients This retrospective study was approved by our local ethics committee and the need for patients’ informed consent was waived. The hospital information system was queried to identify patients admitted during March 2018 to March 2019 with a diagnosis of active pulmonary tuberculosis, proven by positive culture for Mycobacterium tuberculosis (MT). A total of 72 patients were initially identified. From these patients, individuals who underwent unenhanced or contrast-enhanced chest CT during the time of their hospital stay were selected. Forty-three patients were excluded because CT examinations had been performed in outside institutions and were not available for review or had not been performed at all. The study population included 29 patients. There were 24 men and 5 women with a mean age of 40.9 ± 16.7 (standard deviation [SD] years) (range: 18—80 years). Fig. 1 shows patients inclusion and exclusion into the study. Demographic patient characteristics are reported in Table 1.
CT protocol CT examinations were performed using 64-slice CT units (Somatom® Definition AS+ and Edge® , Siemens Healthineers; Revolution HD® and EVO® , GE Healthcare), with 100 or 120 kV depending on the patient weight and automated mA exposure. Images were reconstructed with a slice thickness of 0.625 or 1.25 mm, using both standard and high frequency reconstruction algorithm and iterative reconstruction of various strength. Intravenous iodinated contrast medium had been administered in 10 out of 29 patients.
Image analysis A radiology resident (A.L.) and a board-certified radiologist (K.M.) with six years of experience in thoracic imaging evaluated chest CT examinations for the presence of NRHS. According to Marchiori et al., NRHS was present if the following imaging criteria were met: confluence of small-size micronodules, showing different level of attenuation but a constant distribution, with a central zone of confluence of low attenuation and an area of denser micronodules, organized in a complete or incomplete rim around the central zone [10]. CT examinations where rated as either ‘‘positive’’ when NRHS was present, and ‘‘negative’’ otherwise. CT examinations were additionally evaluated for the presence of consolidation, ‘‘tree-in-bud’’ pattern, cavitations, randomly distributed nodules and pleural effusion. When discordant opinions among the two readers were obtained regarding the presence of one of the lung CT findings, a consensus reading was performed to reach a consensus opinion. Follow-up CT examinations, when available, were analyzed to look for changes of the NRHS over time.
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Nodular reverse halo sign
Figure 1.
Table 1
3
Flow-chart of the study population. Computed tomography (CT), number of patients (n), nodular reverse halo sign (NRHS).
CT findings in patients with proven tuberculosis.
Patient demographics Age (year) Male CT findings Nodular reversed halo sign Pulmonary consolidation Tree-in-bud pattern Cavitation Sparse nodules Pleural effusion
Overall
Positive for NRHS
Negative for NRHS
P-value
40.9 ± 16.7[18—80] 24 (24/29; 83%)
41.2 ± 19.6[27—80] 5 (5/5; 100%)
36.5 ± 16.4[18—76] 19 (19/24; 79%)
0.991 0.553
5 (5/29; 17%) 18 (18/29; 62%) 14 (14/29; 48%) 12 (12/29; 41%) 10 (10/29; 34%) 8 (8/29; 23%)
5 2 2 1 2 0
0 (0/24; 0%) 16 (16/24; 67%) 12 (12/24; 50%) 11 11/24; (46%) 8 (8/24; 33%) 8 (8/24; 33%)
< 0.001 0.339 > 0.999 0.370 > 0.999 < 0.001
(5/5; (2/5; (2/5; (1/5; (2/5; (0/5;
100%) 40%) 40%) 20%) 40%) 0%)
CT: computed tomography; NRHS: nodular reverse halo sign. Quantitative variables are expressed as means ± standard deviations; numbers in brackets are ranges. Qualitative variables are expressed as raw numbers; numbers in parentheses are proportions followed by percentages.
Statistical analysis Continuous variables were expressed as mean ± SD and ranges. Categorical variables were expressed as raw numbers, proportions and percentages. In order to estimate the prevalence of the NRHS in patients with tuberculosis, the proportion of patients presenting with NRHS
among our cohort was calculated. Students t test and Fisher’s exact test were used to investigate for statistically significant differences among groups as appropriate. All statistical analyses were conducted using ‘R’ software (version 3.6.2, R Foundation, Vienna, Austria). A two-tailed P-value ≤ 0.05 was considered to indicate statistical significance.
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Results CT Findings Evaluation of the NRHS On CT examinations the NRHS was present in 5 patients (5/29; 17%). Clinical characteristics of patients with NRHS on CT are given in Table 2. On CT, the common feature in the 5 patients with the NRHS was a confluence of small-size micronodules showing different levels of attenuation. In all 5 patients, the distribution consisted in a central zone of confluence of low attenuation and a peripheral area of denser micronodules, organized in a complete or incomplete rim around the central zone. The mean size of the micronodular rim was 6.7 ± 2.4 (SD) cm (range: 3—11 cm). There was a single NRHS in two patients (patients 1 and 3) whereas the remaining patients presented with multiple areas of NRHS (up to 5 foci in patient 2) (Fig. 2), resulting in an overall number of 13 NRHS foci in the 5 patients. The NRHS foci extended at a supra-lobular scale with the peripheral zone more often in the direction of the pulmonary cortex, in a centrifuge way (Fig. 3). The NRHS foci did not cross the fissures. Six of the 13 NRHS foci were located in the right upper lobe, the remainder being mainly located in the left upper lobe, the middle lobe, or the apical segment of the right or left lower lobes. A small size cavitation was seen in only one patient. The micronodular local concentration and density were also different among the five patients, according to the delay between symptoms onset and date of diagnosis. Marked density was observed in one patient (patient 2) (Fig. 2) with confluent micronodules resulting in a rim of peripheral consolidation, contrasting with low attenuation micronodules in two patients (patients 1 and 4) (Figs. 3 and 4), with only 1- to 3-month duration of symptoms. For two out of the five patients showing the NRHS, follow-up CT examinations were available. For patient 1 no substantial change was seen within a three-month interval (Fig. 3), whereas in another patient (patient 3), repeat CT examination ten months after the first one showed an increased density of the peripheral micronodular zone, with mild signs of retraction (Fig. 5). No increase of the overall size was observed.
Other parenchymal abnormalities Besides the NRHS pattern, CT showed other parenchymal abnormalities in all patients. They consisted in consolidations in 18 patients (18/29; 62%), tree-in-bud pattern in 14 patients (14/29; 48%), cavitation in 12 patients (12/29; 45%), sparse nodules in 10 patients (10/29; 34%), and pleural effusion in 8 patients (8/29; 28%). There were no significant differences among groups with the exception of pleural effusion, which was only present in patients without NRHS (P < 0.001).
Discussion The NRHS is a recently described finding in non-bacillary active tuberculosis. So far, only a few cases have been
reported in the literature and the overall prevalence is supposed to be rare. However, the exact prevalence of this tuberculosis pattern remains unclear. Our retrospective study suggests that the prevalence of NRHS in patients with active tuberculosis reaches 17%, indicating that this rather specific CT sign for active tuberculosis might be far more prevalent than previously thought. The micronodular distribution seen in NRHS is different from the three usual well-known distributions of micronodules, namely centrilobular, perilymphatic and random distributions [11]. It is also different from the micronodular confluence, referred as cluster sign or galaxy sign, that can be found in tuberculosis [12] but more often in pulmonary sarcoidosis [14]. The appearance of NRHS is also different from the ‘‘reverse halo sign’’ or ‘‘atoll sign’’ described in cryptogenic organizing pneumonia, characterized by a central zone of ground-glass opacity surrounded by linear consolidation [14]. The difference between the nodular reverse halo sign (NRHS) and reverse halo sign is the presence of micronodularity in the former. Marchiori et al. were the first to describe the NRHS as a sign suggesting active tuberculosis rather than cryptogenic organizing pneumonia in a series of twelve immunocompetent patients with a mean age of approximately 40 years [7]. In this series, patients had approximately the same age than in our cohort. In the series by Marchiori et al. however, a female predominance of patients was observed (10/12; 83%) [7], whereas in our cohort all patients with NRHS were males. These findings together, may suggest an equal gender distribution of NRHS. Half of the patients in Marchiori et al. series and two of our five patients had a single lesion, with the other patients having from to two to five areas of NRHS [7]. From a physiopathological point of view, the nodular appearance of NRHS could be interpreted as a specific granulomatous reaction in post-primary tuberculosis, with a similar clearance mechanism at the level of the secondary lobule, but on a larger scale. It could reflect the fractal structure of the lungs, and the associated phenomenon of self-similarity, with identical structures or changes occurring at different levels of magnitude [15]. Even though, we did not have histopathologic confirmation in our patients, these findings were observed in one patient of the series by Marchiori et al. who noted the presence of granulomas in the ring component of NRHS [7]. In our study, two out of five patients had followup CT examinations available. No significant changes were observed on CT within a 3-month interval, whereas follow-up at 10 months demonstrated an increased rim of consolidation with a part of retraction. This slow progressive evolution is in line with the hypothesis that the NRHS is due to organizing pneumonia in reaction to tuberculosis, and could represent a form of healing or at least being a sign of a contained process, explaining also the rarity of cavitation. Interestingly, direct sputum microscopy was negative for acid-fast bacilli in all of our patients, and in at least six patients in Marchiori et al. series, with no information regarding the other six patients [7]. Active tuberculosis diagnosis in these patients was based on lavage, sputum or biopsy specimen culture positivity. Sputum examination was also negative in the case of NRHS reported in a 15-year-old boy from India [8]. Lung biopsy via video-assisted thoracoscopy showed multiple caseating granulomas, which were culture
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Age (year)
Ethnicity/place Contact of birth
Revealing symptoms
Delay between symptoms onset and diagnosis (month)
Smoking status
CRP (mg/L)
Number of NRHS foci
Location of NRHS foci
Delay for culture positivity (day)
1
Male
36
Immigrant from Africa
Not found
3
Smoker
<5
1
RUL
17
2
Male
26
Born in France, Caucasian
Not found
GSD Dyspnea Chest pain GSD
6
Never smoker
100
5
15
3
Male
80
Not found
GSD Dyspnea
10
Never smoker
26
1
4
Male
30
Born in France, Caucasian Born in France, Asian descent
RUL, LUL, apical segment of RLL, RLL RUL
Yes
GSD Chest pain
1
Never smoker
<5
4
5
Male
30
Born in Bulgaria, Caucasian descent
Not found
GSD Fatigue Chest pain
2
Smoker
<5
2
RUL, LUL, apical segment of RLL RUL, LUL
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Sex
+Model
Clinical information regarding the 5 patients with nodular reversed halo sign (NRHS).
Patient #
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Nodular reverse halo sign
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Table 2
14
15
14
NRHS: nodular reverse halo sign; CRP: C-reactive protein; GSD: general status deterioration; LUL: left upper lobe; RLL: right lower lobe; RUL: right upper lobe.
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Figure 2. 26-year-old man with general status deterioration for 6 months. CT images in the axial (A) and sagittal (B) planes, show multiple foci of nodular reverse halo sign. High density of the peripheral rim (white arrow) is denoted (A). A small cavitation (black arrow) was visible in the right upper lobe (C).
Figure 3. 36-year-old man, immigrant from Africa, with general status deterioration, dyspnea and chest pain for 3 months. CT images in the axial (A) and coronal (B) plane show a single focus of nodular reverse halo sign in the right upper lobe, with low density of the peripheral rim of micronodules (arrows), oriented towards the lung periphery (A). No significant changes were observed at 3 months (not shown).
Figure 4. 30-year-old man of Asian descent with general status deterioration and chest pain for 1 month. Axial (A) and sagittal CT images of the right (B) and left (C) lung, show multiple foci of nodular reverse halo sign (arrows), with low density of the micronodules.
Figure 5. 80-year-old man, with general status deterioration and dyspnea. (A, B) CT images in the axial plane obtained at 10-month interval show a single area of nodular reverse halo sign of the right upper lobe (arrow). On the second CT scan (B), the density of the peripheral rim (arrow) has increased.
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Nodular reverse halo sign positive for M. tuberculosis. Negativity of direct sputum microscopy can also be explained by the rarity of cavitation associated with NRHS in our series and the series of Marchiori et al. since only one patient in both series was reported to show concomitant cavitation [7]. Of note, NRHS is not an exclusive tuberculosis finding. Zhan et al. evaluated the incidence of NRHS in different pulmonary diseases and found that the sign is relatively nonspecific and can be found in tuberculosis, but as well in cryptogenic organizing pneumonia, lung cancer, sarcoidosis, cryptococcosis, and granulomatosis with polyangiitis [17]. Further, these researchers showed that among granulomatous diseases RRHS is most common in tuberculosis, while in patients with non-granulomatous disease it is mostly found in those with cryptogenic organizing pneumonia [16,17]. Herráez Ortega et al. evaluated the NRHS in patients with sarcoidosis, referring to it as ‘‘sarcoid cluster sign’’. These researchers found this pattern in 9 out of 91 patients, having therefore in their cohort a prevalence of 10% [13]. The main limitation of our study is the lack of histopathological correlation, allowing confirming that the NRHS was due to the presence of tuberculous granulomas but surgical biopsy is not part of the usual clinical care in patients with a confirmed diagnosis of tuberculosis. A second limitation is that the study only gives insights in how frequent NRHS is in a group of patients with tuberculosis, but does not evaluate how often the sign can be encountered in a different etiology. In conclusion, 17% of patients with active tuberculosis exhibit NRHS on CT, indicating that this sign is not as rare as previously thought. Our observations underline the importance for radiologists to be aware of this sign, and to distinguish it from other similar but etiologically different signs of other lung conditions. If encountered, radiologists should suggest the diagnosis of tuberculosis and active search for tuberculosis, even if direct examinations of bronchial samples are negative, should be initiated. It also imposes that other precautions such as air isolation should be undertaken, since non-bacillary tuberculosis remains contagious, and patients with this condition must be investigated in a specialized environment. Timely confirmation of active tuberculosis will avoid delayed diagnosis and risk of contamination.
Authors’ contributions Katharina Martini: investigation, data curation, writing — original draft. Antoine Loubet, Samir Bouam and Philippe Morand: investigation, resources. Alexander Bankier: conceptualization, methodology, writing — original draft, writing — review & editing. Lucie Cassagnes: writing — review & editing. Marie-Pierre Revel: conceptualization, methodology, writing — original draft, writing — review & editing, supervision. Guillaume Chassagnon: methodology, data curation, formal analysis, writing — review & editing.
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Disclosure of interest The authors declare that they have no competing interest.
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Please cite this article in press as: Martini K, et al. Nodular reverse halo sign in active pulmonary tuberculosis: A rare CT feature? Diagnostic and Interventional Imaging (2020), https://doi.org/10.1016/j.diii.2020.01.013