European Journal of Radiology Open 7 (2020) 100297 Contents lists available at ScienceDirect European Journal of Radiology Open journal homepage: www.elsevier.com/locate/ejro Influenza H1N1 virus-associated pneumonia often resembles rapidly progressive interstitial lung disease seen in collagen vascular diseases and COVID-19 pneumonia; CT-pathologic correlation in 24 patients Makiko Murota a, *, Takeshi Johkoh b, Kyung Soo Lee c, Tomas Franquet d, Yasuhiro Kondoh e, Yoshihiro Nishiyama a, Tomonori Tanaka f, Hiromitsu Sumikawa g, Ryoko Egashira h, Norihiko Yamaguchi i, Kiminori Fujimoto j, Junya Fukuoka k, on behalf of the Group of Creation of Radiological Paper from Japan in diffuse lung disease a Department of Radiology, Faculty of Medicine, Kagawa University, Kagawa, Japan b Department of Radiology, Kansai Rosai Hospital, Hyogo, Japan c Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea d Department of Radiology, Hospital de Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain e Department of Respiratory and Allergic Medicine, Tosei General Hospital, Aichi, Japan f Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan g Department of Radiology, Sakai City Medical Center, Osaka, Japan h Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan i Department of Respiratory Medicine, Kinki Central Hospital of Mutual Aid Association of Public School Teachers, Hyogo, Japan j Department of Radiology, Kurume University School of Medicine, Fukuoka, Japan k Department of Laboratory of Pathology, Nagasaki University Hospital, Nagasaki, Japan A R T I C L E I N F O A B S T R A C T Keywords: Purpose: To describe computed tomography (CT) findings of influenza H1N1 virus-associated pneumonia Influenza A (H1N1) virus (IH1N1VAP), and to correlate CT findings to pathological ones. Computed tomography Methods: The study included 24 patients with IH1N1VAP. Two observers independently evaluated the presence, Pneumonia distribution, and extent of CT findings. CT features were divided into either classical form (C-form) or non- Myositis and muscle disease classical form (NC-form). C-form included: A.) broncho-bronchiolitis and bronchopneumonia type, whereas Rheumatoid arthritis COVID-19 NC-forms included: B.) diffuse peribronchovascular type, simulating subacute rheumatoid arthritis-associated (RA) interstitial lung disease (ILD) and C.) lower peripheral and/or peribronchovascular type, resembling dermatomyositis-associated ILD and COVID-19 pneumonia. In 10 cases with IH1N1VAP where lung biopsy was performed, CT and pathology findings were correlated. Results: The most common CT findings were ground-glass opacities (24/24, 100 %) and airspace consolidation (23/24, 96 %). C-form was found in 11 (46 %) patients while NC-form in 13 (54 %). Types A, B, and C were seen in 11(46 %), 4 (17 %), and 9 (38 %) patients, respectively. The lung biopsy revealed organizing pneumonia in all patients and 6 patients (60 %) showed incorporated type organizing pneumonia that was common histological findings of rapidly progressive ILD. Conclusion: In almost half of patients of IH1N1VAP, CT images show NC-form pneumonia pattern resembling either acute or subacute RA or dermatomyositis-associated ILD and COVID-19 pneumonia. 1. Introduction pandemic influenza caused increased morbidity and mortality in a young population who were not generally at risk for severe illness with Influenza A (H1N1) virus infection is reported an outbreak in Mexico the usual seasonal influenza [1]. The most common causes of death due in April 2009 [1]. Since then it has spread rapidly worldwide. This to H1N1 infection are pneumonia and acute respiratory distress * Corresponding author at: Department of Radiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan. E-mail address: mwada@med.kagawa-u.ac.jp (M. Murota). https://doi.org/10.1016/j.ejro.2020.100297 Received 12 October 2020; Received in revised form 18 November 2020; Accepted 23 November 2020 Available online 28 November 2020 2352-0477/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). M. Murota et al. European Journal of Radiology Open 7 (2020) 100297 syndrome [2]. The main pathological finding in patients with H1N1 2.1.3. Image analysis infection was reported to be exudative diffuse alveolar damage (DAD) The images were retrospectively reviewed independently by two with variable degrees of pulmonary hemorrhage and necrotizing bron­ chest radiologists with 18- and 30- years of experience. The radiologists chiolitis [3,4]. There are also few case reports describing pathological were aware that the patients had influenza A (H1N1) pneumonia, but findings of organizing pneumonia (OP) associated with influenza A were blinded to any other clinical information. Radiologists evaluated (H1N1) virus infection [2,5]. Moreover, Cornejo et al. [5] suggested that the CT findings, including the extent of spared areas, as follows: GGO, the clinical symptoms of severe respiratory failure observed in these airspace consolidation, intralobular reticular opacities, emphysema, and patients do not seem to resemble those of OP due to other causes. bronchial dilatation. In addition, the presence of bronchial wall thick­ 　In patients of interstitial lung disease with dermatomyositis (DM), ening, loss of volume in the lower lung zones, subpleural sparing, cen­ polymyositis and antisynthetase syndrome (ASS), it has been reported trilobular nodules, tree-in-bud appearance, lymphadenopathy, and OP with supervening fibrosis described in the American Thoracic Soci­ pleural effusion was evaluated. The definitions of these CT findings were ety and European Respiratory Society (ATS/ERS) statement [6,7]. Its based on the literature [7,14,15], as follows: intralobular reticular characteristic computed tomography (CT) findings are regions of opacities were defined as irregular and randomized linear shadows airspace consolidation bilaterally that show prominent loss of volume, separated by a few millimeters; subpleural sparing was defined as an and distribution predominantly in the basal segments. In patients with area of relative sparing adjacent to the pleura in the presence of fibrotic OP with fibrosis, the condition was reported to develop rapidly pro­ changes in the lung field; and upper lobe subpleural irregular lines were gressive interstitial lung disease (RPILD), and be resistant to therapy [6, defined as irregular lines adjacent to the pleura in the upper lobes. The 8]. extent of CT findings was evaluated separately for 6 pulmonary zones Recently, novel coronavirus (COVID-19) causes worldwide (upper, middle, and lower on each side). The anatomical distribution pandemic and critics in the world. COVID-19 pneumonia often shows was classified as unilateral or bilateral, as predominantly peripheral if bilateral subpleural ground-glass attenuation and /or airspace consoli­ the lesion was in the outer one-third of the lung, as peribronchovascular dation and severe one depicts lower lobe predominant airspace if there was a predominance of abnormalities along the bronchovascular consolidation with loss of volume and traction broncho-bronchiolectasis bundles, or random. The borders between the upper and middle, and [9,10] between middle and lower lung zones were divided by the level of the Several studies have been reported on radiological features of tracheal carina and the inferior pulmonary vein, respectively. The ra­ influenza A (H1N1) pneumonia. The most common CT findings are diologists estimated the percentage of lung with abnormalities in each of ground-glass opacities (GGO) and consolidation, with predominant the zones, which included spared areas, ground-glass attenuation with peribronchovascular and subpleural distribution, resembling OP [2,11, and without traction bronchiectasis, airspace consolidation, intralobular 12]. However, few studies have evaluated radiologic and pathologic reticular opacities, and emphysema. The percentage of whole lung findings of lung specimens. Marchiori et al. [13] reported a correlation involved with abnormalities was calculated by determining the mean of between CT and pathologic findings in six adult patients who died the percentages of involved lung in each lung zone. following Influenza A (H1N1) pneumonia. They concluded that fatal Through reviewing all CT images, CT features were divided into cases of Influenza A (H1N1) pneumonia can present areas of consoli­ either classical or non-classical forms. The classical form included: A.) dation on CT and can be pathologically correlated with DAD [13]. broncho-bronchiolitis and bronchopneumonia type (Fig. 1), showing However, the detailed CT findings and their correlation with pathologic segmental centrilobular nodules and/or areas of airspace consolidation, findings in patients with influenza A (H1N1) pneumonia is still un­ whereas the non-classical forms included: B.) diffuse peri­ known. The aim of this study was to describe the HRCT findings in pa­ bronchovascular type (Fig. 2), depicting areas with ground-glass opac­ tients with Influenza A (H1N1) pneumonia and to correlate them in ities (GGO) or airspace consolidation diffusely distributed along detail with the pathological features. bronchovascular bundles simulating subacute rheumatoid arthritis- associated (RA) interstitial lung disease [16] and C.) lower peripheral 2. Materials and methods and/or peribronchovascular type (Figs. 3 and 4), showing areas of airspace consolidation along pleura and/or peribronchovascular area in 2.1. Description of CT findings bilateral lower lung zones resembling DM-associated interstitial lung disease and COVID-19 pneumonia [9,10,17]. 2.1.1. Patients The institutional review board of the lead institution, where this 2.1.4. Statistical analysis study was carried out, approved this retrospective study and waived the Statistical analysis was performed using SPSS Statistics software need for obtaining the consent of individual patients. We reviewed the (Version 24, 2016; IBM Corp. Japan). Interobserver agreement medical records in our databases of all the patients seen in four in­ regarding the presence/absence of CT findings and overall impression of stitutions. The study included 24 patients (14 males and 10 females; the findings was analyzed by calculating the kappa statistic on the as­ 18–86 years of age, 58 years on average) who were identified with sessments made prior to agreement by consensus, by the chest radiolo­ influenza A (H1N1) pneumonia between March 2009 and September gist who reviewed the images. Interobserver agreement was classified as 2017. The patients were diagnosed based on positive results of real-time follows: poor (κ = 0− 0.20), fair (κ = 0.21− 0.40), moderate polymerase chain reaction (RT-PCR) or PCR on nasal swab or respiratory (κ = 0.41− 0.60), substantial (κ = 0.61− 0.80), and excellent specimen for influenza A (H1N1). And combined infections were (κ = 0.81–1.00). excluded due to a negative sputum and/or blood culture for other pathogens. None of all patients had clinically collagen vascular diseases. 2.2. Radiologic-pathologic correlation 2.1.2. CT scanning We retrospectively reviewed medical records of patients seen at two Thin-section CT was performed using a variety of CT scanners. Data institutions between J March 2009 and September 2017, and identified acquisition was obtained on inspiration, with the patient in the supine ten (five males and five females; 33–71 years of age, 52 years on position. The protocols consisted of 1- or 2.5-mm collimation sections average) patients who had influenza A (H1N1) virus pneumonia and had reconstructed at 1- or 2-mm intervals. The images were viewed at undergone lung biopsy. These were two cases of surgical lung biopsy and window settings optimized for lung (window level − 550 to -600 eight cases of transbronchial cryobiopsy. Pathological patterns were Hounsfield units [HU], window width 1500–1600 HU) and the medi­ described by ATS/ERS classification [6], such as DAD, OP, etc. As far as astinum (window level 300–350 HU, window width30 to 40 HU). OP, we further categorized two subtypes, intraluminal and incorporated 2 M. Murota et al. European Journal of Radiology Open 7 (2020) 100297 Fig. 1. 72-Year-old man with influenza A (H1N1) pneumonia. CT shows airspace consolidation, centrilobular nodules, and tree-in-bud appearance (categorized as type A). Fig. 2. 86-Year-old woman with influenza A (H1N1) pneumonia. CT shows GGO diffusely distribute along peribronchovascular opacities, simulating subacute rheumatoid arthritis-associated interstitial lung disease (categorized as type B). type, according to the previous reports [18,19]. Namely, intraluminal (100 %) and airspace consolidation (96 %), which were bilateral (71 %), OP is characteristic of intraluminal polypoid immature fibrotic lesion lower (63 %), along the peribronchovascular (83 %), or peripheral (29 (Masson type polyp) while incorporated one demonstrated intraluminal %). They were followed by lymphadenopathy (50 %), centrilobular fibrotic lesions incorporated into the alveolar wall. The nodules (46 %), lower volume loss (42 %), subpleural sparing (33 %), radiologic-pathologic correlation was performed together by one radi­ tree-in-bud appearance (29 %), bronchial wall thickening (29 %), and ologist with 30-years of experience and one pathologist with nine-years pleural effusion (29 %). Non-classical form was seen in 13 (54 %) of 24 of experience. The radiologist reviewed CT images and categorized into patients, slightly higher than classical forms that were observed in 11 the three types mentioned above under Image Analysis. The 10 cases patients (46 %). Types A (Fig. 1), B (Fig. 2), and C (Fig. 3,4) were seen in were used for precise radiologic pathologic correlation, including to 11 (46 %), 4 (17 %), and 9 (38 %) patients, respectively. The interob­ distinguish pathologic type of OP. server agreement for identification of CT forms was substantial (κ = 0.75). 3. Results 3.2. Radiologic-pathologic correlation 3.1. Description of CT findings In 10 patients who underwent lung biopsy, CT images in four showed CT findings are shown in Table 1. The main CT findings were GGO classical form (type A) and in six cases non-classical forms including one 3 M. Murota et al. European Journal of Radiology Open 7 (2020) 100297 Fig. 3. 76-Year-old woman with influenza A (H1N1) pneumonia. CT shows areas of GGO and airspace consolidation along pleura in bilateral lower lung zones, resembling dermatomyositis-associated interstitial lung disease (categorized into type C). cases of type B and five cases of type C. All these cases pathologically influenza A (H1N1) pneumonia. showed OP. Six patients demonstrated incorporated type of OP where In the present study, non-classical forms were seen in almost half of granulation tissue incorporated into the alveolar wall with various de­ patients and were slightly higher than in classical form that is type A. Li gree of inflammatory cells. Three patients (30 %) demonstrated intra­ et al. [21] and Ajlan et al. [11] reported the distribution of peri­ luminal type OP. One patient (10 %) has admixture of intraluminal and bronchovascular and peripheral distribution of influenza A (H1N1) incorporated OP. CT pattern of type A included three incorporated and pneumonia and discussed that appearance was similar to that seen in one intraluminal OP, type B included one combined incorporated and cases of OP on CT. We classified non-classical forms into type B and type intraluminal OP, type C included three incorporated OP and two intra­ C. Diffuse peribronchovascular opacities on CT as type B, also called luminal OP. In this cohort, no patients showed DAD, hemorrhage and “twisted appearance” were previously described in subacute RA inter­ necrotizing bronchiolitis. stitial lung disease [16]. The proximal airway is known to be affected in RA interstitial lung disease and drug pneumonitis [16,23]. On the other 4. Discussion hand, lower peripheral and/or peribronchovascular patterns showing areas of airspace consolidation along pleura and/or peri­ In this study, we evaluated the CT images of 24 patients with influ­ bronchovascular in bilateral lower lung zones as type C was reported as enza A (H1N1) pneumonia. The observed CT features were divided into CT findings in DM-associated interstitial lung disease [7,17,24,25]. either classical form or non-classical forms. Further, the classical form However, if CT images of patients with influenza A (H1N1) pneumonia included: A.) broncho-bronchiolitis and bronchopneumonia type, show non-classical forms, it is difficult to differentiate findings of showing segmental centrilobular nodules and/or areas of airspace influenza A (H1N1) pneumonia from other viral pneumonia such as consolidation, whereas the non-classical forms included: B.) diffuse severe acute respiratory syndrome (SARS), Middle East respiratory peribronchovascular type, depicting areas with GGO or airspace syndrome (MERS), and coronavirus disease (COVID-19) pneumonia consolidation diffusely distributed along bronchovascular bundles [26–28]. Yin et al. investigated to compare the CT findings of influenza simulating subacute RA interstitial lung disease and C.) lower peripheral A (H1N1) pneumonia and COVID-19 pneumonia and reported that pe­ and/or peribronchovascular type, showing areas of airspace consolida­ ripheral or peribronchovascular distribution, GGO, and consolidation tion along pleura and/or peribronchovascular area in bilateral lower were not significantly different between them [28]. The CT finding in lung zones resembling DM-associated interstitial lung disease. The lung patients with MERS and SARS was reported that the distribution of the biopsy revealed OP in all 10 patients and 6 patients (60 %) showed abnormalities, such as GGO and consolidation, to the subpleural and incorporated type OP that was common histological findings seen in DM peribronchovascular regions is suggestive of organizing pneumonia and ASS. pattern [26,27]. There have been many reports on CT findings of influenza A (H1N1) In our study, although OP was seen in all patients, DAD was not virus pneumonia [12,20,21]. Previous reports [12,20,21] showed that observed. In past reports, the main pathological findings in patients with the most frequent CT findings were the presence of extensive GGO and influenza A (H1N1) pneumonia include DAD with variable degrees of airspace consolidation, and also the existence of centrilobular nodules, pulmonary hemorrhage and necrotizing bronchiolitis [3]. Our cohort and tree-in-bud appearance as broncho-bronchiolitis and broncho­ include cryobiopsy which is smaller than surgical lung biopsy, so DAD pneumonia. In contrast, Kang et al. [22] reported patterns of CT findings may be missed. We think current cohort consisted with relatively mild in influenza A (H1N1) pneumonia, and classified them into 3 patterns: disease of influenza A (H1N1) pneumonia, the histological discrepancy bronchopneumonia, cryptogenic OP, and acute interstitial pneumonia. may be due to the difference in inclusion criteria. Recently, however, However, in the present study, we have described for the first time not there have been a few case reports described pathologic findings of OP only the CT patterns but also about their correlation with pathology of associated with influenza A (H1N1) pneumonia [2,5,29,30]. Moreover, 4 M. Murota et al. European Journal of Radiology Open 7 (2020) 100297 Fig. 4. 45-Year-old man with influenza A (H1N1) pneumonia. Radiologic-pathologic correlation (type C). (A) CT shows areas of GGO and airspace consolidation along pleura and peribronchovascular zone bilaterally in lower lung resembling dermatomyositis-associated interstitial lung disease (categorized into type C) (B) Photomicrograph shows organizing pneumonia of incorporated pattern (hematoxylin-eosin). Cornejo et al. [5] alerted about the possibility of OP associated with confirm this result, it is necessary to verify with more surgical lung bi­ influenza A (H1N1) pneumonia in patients with severe respiratory opsy cases of influenza A (H1N1) pneumonia. This may be related to a failure. In these patients, the authors also discussed that the clinical poor prognosis in influenza A (H1N1) pneumonia as in patients with symptoms of severe respiratory failure observed do not seem to resemble DM-associated interstitial lung disease and ASS interstitial lung disease. those of OP due to other causes. We surprisingly found that incorporated OP was pathologically seen Histologically, OP is characterized by the presence of granulation not only in cases with non-classical forms (type B and C) but also with tissue (inflammatory cells, fibroblasts and loose connective tissue) in the classical form (type A). The reason for this finding is unclear, however, it alveoli and alveolar ducts [31]. Histological OP is considered a is possible that the cases with type A may represent a milder form than nonspecific tissue reaction to various causes of lung injury, including the type B and C. drugs, radiation, connective tissue diseases, cancers, lung and bone The appearance of anti-melanoma differentiation associated gene 5 marrow transplantation, and bacterial or virus infection [5,31]. A case (MDA5) antibody was reported to be associated with rapidly progressive of COVID-19 pneumonia was also reported which the presence of interstitial lung disease caused by clinically amyopathic DM [38]. MDA5 organizing pneumonia confirmed histologically [32]. A few reports is one of the retinoic acid-inducible gene I (RIG-I) like receptors (RLRs), described pathologically a “bronchiolitis obliterans organizing pneu­ which are involved in the recognition of viral RNAs and play an monia (BOOP)-like pattern” in patients with SARS [33]. Some in­ important role in innate immune response. RIG-I is also one of the RLRs vestigators have indicated that secondary OP associated with collagen reported to be essential for the production of interferons in response to vascular diseases has a poorer prognosis than cryptogenic OP [31,34, RNA viruses including influenza virus, whereas MDA5 is critical for 35]. Histological OP has two subtypes, intraluminal type OP and picornavirus detection [39]. However, it was recently reported the RIG-I incorporated type OP [18,19]. In recent reports, it was described that is not only primary pattern recognition receptor for influenza A virus but incorporated type OP was observed in patients of RPILD with DM and implicated MDA5 is also as a significant contributor to the cellular de­ ASS [36,37]. Current study revealed for the first time that patients with fense against influenza A virus [40]. Thus, CT findings of influenza A influenza A (H1N1) pneumonia frequently demonstrate incorporated (H1N1) pneumonia in the present study may be similar to those of type OP as well. From the histological viewpoint, RPILD of DM/ASS and dermatomyositis-associated interstitial lung disease. influenza A (H1N1) pneumonia have common features. In order to Our study had several limitations. First, it was a retrospective study, 5 M. Murota et al. European Journal of Radiology Open 7 (2020) 100297 Table 1 Takeshi Johkoh: Conceptualization, Methodology, Resources, Writing - CT findings of influenza H1N1 virus-associated pneumonia. review & editing. Kyung Soo Lee: Resources, Investigation. Tomas CT findings Number of κ Franquet: Resources, Investigation. Yasuhiro Kondoh: Resources, patients Investigation. Yoshihiro Nishiyama: Writing - review & editing. Ground-glass opacities 24/24 (100) N.A. Tomonori Tanaka: Investigation. Hiromitsu Sumikawa: Investiga­ Airspace consolidation 23/24 (96) 0.36 tion. Ryoko Egashira: Writing - review & editing. Norihiko Yama­ Intralobular reticular opacities 1/24 (4) 0.16 guchi: Resources, Investigation. Kiminori Fujimoto: Writing - review Emphysema 1/24 (4) 0.36 & editing. Junya Fukuoka: Writing - review & editing. Bronchial dilatation 2/24 (8) − 0.14 Bronchial wall thickening 7/24 (29) 0.48 Lower volume loss 10/24 (42) 0.41 Declaration of Competing Interest Subpleural sparing 8/24 (33) 0.00 Centrilobular nodules 11/24 (46) 0.66 The authors report no declarations of interest. Tree-in-bud appearance 7/24 (29) 0.65 Lymphadenopathy 12/24 (50) 0.25 Pleural effusion 7/24 (29) 0.73 Acknowledgements Predominant overall anatomic This study was performed on the behalf of the Study Group of Cre­ distribution ation of Radiological Paper from Japan in Diffuse Lung Disease. The Peripheral 7/24 (29) 0.63 members are as follows: Hiroaki Arakawa, Ryoko Egashira, Kiminori Peribronchovascular 20/24 (83) 0.21 Fujimoto, Junya Fukuoka, Hiroto Hatabu, Kazuya Ichikado, Tae Iwa­ Bilateral 17/24 (71) 0.36 sawa, Takeshi Johkoh, Yasuhiro Kondoh, Makiko Murota, Takashi Unilateral 7/24 (29) 0.36 Ogura, Fumikazu Sakai, Hiroaki Sugiura, Hiromitsu Sumikawa, Hir­ oyuki Taniguchi, Junya Tominaga, Noriyuki Tomiyama. 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