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The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza
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ScienceDirect Radiology of Infectious Diseases xx (2016) 1e6 www.elsevier.com/locate/jrid
Research article
The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza Feng Feng a,b,*, Ganlin Xia b, Yuxin Shi a,**, Zhiyong Zhang a,*** b
a Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China Department of Radiology, Nantong Tumor Hospital, Nantong University, Nantong, Jiangsu Province, China
Received 8 December 2015; revised 11 February 2016; accepted 24 February 2016 Available online ▪ ▪ ▪
Abstract Purpose: To investigate the correlations of pulmonary high-resolution computed tomography (HRCT) findings and their distribution with the peripheral blood immunological parameters of swine-origin influenza A (H1N1) infection. Materials and methods: 173 patients with H1N1 influenza infection underwent HRCT. CD4þ and CD8þ lymphocyte counts and C-reactive protein (CRP) levels in the peripheral blood were measured on the day of admission. According to the predominant HRCT findings, we created three groups: Group A ¼ normal attenuation, Group B ¼ ground-glass opacity (GGO), Group C ¼ consolidation with or without GGO. We classified the extent of lung lesions into five groups as follows: Group 1 ¼ CT score of 0; Group 2 ¼ CT score of 0.01e0.25; Group 3 ¼ CT score of 0.26e0.50; Group 4 ¼ CT score of 0.51e0.75; Group 5 ¼ CT score of 0.75e1.00. Results: The CD4þ and CD8þ lymphocyte counts decreased with the degree of the attenuation and the extent of the lesions on HRCT (P < 0.001), whereas the CRP levels increased with the degree of the attenuation and the extent of the lesions (P < 0.001). Conclusions: The HRCT findings correlated with the CD4þ and CD8þ lymphocyte counts and the CRP level in the peripheral blood of patients in the initial stage of influenza infections. © 2016 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: HRCT; H1N1 influenza A; Peripheral blood immunological parameters; Lung
1. Introduction A new strain of novel swine-origin influenza A (H1N1) was first recognized in early 2009 and resulted in a worldwide pandemic [1]. Although most patients with H1N1 infections
* Corresponding author. Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China. Tel.: þ86 21 37990333 7335; fax: þ86 21 57247094. ** Corresponding author. Tel.: þ86 21 37990333 7335; fax: þ86 21 57247094. *** Corresponding author. Tel.: þ86 21 37990333 7335; fax: þ86 21 57247094. E-mail addresses: [email protected] (F. Feng), [email protected] (Y. Shi), [email protected] (Z. Zhang). Peer review under responsibility of Beijing You'an Hospital affiliated to Capital Medical University.
experience flu-like symptoms that follow a benign clinical course, some patients may experience a serious acute respiratory illness, such as pneumonia and respiratory distress, occasionally requiring mechanical ventilation and potentially progressing to death [2e5]. Compared with chest radiography, CT scans provide more precise information about the extent and distribution of the disease. Most patients who have novel influenza A will have a normal chest radiograph or CT examination, or they will demonstrate ground-glass opacity (GGO), which is frequently seen in viral pneumonia [6,7]. However, an increasing number of patients undergo CT, particularly high-resolution CT (HRCT), when there is strong clinical suspicion of pneumonia in the presence of normal or questionable radiographic findings. The predominant abnormal pulmonary CT findings in patients with H1N1 infection are ground-glass opacities, areas
http://dx.doi.org/10.1016/j.jrid.2016.02.001 2352-6211/© 2016 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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of consolidation, or a mixed pattern of ground-glass opacities and areas of consolidation [8,9]. The abnormalities are frequently bilateral and may have a peripheral subpleural and peribronchovascular distribution [8,10]. The drop in lymphocyte counts is a general phenomenon seen in humans early after infection. Knowledge of the immune responses associated with severe H1N1 pneumonia may help clinicians identify patients and provide appropriate management. There have been few reports on the immune responses of patients with H1N1 A infections [11,12]. CD4þ cells act as direct effectors in protecting against the influenza A virus and may contribute to immunopathology and generate functionally distinct memory subsets [13,14]. CD8þ T cells are important in the antiviral response to the influenza A virus via direct lysis or via the induction of inflammatory cytokines [15,16]. Pulmonary H1N1 infections can present with a wide variety of CT patterns, none of which is specific to the diagnosis. Clinical and laboratory data and the presence of HRCT imaging seen in H1N1 infections can help to produce the correct diagnosis and to assess the severity of the disease. The purpose of the present study is to investigate the relationship between HRCT findings in patients with new influenza infections and immunological parameters in the peripheral blood. 2. Materials and methods Our study was retrospective and based on register data. Therefore, the approval of the institutional review board was waived according to instructions of our hospital ethical committee. Between May 2009 and January 2010, our institution saw 288 patients who fulfilled the clinical criteria for H1N1 influenza infection established by the National Centers for Disease Control and Prevention. All patients were confirmed as having a novel influenza A viral infection by using a realtime polymerase chain reaction. All patients were evaluated for other respiratory viral infections, and some patients underwent additional microbiological evaluation for bacterial and fungal infections. Cases of H1N1 with superimposed bacterial pneumonia or viral infections were excluded using clinical and laboratory criteria. Of these patients, 173 adult patients underwent HRCT and were evaluated for CD4þ and CD8þ T lymphocyte counts and C-reactive protein (CRP) on the same day, which was 1e7 d after the onset of symptoms. The patients included 110 men and 63 women (aged 18e78 years, with a mean age of 32 years). To avoid unnecessary radiation exposure, HRCT was performed when patients had clinical evidence of pneumonia but chest radiography was insufficient for evaluation and diagnosis. The CT scans were performed on a 16-slice Siemens CT scanner (Somatom Sensation 16, Erlangen, Germany) using the volumetric technique with no contrast enhancement. Spiral scans were obtained with the same scanner and the following parameters: 110 mAs, 120 kVp, 0.75-mm collimations, 1 mm slice, and a high-spatial-frequency reconstruction algorithm. All images were reviewed on a picture archiving and communication system workstation. The images were
obtained with both mediastinal (width 350e450 HU; level 20e40 HU) and parenchymal (width 1200e1600 HU; level 500 to700 HU) window settings. Two experienced radiologists with thoracic imaging experience of 12 years and 22 years reviewed the HRCT scans independently and reached a decision on the final interpretations by consensus. According to the predominant HRCT findings, we created the following three groups: Group A ¼ normal attenuation, Group B ¼ ground-glass opacity (GGO), Group C ¼ consolidation with or without GGO. On the scans, nodules, lymphadenpathy (defined as a lymph node 1 cm in shortaxis diameter), and pleural effusion were also noted. The extent of disease in the HRCT was also evaluated using the HRCT scoring method [17]. The lung was evaluated by lobe (i.e., RU: right upper lobe, RM: right middle lobe, RL: right lower lobe, LU: left upper lobe and LL: left lower lobe). Each lobe was divided into two sections, a peripheral and a central part, the central part of the lobe was defined as the anatomical half of the lobe closest to the hilus, whereas the peripheral part of the lobe was defined as the outer half of the lobe around the central part of the lobe (Fig. 1). The central and peripheral lobes were each given a score of 1, 0 if changes were present, absent, respectively. Each lobe was evaluated for the extent of lesions. To calculate the score for the lungs, the number of positive scores (that is number of score of 1) was obtained. For example, a score of 3 in a double lung corresponds to 3/10 ¼ 0.3. The mean value of the scores from the two observers was used in this study. According to the extent of lung lesions, we created the following five groups: group 1 (CT score ¼ 0), group 2 (CT score ¼ 0.1e0.25), group 3 ¼ (CT score ¼ 0.26e0.50), group 4 (CT score ¼ 0.51e0.75), and group 5 (CT score ¼ 0.76e1.00). All statistical analyses were performed using the SPSS View 16.0 software (SPSS, Chicago, IL). Means, standard deviations and frequencies were calculated. The quantitative data were compared using the Scheffe method for post hoc comparisons only when the results of the one-way analysis of variance were significant at a level of P < 0.05. 3. Results Of all 173 patients, based on the attenuation of lesions according to the HRCT, 83 patients were classified as group A, 36 patients were classified as group B (Fig. 2), and 54 patients were grouped in group C (Fig. 3). As shown in Table 1, the statistical analysis revealed that CD4þ, CD8þ and CRP levels correlated with the degree of attenuation of the lesions on the HRCT (P < 0.001), but the CD4/CD8 ratio did not correlate with the degree of attenuation of the lesions (P > 0.05). The CD4þ lymphocyte counts in group C were significantly lower than in group A (P < 0.05), but there was no significant difference compared to group B. The CD8þ lymphocyte counts of group C were lower than those of group A (P < 0.05), but there was no significant difference in CD8þ lymphocyte counts between group C and group B. In addition, the CRP level of group C was higher than the levels in group A or group B (P < 0.05). Centrilobular nodules were only noted in
Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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Fig. 1. The flow chart of the HRCT scoring method. RU: right upper lobe, RM: right middle lobe, RL: right lower lobe, LU: left upper lobe and LL: left lower lobe, OL: outer half of the lobe around the central part of the lobe, CL: central part of the lobe.
Fig. 2. A 36-year-old woman with H1N1 pneumonia. The HRCT image shows patchy GGO in the lower left lung (CT score of 0.1). The right lung is normal.
3 patients from group A. Pleural effusion was only observed in 7 patients from group C. Axillary and mediastinal lymphadenopathy were noted in a total of 5 patients. Patients were classified three groups based on the HRCT scoring, 83 patients were classified as group 1, 33 patients were classified as group 2, 23 patients were grouped in group 3, 21 patients were classified as group 4 (Fig. 4), and 13 patients were classified as group 5 (Fig. 5). As shown in Table 2, the statistical analysis revealed that the CD4þ, CD8þ and CRP levels correlated with the degree of lesion distribution on the HRCT (p < 0.001). The CD4þ lymphocyte counts in group 5 were significantly lower compared to groups 1, 2 or 3 (P < 0.05). There were significant differences in the CD4þ lymphocyte counts between group 4 and group 1 (P < 0.05). The CD8þ lymphocyte count of group 5 was lower than that of group 1 and group 2 (P < 0.05), and group 4 had a lower count than group 1 (P < 0.05). The level of CRP in group 5 was higher than in group 1 and group 2 (P < 0.05), and group 4 had a higher level than group 1 and group 2 (P < 0.05). There was a significant difference between the CRP levels of group 3 and those of group 1 (P < 0.05). There were no significant differences in the CD4þ/CD8þ ratios of groups 1, 2, 3, 4 and 5 (P > 0.05). 4. Discussion
Fig. 3. A 31-year-old man with H1N1 pneumonia. The HRCT image shows segmental consolidations in the left upper lung (CT score of 0.2), with an air bronchogram. The right lung is normal.
The HRCT shows the extent of pulmonary lesions and assesses damage in the initial detection of influenza A, and findings of the HRCT scan determine the degree of infectiousness of patients with influenza A. However, the relationship between the density and the extent of the lesions of
Table 1 The peripheral blood immunological parameters by the attenuation level of lesions in HRCT. Group A (n ¼ 83) CD4þ (/mL) CD8þ (/mL) CD4þ/CD8þ CRP (mg/L)
493.6 386.7 1.4 13.4
± ± ± ±
21.9 21.2 0.1 1.0
Group B (n ¼ 36) 396.0 318.3 1.4 20.5
± ± ± ±
30.6 26.3 0.1 3.4
Group C (n ¼ 54) 315.4 251.1 1.3 62.9
± ± ± ±
27.3 20.8 0.1 9.7
PAB
PBC
PAC
PABC
0.048 0.148 0.866 0.694
0.166 0.205 0.759 <0.001
<0.001 <0.001 0.314 <0.001
<0.001 <0.001 0.314 <0.001
The data are presented as the mean ± S.D. CRP ¼ C-reactive protein. Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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Fig. 4. A 40-year-old man with H1N1 pneumonia. (a) The HRCT image shows extensive consolidations in both lower lobes and a focal consolidation in the left upper lobe. (b) HRCT exhibits consolidations in the right middle lobe and both lower lobes. (CT score of 0.6).
Fig. 5. A 58-year-old man with H1N1 pneumonia. (a) HRCT exhibits consolidations and GGOs in both upper lobes. (b) HRCT shows diffuse bilateral consolidations and GGOs in middle and lower lobes. (CT score of 0.9).
Table 2 The peripheral blood immunological parameters by the extent of the lesions in HRCT. Group 1 (n ¼ 83) CD4þ (/mL) CD8þ (/mL) CD4þ/CD8þ CRP (mg/L)
493.6 386.7 1.4 13.4
± ± ± ±
21.9 21.2 0.1 1.0
Group 2 (n ¼ 33) 406.7 324.2 1.4 20.8
± ± ± ±
32.5 28.0 0.1 3.7
Group 3 (n ¼ 23) 395.5 316.5 1.3 44.5
± ± ± ±
40.5 34.6 0.1 8.7
Group 4 (n ¼ 21) 313.9 250.7 1.3 60.9
± ± ± ±
42.1 27.6 0.1 15.1
Group 5 (n ¼ 13) 167.6 136.3 1.3 88.1
± ± ± ±
32.0 20.5 0.1 28.4
P <0.001 <0.001 0.654 <0.001
The data are presented as the mean ± S.D. CRP ¼ C-reactive protein. There were significant differences between the CD4þ levels of group 5 and groups 1, 2 and 3, P < 0.05. There were significant differences between the CD4þ level of group 4 and the level of group 1, P < 0.05. There was a significant difference in CD8þ between group 5 and groups 1 and 2, P < 0.05. There was a significant difference in CD8þ between group 4 and group 1, P < 0.05. There was a significant difference in CRP between group 5 and groups 1 and 2, P < 0.05. There was a significant difference in CRP between group 4 and groups 1 and 2, P < 0.05. There was a significant difference in CRP between group 3 and group 1, P < 0.05. There were no significant differences in the CD4þ/CD8þ ratio among groups 1, 2, 3, 4 and 5.
influenza A infection and the immunological parameters in the peripheral blood has not, to the best of our knowledge, been investigated. The present study found that the levels of CD4þ and CD8þ T cells decreased and the CRP level increased with the degree of attenuation and the extent of lesions in the acute phase of influenza A infection. In the study, we compared the different pulmonary CT findings of influenza A patients with clinical manifestations of different severities. The initial HRCT imaging in all patients revealed normal performance in 83/173 patients, GGO in 36/ 173 patients, and consolidation with or without GGO in 54/ 173 patients, consistent with the results of previous studies
[18e22]. Yuan et al. reported that 40.5% (66/163) of patients with mild influenza infections had normal performances, and 36.1% (33/97) showed GGO [18]. Several studies reported that most influenza A pneumonia patients had unilateral or bilateral distribution consolidation associated with GGO or consolidation [8,9,20]. The HRCT findings were correlated with the severity of disease. In our study, as the condition of the lungs progressed from normal to GGO and consolidations, the number of CD4þ and CD8þ T cells decreased and the CRP level increased. The same changes were observed associated with the progression from normal to focal and diffuse distribution: a statistically significant
Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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decrease in CD4þ and CD8þ lymphocyte counts and a significant increase in the CRP level. The result suggested that impaired cellular immune function may be one of the immunological characteristics of the disease and may be related to the degree of disease. The H1N1 virus is capable of inhibiting cellular immune function and is most likely related to the induction of excessive apoptosis of lymphocytes. Mozdzanowska et al. found that patients infected with the influenza A virus had decreased CD4þ T lymphocytes [23]. Mackemie et al. found that mice infected with influenza A showed decreased CD8þ T lymphocytes counts and that CD8þ T lymphocytes play an important role in inhibiting influenza A virus replication and in reducing the severity of the disease [24]. The elevated CRP suggests that influenza viral infection caused a change in the acute inflammatory response in vivo. The level increased more in the severe patients than in the mild patients, the severe patients had a stronger inflammation reaction. In addition, the main pathological feature of H1N1 infection consisted of diffuse alveolar damage with hyaline membrane formation, which is associated with various degrees of pulmonary edema, hemorrhage, inflammatory exudate and bronchiolitis [25]. The pathogenesis of membrane damage is complex and related to both the release of inflammatory cytokines and the aberrant immune response mediated by the CD8þ T and B lymphocytes [26]. It produces a peculiar pathological and initial HRCT pattern. Because it correlates with HRCT findings, the GGO reflected alveolar septal thickening, whether or not it was associated with partial airspace filling. The areas of consolidation corresponded to alveoli filled with edema fluid, inflammatory exudate or hemorrhagy. The patients who present with consolidations on HRCT scans have more severe laboratory data than those who present with GGO [9]. Most of the patients with consolidations have elevated lactate dehydrogenase levels and an oxygen saturation level in room air 88% [26]. In our study, the 54 patients who presented with consolidations on HRCT scans had lower levels of CD4þ and CD8þ T lymphocytes and higher CRP levels. HRCT findings of peripheral scattered areas of consolidation or ground-glass opacities are not specific for influenza pneumonia. These findings often overlap with those of other viral infections, bacterial, fungal, or mycobacterial infection. Thus, imaging findings are often nonspecific for an infection agent and the differential diagnosis is important to avoid the interpretation of the results [9]. However, imaging findings are most useful in the context of clinical symptoms, contact history, and laboratory results. In our study, all patients included fulfill the criteria established by the Centers for Disease Control and Prevention for confirmed H1N1 cases, which are influenzalike illness and positive findings for influenza A (H1N1) virus on reverse transcriptase polymerase chain reaction. Cases of H1N1 with superimposed other viral infections and bacterial pneumonia were excluded using clinical and laboratory criteria. There were some limitations to our study. First, the measurements of the peripheral immunological parameters and the HRCT scans were conducted within 24 h of admission. The
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number of CD4þ and CD8þ T lymphocytes may differ and the HRCT findings may change according to the amount of time elapsed since the influenza infection. We could not monitor the relationship between the HRCT findings and the immunological parameters until they recovered to the normal range. Second, no information on the relationship between CT and histopathology could be obtained because none of the patients underwent a lung biopsy or an autopsy. HRCT showed abnormal lung damage in real time, and it is useful for accurately determining the degree of lung lesions, as well as the site of damage in the lung parenchyma. In addition, the CD4þ and CD8þ T lymphocytes and the CRP level correlate well with the degree of infectiousness indicated on the HRCT of the influenza patient during the initial phase of infection. It is essential to further explore the relationship between peripheral blood immunological parameters and the attenuation and extent of legions shown on HRCT to improve the diagnosis of initial influenza infections and the staging of the disease, especially in severe cases. References [1] World Health Organization. Global alert and response: pandemic (H1N1) 2009: update 112. Geneva: World Health Organization; 2009. See, http:// www.who.int/csr/don/2010_08_06/en/index.html. [2] Laguna-Torres VA, Benavides JG. Infection and death from influenza A H1N1 virus in Mexico. Lancet 2009;374:2032e3. [3] Echevarria-Zuno S, Mejia-Arangure JM, Mar-Obeso AJ, GrajalesMuniz C, Robles-Perez E, Gonzalez-Leon M, et al. Infection and death from influenza A H1N1 virus in Mexico: a retrospective analysis. Lancet 2009;374:2072e9. [4] Grieser C, Goldmann A, Steffen IG, Kastrup M, Fernandez CM, Engert U, et al. Computed tomography findings from patients with ARDS due to influenza A (H1N1) virus-associated pneumonia. Eur J Radiol 2012;81:389e94. [5] Cortes GM, Sierra MM, Santa-Olalla PP, Hernandez-Barrera V, JimenezGarcia R, Pachon I. Clinical characteristics and outcomes of diabetic patients who were hospitalised with 2009 pandemic influenza A H1N1 infection. J Infect 2012;64:218e24. [6] Kumar D, Michaels MG, Morris MI, Green M, Avery RK, Liu C, et al. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis 2010;10:521e6. [7] Aviram G, Bar-Shai A, Sosna J, Rogowski O, Rosen G, Weinstein I, et al. H1N1 influenza: initial chest radiographic findings in helping predict patient outcome. Radiology 2010;255:252e9. [8] Marchiori E, Zanetti G, Hochhegger B, Rodrigues RS, Fontes CA, Nobre LF, et al. High-resolution computed tomography findings from adult patients with influenza A (H1N1) virus-associated pneumonia. Eur J Radiol 2010;74:93e8. [9] Marchiori E, Zanetti G, D'Ippolito G, Santos ML, Valiante PM, Mano CM, et al. Swine-origin influenza A (H1N1) viral infection: thoracic findings on CT. AJR Am J Roentgenol 2011;196:W723e8. [10] Ajlan AM, Quiney B, Nicolaou S, Muller NL. Swine-origin influenza A (H1N1) viral infection: radiographic and CT findings. AJR Am J Roentgenol 2009;193:1494e9. [11] Cui W, Zhao H, Lu X, Wen Y, Zhou Y, Deng B, et al. Factors associated with death in hospitalized pneumonia patients with 2009 H1N1 influenza in Shenyang, China. BMC Infect Dis 2010;10:145. [12] Kim JE, Bauer S, La KS, Lee KH, Choung JT, Roh KH, et al. CD4þ/ CD8þ T lymphocytes imbalance in children with severe 2009 pandemic influenza A (H1N1) pneumonia. Korean J Pediatr 2011;54:207e11.
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[13] Brown DM, Roman E, Swain SL. CD4 T cell responses to influenza infection. Semin Immunol 2004;16:171e7. [14] Schanen BC, De Groot AS, Moise L, Ardito M, McClaine E, Martin W, et al. Coupling sensitive in vitro and in silico techniques to assess crossreactive CD4(þ) T cells against the swine-origin H1N1 influenza virus. Vaccine 2011;29:3299e309. [15] Mauad T, Hajjar LA, Callegari GD, Da SL, Schout D, Galas FR, et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med 2010;181:72e9. [16] Bruder D, Srikiatkhachorn A, Enelow RI. Cellular immunity and lung injury in respiratory virus infection. Viral Immunol 2006;19:147e55. [17] Belmaati E, Jensen C, Kofoed KF, Iversen M, Steffensen I, Nielsen MB. Primary graft dysfunction; possible evaluation by high resolution computed tomography, and suggestions for a scoring system. Interact Cardiovasc Thorac Surg 2009;9:859e67. [18] Yuan Y, Tao XF, Shi YX, Liu SY, Chen JQ. Initial HRCT findings of novel influenza A (H1N1) infection. Influenza Other Respir Viruses 2012;6:e114e9. [19] Coppola M, Porto A, De Santo D, De Fronzo S, Grassi R, Rotondo A. Influenza A virus: radiological and clinical findings of patients hospitalised for pandemic H1N1 influenza. Radiol Med 2011;116:706e19. [20] Li P, Su DJ, Zhang JF, Xia XD, Sui H, Zhao DH. Pneumonia in novel swine-origin influenza A (H1N1) virus infection: high-resolution CT findings. Eur J Radiol 2011;80:e146e52.
[21] Agarwal PP, Cinti S, Kazerooni EA. Chest radiographic and CT findings in novel swine-origin influenza A (H1N1) virus (S-OIV) infection. AJR Am J Roentgenol 2009;193:1488e93. [22] Jartti A, Rauvala E, Kauma H, Renko M, Kunnari M, Syrjala H. Chest imaging findings in hospitalized patients with H1N1 influenza. Acta Radiol 2011;52:297e304. [23] Mozdzanowska K, Furchner M, Zharikova D, Feng J, Gerhard W. Roles of CD4þ T-cell-independent and -dependent antibody responses in the control of influenza virus infection: evidence for noncognate CD4þ Tcell activities that enhance the therapeutic activity of antiviral antibodies. J Virol 2005;79:5943e51. [24] Mackenzie CD, Taylor PM, Askonas BA. Rapid recovery of lung histology correlates with clearance of influenza virus by specific CD8þ cytotoxic T cells. Immunology 1989;67:375e81. [25] Marchiori E, Zanetti G, Fontes CA, Verrastro CG, Meirelles GS, Capobianco J, et al. Influenza A (H1N1) virus-associated pneumonia: high-resolution computed tomography-pathologic correlation. Eur J Radiol 2011;80:e500e4. [26] Mineo G, Ciccarese F, Modolon C, Landini MP, Valentino M, Zompatori M. Post-ARDS pulmonary fibrosis in patients with H1N1 pneumonia: role of follow-up CT. Radiol Med 2012;117:185e200.
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Research article
The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza Feng Feng a,b,*, Ganlin Xia b, Yuxin Shi a,**, Zhiyong Zhang a,*** b
a Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China Department of Radiology, Nantong Tumor Hospital, Nantong University, Nantong, Jiangsu Province, China
Received 8 December 2015; revised 11 February 2016; accepted 24 February 2016 Available online ▪ ▪ ▪
Abstract Purpose: To investigate the correlations of pulmonary high-resolution computed tomography (HRCT) findings and their distribution with the peripheral blood immunological parameters of swine-origin influenza A (H1N1) infection. Materials and methods: 173 patients with H1N1 influenza infection underwent HRCT. CD4þ and CD8þ lymphocyte counts and C-reactive protein (CRP) levels in the peripheral blood were measured on the day of admission. According to the predominant HRCT findings, we created three groups: Group A ¼ normal attenuation, Group B ¼ ground-glass opacity (GGO), Group C ¼ consolidation with or without GGO. We classified the extent of lung lesions into five groups as follows: Group 1 ¼ CT score of 0; Group 2 ¼ CT score of 0.01e0.25; Group 3 ¼ CT score of 0.26e0.50; Group 4 ¼ CT score of 0.51e0.75; Group 5 ¼ CT score of 0.75e1.00. Results: The CD4þ and CD8þ lymphocyte counts decreased with the degree of the attenuation and the extent of the lesions on HRCT (P < 0.001), whereas the CRP levels increased with the degree of the attenuation and the extent of the lesions (P < 0.001). Conclusions: The HRCT findings correlated with the CD4þ and CD8þ lymphocyte counts and the CRP level in the peripheral blood of patients in the initial stage of influenza infections. © 2016 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: HRCT; H1N1 influenza A; Peripheral blood immunological parameters; Lung
1. Introduction A new strain of novel swine-origin influenza A (H1N1) was first recognized in early 2009 and resulted in a worldwide pandemic [1]. Although most patients with H1N1 infections
* Corresponding author. Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China. Tel.: þ86 21 37990333 7335; fax: þ86 21 57247094. ** Corresponding author. Tel.: þ86 21 37990333 7335; fax: þ86 21 57247094. *** Corresponding author. Tel.: þ86 21 37990333 7335; fax: þ86 21 57247094. E-mail addresses: [email protected] (F. Feng), [email protected] (Y. Shi), [email protected] (Z. Zhang). Peer review under responsibility of Beijing You'an Hospital affiliated to Capital Medical University.
experience flu-like symptoms that follow a benign clinical course, some patients may experience a serious acute respiratory illness, such as pneumonia and respiratory distress, occasionally requiring mechanical ventilation and potentially progressing to death [2e5]. Compared with chest radiography, CT scans provide more precise information about the extent and distribution of the disease. Most patients who have novel influenza A will have a normal chest radiograph or CT examination, or they will demonstrate ground-glass opacity (GGO), which is frequently seen in viral pneumonia [6,7]. However, an increasing number of patients undergo CT, particularly high-resolution CT (HRCT), when there is strong clinical suspicion of pneumonia in the presence of normal or questionable radiographic findings. The predominant abnormal pulmonary CT findings in patients with H1N1 infection are ground-glass opacities, areas
http://dx.doi.org/10.1016/j.jrid.2016.02.001 2352-6211/© 2016 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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of consolidation, or a mixed pattern of ground-glass opacities and areas of consolidation [8,9]. The abnormalities are frequently bilateral and may have a peripheral subpleural and peribronchovascular distribution [8,10]. The drop in lymphocyte counts is a general phenomenon seen in humans early after infection. Knowledge of the immune responses associated with severe H1N1 pneumonia may help clinicians identify patients and provide appropriate management. There have been few reports on the immune responses of patients with H1N1 A infections [11,12]. CD4þ cells act as direct effectors in protecting against the influenza A virus and may contribute to immunopathology and generate functionally distinct memory subsets [13,14]. CD8þ T cells are important in the antiviral response to the influenza A virus via direct lysis or via the induction of inflammatory cytokines [15,16]. Pulmonary H1N1 infections can present with a wide variety of CT patterns, none of which is specific to the diagnosis. Clinical and laboratory data and the presence of HRCT imaging seen in H1N1 infections can help to produce the correct diagnosis and to assess the severity of the disease. The purpose of the present study is to investigate the relationship between HRCT findings in patients with new influenza infections and immunological parameters in the peripheral blood. 2. Materials and methods Our study was retrospective and based on register data. Therefore, the approval of the institutional review board was waived according to instructions of our hospital ethical committee. Between May 2009 and January 2010, our institution saw 288 patients who fulfilled the clinical criteria for H1N1 influenza infection established by the National Centers for Disease Control and Prevention. All patients were confirmed as having a novel influenza A viral infection by using a realtime polymerase chain reaction. All patients were evaluated for other respiratory viral infections, and some patients underwent additional microbiological evaluation for bacterial and fungal infections. Cases of H1N1 with superimposed bacterial pneumonia or viral infections were excluded using clinical and laboratory criteria. Of these patients, 173 adult patients underwent HRCT and were evaluated for CD4þ and CD8þ T lymphocyte counts and C-reactive protein (CRP) on the same day, which was 1e7 d after the onset of symptoms. The patients included 110 men and 63 women (aged 18e78 years, with a mean age of 32 years). To avoid unnecessary radiation exposure, HRCT was performed when patients had clinical evidence of pneumonia but chest radiography was insufficient for evaluation and diagnosis. The CT scans were performed on a 16-slice Siemens CT scanner (Somatom Sensation 16, Erlangen, Germany) using the volumetric technique with no contrast enhancement. Spiral scans were obtained with the same scanner and the following parameters: 110 mAs, 120 kVp, 0.75-mm collimations, 1 mm slice, and a high-spatial-frequency reconstruction algorithm. All images were reviewed on a picture archiving and communication system workstation. The images were
obtained with both mediastinal (width 350e450 HU; level 20e40 HU) and parenchymal (width 1200e1600 HU; level 500 to700 HU) window settings. Two experienced radiologists with thoracic imaging experience of 12 years and 22 years reviewed the HRCT scans independently and reached a decision on the final interpretations by consensus. According to the predominant HRCT findings, we created the following three groups: Group A ¼ normal attenuation, Group B ¼ ground-glass opacity (GGO), Group C ¼ consolidation with or without GGO. On the scans, nodules, lymphadenpathy (defined as a lymph node 1 cm in shortaxis diameter), and pleural effusion were also noted. The extent of disease in the HRCT was also evaluated using the HRCT scoring method [17]. The lung was evaluated by lobe (i.e., RU: right upper lobe, RM: right middle lobe, RL: right lower lobe, LU: left upper lobe and LL: left lower lobe). Each lobe was divided into two sections, a peripheral and a central part, the central part of the lobe was defined as the anatomical half of the lobe closest to the hilus, whereas the peripheral part of the lobe was defined as the outer half of the lobe around the central part of the lobe (Fig. 1). The central and peripheral lobes were each given a score of 1, 0 if changes were present, absent, respectively. Each lobe was evaluated for the extent of lesions. To calculate the score for the lungs, the number of positive scores (that is number of score of 1) was obtained. For example, a score of 3 in a double lung corresponds to 3/10 ¼ 0.3. The mean value of the scores from the two observers was used in this study. According to the extent of lung lesions, we created the following five groups: group 1 (CT score ¼ 0), group 2 (CT score ¼ 0.1e0.25), group 3 ¼ (CT score ¼ 0.26e0.50), group 4 (CT score ¼ 0.51e0.75), and group 5 (CT score ¼ 0.76e1.00). All statistical analyses were performed using the SPSS View 16.0 software (SPSS, Chicago, IL). Means, standard deviations and frequencies were calculated. The quantitative data were compared using the Scheffe method for post hoc comparisons only when the results of the one-way analysis of variance were significant at a level of P < 0.05. 3. Results Of all 173 patients, based on the attenuation of lesions according to the HRCT, 83 patients were classified as group A, 36 patients were classified as group B (Fig. 2), and 54 patients were grouped in group C (Fig. 3). As shown in Table 1, the statistical analysis revealed that CD4þ, CD8þ and CRP levels correlated with the degree of attenuation of the lesions on the HRCT (P < 0.001), but the CD4/CD8 ratio did not correlate with the degree of attenuation of the lesions (P > 0.05). The CD4þ lymphocyte counts in group C were significantly lower than in group A (P < 0.05), but there was no significant difference compared to group B. The CD8þ lymphocyte counts of group C were lower than those of group A (P < 0.05), but there was no significant difference in CD8þ lymphocyte counts between group C and group B. In addition, the CRP level of group C was higher than the levels in group A or group B (P < 0.05). Centrilobular nodules were only noted in
Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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Fig. 1. The flow chart of the HRCT scoring method. RU: right upper lobe, RM: right middle lobe, RL: right lower lobe, LU: left upper lobe and LL: left lower lobe, OL: outer half of the lobe around the central part of the lobe, CL: central part of the lobe.
Fig. 2. A 36-year-old woman with H1N1 pneumonia. The HRCT image shows patchy GGO in the lower left lung (CT score of 0.1). The right lung is normal.
3 patients from group A. Pleural effusion was only observed in 7 patients from group C. Axillary and mediastinal lymphadenopathy were noted in a total of 5 patients. Patients were classified three groups based on the HRCT scoring, 83 patients were classified as group 1, 33 patients were classified as group 2, 23 patients were grouped in group 3, 21 patients were classified as group 4 (Fig. 4), and 13 patients were classified as group 5 (Fig. 5). As shown in Table 2, the statistical analysis revealed that the CD4þ, CD8þ and CRP levels correlated with the degree of lesion distribution on the HRCT (p < 0.001). The CD4þ lymphocyte counts in group 5 were significantly lower compared to groups 1, 2 or 3 (P < 0.05). There were significant differences in the CD4þ lymphocyte counts between group 4 and group 1 (P < 0.05). The CD8þ lymphocyte count of group 5 was lower than that of group 1 and group 2 (P < 0.05), and group 4 had a lower count than group 1 (P < 0.05). The level of CRP in group 5 was higher than in group 1 and group 2 (P < 0.05), and group 4 had a higher level than group 1 and group 2 (P < 0.05). There was a significant difference between the CRP levels of group 3 and those of group 1 (P < 0.05). There were no significant differences in the CD4þ/CD8þ ratios of groups 1, 2, 3, 4 and 5 (P > 0.05). 4. Discussion
Fig. 3. A 31-year-old man with H1N1 pneumonia. The HRCT image shows segmental consolidations in the left upper lung (CT score of 0.2), with an air bronchogram. The right lung is normal.
The HRCT shows the extent of pulmonary lesions and assesses damage in the initial detection of influenza A, and findings of the HRCT scan determine the degree of infectiousness of patients with influenza A. However, the relationship between the density and the extent of the lesions of
Table 1 The peripheral blood immunological parameters by the attenuation level of lesions in HRCT. Group A (n ¼ 83) CD4þ (/mL) CD8þ (/mL) CD4þ/CD8þ CRP (mg/L)
493.6 386.7 1.4 13.4
± ± ± ±
21.9 21.2 0.1 1.0
Group B (n ¼ 36) 396.0 318.3 1.4 20.5
± ± ± ±
30.6 26.3 0.1 3.4
Group C (n ¼ 54) 315.4 251.1 1.3 62.9
± ± ± ±
27.3 20.8 0.1 9.7
PAB
PBC
PAC
PABC
0.048 0.148 0.866 0.694
0.166 0.205 0.759 <0.001
<0.001 <0.001 0.314 <0.001
<0.001 <0.001 0.314 <0.001
The data are presented as the mean ± S.D. CRP ¼ C-reactive protein. Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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Fig. 4. A 40-year-old man with H1N1 pneumonia. (a) The HRCT image shows extensive consolidations in both lower lobes and a focal consolidation in the left upper lobe. (b) HRCT exhibits consolidations in the right middle lobe and both lower lobes. (CT score of 0.6).
Fig. 5. A 58-year-old man with H1N1 pneumonia. (a) HRCT exhibits consolidations and GGOs in both upper lobes. (b) HRCT shows diffuse bilateral consolidations and GGOs in middle and lower lobes. (CT score of 0.9).
Table 2 The peripheral blood immunological parameters by the extent of the lesions in HRCT. Group 1 (n ¼ 83) CD4þ (/mL) CD8þ (/mL) CD4þ/CD8þ CRP (mg/L)
493.6 386.7 1.4 13.4
± ± ± ±
21.9 21.2 0.1 1.0
Group 2 (n ¼ 33) 406.7 324.2 1.4 20.8
± ± ± ±
32.5 28.0 0.1 3.7
Group 3 (n ¼ 23) 395.5 316.5 1.3 44.5
± ± ± ±
40.5 34.6 0.1 8.7
Group 4 (n ¼ 21) 313.9 250.7 1.3 60.9
± ± ± ±
42.1 27.6 0.1 15.1
Group 5 (n ¼ 13) 167.6 136.3 1.3 88.1
± ± ± ±
32.0 20.5 0.1 28.4
P <0.001 <0.001 0.654 <0.001
The data are presented as the mean ± S.D. CRP ¼ C-reactive protein. There were significant differences between the CD4þ levels of group 5 and groups 1, 2 and 3, P < 0.05. There were significant differences between the CD4þ level of group 4 and the level of group 1, P < 0.05. There was a significant difference in CD8þ between group 5 and groups 1 and 2, P < 0.05. There was a significant difference in CD8þ between group 4 and group 1, P < 0.05. There was a significant difference in CRP between group 5 and groups 1 and 2, P < 0.05. There was a significant difference in CRP between group 4 and groups 1 and 2, P < 0.05. There was a significant difference in CRP between group 3 and group 1, P < 0.05. There were no significant differences in the CD4þ/CD8þ ratio among groups 1, 2, 3, 4 and 5.
influenza A infection and the immunological parameters in the peripheral blood has not, to the best of our knowledge, been investigated. The present study found that the levels of CD4þ and CD8þ T cells decreased and the CRP level increased with the degree of attenuation and the extent of lesions in the acute phase of influenza A infection. In the study, we compared the different pulmonary CT findings of influenza A patients with clinical manifestations of different severities. The initial HRCT imaging in all patients revealed normal performance in 83/173 patients, GGO in 36/ 173 patients, and consolidation with or without GGO in 54/ 173 patients, consistent with the results of previous studies
[18e22]. Yuan et al. reported that 40.5% (66/163) of patients with mild influenza infections had normal performances, and 36.1% (33/97) showed GGO [18]. Several studies reported that most influenza A pneumonia patients had unilateral or bilateral distribution consolidation associated with GGO or consolidation [8,9,20]. The HRCT findings were correlated with the severity of disease. In our study, as the condition of the lungs progressed from normal to GGO and consolidations, the number of CD4þ and CD8þ T cells decreased and the CRP level increased. The same changes were observed associated with the progression from normal to focal and diffuse distribution: a statistically significant
Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001
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decrease in CD4þ and CD8þ lymphocyte counts and a significant increase in the CRP level. The result suggested that impaired cellular immune function may be one of the immunological characteristics of the disease and may be related to the degree of disease. The H1N1 virus is capable of inhibiting cellular immune function and is most likely related to the induction of excessive apoptosis of lymphocytes. Mozdzanowska et al. found that patients infected with the influenza A virus had decreased CD4þ T lymphocytes [23]. Mackemie et al. found that mice infected with influenza A showed decreased CD8þ T lymphocytes counts and that CD8þ T lymphocytes play an important role in inhibiting influenza A virus replication and in reducing the severity of the disease [24]. The elevated CRP suggests that influenza viral infection caused a change in the acute inflammatory response in vivo. The level increased more in the severe patients than in the mild patients, the severe patients had a stronger inflammation reaction. In addition, the main pathological feature of H1N1 infection consisted of diffuse alveolar damage with hyaline membrane formation, which is associated with various degrees of pulmonary edema, hemorrhage, inflammatory exudate and bronchiolitis [25]. The pathogenesis of membrane damage is complex and related to both the release of inflammatory cytokines and the aberrant immune response mediated by the CD8þ T and B lymphocytes [26]. It produces a peculiar pathological and initial HRCT pattern. Because it correlates with HRCT findings, the GGO reflected alveolar septal thickening, whether or not it was associated with partial airspace filling. The areas of consolidation corresponded to alveoli filled with edema fluid, inflammatory exudate or hemorrhagy. The patients who present with consolidations on HRCT scans have more severe laboratory data than those who present with GGO [9]. Most of the patients with consolidations have elevated lactate dehydrogenase levels and an oxygen saturation level in room air 88% [26]. In our study, the 54 patients who presented with consolidations on HRCT scans had lower levels of CD4þ and CD8þ T lymphocytes and higher CRP levels. HRCT findings of peripheral scattered areas of consolidation or ground-glass opacities are not specific for influenza pneumonia. These findings often overlap with those of other viral infections, bacterial, fungal, or mycobacterial infection. Thus, imaging findings are often nonspecific for an infection agent and the differential diagnosis is important to avoid the interpretation of the results [9]. However, imaging findings are most useful in the context of clinical symptoms, contact history, and laboratory results. In our study, all patients included fulfill the criteria established by the Centers for Disease Control and Prevention for confirmed H1N1 cases, which are influenzalike illness and positive findings for influenza A (H1N1) virus on reverse transcriptase polymerase chain reaction. Cases of H1N1 with superimposed other viral infections and bacterial pneumonia were excluded using clinical and laboratory criteria. There were some limitations to our study. First, the measurements of the peripheral immunological parameters and the HRCT scans were conducted within 24 h of admission. The
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number of CD4þ and CD8þ T lymphocytes may differ and the HRCT findings may change according to the amount of time elapsed since the influenza infection. We could not monitor the relationship between the HRCT findings and the immunological parameters until they recovered to the normal range. Second, no information on the relationship between CT and histopathology could be obtained because none of the patients underwent a lung biopsy or an autopsy. HRCT showed abnormal lung damage in real time, and it is useful for accurately determining the degree of lung lesions, as well as the site of damage in the lung parenchyma. In addition, the CD4þ and CD8þ T lymphocytes and the CRP level correlate well with the degree of infectiousness indicated on the HRCT of the influenza patient during the initial phase of infection. It is essential to further explore the relationship between peripheral blood immunological parameters and the attenuation and extent of legions shown on HRCT to improve the diagnosis of initial influenza infections and the staging of the disease, especially in severe cases. References [1] World Health Organization. Global alert and response: pandemic (H1N1) 2009: update 112. Geneva: World Health Organization; 2009. See, http:// www.who.int/csr/don/2010_08_06/en/index.html. [2] Laguna-Torres VA, Benavides JG. Infection and death from influenza A H1N1 virus in Mexico. Lancet 2009;374:2032e3. [3] Echevarria-Zuno S, Mejia-Arangure JM, Mar-Obeso AJ, GrajalesMuniz C, Robles-Perez E, Gonzalez-Leon M, et al. Infection and death from influenza A H1N1 virus in Mexico: a retrospective analysis. Lancet 2009;374:2072e9. [4] Grieser C, Goldmann A, Steffen IG, Kastrup M, Fernandez CM, Engert U, et al. Computed tomography findings from patients with ARDS due to influenza A (H1N1) virus-associated pneumonia. Eur J Radiol 2012;81:389e94. [5] Cortes GM, Sierra MM, Santa-Olalla PP, Hernandez-Barrera V, JimenezGarcia R, Pachon I. Clinical characteristics and outcomes of diabetic patients who were hospitalised with 2009 pandemic influenza A H1N1 infection. J Infect 2012;64:218e24. [6] Kumar D, Michaels MG, Morris MI, Green M, Avery RK, Liu C, et al. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis 2010;10:521e6. [7] Aviram G, Bar-Shai A, Sosna J, Rogowski O, Rosen G, Weinstein I, et al. H1N1 influenza: initial chest radiographic findings in helping predict patient outcome. Radiology 2010;255:252e9. [8] Marchiori E, Zanetti G, Hochhegger B, Rodrigues RS, Fontes CA, Nobre LF, et al. High-resolution computed tomography findings from adult patients with influenza A (H1N1) virus-associated pneumonia. Eur J Radiol 2010;74:93e8. [9] Marchiori E, Zanetti G, D'Ippolito G, Santos ML, Valiante PM, Mano CM, et al. Swine-origin influenza A (H1N1) viral infection: thoracic findings on CT. AJR Am J Roentgenol 2011;196:W723e8. [10] Ajlan AM, Quiney B, Nicolaou S, Muller NL. Swine-origin influenza A (H1N1) viral infection: radiographic and CT findings. AJR Am J Roentgenol 2009;193:1494e9. [11] Cui W, Zhao H, Lu X, Wen Y, Zhou Y, Deng B, et al. Factors associated with death in hospitalized pneumonia patients with 2009 H1N1 influenza in Shenyang, China. BMC Infect Dis 2010;10:145. [12] Kim JE, Bauer S, La KS, Lee KH, Choung JT, Roh KH, et al. CD4þ/ CD8þ T lymphocytes imbalance in children with severe 2009 pandemic influenza A (H1N1) pneumonia. Korean J Pediatr 2011;54:207e11.
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Please cite this article in press as: Feng F, et al., The relationship between pulmonary HRCT findings and peripheral blood immunological parameters in adults with H1N1 influenza, Radiology of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.jrid.2016.02.001