Chest Imaging Findings for Evaluation HIV-related Pulmonary Diseases Comparing between Patients Receiving and Non-Receiving Antiretroviral Therapy

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1 Chest Imaging Findings for Evaluation HIV-related Pulmonary Diseases Comparing between Patients Receiving and Non-Receiving Antiretroviral Therapy Yutthaphan Wannasopha MD a, *, Natthaphong Nimitrungtavee MD a, Juntima Euathrongchit MD a, Apichat Tantraworasin MD b a Department of Radiology, Faculty of Medicine, Chiang Mai University, Thailand b General Thoracic Unit, Department of Surgery, Faculty of Medicine, Chiang Mai University, Thailand Abstract Objective: To compare chest imaging findings in HIV-related pulmonary diseases presenting with chest symptoms between patients receiving and non-receiving anti-retroviral therapy (ART). Materials and methods: From August 2010 to August 2015, the chest radiographs or chest computed tomography (CT) of 174 HIV infected patients who had chest symptoms (cough, dyspnea and hemoptysis) in Maharaj Nakorn Chiangmai hospital were retrospectively reviewed by three blinded reviewers with consensus. Presence and character of opacities, nodules, cavities, pleural effusion, pneumothorax and adenopathy were documented in each patient. All of the patients have been diagnosed of HIV-related pulmonary diseases which confirmed by laboratory investigations, cytology, pathology or improvement of clinical or imaging after treatment. Results: Of the 174 HIV-infected patients, 59 (33.9%) had been received ART with good compliance and 115 (66.1%) were non-receiving ART patients. The median CD4 lymphocyte count was statistically significant higher in patients receiving ART. The most common HIVrelated pulmonary disease was Pneumocystis jiroveci pneumonia (PCP) in non-receiving ART patients (38.3 %) and bacterial pneumonia in the ART group (47.5 %). Segmental or lobar air-space consolidations were the typical radiographic finding for bacterial pneumonia in both groups. However, about one-third of ART-treated patients with bacterial pneumonia disclosed interstitial pulmonary opacity with significant difference (p=0.040). Cavitary lesions were observed only in non-art group with bacterial pneumonia. Conclusion: In HIV-infected patients with bacterial pneumonia, pulmonary interstitial opacities are more frequently found in the patients receiving ART whereas the cavitary lesions are solely demonstrated in the patients not receiving ART. No significant difference in radiographic manifestation of other HIV-related pulmonary diseases regardless of antiretroviral therapy.

2 Introduction The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are global healthcare problem. In 2012, there were approximately 35 million people worldwide suffering from HIV infection and its related diseases and also responsible for death about million people per year (1). There were new HIV infected patients approximately million peoples per year globally and in Thailand, an estimated 450,000 people were living with HIV in 2014 (1, 2). Nowadays, HIV infection can be effectively managed with antiretroviral therapy (ART). After incoming of ART since 1996, HIV infected patients have longer life expectancy, dramatically decreased prevalence of opportunistic infection and mortality rate (3-5). However even in the ART era, many HIV-infected patients still have HIV-related diseases due to noncompliance, medication treatment failure or absence of medication assessment (6). Among HIV-related diseases, the respiratory tract has been one of most frequently affected by the disease and up to 70% of HIV patients have at least one pulmonary complication during the evolution of the disease (7, 8). Pulmonary complications in HIV patients can be either infectious or non-infectious diseases. Generally, the approach to the diagnosis of pulmonary diseases includes the clinical history, physical examination, CD4 count, imaging studies and specific diagnostic tests. Plain chest radiograph is an appropriate initial imaging for diagnostic evaluation while chest computed tomography (CT) is more sensitive to detect subtle findings and gives more imaging details. Imaging recognition patterns can assist in the initial diagnosis and also narrow differential diagnosis. Many studies have been proposed the imaging findings of HIV-related pulmonary diseases in the pre-art era. On the contrary, only a few studies have been reported about imaging findings in the post-art era. The objective of this study is to evaluate chest imaging findings in HIV-related pulmonary diseases presenting with chest symptoms between patients receiving and nonreceiving anti-retroviral therapy. Materials and methods Patients and radiological evaluation After institutional review board approval (No: RAD ), this retrospective study obtained data from 180 HIV infected patients who had chest symptoms (cough, dyspnea and hemoptysis) and subsequently underwent chest radiograph or chest CT in Maharaj Nakorn ChiangMai hospital from August 2010 to August All of the patients have been diagnosed of HIV-related pulmonary diseases which confirmed by laboratory investigations, cytology, pathology or improvement of clinical or imaging after treatment. Six patients were excluded due to no available radiographic imaging. Therefore, the study population consisted of 174 patients. Patient characteristics including age and gender, clinical presentations, CD4 lymphocyte count, assessment and compliance of ART, HIV-related

3 pulmonary diseases and radiologic findings were extracted from medical recording system (Digicard) and CMU-PACS. The chest radiographs and chest CT of the study population were reviewed by consensus of two experienced radiologists (7 and 15 years of experience in cardiothoracic radiology) and a third year radiology resident. All reviewers were blinded with regard to the clinical presentation, diagnosis of HIV-related diseases and ART status. Presence and character of opacities, nodules, cavities, pleural effusion, pneumothorax and adenopathy were documented in each patient. Lymph nodes were considered enlarged if they had short axis diameter greater than 1 cm. The locations of pulmonary opacities were recorded as diffuse or focal distribution which specified by dividing of the lungs into three zones (upper, middle and lower lung zones). Pulmonary opacities were classified as alveolar pattern, interstitial pattern or groundglass pattern. Alveolar or airspace patterns were documented if they displayed an infiltration with indistinct margin (Figure 1). Interstitial patterns were linear, reticular or reticulonodular opacities with well demarcated margin (Figure 2). Ground-glass patterns were defined as areas of haziness with preserved intervening bronchovascular margins (Figure 3). The PA and AP chest radiographs were performed with Shimadzu R-20J (Shimadzu, Tokyo, Japan). Portable chest radiographs were performed with mobile computed radiography Mobilett Plus HP (Siemen, Erlangen, Germany). The chest CT scans were performed by using multidetector CT scanners 64 slices MDCT scan Somatom definition (Siemens, Erlangen, Germany) or 16 slices MDCT scan Aquilion (Toshiba, Tochigi-ken, Japan). The slice thickness was 1 mm and the interval was 0.6 mm, each. Soft copy DICOM images were evaluated with synapse software workstation version 4.1. Statistical analysis The continuous data were reported as mean ± standard deviation (SD) or Median ± iqr depended on data distribution. The categorical data were reported as frequency and percent. Fisher exact test was used for comparing the categorical data between two groups and student t-test or Wilcoxon ranksum test was used for comparing the continuous data depending on data distribution. P-value of less than 0.05 was indicated as statistically significant difference. All statistical analyses were performed by using STATA program version Results Of the 174 HIV-infected patients in this study, 59 (33.9%) had been received ART with good compliance and 115 (66.1%) were non-receiving ART patients. Among the 59 patients receiving ART, 40 (67.8%) were men and 19 (32.2) were women. The ages ranged from years and the mean age was about 44.4 years. Of the 115 non-receiving ART patients, there were 83 (72.2%) men and 32 (27.8%) women and the ages ranged from 6-67 years with 39.0 years of mean age. The median CD4 lymphocyte count was statistically significant higher in patients receiving ART (226 cell/mm 3; p<0.001). These data were summarized in Table 1.

4 Most of the HIV-infected patients had infectious diseases (93.7%). Pneumocystis jiroveci pneumonia (PCP) was the most common disease in non-receiving ART patients (38.3 %; p <0.001) whereas bacterial pneumonia was the most diagnosis in the ART group (47.5%; p=0.002). Pulmonary tuberculosis was also commonly found in both the patients receiving ART (22.0%) and not receiving ART (24.4%) without statistically significant difference. Primary lung cancer was only found in the patient receiving ART. The other HIV-related diseases were noticed in a small number and there was no statistically significant difference between ART-treated patients and non-art-treated patients. Pulmonary disease in HIVinfected patients between both groups were demonstrated in Table 2. The relationships between chest radiographic findings of each common HIV-related pulmonary disease and the status of anti-retroviral therapy were summarized in Table 3. All of the PCP patients had pulmonary opacities and the most common opacity were ground-glass pattern (Figure 4) in both ART group and non-art group without statistical significance. Diffuse distribution of the pulmonary opacities were also the most frequent location in both groups. Cavitary lesions and pleural effusion were found in minority cases (4.6%) of PCP patients not received ART. No pulmonary nodule was detected in all of the PCP patients. Pulmonary opacities were the most common findings depicted in bacterial pneumonia in both the ART group (96.4%) and non-art group (81.5%) (p=0.030). In details, we found that interstitial pattern (Figure 5) was the statistically significant different parameter between both groups of bacterial pneumonia (p=0.040). Diffuse pulmonary distribution were the most documented location; however, no significant difference of the pulmonary location between both groups was demonstrated (p=0.858). Cavitary lesions (Figure 6) were observed only in the non-art group with bacterial pneumonia (22.2%, p=0.010). Pulmonary opacities in tuberculosis were found just about the same in every pattern in either patient receiving ART or patient not receiving ART. Upper lung zone (Figure 7) was the most common location in both groups. There were no statistically significant difference of any radiographic finding between ART receiving patents and non-art receiving patients with tuberculosis. Discussion Since 1996, highly active antiretroviral therapy has been introduced to the HIVinfected patients, resulting in drastic reduction of opportunistic infections and mortality rate (3-5). Even through in the ART era, many HIV-infected patients, especially in resource-limited countries such as Thailand, still have HIV-related diseases due to absence of medication assessment, noncompliance or medication treatment failure (6). Among HIV-related diseases, the pulmonary system has been the most commonly involved and pulmonary infections including tuberculosis, PCP and bacterial pneumonia account for the majority of the HIV-related diseases (7-9). The relative incidence of bacterial pneumonia has been increased replacing the PCP as the most frequently cause of HIV-related pulmonary infection in the post-art era (10). Our study also supports the aforementioned

5 point of view. From the result exhibited in Table 2, we found that bacterial pneumonia was the most common disease in the ART-treated group whereas PCP was still the most frequently HIV-related pulmonary disease in non-art receiving group with statistically significant difference. Because ART has had a substantial influence on viral load and CD4 lymphocyte level, most of the HIV-related patients receiving ART with good compliance should have higher level of CD4 count as compared to the non-art receiving patients (11). Our study also showed the result supporting this point that the median CD4 lymphocyte count was statistically significant higher in patients receiving ART (226 cell/mm 3 ; p<0.001). The CD4 lymphocyte level represents the degree of the immune status which is the potential risk in developing of each infection (7, 11, 12). In this regard, a CD4 level above 200 cells/mm 3 increases risk for bacterial pneumonia or tuberculosis while a CD4 level below 200 cells/mm 3 tends to develop PCP, disseminated tuberculosis or other virulent opportunistic infections. The accurate diagnosis of HIV-related pulmonary diseases is strongly influenced by clinical history, laboratory data and radiographic findings. A confident radiographic diagnosis can lead to administration of the proper empirical treatment and may also prevent the need for other invasive procedures. Segmental or lobar air-space consolidation is the typical radiographic finding for bacterial pneumonia in either HIV-infected patients or non-hiv-infected patients (7). Our study revealed that air-space patterns were documented the most common pulmonary opacity in both HIV-infected receiving and not receiving ART patients. Nevertheless, about one-third of ART-treated patients with bacterial pneumonia disclosed interstitial pulmonary opacity (32.1%, p=0.040). In general, interstitial pulmonary infiltrations are the character of viral pneumonia, however; some previous studies have been proposed that diffuse bilateral interstitial opacities can be the manifestations of bacterial pneumonia, especially Haemophilus infuenzae (up to 50%) (7, 13). Mycoplasma pneumoniae and Chlamydia pneumoniae can also manifest with bilateral interstitial patterns even appear to be relatively uncommon in HIV-infected patients (7). As mentioned earlier, the HIV-infected patients receiving ART had significantly better immune status and we assumed that the incidence of bacterial pneumonia in these patients should be similar to the non-hiv infected population; therefore interstitial bacterial pneumonia patterns such as Haemophilus infuenzae, Mycoplasma pneumoniae and Chlamydia pneumoniae may be commonly found in the ARTtreated patients as comparable to the non-art-treated patients. Pulmonary cavity is defined as an air-filled space within either a mass, nodule or area of consolidation with or without containing fluid (14). A previous study reported that 85% of HIV-infected cases with cavitary lesion were bacterial in etiology and the most frequently organisms were Staphylococcus aureus and Pseudomonas aeruginosa (15). In our study, we observed cavitary lesions due to bacterial pneumonia only in the non-art group (22.2%, p=0.010). This results could be due to the effects of advanced immune suppression in the non-art receiving patients. Bacterial pneumonia in AIDS has a tendency to develop significant complications such as bacteremia, septic emboli and cavitary abscess, especially in S. aureus and P. aeruginosa infection. Moreover, several studies have been reported some unusual pathogens including Nocardia asteroides and Rhodococcus equi which can produce cavitary lesions in severely immunocompromised HIV-infected patients (CD4 count < 200 cell/mm 3 ) (12, 14, 16).

6 The results of this study come from a univariate statistical analysis because of small population size; there will be some confounders influenced the diagnosis of each HIV-related pulmonary disease. Another limitation of our study is that evaluation of HIV-related pulmonary diseases based on only imaging findings without including the clinical manifestations or laboratory results. Other limitations of this study include retrospective review of medical records and imaging interpretations by consensus reading without interobserver variability assessment. Conclusion In HIV-infected patients with bacterial pneumonia, pulmonary interstitial opacities are more frequently found in the patients receiving ART whereas the cavitary lesions are solely demonstrated in the patients not receiving ART. No significant difference in radiographic manifestation of other HIV-related pulmonary diseases regardless of antiretroviral therapy. References 1. Joint United N, Programme, on HIV/AIDS, (UNAIDS). Global Report: UNAIDS Report on the Global AIDS Epidemic Joint United N, Programme, on HIV/AIDS, (UNAIDS) HIV and AIDS estimates (2014). Available from: 3. Grubb JR, Moorman AC, Baker RK, Masur H. The changing spectrum of pulmonary disease in patients with HIV infection on antiretroviral therapy. AIDS. 2006;20(8): Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13): Torres RA, Barr M. Impact of combination therapy for HIV infection on inpatient census. N Engl J Med. 1997;336(21): Chou SH, Prabhu SJ, Crothers K, Stern EJ, Godwin JD, Pipavath SN. Thoracic diseases associated with HIV infection in the era of antiretroviral therapy: clinical and imaging findings. Radiographics. 2014;34(4): Benito N, Moreno A, Miro JM, Torres A. Pulmonary infections in HIV-infected patients: an update in the 21st century. Eur Respir J. 2012;39(3): Miller R. HIV-associated respiratory diseases. Lancet. 1996;348(9023): Boiselle PM, Tocino I, Hooley RJ, Pumerantz AS, Selwyn PA, Neklesa VP, et al. Chest radiograph interpretation of Pneumocystis carinii pneumonia, bacterial pneumonia, and pulmonary tuberculosis in HIV-positive patients: accuracy, distinguishing features, and mimics. J Thorac Imaging. 1997;12(1): Crothers K, Huang L, Goulet JL, Goetz MB, Brown ST, Rodriguez-Barradas MC, et al. HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era. Am J Respir Crit Care Med. 2011;183(3): Castaner E, Gallardo X, Mata JM, Esteba L. Radiologic approach to the diagnosis of infectious pulmonary diseases in patients infected with the human immunodeficiency virus. Eur J Radiol. 2004;51(2): Aviram G, Fishman JE, Boiselle PM. Thoracic infections in human immunodeficiency virus/acquired immune deficiency syndrome. Semin Roentgenol. 2007;42(1):23-36.

7 13. Amorosa JK, Nahass RG, Nosher JL, Gocke DJ. Radiologic distinction of pyogenic pulmonary infection from Pneumocystis carinii pneumonia in AIDS patients. Radiology. 1990;175(3): Gallant JE, Ko AH. Cavitary pulmonary lesions in patients infected with human immunodeficiency virus. Clin Infect Dis. 1996;22(4): Aviram G, Fishman JE, Sagar M. Cavitary lung disease in AIDS: etiologies and correlation with immune status. AIDS Patient Care STDS. 2001;15(7): Muntaner L, Leyes M, Payeras A, Herrera M, Gutierrez A. Radiologic features of Rhodococcus equi pneumonia in AIDS. Eur J Radiol. 1997;24(1):66-70.

8 Table 1: Patient characteristics compared between untreated and treated-hiv patients Treated-HIV group N = 59 Untreated-HIV group N = 115 p-value Mean age (year) ± SD 44.4 ± ± 11.9 Gender, N(%) Female 19 (32.2) 32 (27.8) Male 40 (67.8) 83 (72.2) CD4 count (cells/ mm 3 ) Median ± IQR (min-max) 226 ± 245 (1,124) 33 ± 85 (1,954) <0.001

9 Table 2: Pulmonary diseases in HIV-infected patients between both groups Diseases Treated-HIV group N = 59 Untreated-HIV group N = 115 p-value Pulmonary tuberculosis 13 (22.0) 28 (24.4) Pneumocystis jirovecii pneumonia (PCP) 7 (11.9) 44 (38.3) < Bacterial pneumonia 28 (47.5) 27 (23.5) Fungal infection 4 (6.8) 9 (7.8) Non-tuberculous mycobacterial infection 1 (1.7) 2 (1.7) Lung cancer 4 (6.8) 0 - Lymphoma 1 (1.7) 4 (3.5) Kaposi sarcoma 1 (1.7) 1 (0.9) 1.000

10 Table 3: The relationships between chest radiographic findings of each common HIV-related pulmonary disease and the status of anti-retroviral therapy Treated-HIV group Untreated-HIV group p-value Pulmonary tuberculosis Opacity, N (%) 9 (69.2) 19 (67.9) Patchy 3 (23.1) 9 (32.1) GGO 0 3 (10.7) Interstitial 7 (25.0) 6 (46.2) Predominant lobe Diffuse 3 (33.3) 4 (21.1) Upper lobe 5 (55.6) 14 (73.7) Middle lobe 1 (11.1) 1 (5.3) Lower lobe 0 0 Nodule 5 (38.5) 6 (21.4) Adenopathy 1 (7.7) 5 (17.9) Cavitary lesion 1 (7.7) 8 (28.6) Pleural effusion 2 (15.4) 6 (21.4) Pneumocystis jiroveci pneumonia (PCP) Opacity 7 (100) 44 (100) Patchy 0 9 (20.5) GGO 5 (71.4) 30 (68.2) Interstitial 2 (28.6) 5 (11.4) Predominant lobe Diffuse 4 (57.1) 35 (79.6) Upper lobe 1 (14.3) 3 (6.8) Middle lobe 0 0 Lower lobe 2 (28.6) 6 (13.6) Nodule 0 0 Adenopathy 1 (14.3) 5 (2.3) Cavitary lesion 0 2 (4.6) Pleural effusion 0 2 (4.6) Bacterial pneumonia Opacity 27 (96.4) 22 (81.5) Patchy 15 (53.6) 19 (70.4) GGO 3 (10.7) 1 (3.7) Interstitial 9 (32.1) 2 (7.4) Predominant lobe Diffuse 11 (40.7) 11 (50.0) Upper lobe 3 (11.1) 1 (4.6) Middle lobe 3 (11.1) 2 (9.1) Lower lobe 10 (37.0) 8 (36.4) Nodule 4 (14.3) 3 (11.1) Adenopathy 1 (3.6) 3 (11.1) Cavitary lesion 0 6 (22.2) Pleural effusion 8 (28.6) 5 (18.5) 0.528

11 Figure 1 A 29-year-old man with AIDS (on ARV). He presents with progressive dyspnea. The chest radiograph shows alveolar infiltration involving nearly entire the left lung. The sputum culture shows mixed bacterial organism.

12 Figure 2 A 52-year-old man with AIDS (on ARV). He presents with cough and progressive dyspnea. The chest radiograph shows reticular opacities in bilateral middle to lower lung fields. Small amount of right pleural effusion is also noted (arrow). After empirical antibiotics administration, the clinical was improved.

13 Figure 3 Pneumocystis jiroveci pneumonia in a 31-year-old man with AIDS (on ARV). He presents with progressive dyspnea. The chest radiograph shows diffuse ground grass opacities in bilateral lungs.

14 Figure 4 Pneumocystis jiroveci pneumonia in a 26-year-old man with AIDS (no ARV) who developed progressive dyspnea. Chest radiograph reveals diffuse bilateral ground grass opacities.

15 Figure 5 A 41-year-old man with AIDS (on ARV). He presents with fever and dyspnea. Chest radiograph shows diffuse bilateral coarse reticular opacities. After empirical antibiotics administration, the clinical was improved.

16 Figure 6 A 42-year-old woman with AIDS (no ARV). She presents with severe sepsis and hemoculture shows salmonellar septicemia. The chest radiograph (right) shows a cavity in left middle lung field (arrow). Contrastenhanced chest CT (left) on 2 weeks later shows multiple cavities in both lungs.

17 Figure 7 A 42-year-old man with AIDS (no ARV). He presents with chronic cough. PA chest radiograph shows reticular opacity predominately involving both upper lobes. The sputum culture show Mycobacterium tuberculosis.