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A pathologically proven case of adult-onset HIV-related lymphocytic interstitial pneumonia with acute exacerbation treated with steroid and antiretroviral therapy
J Infect Chemother 21 (2015) 868e872
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
A pathologically proven case of adult-onset HIV-related lymphocytic interstitial pneumonia with acute exacerbation treated with steroid and antiretroviral therapy Makoto Saito a, Shuji Hatakeyama a, b, c, *, Yoshitaka Wakabayashi a, Shintaro Yanagimoto a, Tamiko Takemura d, Hiroshi Yotsuyanagi a a
Department of Infectious Diseases, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Division of General Internal Medicine, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan Division of Infectious Diseases, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan d Department of Pathology, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shibuya-ku, Tokyo 150-8935, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 May 2015 Received in revised form 12 July 2015 Accepted 20 July 2015 Available online 19 August 2015
Lymphocytic interstitial pneumonia (LIP) is a rare opportunistic illness in human immunodeficiency virus (HIV)-infected adults, although it is relatively common among HIV-infected children. Most adult cases have been reported in African and Afro-Caribbean patients and few cases have been reported from Asia. Acute exacerbation of HIV-related LIP has not been well described. Here we report a pathologically proven case of acute exacerbation of adult-onset HIV-related LIP. The patient was an African immigrant living in Japan who presented with chronic dyspnea and diffuse bilateral pulmonary infiltrates. His clinical, radiological, and pathological findings were consistent with those of LIP. After a diagnostic surgical lung biopsy, his hypoxemia and pulmonary infiltrates exacerbated rapidly over a few days, although his condition had not progressed during the previous year. LIP may be an important differential diagnosis among adult patients in Asian countries, especially patients of non-Asian ethnicity. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Lymphocytic interstitial pneumonia Human immunodeficiency virus Adult onset Antiretroviral therapy Lymphoproliferative disorder
1. Introduction Lymphocytic interstitial pneumonia (LIP) is an opportunistic illness in patients infected with human immunodeficiency virus (HIV). It is rare in HIV-infected adults, although it is fairly common among HIV-infected children [1]. LIP is categorized as one of the Japan's acquired immune deficiency syndrome (AIDS)-defining conditions in children younger than 13 years and was also formerly included in the Centers for Disease Control and Prevention (CDC)'s case definition in HIV-infected children. The CDC has now excluded LIP from AIDS-defining conditions in HIV-infected children in 2014 because LIP is known to be associated with moderate immunodeficiency [2]. Clinically, LIP is a bilaterally diffuse pulmonary disease characterized by dyspnea and dry cough that progress gradually
* Corresponding author. Division of General Internal Medicine/Division of Infectious Diseases, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsukeshi, Tochigi 329-0498, Japan. Tel.: þ81 285 58 7394; fax: þ81 285 44 0628. E-mail address: [email protected] (S. Hatakeyama).
over months to years. Clinical and radiological features of LIP may be indistinguishable from those of pneumonia caused by Pneumocystis jirovecii [1,3]. Because of the rarity of the disease, the optimal treatment for HIV-related LIP is not currently known. Acute exacerbation of HIV-related LIP has not been well described. We present a pathologically proven case of adult-onset HIV-related LIP with acute exacerbation that was successfully treated with antiretroviral therapy (ART) and corticosteroids. This report reviews the literature and discusses the etiology, clinical presentation, diagnosis, and clinical management of adult-onset HIV-related LIP. 2. Case report A black man in his 50s from a West African country was referred to our hospital because of a bilateral diffuse pulmonary infiltrate found on a thoracic radiograph that was taken during a health screening at the time of his employment in Japan (Fig. 1). He tested positive for HIV-1, which had been undiagnosed until that time. He reported a 1-year history of dyspnea and a 9-month history of dry cough, but had never had a chest radiograph taken before. His
http://dx.doi.org/10.1016/j.jiac.2015.07.008 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
M. Saito et al. / J Infect Chemother 21 (2015) 868e872
Fig. 1. A posteroanterior chest radiograph of the patient at presentation showing bilateral diffuse reticular infiltrates and bilateral hilar lymphadenopathy.
height was 165 cm and he weighed 49.4 kg; his weight had decreased by 10 kg in 1 year. He had no history of any notable diseases, was taking no medications regularly, and did not smoke or drink alcohol. On physical examination, his temperature was 37.0 C, his pulse rate was 120 beats per minute, his oxygen
869
saturation was 95% while breathing ambient air, and his blood pressure was 108/66 mmHg. His sclerae were anicteric, his conjunctivae were pale, and he had no superficial lymphadenopathy. Finger clubbing was not apparent. Upon thoracic auscultation, his heart sounds were regular and without murmurs, and his lung sounds were clear. The patient was anemic (hemoglobin, 10.3 g/dL), and serum lactate dehydrogenase (LDH) was moderately elevated at 438 U/L (reference range, 124e222 U/L). Routine blood tests were within reference ranges otherwise. His serum HIV-RNA was 510,000 copies/mL, and his CD4þ and CD8þ T lymphocyte counts were 380 cells/mL and 1487 cells/mL, respectively. His human leukocyte antigen (HLA)-DR haplotype was DR8 and DR15. His serum IgG was elevated at 5250 mg/dL (reference range, 861e1747 mg/dL), indicating polyclonal gammopathy, and serum KL-6 was 8451 U/mL (reference range, <500 U/mL). His plasma concentration of b-D-glucan was <6.0 pg/mL, as determined using the b-glucan test Wako (Wako Pure Chemical Industries, Ltd., Osaka, Japan), which has an established cut-off value of 11 pg/mL for a positive test result. Antibody tests for EpsteineBarr virus (EBV) were consistent with past infection (viral capsid antigenIgG 160, viral capsid antigen-IgM less than 10, early antigenIgG 40, EBV nuclear antigen-IgG 20). An assay for human Tlymphotropic virus (HTLV)-1 antibody was negative. Serum human herpesvirus 8 (HHV8)-DNA was not detected, and EBV-DNA was 340 copies/mL. Thyroid function was normal, and autoantibody tests were not suggestive of autoimmune diseases (thyroidstimulating hormone, 3.35 mIU/mL; free thyroxine (T4), 0.94 ng/ dL; antinuclear antibody, 1:40; SS-A and SS-B antibodies, negative.). PaO2 was 54.2 mmHg and PaCO2 was 38.6 mmHg with the patient breathing ambient air (alveolar to arterial oxygen pressure difference [AaDO2], 47 mmHg). Respiratory function test results were consistent with a restrictive ventilatory defect with decreased diffusion capacity: vital capacity (VC), 51% of predicted value; forced expiratory volume in 1 s/forced vital volume
Fig. 2. Computed tomography (CT) scan of the chest at presentation showing bilateral diffuse ground-glass attenuation with small nodules and cysts (a, b). Contrast-enhanced CT scan showing enlargement of mediastinal lymph nodes (c). Positron emission tomography with 18-fluoro-D-glucose showing uptake in the enlarged lymph nodes (d).
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(FEV1.0%), 88%; diffusing capacity of the lung for carbon monoxide per unit of alveolar volume (DL,CO/VA), 59% of predicted value. Thoracic computed tomography (CT) scans revealed bilateral diffuse ground-glass attenuation with several small nodules and cysts (Fig. 2). Hilar, mediastinal, and para-aortic lymph nodes were bilaterally enlarged, and signal uptake was observed at these lymph nodes using positron emitted tomography with 18-fluoroD-glucose. Bronchoalveolar lavage (BAL) fluid analysis revealed macrophages (76%) and lymphocytes (8%), with an increased total cell count of 597,000/mL. The predominant lymphocyte subtype in the BAL fluid was CD8þ lymphocytes (CD4þ lymphocytes, 4.5%; CD8þ lymphocytes, 94.7%). All of the tests for infectious pathogens in the BAL fluid were negative, including bacterial culture, Gram
stain, Grocott stain, acid-fast stain, and polymerase chain reaction tests for Mycobacterium tuberculosis, Mycobacterium avium complex, P. jirovecii, and HHV8. HIV-related LIP was suspected, but pulmonary disease associated with multicentric Castleman disease and EBV-associated lymphoproliferative disorders were also possible, based on the clinical presentation. In order to confirm the diagnosis by pathology, a biopsy of the right middle lung lobe (S4) was performed using video-assisted thoracoscopic surgery. The pathological findings of the biopsy specimen were consistent with LIP; diffuse and homogenous infiltrates of CD8þ lymphocytes and plasma cells were observed in the alveolar septal interstitium, which was thickened with fibrosis (Fig. 3). In situ hybridization for EBV-encoded RNA
Fig. 3. Histopathology of the surgical biopsy specimen from the right middle lobe of the lung (S4) showing changes consistent with lymphocytic interstitial pneumonia. The pathological changes are distributed in a homogenous and panlobular pattern (a: hematoxylineeosin stain, 4). Diffuse and homogenous infiltration of the cells, which are composed predominantly of lymphocytes and plasma cells, is observed around alveolar septal interstitium (b: hematoxylineeosin stain, 200). The alveolar interstitium is thickened with fibrosis, but the alveolar structure is retained (c: Elastica van Gieson stain, 100). Hyperplasia of type II pneumocytes can be observed. Infiltrating cells are predominantly CD3þCD8þ (d: CD3 immunostain, 100). CD20þ cells are gathered, forming germinal centers around vessels and bronchioles (e: CD20 immunostain, 40). Monoclonality is not detected.
M. Saito et al. / J Infect Chemother 21 (2015) 868e872
showed only scarce positivity in the lung tissue. After the videoassisted thoracoscopic surgery, the patient's hypoxemia became exacerbated and fine crackles were heard on both sides. Bilateral pulmonary interstitial shadowing progressed rapidly over the course of a few days, despite having not progressed for over a year previously. The acute exacerbation was treated with methylprednisolone (250 mg/day intravenously) for 1 day followed by oral prednisolone (1 mg/kg body weight/day). The prednisolone dosage was tapered over the course of 1 month because of the rapid improvement of the lung disease and lymph node enlargement (Fig. 4). Oxygenation evaluated by arterial blood gas analyses while breathing ambient air also improved rapidly from PaO2 35.9 mmHg, PaCO2 32.7 mmHg, and AaDO2 73.0 mmHg at the time of acute exacerbation to PaO2 80.2 mmHg, PaCO2 48.9 mmHg, and AaDO2 8.4 mmHg 5 days after initiating corticosteroid therapy. ART (darunavir/ritonavir plus emtricitabine/tenofovir) was begun in the following month. The patient's lung disease has been well controlled without progression for 3 years. Serum LDH and KL-6 levels gradually decreased from 715 U/L and 19,460 U/mL at the time of acute exacerbation, respectively, to 249 U/L and 2530 U/mL, respectively, 11 months after starting ART.
3. Discussion Although HIV-related LIP rarely occurs in adults, most adult cases have been reported in African and Afro-Caribbean patients [1,4]. Presumably, because of this ethnic predisposition, few cases have been reported from Asia. Dyspnea and dry cough that progress gradually over several months are the most common clinical signs [4]. Fever and weight loss have been reported in patients with HIV, although these signs are less common [1,4e7]. Finger clubbing is common among children [1] but may not be seen among adults [8]. Asymptomatic cases of LIP have also been found on thoracic
Fig. 4. Computed tomography scan of the chest 8 days after the initiation of corticosteroids, showing resolution of both ground-glass attenuation and enlargement of lymph nodes.
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radiographs [9]. LIP causes a restrictive ventilatory defect in which the diffusion capacity of the lungs reportedly decreases to 28e65% and the PaO2 decreases to 50e85 mmHg [5]. Clinical features and findings of HIV-related LIP in adults, based on 5 case series and the report of this patient, are summarized in Table 1 [5,6,8,10,11]. LIP is characterized by a reticular or reticulonodular interstitial infiltrate on thoracic radiographs [11] and by ground-glass attenuation with poorly defined centrilobular nodules on CT images [3]. Other common thoracic CT findings include thickening of bronchovascular bundles, interlobular septal thickening, and cystic airspaces [3]. Thickening of interlobular septa and lymphadenopathy are more characteristic of LIP than of P. jirovecii pneumonia, although it may be difficult to distinguish the two diseases on CT images [3]. Therefore, radiographic findings alone cannot provide a definitive diagnosis of LIP [3,11]. Lung biopsy is necessary for the definitive diagnosis of LIP in adults. Histologically, LIP is characterized by extensive infiltration of benign polyclonal lymphocytes into the alveolar septal interstitium [12]. T cells and plasma cells infiltrate the interstitial space, while B cells aggregate to form peribronchial germinal centers [4]. In HIV-positive patients, T cells (especially CD8þ T cells) are predominant [4,6,8]; B cells are predominant in HIV-negative patients [4]. The alveolar structure remains intact [12]. Formation of germinal centers, hyperplasia of type II pneumocytes, and fibrosis in the alveolar spaces may also be observed [12]. The etiology and pathogenesis of LIP are not well known. LIP has been diagnosed in patients with autoimmune disorders such as € gren's syndrome and Hashimoto's disease and with viral inSjo fections such as EBV, HIV, and HTLV-1 [1,4]. Adult-onset HIV-related LIP may be associated with a cellular immune response against the HIV antigen [4,5]. CD8þ lymphocytes in particular are considered to play a major role in the pathology of LIP; the level of CD8þ lymphocytes in BAL fluid may be increased, as was the case with our patient [5]. Adult patients with HIV-related LIP have reportedly presented with relatively high CD4 cell counts (median, 269 cells/mL; range, 39e730), high CD8 cell counts (median, 1204 cells/mL; range, 505e3015) and high serum gamma globulin levels (range, 2.6e7.0 g/dL) [5]. Enlargement of intrathoracic lymph nodes is uncommon among patients testing negative for HIV [4] but is occasionally reported among HIV-positive patients, including the patient in this report [1,5,6,8,10,11] (Table 1). Diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by infiltration of CD8þ lymphocytes into systemic organs, has been reported among HIV-positive patients [13]. Infiltration of CD8þ lymphocytes causes parotid gland enlargement, sicca syndrome, and generalized lymph node enlargement. In addition, LIP is present in nearly one-half of the patients with DILS [4,14,15]. Patients with DILS are predominantly black HIV-positive adults [15]. The HLA-DR5 and DR-6 haplotypes have been genetically associated with DILS in this population [14,15], although the HLA haplotypes of our patient were DR8 and DR15. Another possible etiology for LIP is suggested by the difference in the distribution of lymphoid tissue between children and adults. Bronchus-associated lymphoid tissue, which may be associated with LIP [4], is found in children but is uncommon in healthy adult lungs [16]. The presence of bronchus-associated lymphoid tissue may explain the age distribution of HIV-related LIP. Although the ideal treatment for HIV-related LIP is unclear, partly because of the rarity of the disease, the mainstay of treatment has been ART. The effectiveness of this treatment may be related to the decreased viral load rather than to an improved immune response [5]. Many patients have achieved clinical and radiological improvement using only ART [7,9], although some have resolved spontaneously without ART [1]. Symptoms reportedly improve by 3.5 months on average after beginning ART,
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Table 1 Clinical features of HIV-related LIP in adults: summary of 5 case series and this patient's case. Clinical features
Current patient
Number of adult patients Dyspnea Cough Sputum production Fever Finger clubbing Extrathoracic lymphadenopathy Intrathoracic lymphadenopathy Restrictive lung function
Yes Yes No No No Yes Yes Yes
Morris et al. (1987) [6]
Oldham et al. (1989) [11]
Kramer et al. (1992) [10]
Dufour et al. (2003) [5]
van Zyl-Smit et al. (2015) [8]
3 100% (3/3) 100% (3/3) 33% (1/3) 67% (2/3) NA 67% (2/3) NA 67% (2/3)
14 NA NA NA NA NA 94% (15/16)a 25% (4/16)a,b NA
5 100% (5/5) 100% (5/5) 0% (0/5) NA NA NA NA NA
5 100% (5/5) 100% (5/5) NA 40% (2/5) NA 60% (3/5) 20% (1/5)c 20% (1/5)
13 92% (12/13) 91% (10/11) 70% (7/10) NA 0% (0/11) NA 50% (6/12)b 75% (6/8)
Abbreviations: LIP, lymphocytic interstitial pneumonia; HIV, human immunodeficiency virus; NA, data not available. a Including two pediatric patients. b Ascertained by chest radiography. c Ascertained by computed tomography.
and thoracic radiography images improve by 6e8 months after beginning ART [5]. ART alone is effective treatment for most cases of LIP that are not severe; steroid therapy may be used for severe cases and for those that are refractory to ART [6]. Scant information regarding the treatment of acute exacerbation of HIV-related LIP is available. Our patient was treated initially with a steroid because of an acute exacerbation after the surgical procedure. Radiological findings improved shortly after the initiation of steroid treatment and have since been maintained in stable condition solely by ART. Conflict of interest Makoto Saito received a student grant from the GlaxoSmithKline International Scholarship Charitable Trust Fund. This funding body had no role in this study. References [1] Das S, Miller RF. Lymphocytic interstitial pneumonitis in HIV infected adults. Sex Transm Infect 2003;79:88e93. [2] Centers for Disease Control and Prevention. Revised surveillance case definition for HIV infectiondUnited States, 2014. MMWR Recomm Rep 2014;63: 1e10. [3] Johkoh T, Muller NL, Pickford HA, Hartman TE, Ichikado K, Akira M, et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology 1999;212:567e72. [4] Swigris JJ, Berry GJ, Raffin TA, Kuschner WG. Lymphoid interstitial pneumonia: a narrative review. Chest 2002;122:2150e64. [5] Dufour V, Wislez M, Bergot E, Mayaud C, Cadranel J. Improvement of symptomatic human immunodeficiency virus-related lymphoid interstitial pneumonia in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2003;36:e127e30.
[6] Morris JC, Rosen MJ, Marchevsky A, Teirstein AS. Lymphocytic interstitial pneumonia in patients at risk for the acquired immune deficiency syndrome. Chest 1987;91:63e7. [7] Ripamonti D, Rizzi M, Maggiolo F, Arici C, Suter F. Resolution of lymphocytic interstitial pneumonia in a human immunodeficiency virus-infected adult following the start of highly active antiretroviral therapy. Scand J Infect Dis 2003;35:348e51. [8] van Zyl-Smit RN, Naidoo J, Wainwright H, Said-Hartley Q, Davids M, Goodman H, et al. HIV associated lymphocytic interstitial pneumonia: a clinical, histological and radiographic study from an HIV endemic resourcepoor setting. BMC Pulm Med 2015;15:38. [9] Innes AL, Huang L, Nishimura SL. Resolution of lymphocytic interstitial pneumonitis in an HIV infected adult after treatment with HAART. Sex Transm Infect 2004;80:417e8. [10] Kramer MR, Saldana MJ, Ramos M, Pitchenik AE. High titers of EpsteineBarr virus antibodies in adult patients with lymphocytic interstitial pneumonitis associated with AIDS. Respir Med 1992;86:49e52. [11] Oldham SA, Castillo M, Jacobson FL, Mones JM, Saldana MJ. HIV-associated lymphocytic interstitial pneumonia: radiologic manifestations and pathologic correlation. Radiology 1989;170:83e7. [12] Travis WD, Fox CH, Devaney KO, Weiss LM, O'Leary TJ, Ognibene FP, et al. Lymphoid pneumonitis in 50 adult patients infected with the human immunodeficiency virus: lymphocytic interstitial pneumonitis versus nonspecific interstitial pneumonitis. Hum Pathol 1992;23:529e41. [13] Ghrenassia E, Martis N, Boyer J, Burel-Vandenbos F, Mekinian A, Coppo P. The diffuse infiltrative lymphocytosis syndrome (DILS). A comprehensive review. J Autoimmun 2015;59:19e25. [14] Itescu S, Brancato LJ, Buxbaum J, Gregersen PK, Rizk CC, Croxson TS, et al. A diffuse infiltrative CD8 lymphocytosis syndrome in human immunodeficiency virus (HIV) infection: a host immune response associated with HLADR5. Ann Intern Med 1990;112:3e10. [15] Kazi S, Cohen PR, Williams F, Schempp R, Reveille JD. The diffuse infiltrative lymphocytosis syndrome. Clinical and immunogenetic features in 35 patients. AIDS 1996;10:385e91. [16] Tschernig T, Pabst R. Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology 2000;68:1e8.
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
A pathologically proven case of adult-onset HIV-related lymphocytic interstitial pneumonia with acute exacerbation treated with steroid and antiretroviral therapy Makoto Saito a, Shuji Hatakeyama a, b, c, *, Yoshitaka Wakabayashi a, Shintaro Yanagimoto a, Tamiko Takemura d, Hiroshi Yotsuyanagi a a
Department of Infectious Diseases, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Division of General Internal Medicine, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan Division of Infectious Diseases, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan d Department of Pathology, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shibuya-ku, Tokyo 150-8935, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 May 2015 Received in revised form 12 July 2015 Accepted 20 July 2015 Available online 19 August 2015
Lymphocytic interstitial pneumonia (LIP) is a rare opportunistic illness in human immunodeficiency virus (HIV)-infected adults, although it is relatively common among HIV-infected children. Most adult cases have been reported in African and Afro-Caribbean patients and few cases have been reported from Asia. Acute exacerbation of HIV-related LIP has not been well described. Here we report a pathologically proven case of acute exacerbation of adult-onset HIV-related LIP. The patient was an African immigrant living in Japan who presented with chronic dyspnea and diffuse bilateral pulmonary infiltrates. His clinical, radiological, and pathological findings were consistent with those of LIP. After a diagnostic surgical lung biopsy, his hypoxemia and pulmonary infiltrates exacerbated rapidly over a few days, although his condition had not progressed during the previous year. LIP may be an important differential diagnosis among adult patients in Asian countries, especially patients of non-Asian ethnicity. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Lymphocytic interstitial pneumonia Human immunodeficiency virus Adult onset Antiretroviral therapy Lymphoproliferative disorder
1. Introduction Lymphocytic interstitial pneumonia (LIP) is an opportunistic illness in patients infected with human immunodeficiency virus (HIV). It is rare in HIV-infected adults, although it is fairly common among HIV-infected children [1]. LIP is categorized as one of the Japan's acquired immune deficiency syndrome (AIDS)-defining conditions in children younger than 13 years and was also formerly included in the Centers for Disease Control and Prevention (CDC)'s case definition in HIV-infected children. The CDC has now excluded LIP from AIDS-defining conditions in HIV-infected children in 2014 because LIP is known to be associated with moderate immunodeficiency [2]. Clinically, LIP is a bilaterally diffuse pulmonary disease characterized by dyspnea and dry cough that progress gradually
* Corresponding author. Division of General Internal Medicine/Division of Infectious Diseases, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsukeshi, Tochigi 329-0498, Japan. Tel.: þ81 285 58 7394; fax: þ81 285 44 0628. E-mail address: [email protected] (S. Hatakeyama).
over months to years. Clinical and radiological features of LIP may be indistinguishable from those of pneumonia caused by Pneumocystis jirovecii [1,3]. Because of the rarity of the disease, the optimal treatment for HIV-related LIP is not currently known. Acute exacerbation of HIV-related LIP has not been well described. We present a pathologically proven case of adult-onset HIV-related LIP with acute exacerbation that was successfully treated with antiretroviral therapy (ART) and corticosteroids. This report reviews the literature and discusses the etiology, clinical presentation, diagnosis, and clinical management of adult-onset HIV-related LIP. 2. Case report A black man in his 50s from a West African country was referred to our hospital because of a bilateral diffuse pulmonary infiltrate found on a thoracic radiograph that was taken during a health screening at the time of his employment in Japan (Fig. 1). He tested positive for HIV-1, which had been undiagnosed until that time. He reported a 1-year history of dyspnea and a 9-month history of dry cough, but had never had a chest radiograph taken before. His
http://dx.doi.org/10.1016/j.jiac.2015.07.008 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
M. Saito et al. / J Infect Chemother 21 (2015) 868e872
Fig. 1. A posteroanterior chest radiograph of the patient at presentation showing bilateral diffuse reticular infiltrates and bilateral hilar lymphadenopathy.
height was 165 cm and he weighed 49.4 kg; his weight had decreased by 10 kg in 1 year. He had no history of any notable diseases, was taking no medications regularly, and did not smoke or drink alcohol. On physical examination, his temperature was 37.0 C, his pulse rate was 120 beats per minute, his oxygen
869
saturation was 95% while breathing ambient air, and his blood pressure was 108/66 mmHg. His sclerae were anicteric, his conjunctivae were pale, and he had no superficial lymphadenopathy. Finger clubbing was not apparent. Upon thoracic auscultation, his heart sounds were regular and without murmurs, and his lung sounds were clear. The patient was anemic (hemoglobin, 10.3 g/dL), and serum lactate dehydrogenase (LDH) was moderately elevated at 438 U/L (reference range, 124e222 U/L). Routine blood tests were within reference ranges otherwise. His serum HIV-RNA was 510,000 copies/mL, and his CD4þ and CD8þ T lymphocyte counts were 380 cells/mL and 1487 cells/mL, respectively. His human leukocyte antigen (HLA)-DR haplotype was DR8 and DR15. His serum IgG was elevated at 5250 mg/dL (reference range, 861e1747 mg/dL), indicating polyclonal gammopathy, and serum KL-6 was 8451 U/mL (reference range, <500 U/mL). His plasma concentration of b-D-glucan was <6.0 pg/mL, as determined using the b-glucan test Wako (Wako Pure Chemical Industries, Ltd., Osaka, Japan), which has an established cut-off value of 11 pg/mL for a positive test result. Antibody tests for EpsteineBarr virus (EBV) were consistent with past infection (viral capsid antigenIgG 160, viral capsid antigen-IgM less than 10, early antigenIgG 40, EBV nuclear antigen-IgG 20). An assay for human Tlymphotropic virus (HTLV)-1 antibody was negative. Serum human herpesvirus 8 (HHV8)-DNA was not detected, and EBV-DNA was 340 copies/mL. Thyroid function was normal, and autoantibody tests were not suggestive of autoimmune diseases (thyroidstimulating hormone, 3.35 mIU/mL; free thyroxine (T4), 0.94 ng/ dL; antinuclear antibody, 1:40; SS-A and SS-B antibodies, negative.). PaO2 was 54.2 mmHg and PaCO2 was 38.6 mmHg with the patient breathing ambient air (alveolar to arterial oxygen pressure difference [AaDO2], 47 mmHg). Respiratory function test results were consistent with a restrictive ventilatory defect with decreased diffusion capacity: vital capacity (VC), 51% of predicted value; forced expiratory volume in 1 s/forced vital volume
Fig. 2. Computed tomography (CT) scan of the chest at presentation showing bilateral diffuse ground-glass attenuation with small nodules and cysts (a, b). Contrast-enhanced CT scan showing enlargement of mediastinal lymph nodes (c). Positron emission tomography with 18-fluoro-D-glucose showing uptake in the enlarged lymph nodes (d).
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M. Saito et al. / J Infect Chemother 21 (2015) 868e872
(FEV1.0%), 88%; diffusing capacity of the lung for carbon monoxide per unit of alveolar volume (DL,CO/VA), 59% of predicted value. Thoracic computed tomography (CT) scans revealed bilateral diffuse ground-glass attenuation with several small nodules and cysts (Fig. 2). Hilar, mediastinal, and para-aortic lymph nodes were bilaterally enlarged, and signal uptake was observed at these lymph nodes using positron emitted tomography with 18-fluoroD-glucose. Bronchoalveolar lavage (BAL) fluid analysis revealed macrophages (76%) and lymphocytes (8%), with an increased total cell count of 597,000/mL. The predominant lymphocyte subtype in the BAL fluid was CD8þ lymphocytes (CD4þ lymphocytes, 4.5%; CD8þ lymphocytes, 94.7%). All of the tests for infectious pathogens in the BAL fluid were negative, including bacterial culture, Gram
stain, Grocott stain, acid-fast stain, and polymerase chain reaction tests for Mycobacterium tuberculosis, Mycobacterium avium complex, P. jirovecii, and HHV8. HIV-related LIP was suspected, but pulmonary disease associated with multicentric Castleman disease and EBV-associated lymphoproliferative disorders were also possible, based on the clinical presentation. In order to confirm the diagnosis by pathology, a biopsy of the right middle lung lobe (S4) was performed using video-assisted thoracoscopic surgery. The pathological findings of the biopsy specimen were consistent with LIP; diffuse and homogenous infiltrates of CD8þ lymphocytes and plasma cells were observed in the alveolar septal interstitium, which was thickened with fibrosis (Fig. 3). In situ hybridization for EBV-encoded RNA
Fig. 3. Histopathology of the surgical biopsy specimen from the right middle lobe of the lung (S4) showing changes consistent with lymphocytic interstitial pneumonia. The pathological changes are distributed in a homogenous and panlobular pattern (a: hematoxylineeosin stain, 4). Diffuse and homogenous infiltration of the cells, which are composed predominantly of lymphocytes and plasma cells, is observed around alveolar septal interstitium (b: hematoxylineeosin stain, 200). The alveolar interstitium is thickened with fibrosis, but the alveolar structure is retained (c: Elastica van Gieson stain, 100). Hyperplasia of type II pneumocytes can be observed. Infiltrating cells are predominantly CD3þCD8þ (d: CD3 immunostain, 100). CD20þ cells are gathered, forming germinal centers around vessels and bronchioles (e: CD20 immunostain, 40). Monoclonality is not detected.
M. Saito et al. / J Infect Chemother 21 (2015) 868e872
showed only scarce positivity in the lung tissue. After the videoassisted thoracoscopic surgery, the patient's hypoxemia became exacerbated and fine crackles were heard on both sides. Bilateral pulmonary interstitial shadowing progressed rapidly over the course of a few days, despite having not progressed for over a year previously. The acute exacerbation was treated with methylprednisolone (250 mg/day intravenously) for 1 day followed by oral prednisolone (1 mg/kg body weight/day). The prednisolone dosage was tapered over the course of 1 month because of the rapid improvement of the lung disease and lymph node enlargement (Fig. 4). Oxygenation evaluated by arterial blood gas analyses while breathing ambient air also improved rapidly from PaO2 35.9 mmHg, PaCO2 32.7 mmHg, and AaDO2 73.0 mmHg at the time of acute exacerbation to PaO2 80.2 mmHg, PaCO2 48.9 mmHg, and AaDO2 8.4 mmHg 5 days after initiating corticosteroid therapy. ART (darunavir/ritonavir plus emtricitabine/tenofovir) was begun in the following month. The patient's lung disease has been well controlled without progression for 3 years. Serum LDH and KL-6 levels gradually decreased from 715 U/L and 19,460 U/mL at the time of acute exacerbation, respectively, to 249 U/L and 2530 U/mL, respectively, 11 months after starting ART.
3. Discussion Although HIV-related LIP rarely occurs in adults, most adult cases have been reported in African and Afro-Caribbean patients [1,4]. Presumably, because of this ethnic predisposition, few cases have been reported from Asia. Dyspnea and dry cough that progress gradually over several months are the most common clinical signs [4]. Fever and weight loss have been reported in patients with HIV, although these signs are less common [1,4e7]. Finger clubbing is common among children [1] but may not be seen among adults [8]. Asymptomatic cases of LIP have also been found on thoracic
Fig. 4. Computed tomography scan of the chest 8 days after the initiation of corticosteroids, showing resolution of both ground-glass attenuation and enlargement of lymph nodes.
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radiographs [9]. LIP causes a restrictive ventilatory defect in which the diffusion capacity of the lungs reportedly decreases to 28e65% and the PaO2 decreases to 50e85 mmHg [5]. Clinical features and findings of HIV-related LIP in adults, based on 5 case series and the report of this patient, are summarized in Table 1 [5,6,8,10,11]. LIP is characterized by a reticular or reticulonodular interstitial infiltrate on thoracic radiographs [11] and by ground-glass attenuation with poorly defined centrilobular nodules on CT images [3]. Other common thoracic CT findings include thickening of bronchovascular bundles, interlobular septal thickening, and cystic airspaces [3]. Thickening of interlobular septa and lymphadenopathy are more characteristic of LIP than of P. jirovecii pneumonia, although it may be difficult to distinguish the two diseases on CT images [3]. Therefore, radiographic findings alone cannot provide a definitive diagnosis of LIP [3,11]. Lung biopsy is necessary for the definitive diagnosis of LIP in adults. Histologically, LIP is characterized by extensive infiltration of benign polyclonal lymphocytes into the alveolar septal interstitium [12]. T cells and plasma cells infiltrate the interstitial space, while B cells aggregate to form peribronchial germinal centers [4]. In HIV-positive patients, T cells (especially CD8þ T cells) are predominant [4,6,8]; B cells are predominant in HIV-negative patients [4]. The alveolar structure remains intact [12]. Formation of germinal centers, hyperplasia of type II pneumocytes, and fibrosis in the alveolar spaces may also be observed [12]. The etiology and pathogenesis of LIP are not well known. LIP has been diagnosed in patients with autoimmune disorders such as € gren's syndrome and Hashimoto's disease and with viral inSjo fections such as EBV, HIV, and HTLV-1 [1,4]. Adult-onset HIV-related LIP may be associated with a cellular immune response against the HIV antigen [4,5]. CD8þ lymphocytes in particular are considered to play a major role in the pathology of LIP; the level of CD8þ lymphocytes in BAL fluid may be increased, as was the case with our patient [5]. Adult patients with HIV-related LIP have reportedly presented with relatively high CD4 cell counts (median, 269 cells/mL; range, 39e730), high CD8 cell counts (median, 1204 cells/mL; range, 505e3015) and high serum gamma globulin levels (range, 2.6e7.0 g/dL) [5]. Enlargement of intrathoracic lymph nodes is uncommon among patients testing negative for HIV [4] but is occasionally reported among HIV-positive patients, including the patient in this report [1,5,6,8,10,11] (Table 1). Diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by infiltration of CD8þ lymphocytes into systemic organs, has been reported among HIV-positive patients [13]. Infiltration of CD8þ lymphocytes causes parotid gland enlargement, sicca syndrome, and generalized lymph node enlargement. In addition, LIP is present in nearly one-half of the patients with DILS [4,14,15]. Patients with DILS are predominantly black HIV-positive adults [15]. The HLA-DR5 and DR-6 haplotypes have been genetically associated with DILS in this population [14,15], although the HLA haplotypes of our patient were DR8 and DR15. Another possible etiology for LIP is suggested by the difference in the distribution of lymphoid tissue between children and adults. Bronchus-associated lymphoid tissue, which may be associated with LIP [4], is found in children but is uncommon in healthy adult lungs [16]. The presence of bronchus-associated lymphoid tissue may explain the age distribution of HIV-related LIP. Although the ideal treatment for HIV-related LIP is unclear, partly because of the rarity of the disease, the mainstay of treatment has been ART. The effectiveness of this treatment may be related to the decreased viral load rather than to an improved immune response [5]. Many patients have achieved clinical and radiological improvement using only ART [7,9], although some have resolved spontaneously without ART [1]. Symptoms reportedly improve by 3.5 months on average after beginning ART,
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Table 1 Clinical features of HIV-related LIP in adults: summary of 5 case series and this patient's case. Clinical features
Current patient
Number of adult patients Dyspnea Cough Sputum production Fever Finger clubbing Extrathoracic lymphadenopathy Intrathoracic lymphadenopathy Restrictive lung function
Yes Yes No No No Yes Yes Yes
Morris et al. (1987) [6]
Oldham et al. (1989) [11]
Kramer et al. (1992) [10]
Dufour et al. (2003) [5]
van Zyl-Smit et al. (2015) [8]
3 100% (3/3) 100% (3/3) 33% (1/3) 67% (2/3) NA 67% (2/3) NA 67% (2/3)
14 NA NA NA NA NA 94% (15/16)a 25% (4/16)a,b NA
5 100% (5/5) 100% (5/5) 0% (0/5) NA NA NA NA NA
5 100% (5/5) 100% (5/5) NA 40% (2/5) NA 60% (3/5) 20% (1/5)c 20% (1/5)
13 92% (12/13) 91% (10/11) 70% (7/10) NA 0% (0/11) NA 50% (6/12)b 75% (6/8)
Abbreviations: LIP, lymphocytic interstitial pneumonia; HIV, human immunodeficiency virus; NA, data not available. a Including two pediatric patients. b Ascertained by chest radiography. c Ascertained by computed tomography.
and thoracic radiography images improve by 6e8 months after beginning ART [5]. ART alone is effective treatment for most cases of LIP that are not severe; steroid therapy may be used for severe cases and for those that are refractory to ART [6]. Scant information regarding the treatment of acute exacerbation of HIV-related LIP is available. Our patient was treated initially with a steroid because of an acute exacerbation after the surgical procedure. Radiological findings improved shortly after the initiation of steroid treatment and have since been maintained in stable condition solely by ART. Conflict of interest Makoto Saito received a student grant from the GlaxoSmithKline International Scholarship Charitable Trust Fund. This funding body had no role in this study. References [1] Das S, Miller RF. Lymphocytic interstitial pneumonitis in HIV infected adults. Sex Transm Infect 2003;79:88e93. [2] Centers for Disease Control and Prevention. Revised surveillance case definition for HIV infectiondUnited States, 2014. MMWR Recomm Rep 2014;63: 1e10. [3] Johkoh T, Muller NL, Pickford HA, Hartman TE, Ichikado K, Akira M, et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology 1999;212:567e72. [4] Swigris JJ, Berry GJ, Raffin TA, Kuschner WG. Lymphoid interstitial pneumonia: a narrative review. Chest 2002;122:2150e64. [5] Dufour V, Wislez M, Bergot E, Mayaud C, Cadranel J. Improvement of symptomatic human immunodeficiency virus-related lymphoid interstitial pneumonia in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2003;36:e127e30.
[6] Morris JC, Rosen MJ, Marchevsky A, Teirstein AS. Lymphocytic interstitial pneumonia in patients at risk for the acquired immune deficiency syndrome. Chest 1987;91:63e7. [7] Ripamonti D, Rizzi M, Maggiolo F, Arici C, Suter F. Resolution of lymphocytic interstitial pneumonia in a human immunodeficiency virus-infected adult following the start of highly active antiretroviral therapy. Scand J Infect Dis 2003;35:348e51. [8] van Zyl-Smit RN, Naidoo J, Wainwright H, Said-Hartley Q, Davids M, Goodman H, et al. HIV associated lymphocytic interstitial pneumonia: a clinical, histological and radiographic study from an HIV endemic resourcepoor setting. BMC Pulm Med 2015;15:38. [9] Innes AL, Huang L, Nishimura SL. Resolution of lymphocytic interstitial pneumonitis in an HIV infected adult after treatment with HAART. Sex Transm Infect 2004;80:417e8. [10] Kramer MR, Saldana MJ, Ramos M, Pitchenik AE. High titers of EpsteineBarr virus antibodies in adult patients with lymphocytic interstitial pneumonitis associated with AIDS. Respir Med 1992;86:49e52. [11] Oldham SA, Castillo M, Jacobson FL, Mones JM, Saldana MJ. HIV-associated lymphocytic interstitial pneumonia: radiologic manifestations and pathologic correlation. Radiology 1989;170:83e7. [12] Travis WD, Fox CH, Devaney KO, Weiss LM, O'Leary TJ, Ognibene FP, et al. Lymphoid pneumonitis in 50 adult patients infected with the human immunodeficiency virus: lymphocytic interstitial pneumonitis versus nonspecific interstitial pneumonitis. Hum Pathol 1992;23:529e41. [13] Ghrenassia E, Martis N, Boyer J, Burel-Vandenbos F, Mekinian A, Coppo P. The diffuse infiltrative lymphocytosis syndrome (DILS). A comprehensive review. J Autoimmun 2015;59:19e25. [14] Itescu S, Brancato LJ, Buxbaum J, Gregersen PK, Rizk CC, Croxson TS, et al. A diffuse infiltrative CD8 lymphocytosis syndrome in human immunodeficiency virus (HIV) infection: a host immune response associated with HLADR5. Ann Intern Med 1990;112:3e10. [15] Kazi S, Cohen PR, Williams F, Schempp R, Reveille JD. The diffuse infiltrative lymphocytosis syndrome. Clinical and immunogenetic features in 35 patients. AIDS 1996;10:385e91. [16] Tschernig T, Pabst R. Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology 2000;68:1e8.