Mycobacterial Cervicofacial Lymphadenitis in Human Immunodeficiency Virus Infected Individuals After Antiretroviral Therapy Initiation

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Mycobacterial Cervicofacial Lymphadenitis in Human Immunodeficiency Virus Infected Individuals After Antiretroviral Therapy Initiation Yuria Ablanedo-Terrazas, MD, MSc; Claudia Alvarado-de la Barrera, PhD; Matilde Ruiz-Cruz, MD, MSc; Gustavo Reyes-Teran, MD Objectives/Hypothesis: Mycobacterial infections are the leading cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals worldwide. Cervical lymph nodes are the most frequently affected extrapulmonary sites. Despite the substantial reduction in complications of HIV tuberculosis coinfection, a proportion of individuals develop immune reconstitution inflammatory syndrome (IRIS), a term used for a clinical deterioration following initiation of antiretroviral therapy (ART). The objective of this study was to describe mycobacterial-associated IRIS in cervical lymph nodes of HIV-infected individuals receiving ART. Study Design: Retrospective cohort study, set in a tertiary referral center in Mexico City. Methods: We included ART-naive subjects who had at least one follow-up ear, nose, and throat examination, and were diagnosed with lymph node mycobacterial infection before or during the first 3 months of ART initiation. Mycobacterialassociated IRIS in cervical lymph nodes was determined retrospectively through clinical case definition and medical chart review. Results: Thirty-three subjects who initiated ART were diagnosed with cervical lymph node mycobacteriosis; 24 had Mycobacterium tuberculosis infection and nine had nontuberculous disease. Conclusions: M. tuberculosis was the most common pathogen isolated from cervical lymph nodes. The only factor associated with IRIS was infection with a nontuberculous mycobacteria. The unexpectedly high incidence of mycobacterialassociated IRIS underlines the relevance of head and neck examination before ART initiation. Key Words: Human immunodeficiency virus, cervical lymphadenitis, lymph node tuberculosis, nontuberculous lymphadenitis, immune reconstitution inflammatory syndrome. Level of Evidence: 4 Laryngoscope, 125: , 2015 INTRODUCTION Tuberculosis (TB) is the most common opportunistic infection and the leading cause of death among people living with human immunodeficiency virus (HIV). 1 Individuals with HIV infection are 30 times more likely to develop TB, as well as extrapulmonary TB due to increased susceptibility for mycobacterial reactivation and dissemination. 2 Lymphatic TB is the most common extrapulmonary form, and cervical lymph nodes the From the Infectious Diseases Research Center, National Institute of Respiratory Diseases, Mexico City, Mexico. Editor s Note: This Manuscript was accepted for publication June 5, This work was supported by grants from the Mexican Government (Comision de Equidad y Genero de la Honorable Camara de Diputados de la LXI Legislatura de Mexico). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Dr. Yuria Ablanedo-Terrazas or Dr. Gustavo Reyes-Teran, Infectious Diseases Research Center (CIENI), National Institute of Respiratory Diseases Ismael Cosıo Villegas, Mexico City, Mexico, Calz. de Tlalpan 4502, Col. Seccion XVI, CP 14080, Mexico D.F., Mexico. yablanedo@yahoo.com, yuria.ablanedo@ cieni.org.mx, or gustavo.reyesteran@gmail.com DOI: /lary most frequent localization. 3 People living with HIV are also more likely to have coinfections with nontuberculous mycobacterias, with three- to seven-fold increased risk compared to the non HIV-infected population. 4,5 Antiretroviral therapy (ART) has dramatically decreased mortality rates among HIV-infected individuals. Nevertheless, approximately 30% of those starting ART develop unmasking of opportunistic infections or worsening of preexisting conditions, due to restoration of their capacity to mount an inflammatory response. 6 9 This phenomenon, known as immune reconstitution inflammatory syndrome (IRIS), usually occurs within the first 3 months after ART initiation. Mycobacteria are the pathogens most frequently associated with IRIS. Mycobacteria-associated IRIS is a consequence of the restoration of Th1 immune responses against mycobacterial antigens. 10 Two different categories of tuberculosisassociated IRIS have been proposed: 1) paradoxical IRIS, for individuals who receive successful anti-tb treatment, and then develop clinical deterioration under ART; and 2) unmasking IRIS, for individuals without previous diagnosis of TB, in whom this condition is unmasked within a few weeks or months after ART initiation. 11 In both cases, a successful viral suppression > 1log 10 is necessary for making the diagnosis. 2498

2 Fig. 1. Study case definitions. ART 5antiretroviral therapy; IRIS 5 immune reconstitution inflammatory syndrome. The aim of this study was to describe mycobacterialassociated IRIS in cervical lymph nodes of a retrospective cohort of HIV-infected subjects initiating ART. MATERIALS AND METHODS The study was conducted at the Infectious Diseases Research Center of the National Institute of Respiratory Diseases, a tertiary referral center in Mexico City. We retrospectively studied HIV-infected subjects who were diagnosed with mycobacterial infection of cervical lymph nodes during the period between July 2008 and June Biopsy specimens were obtained in the operating room either by excisional procedure under local anesthesia, or by fine-needle aspiration if there were fluctuating lymph nodes on palpation. Cervical lymph node mycobacterial infection was defined by growth detection of Mycobacterium tuberculosis or nontuberculous mycobacteria in solid culture (Lowenstein-Jensen) and/or automated liquid culture (MGIT 960; Becton Dickinson Biosciences, Sparks, MD). We identified mycobacteria to the species level by using the Amplified MTD Test (Hologic Gen-Probe, San Diego, CA) according to Centers for Disease Control and Prevention guidelines. A positive test result on Xpert MTB/RIF (Cepheid, Sunnyvale, CA) in cervical lymph node aspiration or biopsy was also considered as lymph node tuberculosis. All specimens were also analyzed with Ziehl-Nelsen staining, Grocott methenamine silver staining, and hematoxylin eosin stain. Histopathological analysis was not routinely performed. We included HIV-infected subjects diagnosed with lymph node mycobacterial infection before or during the first 3 months after ART initiation, who had at least two head and neck examinations, determinations of CD4 and CD8 T-cell counts, and HIV RNA viral load. A certified otorhinolaryngologist performed head and neck examinations. As careful clinical examination allowed detection of small lymph nodes (<1 cm), contrast computed tomography (CT) was not deemed essential in most cases. Imaging was only used if deep-neck space involvement was suspected. We excluded individuals with ART failure (reduction < 1 log 10 in the viral load during the first 6 months), lack of adherence or resistance to antimycobacterial drugs, or insufficient follow-up. Case Definitions for Cervical Nodes An IRIS event was defined according to the consensus criteria of the International Network for the Study of HIV- Associated IRIS, as first presentation or paradoxical worsening of preexisting cervical lymph node mycobacteriosis following initiation of ART, in a context of viral success (decrease in plasma HIV RNA load > 1 log 10 ), and inability to explain symptoms by expected clinical course of the disease. 12 Each case of suspected 2499

3 Fig. 2. Study diagram. IRIS 5 immune reconstitution inflammatory syndrome; M. gen 5 Mycobacterium genavense; M. gor 5 Mycobacterium gordonae; MAC 5 Mycobacterium avium complex; MTB 5 Mycobacterium tuberculosis. mycobacterial IRIS was validated by the agreement of two experienced physicians. Clinical improvement was defined by size reduction of cervical lymph nodes, with neither new lymph node formation nor systemic symptoms (Fig. 1). The Research and Ethics Committee of the National Institute of Respiratory Diseases Ismael Cosıo Villegas in Mexico City approved the study and informed consent. Statistical Analysis Demographic characteristics were analyzed using the Fisher exact test for categorical variables and Wilcoxon ranksum test for continuous variables. The possible risk factors were entered into the model of binary logistic regression. All analyses were performed using SPSS software (IBM, Armonk, NY). A two-sided probability value <.05 was considered to be significant. RESULTS We reviewed the medical records of 59 individuals diagnosed with cervical lymph node mycobacteriosis who started ART during the period between July 2008 and June 2014 (Fig. 2). Twenty-six individuals were excluded: three lacked a head and neck examination before or during the first 3 months after ART initiation; 16 had insufficient follow-up; three had a negative culture or Xpert MTB/RIF test result; two had a negative HIV test result; and two had insufficient adherence or virologic failure to ART. Of the 33 individuals included in the study, 24 had M. tuberculosis infection (72.7%) and nine (27.2%) had nontuberculous mycobacterial infection (seven had Mycobacterium avium complex [MAC] infection, one had Mycobacterium gordonae, and one had Mycobacterium genavense). Twenty-five individuals had IRIS; nine had unmasking IRIS and 16 had paradoxical worsening. Eight individuals had clinical improvement after administration of antimycobacterial treatment. The general characteristics of the subjects included in the study are summarized in Table I. Patients were mostly young (median age 5 30 years, interquartile TABLE I. Baseline Characteristics of Patients With and Without Mycobacterial-Associated IRIS. Characteristic IRIS Non-IRIS Total P Male sex, No. (%) 23/25 (92) 8/8 (100) 31/33 (93.9) 1 Age, median yr [IQR] 30 [ ] 30.5 [ ] 30 [ ].801 Scrofula formation, No. (%) 13/25 (52) 3/8 (18.8) 16/33 (48.5).688 Nontuberculous mycobacterial infection, No. (%) 9/25 (36) 0/8 (0) 9/33 (27.3).073 Before ART initiation CD4 1 cell count, median cells/mm 3 [IQR] 58 [17 89] 111 [ ] 71 [18 124].049* CD4 1 cell percentage, median % [IQR] 5.5 [3.7 11] 15 [ ] 8 [4 15].015* CD8 1 cell count, median cells/mm 3 [IQR] 450 [ ] 539 [ ] [ ].673 CD8 1 cell percentage, median % [IQR] 61 [ ] 63.5 [ ] 61 [56 73].888 HIV-1 RNA, median copies/ml blood [IQR] 217,552 [136, ,010] 131,465 [57, ,439,658.5] 207,000 [103, ,292] HIV-1 RNA level, median log 10 copies/ml [IQR] 5.33 [5 5.73] 5.1 [ ] 5.26 [ ].833 *Statistically significant. ART 5antiretroviral therapy; HIV 5 human immunodeficiency virus; IQR 5 interquartile range; IRIS 5 immune reconstitution inflammatory syndrome

4 deep-neck space involvement. The median time to unmasking IRIS after ART initiation was 2.5 months (IQR months), and the median time to paradoxical worsening was 1.5 months (IQR months). Fig. 3. Supraclavicular lymph node enlargement. [Color figure can be viewed in the online issue, which is available at range [IQR] ), and 93.5% were men. The median nadir CD4 T-cell count before ART initiation was 71 cells/ll (IQR ), with 8% CD4 T cells (IQR ). The median CD8 T-cell count was cells/ll (IQR ), with 61% CD8 T cells (IQR ). The median baseline viral load was 207,000 copies/ml (IQR 5 103, ,292) or 5.26 log 10 copies/ml (IQR ). Eighteen cases (54.5%) were diagnosed by culturing samples obtained through neck puncture and 15 cases (45.5%) by open biopsy. Posterior neck triangle was the most common localization (16 of 33, 48.4%), followed by supraclavicular lymph node involvement (eight of 33, 24.2%, Fig. 3). Two subjects developed retropharyngeal tuberculous abscess and required surgical drainage. Sixteen subjects developed scrofula (48.4%). Enhanced CT scan was performed in 13 patients (39.4%) to assess IRIS Versus Clinical Improvement A total of 25 subjects (75.8%) developed IRIS (Table II). Median ART-induced decrease of HIV viral load in this group was of 3.55 log 10 copies/ml (IQR log 10 copies/ml). Subjects with IRIS had lower baseline CD4 T-cell counts than those with clinical improvement (58 cells/ll vs. 111 cells/ll; P 5.048). Subjects with paradoxical IRIS had lower CD4 T-cell counts than those with unmasking IRIS (23 cells/ll vs. 89 cells/ll) and those with clinical improvement (110 cells/ll, P 5.04); nevertheless, this difference was not statistically significant in the multivariate analysis. IRIS was observed in all subjects of the non-tb group (nine of nine, 100%); five had paradoxical worsening and four had unmasking IRIS. By contrast, of the 24 individuals in the TB group, only 16 had IRIS (64%). Patients with a nontuberculous mycobacterial infection had an increased risk for developing IRIS (relative risk , 95% confidence interval ). Tuberculosis Versus Nontuberculosis The median CD4 T-cell count in the TB group was higher than in the non-tb group (74.5 cells/ll vs. 18 cells/ll; P 5.03). No differences in the time to IRIS after ART initiation were observed between the TB group and the non-tb group (2 vs. 3 weeks, P 5.82). DISCUSSION To the best of our knowledge, this is the first study reporting the incidence of mycobacterial-associated IRIS TABLE II. Patients With Mycobacterial-Associated IRIS. Characteristic Unmasking, n 5 9 Paradoxical, n 5 16 P Male sex, No. (%) 9 (100) 16 (87.5).520 Age, median yr [IQR] 29 [23.5 to 38.5] 31 [27.5 to 35.75].335 Time from initiation of ART to IRIS [median mo, IQR] 2.5 [1.87 to 4.5] 1.5 [0.93 to 4].279 Nontuberculous mycobacterial infection, No. (%) 4 (44.4) 5 (31.2).671 Before ART initiation CD4 1 cell count, median cells/mm 3 [IQR] 89 [17.5 to 141] 23 [15.5 to 73].095 CD4 1 cell percentage, median % [IQR] 9.5 [3.7 to 13.2] 5 [3.5 to 9.5].288 CD8 1 cell count, median cells/mm 3 [IQR] [462 to 809.5] 355 [210 to 587.2].065 CD8 1 cell percentage, median % [IQR] 62 [57.2 to 71.7] 60.5 [56 to 75].973 HIV-1 RNA, median copies/ml blood [IQR] 139,700 [53,039 to 202,564] 327,531 [154,092 to 533,554].028* HIV-1 RNA level, median log 10 copies/ml [IQR] 5.07 [4.13 to 5.3] 5.61 [5.18 to 5.91].013* Immunological change from baseline CD4 1 cell count, median cells/mm 3 [IQR] 61 [36.5 to 146] 24 [12.25 to 78.5].864 HIV-1 RNA level, median log 10 copies/ml [IQR] 2.97 [1.33 to 3.34] 4.03 [2.98 to 5.22].050* *Statistically significant. ART 5antiretroviral therapy; HIV 5 human immunodeficiency virus; IQR 5 interquartile range; IRIS 5 immune reconstitution inflammatory syndrome. 2501

5 in cervical lymph nodes of HIV-infected subjects. Most individuals in this retrospective cohort initiating ART experienced IRIS (75.8%). M. tuberculosis was the most common mycobacteria isolated from cervical lymph nodes (72.7%), and MAC was the most frequent nontuberculous mycobacterial infection. The only factor associated with IRIS was the nontuberculous mycobacterial infection. This finding can be explained in part by the fact that the median CD4 T-cell count in this group was 18 cells/ll, and it is known that the main risk factor for IRIS is a low CD4 T-cell count before ART initiation, with a higher risk in subjects with CD4 T-cell counts < 50 cells/ll. 8 A trend toward a lower level of CD4 T-cell count was observed in the IRIS group (58 cells/ll vs. 111 cells/ll); however, these results showed no significance in the multivariate analysis. Another possible explanation for the association of IRIS with nontuberculous mycobacterial infection is that we used the Xpert MTB/RIF assay for diagnosis of TB infection, which is not aimed at diagnosis of nontuberculous mycobacteria. That is, the use of a rapid, sensitive, and specific method for detection of TB infection may have reduced the number of TB-IRIS cases. The main limitation of our study is derived from the retrospective design. Because we were unable to schedule the follow-up visits of subjects initiating ART, mild lymph node enlargement might have passed unnoticed, so we may have underestimated the true incidence of IRIS. Another limitation was the conduction of the study in a referral center, as this represents a potential source of referral bias affecting the generalizability of study results (e.g., a higher incidence of subjects with mycobacterial cervical lymphadenitis). We found that a large proportion of subjects with M. tuberculosis infection diagnosed before ART initiation developed paradoxical worsening IRIS (66.7%), despite all of them had received antimycobacterial treatment and had undergone drug sensitivity testing. This unexpectedly high incidence of TB-associated IRIS could be attributed to our only including individuals with cervical lymph node involvement; extrapulmonary tuberculosis has been described as a risk factor for developing IRIS. 13 This also indicates the importance of an exhaustive head and neck examination for detection of palpable lymph nodes before ART initiation. It is possible that some mycobacterial-associated unmasking IRIS cases are paradoxical reactions of mycobacterial infections that were not diagnosed before ART administration. The elevated incidence of TB-IRIS found here may also be explained by those cases with latent tuberculosis infection (LTBI), a state of persistent immune response to stimulation by M. tuberculosis antigens without evidence of clinically manifested active TB. According to the World Health Organization, one-third of the world s population is estimated to have LTBI, being the risk of progression to active disease considerably higher in HIV-infected individuals. 14 With an estimated TB incidence of 21 cases per 100,000 population, Mexico was included in the list of primary target countries for the guidelines on latent TB management. 15 In HIV-infected population, the prevalence of tuberculous lymphadenopathy is closely related to the prevalence of tuberculosis, varying according to the geographical region. The Antiretroviral Therapy Cohort Collaboration reported an incidence of 4.69 TB cases per 1,000 person-years during the 3 first years of ART initiation among HIV-infected individuals in Europe and North America. 16 CONCLUSION The only factor associated with IRIS was the infection with nontuberculous mycobacteria. The elevated incidence of mycobacterial-associated IRIS underlines the relevance of head and neck examination before ART initiation. BIBLIOGRAPHY 1. Global Tuberculosis Control: WHO Report Geneva, Switzerland: World Health Organization, Leeds IL, Magee MJ, Kurbatova EV, et al. Site of extrapulmonary tuberculosis is associated with HIV infection. Clin Infect Dis 2012;55: Peto HM, Pratt RH, Harrington TA, LoBue PA, Armstrong LR. Epidemiology of extrapulmonary tuberculosis in the United States, Clin Infect Dis 2009;49: Aliyu G, El-Kamary SS, Abimiku A, et al. Prevalence of non-tuberculous mycobacterial infections among tuberculosis suspects in Nigeria. PLoS One 2013;8:e Mirsaeidi M, Machado R, Garcia JG, Schraufnagel DE. Nontuberculous mycobacterial disease mortality in the United States, : a population-based comparative study. PLoS One 2014;9:e Ratnam I, Chiu C, Kandala NB, Easterbrook PJ. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clin Infect Dis 2006;42: Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008;22: M uller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010;10: Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 2006;42: Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5: Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8: International Network for the Study of HIV-Associated IRIS. General case definition. Available at: RIS/home.html. Accessed January 30, Leone S, Nicastri E, Giglio S, Narciso P, Ippolito G, Acone N. Immune reconstitution inflammatory syndrome associated with Mycobacterium tuberculosis infection: a systematic review. Int J Infect Dis 2010;14: e282 e World Health Organization. Latent tuberculosis infection. Available at: Accessed March 2, Guidelines on the management of latent tuberculosis infection of the World Health Organization Available at: bitstream/10665/136471/1/ _eng.pdf?ua51&ua51. Accessed March 2, The Antiretroviral Therapy Cohort Collaboration. Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 2005;41: