Open Forum Infectious Diseases BRIEF REPORT here describe successful treatment using adalimumab in an Adalimumab for Corticosteroid HIV-infected patient with steroid-refractory tuberculosis-asso- and Infliximab-Resistant Immune ciated systemic and neurological IRIS. Reconstitution Inflammatory Syndrome CASE REPORT in the Setting of TB/HIV Coinfection A 51-year-old man was diagnosed with HIV infection in 2007, 1 1,2 1,2,3 Nilar. Lwin, Michael Boyle, and Joshua S. Davis with a CD4 count of 680/microL, and was offered but declined Department of Immunology and Infectious Diseases, John Hunter Hospital, Newcastle, NSW, treatment. He presented in December 2016 with a 4-week Australia; School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia; Global and Tropical Health Division, Menzies School of Health Research, Darwin, history of night sweats, fever, cough, and weight loss and sev- NT, Australia eral days of worsening confusion and headache. On presenta- tion, his CD4 count was low at 172/microL, and his HIV viral Corticosteroids are the mainstay of therapy for immune recon- load was 2 million copies/mL. Pulmonary and brain imaging stitution inflammatory syndrome (IRIS). However, little is (Figure 2A and B) was suggestive of miliary TB and 2 frontal known about how to treat IRIS unresponsive to steroids. We cerebral tuberculomas. Cerebrospinal fluid polymerase chain report a patient with HIV-TB coinfection who was unrespon- reaction (GeneXpert) and subsequent culture demonstrated sive to first prednisolone and then infliximab but whose IRIS resolved with adalimumab. Mycobacterium tuberculosis. He underwent bilateral frontal Keywords. adalimumab; HIV; immune reconstitution; craniotomies for diagnostic and therapeutic purposes, and cul- steroid; tuberculosis. ture of tissue obtained intraoperatively confirmed pan-sensitive Mycobacterium tuberculosis. Rifampicin 600 mg, pyrazinamide 2000 mg, isoniazid 300 mg, and ethambutol 900 mg were ini- Immune reconstitution inflammatory syndrome (IRIS) is com- tiated, along with prednisolone 60 mg as prophylaxis against monly described in patients with HIV and opportunistic infec- IRIS. Three weeks after TB treatment commenced, abacavir tions such as tuberculosis (TB), particularly aer t ft he initiation 600 mg, lamivudine 300 mg daily, and dolutegravir 50 mg twice of antiretroviral therapy (ART) and subsequent CD4 cell count daily were initiated. Over the following 3 weeks, his symptoms recovery. IRIS may have a broad range of manifestations, and improved significantly with resolution of chest radiograph diagnosis relies on ruling out an infectious cause. IRIS may (CXR) changes as well as immune recovery with an increase in involve the central nervous system, manifesting as enlarging CD4 count to 400/microL. space-occupying lesions, meningitis, leptomeningeal involve- Aer 6 w ft eeks of TB treatment and 3 weeks of antiretroviral ment, vasculopathy, or radiculomyelopathy. IRIS is most fre- therapy (Figure 1), while on a tapering dose of prednisolone quently associated with cryptococcosis, TB, and JC virus . In (25 mg daily), he re-presented with fevers up to 40°C (104°F), addition to difficulties in defining IRIS, there is a lack of clear headache, and photophobia. Investigations including multiple evidence to guide its management. Corticosteroids are gener- blood cultures, cerebrospinal fluid (CSF) mycobacterial cul- ally used as firstline therapy, but a small proportion of patients tures, cryptococcal antigen, and virology tests showed no other fail to respond to this treatment. In this situation, either the causes of meningitis. A diagnosis of TB IRIS was made aer ft diagnosis is wrong (ie, there is an untreated infection) or the exclusion of concomitant infections. The prednisolone dose was immune activation is so potent and established that corticoster- increased to 60 mg daily, but daily fevers up to 40°C persisted oid therapy fails to attenuate it. There is no clear guideline on for a further 3 weeks. Following a thorough re-evaluation for how to treat patients with corticosteroid-refractory IRIS. We a missed diagnosis, tumor necrosis factor (TNF)–alpha block- ade with infliximab 300 mg by intravenous infusion was com- menced. There was no significant improvement aer 2 dos ft es of Received 10 October 2017; editorial decision 18 January 2018; accepted 24 January 2018. Correspondence: Nilar Lwin, MBBS MRCP, Department of Immunology and Infectious infliximab 2 weeks apart, with ongoing daily high fevers. The Diseases, John Hunter Hospital, Lookout road, New Lambton Heights, Newcastle, NSW 2305, patient then developed new-onset dysarthria, diplopia, and Australia (firstname.lastname@example.org). nystagmus. A cerebral magnetic resonance imaging (MRI) scan Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases (Figure 2C and D) showed focal basal ganglia infarcts, inter- Society of America. This is an Open Access article distributed under the terms of the Creative preted as intracranial vasculitis due to progressive neurologic Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any IRIS. Repeat cultures and polymerase chain reaction testing medium, provided the original work is not altered or transformed in any way, and that the work of blood and CSF revealed no pathogen. He was pulsed with is properly cited. For commercial re-use, please contact email@example.com DOI: 10.1093/ofid/ofy027 intravenous methylprednisolone 500 mg daily for 3 days with BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy027/4829756 by Ed 'DeepDyve' Gillespie user on 16 March 2018 First Admission Second Admission Week 14 71013161922252831 CD4 count 172 400 380 340 390 480 *TB therapy HRZE HR HIV therapy Prednisolone 60 25 60 75 75 50 37.5 25 12.5 7.5 5 2.5 (mg/d) Inﬂiximab (fortnightly) 300 Adalimumab (fortnightly) 40 40 40 20 Temperature above 38°C (100.4°F) Figure 1. Clinical course of the patient. *Tuberculosis therapy HRZE. Abbreviations: HRZE, isoniazid, ethambutol, rifampicin, pyrazinamide; TB, tuberculosis. no improvement. Infliximab was then discontinued, and adal- Health Organization guideline supports early initiation of ART imumab 40 mg subcutaneous injection was commenced. Two in patients with CD4+ T-cell counts of less than 50 per cubic days following the first dose of adalimumab, the patient’s fever millimeter due to increased AIDS-free survival. For higher settled. His neurological symptoms and signs resolved over CD4+ T-cell counts, deferral of the initiation of ART after com- the following 48 hours. Adalimumab injections were contin- pletion of intensive 2-month tuberculosis therapy should be ued every 2 weeks for a total of 3 months, and prednisolone considered because it reduces the risks of developing IRIS and was slowly withdrawn. At follow-up 7 months aer t ft he initial the side effects due to ART with no increase in mortality . presentation, the patient remains well, off prednisolone, while We report 1 of the few cases in the literature of steroid-refrac- continuing rifampicin, isoniazid, and his initial ART regimen. tory IRIS treated successfully with adalimumab. Adalimumab use has been previously reported in 3 cases of IRIS: 1 in the con- DISCUSSION text of TB in an HIV-negative patient  and 2 in HIV-related The incidence of TB-IRIS is estimated in different studies to cryptococcal infection [5, 6]. Infliximab use is also reported, range from 2% to 23% of patients in non-HIV patients and with 4 TB cases and 1 MAC-IRIS [7–9]. Duration of therapy 15.7% in HIV patients on ART treatment . Neurologic varied from 1 dose to 6 months. Like 2 previously described TB-IRIS accounts for 12% of all TB -IRIS cases in a single cen- neurological TB-IRIS cases [4, 7], our patient’s IRIS settled ter in South Africa. It is potentially a life-threatening condition with anti-TNF therapy. Our case did not respond to the first and associated with high mortality: 12%–25% . Risk factors TNF antagonist, infliximab, but responded rapidly to adali- for the development of IRIS include early initiation of antiretro- mumab. Most likely this relates to the delay in onset of clinical viral therapy (2–4 weeks after commencing antituberculosis improvement aer ft starting TNF therapy (generally 3–6 weeks) treatment), marked recovery of CD4 count, or rapid suppres- . His response occurred 4 weeks aer ft starting TNF block- sion of HIV viral load with ART therapy or disseminated TB, ade first with infliximab and then with adalimumab. Both are all of which were present in our case . The current World effective agents, though infliximab is a chimeric murine/human AB CD Figure 2. A and B, Initial cerebral magnetic resonance images (MRIs) suggestive of 2 frontal tuberculous cerebral abscesses. C and D, Repeated cerebral MRIs showing high signal focus in the right basal ganglia and right caudate nucleus with restricted diffusion suggestive of focal infarct. 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy027/4829756 by Ed 'DeepDyve' Gillespie user on 16 March 2018 monoclonal given by intravenous infusion, with a higher rate of In conclusion, TNF antagonism is an effective alternative infusion and febrile reactions. His therapy was switched to adal- strategy for steroid-refractory TB-IRIS in HIV-infected patients. imumab as we could not be sure whether his continued fevers Our case highlights the therapeutic effect on IRIS without neg- and arthralgia, which flared aer ft his second dose of inflixi- ative impact on immunological and virological control of HIV mab, were related to the chimeric antibody. The timing of his infection in short-term follow-up. Long-term adverse reactions, response to anti-TNF therapy at 3–4 weeks is consistent with however, need to be carefully monitored. This warrants add- previous reports of the time to effect of TNF therapy in other itional studies to explore the role of anti-TNF agents as salvage conditions . It is also possible that our patient had antibod- therapy in IRIS. ies to the active site of infliximab, blocking its efficacy, but such Acknowledgments antibodies are rare in previously untreated patients. Potential conifl cts of interest. All authors: no reported conflicts of e Th pathogenesis of mycobacterial IRIS requires an exces- interest. All authors have submitted the ICMJE Form for Disclosure of sive or paradoxical inflammatory response characterized Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. by increased levels of gamma interferon and TNF- α . Granuloma formation is a key component of the host response References to TB, sequestering TB bacteria within active inflammatory sites 1. Pepper DJ, Marais S, Maartens G, et al. Neurologic manifestations of paradoxical and maintaining latency. TNF is vital to that process, and block- tuberculosis-associated immune reconstitution inflammatory syndrome: a case series. Clin Infect Dis 2009; 48:e96–107. ing TNF leads to high rates of TB reactivation in normal hosts. 2. Lanzafame M, Vento S. Tuberculosis-immune reconstitution inflammatory syn- TNF-α inhibitors are oen w ft ithheld in patients who develop drome. J Clin Tuberc Other Mycobact Dis 2016; 3:6–9. 3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the active tuberculosis. However, withholding TNF-α inhibitors use of antiretroviral agents in HIV-1-infected adults and adolescents. Department may lead to paradoxical reactions, and improvement with the of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/ lvguidelines/AdultandAdolescentGL.pdf. Accessed 16 September 2017. resumption of these agents has been extensively reported . 4. Lee HS, Lee Y, Lee SO, et al. Adalimumab treatment may replace or enhance In our patient, interrupting very active inflammation and gran- the activity of steroids in steroid-refractory tuberculous meningitis. J Infect Chemother 2012; 18:555–7. uloma formation by TNF blockade may have discouraged the 5. Gaube G, De Castro N, Gueguen A, et al. Treatment with adalimumab for severe exaggerated immune response, which is important to the devel- immune reconstitution inflammatory syndrome in an HIV-infected patient pre- opment of IRIS, while enhancing bacteria killing by maximizing senting with cryptococcal meningitis. Med Mal Infect 2016; 46:154–6. 6. Sitapati AM, Kao CL, Cachay ER, et al. Treatment of HIV-related inflam- drug penetration into the granulomas . Our case demon- matory cerebral cryptococcoma with adalimumab. Clin Infect Dis 2010; strates that adalimumab is not only effective in controlling IRIS, 50:e7–10. 7. Blackmore TK, Manning L, Taylor WJ, Wallis RS. Therapeutic use of infliximab in but that it does so without interfering with mycobacterial or tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. HIV infection control. Clin Infect Dis 2008; 47:e83–5. 8. Richaud C, Ghosn J, Amazzough K, et al. Anti-tumor necrosis factor monoclonal Other immunomodulatory agents such as hydroxychloro- antibody for steroid-dependent TB-IRIS in AIDS. AIDS 2015; 29:1117–9. quine, pentoxifylline, and thalidomide have been reported as 9. Hsu DC, Faldetta KF, Pei L, et al. A paradoxical treatment for a paradoxical con- dition: infliximab use in three cases of mycobacterial IRIS. Clin Infect Dis 2016; therapies for IRIS in anecdotal case reports. Pentoxifylline, 62:258–61. a nonspecific phosphodiesterase inhibitor and TNF inhibi- 10. Nast A, Sporbeck B, Rosumeck S, et al. Which antipsoriatic drug has the fastest tor, has been used in treating IRIS and shown to be safe in onset of action? Systematic review on the rapidity of the onset of action. J Invest Dermatol 2013; 133:1963–70. TB-HIV coinfected patients . Thalidomide has shown 11. Ravimohan S, Tamuhla N, Steenhoff AP, et al. Immunological profiling of tuber- in vitro TNF-inhibiting effects and has been used success- culosis-associated immune reconstitution inflammatory syndrome and non-im- mune reconstitution inflammatory syndrome death in HIV-infected adults with fully for steroid refractory immune reconstitution syndrome. pulmonary tuberculosis starting antiretroviral therapy: a prospective observa- However, there is limited evidence of efficacy in severe dis- tional cohort study. Lancet Infect Dis 2015; 15:429–38. 12. Wallis RS, van Vuuren C, Potgieter S. Adalimumab treatment of life-threatening ease, and lack of potency seems a major limitation. For tuberculosis. Clin Infect Dis 2009; 48:1429–32. example, COX inhibitors have TNF-blocking effects and can 13. Wallis RS. Reconsidering adjuvant immunotherapy for tuberculosis. Clin Infect Dis 2005; 41:201–8. decrease macrophage activation, but they are ineffective for 14. Wallis RS, Johnson JL, Okwera A, et al. Pentoxifylline in human immuno- the treatment of chronic granulomatous inflammatory condi- deficiency virus- positive tuberculosis: safety at 4 years. J Infect Dis 1998; tions. In addition, drug-to-drug interaction with antitubercu- 178:1861. 15. Wallis RS, Hafner R. Advancing host-directed therapy for tuberculosis. Nat Rev lous medications is important to consider . Immunol 2015; 15:255–63. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy027/4829756 by Ed 'DeepDyve' Gillespie user on 16 March 2018
Open Forum Infectious Diseases – Oxford University Press
Published: Feb 1, 2018
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