Review
Immune reconstitution inflammatory syndrome associated with bacterial infections
1.
Introduction
2.
Methods
3.
Immune reconstitution
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inflammatory syndrome 4.
Therapeutic management
5.
Conclusion
6.
Expert opinion
Jean-Christophe Lagier & Didier Raoult† Aix-Marseille Universite´, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte´ de Me´decine, Marseille, France
Introduction: Immune reconstitution inflammatory syndrome (IRIS) is defined by various clinical manifestations following the initiation of antiretroviral treatment (ART) in HIV patients primarily infected with Mycobacteria. IRIS has clinical similarities with lepromatous reactions in patients with leprosy following antibiotic initiation. Areas covered: Tuberculosis and more rarely lepromatous leprae and Whipple’s disease are the main diseases caused by actinobacteria associated with IRIS, regardless of HIV status. The pathogenesis of this syndrome remains complex and partially understood. The treatment for IRIS is non-evidencebased, except for corticosteroids in tuberculosis-IRIS. Thalidomide and other immunomodulatory drugs have been successfully used in case series. Expert opinion: IRIS is mainly observed during infections (viral, fungal or bacterial) which involve inefficient macrophages for the clearance of bacteria, namely Actinobacteria such as Mycobacterium leprae, M. tuberculosis and Tropheryma whipplei. The restoration of macrophage competence after ART or antibiotic initiation results from a complex mechanism, probably involving a sudden and violent immune reaction with a cytokine storm, such as TNF-a and IFN-g. This overreaction might be controlled using corticosteroids and thalidomide. Keywords: corticosteroids, human immunodeficiency virus, immune reconstitution inflammatory syndrome, lepromatous leprosy, macrophages, thalidomide, Tropheryma whipplei Expert Opin. Drug Saf. (2014) 13(3):341-350
1.
Introduction
Immune reconstitution inflammatory syndrome (IRIS) involves a broad range of heterogeneous clinical manifestations caused by an excessive and deregulated immune response due to modifications of immune status [1]. A similar clinical entity results from a lerpomatous reaction during Mycobacterium leprae infections. IRIS was first described in 1992 by French et al. [2] and has emerged as a frequent complication of antiretroviral therapy (ART), notably in patients with tuberculosis [3,4]. In HIV-infected patients, IRIS is also mainly associated with M. aviumintracellulare, Cryptococcus neoformans, Cytomegalovirus, Pneumocystis jirovecii, human herpes virus-8 (HHV8) (associated with Kaposi’s sarcoma) and herpes simplex virus [5]. This syndrome is also observed during many cases of autoimmune and inflammatory diseases [6], and exacerbations of IRIS have been described during pregnancy [7,8]. Notably, most of the bacterial species associated with IRIS are Actinobacteria, namely, Mycobacterium spp. in HIV or non-HIV infected patients or Tropheryma whipplei in non-HIV patients [9,10]. Regarding the pathogenesis and treatment target, it also seems to be essential to note that 10.1517/14740338.2014.887677 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . . . .
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.
Immune reconstitution inflammatory syndrome (IRIS) can cause large range of clinical manifestations. Lepromatous reaction during leprosy and IRIS has similarities. Mycobacterium tuberculosis is the main pathogen associated with IRIS in HIV-infected patient. Corticosteroids are the recommended first line treatment in IRIS associated with Mycobacterium spp. infections. Thalidomide, probably thanks to a TNF-a downregulation, can be a treatment for IRIS associated with Whipple’s disease.
This box summarizes key points contained in the article.
Mycobacterium spp. Infections, including leprosy and tuberculosis, and Whipple’s disease have been associated with macrophages infections [11-13]. The prognosis of IRIS can be serious with sometimes a fatal outcome after the initiation of anti-infective treatments, such as ART [14-17] or antibiotics [9,18]. In addition, clinical deterioration during anti-infective treatment might be interpreted as a treatment failure, leading clinicians to change or prolong anti-infective treatment or resort to unnecessary surgery in rare cases [19,20]. Consequently, as different definitions exist [5,21-23] and no diagnostic test available [24], diagnosis is key to the clinical understanding of this entity. This review will describe the different aspects of IRIS, including classic cases involving ART, and the use of antibiotics. 2.
Methods
To comprehensively describe cases of IRIS, we first conducted a literature search using the MEDLINE database, without time limits, cross-referencing the following terms: ‘immune reconstitution inflammatory syndrome’, ‘immune restoration disease’, ‘immune reconstitution disease’ and ‘bacterial infections’, ‘treatment’, ‘antibiotics’, ‘management’, ‘corticosteroids’ and ‘thalidomide’. Only studies published in English were considered relevant for this review. A reference list of the more relevant articles has been assessed. All article categories, including major articles, reviews, brief reports, case reports and letters to the editor, were included.
Immune reconstitution inflammatory syndrome 3.
Definition ‘Immune reconstitution inflammatory syndrome’, also referred as ‘immune reconstitution disease’ or ‘immune restoration disease’, generally results from the rapid restoration of pathogen-specific immune responses to opportunistic infections [3], which can complicate ART initiation. A lack of 3.1
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consensus regarding the definition cases exists (Table 1). Typically, IRIS occurs during the initial months of ART (typically within 1 week to 3 months and occasionally up to 6 months [25]), and a wide spectrum of clinical manifestations caused by a broad range of pathogens has been described [24]. IRIS includes two main syndromes, including a paradoxical reaction in the first weeks after the initiation of ART (named ‘paradoxical-associated IRIS’), with a worsening of clinical signs or the appearance or new manifestations in patients with a known infection. More rarely, in ‘unmasking IRIS’, the opportunistic infection preexists before ART treatment but was clinically latent [3,25]. Nevertheless, because of a lack of clinical definition, the frequency of unmasking IRIS has never been accurately determined. A recent meta-analysis, analyzing 54 cohort studies, including 13,103 patients with a median CD4 count of 57/mm3 (ranging from 17 to 174 CD4/mm3), starting ART for HIV infection, revealed an IRIS incidence of 12.9%. Most of the pathogens associated with IRIS were M. tuberculosis, M. avium-intracellulare, cytomegalovirus and C. neoformans. Other clinical manifestations included Kaposi’s sarcoma, herpes zoster infections and progressive multifocal leukoencephalitis caused by John Cunningham virus [4]. Physiopathology of IRIS IRIS associated with AIDS pathogenesis remains incompletely understood. Nevertheless, evidence exist regarding a higher risk of IRIS in HIV-infected patients with lower CD4 counts, particularly those with < 50 CD4/mm3 [4]. The increase of CD4 that occurs generally in the first 15 days after ART initiation results in a large redistribution of CD45 Ro memory cells. Most of the IRIS associated with mycobacteria occurs during this phase [26]. In addition, genetic studies have detected polymorphisms in the genes encoding IL-6 and TNF-a associated with mycobacterial IRIS [27]. Mycobacterial IRISs are characterized by a granulomatous inflammation [28], but both innate and adaptive immunity are potentially involved during IRIS [29]. The release of numerous cytokines, including IFN- and TNF-a and elevated T-helper cell-1 (Th1) and inflammatory cytokine and chemokine levels, but not Th2 cytokines [23,30], have been associated with tuberculosis-IRIS (TB-IRIS). Conversely, Meintjes et al. showed that patients with TB-IRIS had greater T-cell expansions in response to mycobacterial antigens; nevertheless, in both controls and patients, the responses were heterogeneous [31]. Conesa-Botella et al. observed that IL-6, IL-8, IL-12p40, IL-18, interferon g-induced protein 10 and TNF-a increased at 2 weeks after the initiation of ART [32]. The role of the innate system in IRIS is poorly understood, but as in M. leprae infections [26], a central role of macrophages in TB-IRIS has been strongly suggested [33,34]. This hypothesis is supported by the histological necropsy of a patient who died of TB-IRIS revealing for the first time lesions characteristics of bronchiolitis obliterans organizing pneumonia with macrophage lung infiltrates [35]. Finally, 3.2
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IRIS associated with bacterial infections
Table 1. Case definition of immune reconstitution inflammatory syndrome associated with HIV infection.
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French et al. [5]: diagnosis requires either one major criteria or one major criteria + two minor criteria Major criteria Atypical presentation of opportunistic infections or tumors in patients under ART Decrease in plasma HIV RNA concentration by > 1 log copies per ml Minor criteria Increase in CD4 cell counts after ART Increase in an immune response specific to the relevant pathogen Spontaneous resolution of disease without specific antimicrobial treatment or chemotherapy with continued ART Shelburne et al. [22]: criteria for diagnosis HIV-infected patients Treated effectively with ART with decrease of HIV RNA concentration from baseline or increase of CD4 cell count from baseline Clinical symptoms of systemic inflammation Not expected clinical course or new opportunistic infection Additional criteria for cryptococcal meningitis Decrease in CSF antigen concentration Negative CSF fungal cultures Increased of white blood cell count in CSF ART: Antiretroviral treatment; CSF: Cerebrospinal fluid.
TB-IRIS likely reflects a rapid change in the innate response with consequent influence on the acquired response [29]. The host response in lepromatous leprosy represents the prototype of the IRIS [26,36]. Lepromatous leprosy is characterized by the absence of cellular immunity. This disease is characterized by a systemic inflammatory storm following the deposition of extravascular immune complexes, with neutrophils infiltration and activation of the complement as consequence in several clinical sites. Macrophages play a central role in this disease because they are unable to kill M. leprae [13]. Foamy macrophages containing numerous leprae bacilli are detected in histological lesions, and high level of cytokines, such as IL-4 and IL-10, have been detected [26]. The histological examination of erythema nodosum leprosum lesions reveals inflammatory infiltration caused by macrophages and neutrophils rarely associated with vasculitis or panniculitis [36], and the clinical entity is primarily associated with the release of TNF-a [37,38], explaining why thalidomide is considered as the first-line treatment of choice [36]. Several dysregulated T-cell functions have been detected in patients with classic Whipple’s disease, including the persistent deficiency of a T. whipplei-specific Th1 response in patients [39]. In contrast, the T. whipplei-specific Th2 answer increases in lymphocytes from the duodenal mucosa and the peripheral blood [40]. The cytokine profile of Whipple’s disease patients
is modified toward Th2 and regulatory T-cell responses with an increasing secretion of IL-10 and IL-4, which are inefficient against intracellular pathogens [40]. The impairment of antigen-presenting cells, with an alternative activation of macrophages, and the lack of an anti-inflammatory answer against T. whipplei also inadequately stimulate T cells [40-42]. In vitro, T. whipplei is multiplied in monocytes sampled from patients with Whipple’s disease but not from those of healthy individuals [41]. Moreover, the replication in macrophages is associated with an apoptosis that might facilitate bacterial dissemination. Replication is correlated with the expression and release of IL-16. T. whipplei IRIS pathogenesis was recently well described by Moos et al. Twenty-four patients with IRIS were compared with healthy individuals and patients with classic Whipple’s disease without IRIS. The findings revealed that IRIS is primarily mediated through the non-specific activation of CD4 T cells and suggested an increase in TNF-a expression [43]. 3.3
Bacterial infections in AIDS patients Mycobacterium tuberculosis
3.3.1
Mycobacterium tuberculosis is the main bacterium associated with IRIS in HIV-infected patients. The frequency of tuberculosis-associated IRIS is difficult to precisely assess because of the definition heterogeneity, but the incidence of this disease ranges from approximately 10 to 40%. Indeed, a lack of consensus in case definition exists (Table 2) [24]. A broad range of clinical manifestations have been described, including fever; night sweats; weight loss; new or enlarging lymph nodes; new respiratory symptoms, such as cough or dyspnea; and cold abscesses [21,24,44]. Neurological TB-IRIS occurs in 12% of the TB-IRIS cases in one center in a TB endemic area [45]. A recent prospective study included 34 TB meningitis cases in the analysis, with 16 patients who developed IRIS. The clinical manifestations, developed after a median of 14 days after ART initiation, included worsening headaches, generalized tonic--clonic seizures or neurological focalized defects. The prognosis was poor, with 13% of death resulting from TB meningitis IRIS. Interestingly, the combination of a high level of TNF-a and a low level of IFN-g in cerebrospinal fluid at the time of diagnosis might predict TB meningitis IRIS [45]. Non-tuberculous Mycobacteria Mycobacterium avium-intracellulare complexes are the more frequently detected non-tuberculous Mycobacteria (NTM) species associated with IRIS [10]. The patients commonly present fever and lymphadenopathy. The second clinical manifestation is pulmonary involvement with parenchymal lesions or rare endobronchial tumors as recently reported in a 33-year-old woman [46]. Other unusual manifestations, including pericarditis [47], arthritis or osteomyelitis [48,49], pyomyositis or psoas abscess [50,51], skin lesions [2,51,52], otomastoiditis [53] or parotitis [54], or enteritis sometimes mistaken with Whipple’s disease [55], have also been observed. 3.3.2
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Table 2. Definition of immune reconstitution inflammatory syndrome-associated with TB. Wendel et al. 2001 [99]: paradoxical worsening of tuberculosis Worsening of fever, cough or adenopathy or exacerbation of the disease at other extrapulmonary sites despite an appropriate treatment Radiographic worsening on chest radiograph or CT scan
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Meintjes et al. 2008 [24]: tuberculosis-associated cases in resource-poor setting Antecedents TB diagnosed before ART initiation Clinical criteria (major) New lymph nodes New or worsening radiological signs of TB New or worsening CNS TB New or worsening serositis Clinical criteria (minor) New or worsening symptoms such as fever, night sweats or weight loss New or worsening respiratory symptoms such as cough or dyspnea New or worsening abdominal pain with peritonitis, lymph nodes, hepatomegaly or splenomegaly Excluded criteria Drug resistance Poor adherence to treatment Another opportunistic infection of neoplasm Drug toxicity Adapted from [4] and [98]. ART: Antiretroviral treatment; CT: Computed tomography.
the clinical and histological spectrum of leprosy [71]. This idea is intriguing because M. leprae is a closely related bacteria of M. tuberculosis, which, conversely, has profound interactions with HIV and IRIS [3]. Leprosy associated with IRIS is similar to a leprosy type 1 reaction, with an unexplained and sudden switch in the Th1 type responses to M. leprae antigens [69]. The host granulomatous response to M. leprae is maintained in HIV-infected patients. Nevertheless, differences between the immunological activation of M. tuberculosis and M. leprae granulomas are suspected [69]. In addition, compared with M. leprae, M. tuberculosis has a greater capacity to induce the secretion of TNF-a [73], potentially explaining the difference in the prevalence of IRIS associated with these mycobacterial species.
3.4
Bacterial infections in non-AIDS patients Mycobacterium leprae
3.4.1
Mycobacterium leprae causes chronic granulomatous inflammation in the skin and peripheral nerves, depending on the leprosy type (tuberculoid disease or lepromatous leprosy) [13]. Few lesions, an adequate cell-mediated response and the absence of detected mycobacteria characterize tuberculoid disease, whereas in lepromatous leprosy, patients exhibit multiple skin lesions with frequent fever and malaise and a poor cell-mediated response [36]. Erythema nodosum leprosum occurs in ~ 50% of patients with lepromatous after the initiation of therapy [13,38] and is characterized by the systemic inflammation of the skin, nerves and eyes. Mycobacterium spp. Paradoxical reactions after the initiation of treatment with antibiotics in M. tuberculosis infections are observed among 2 -- 23% of non-HIV-infected patients, leading to various clinical manifestations, such as fever, lymphadenitis or severe pulmonary or neurological involvement [74,75]. These reactions have been associated with an intense cell-mediated immune response and an increase in TNF-a serum levels resulting from macrophage activation [10]. Mycobacterium ulcerans causes Buruli ulcer, which is safely and efficiently treated through both limited surgical debridement and antibiotics. In a group of 163 Buruli ulcer patients followed in a reference center (Victoria, Australia), 31 patients (19%) developed paradoxical effects at 2 -- 13 weeks after the initiation of antibiotic treatment. It is important to know this entity because the outcome is classically spontaneously favorable without supplementary treatment and avoids unnecessary antibiotics switch or extensive surgery [20]. Whereas the histopathology of Buruli ulcer reveals a poor inflammatory response, paradoxical histological lesions were observed in IRIS, with ulceration, necrosis, inflammatory infiltrate with neutrophils and negative mycobacterial cultures [76]. Among the 31 patients, 5 patients needed corticosteroids because of severe lesions [76]. 3.4.2
Disseminated infections, including central nervous system involvement, have also been rarely described [56,57]. Among other NTM species associated with IRIS, patients with lung involvement caused by M. simiae [58] and disseminated disease with cerebrospinal fluid involvement [59] have been previously described. M. kansasii causes cutaneous lesions, such as pustule, followed by small-healing ulcers [60], cutaneous abscesses [61] or pulmonary involvement [62]. Most of the cases caused by M. xenopi involved pulmonary or pleural manifestations [10,63,64]. The other observed NTM species were anecdotal, causing more or less severe manifestations, as in cases of acute bilateral parotitis caused by M. scrofulaceum [54], infrapatellar bursitis associated with M. malmoense [65], cervical lymphadenitis caused by M. genavense [66], pulmonary infection caused by M. parascrofulaceum [67] or disseminated infection caused by M. sherrisii [68]. In Brazil, India and South and Southeast Asia, fewer cases of leprosy, as a manifestation of IRIS after the initiation of ART, have been described compared with M. tuberculosis and M. avium-complex infections [26,69-72]. A paradox exists because although a shift in the clinical spectrum of leprosy from the tuberculoid form to lepromatous involvement was predicted in AIDS patients, HIV infection does not modify 344
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3.4.3
Tropheryma whipplei
Whipple’s disease is a chronic infectious disease caused by T. whipplei, typically involving middle-aged Caucasian male patients with arthralgia and diarrhea [77]. Specific immune defects are strongly suspected, explaining how ubiquitous bacteria cause rare diseases and why re-infections with genetically different strains are possible [78,79]. IRIS can occur in a few weeks after antibiotic initiation and might be fatal [9,80]. Treatment with immunosuppressive therapies has been frequently prescribed because of misdiagnosed inflammatory diseases, thereby increasing the risk of developing IRIS [80]. The clinical manifestations, including fever, erythema nodosum leprosum-like lesions and arthritis, are varied [9,19,81]. A supplementary parallel can be drawn with M. leprae because these diseases are caused by Actinobacteria bacteria, and macrophages play a key role in the host defense [19]. Indeed, although treatment is typically based on corticosteroids, we propose that thalidomide, which is the best treatment proposed in erythema nodosum leprosum reactions, should be considered as a first-line treatment in patients with IRIS cause by T. whipplei [9,19]. 4.
Therapeutic management
It is fundamental to know the IRIS entity to avoid unnecessary and unsuitable antibiotic changes. Nevertheless, the use of corticosteroids, commonly considered as a reasonable alternative in IRIS, should be cautiously prescribed. Indeed, the lack of evidence-based treatment in IRIS patients presents a challenge in the management of these patients. Recently, a retrospective study reported the management of TB-associated IRIS in 34 HIV-infected patients. IRIS was defined according to a previously described reasonable definition [5,24]. Four treatment groups were designed: no treatment and nonsteroidal anti-inflammatory drugs, ART interruption, ART interruption and corticosteroids or corticosteroids [21]. The outcome was favorable, regardless of the treatment choice, suggesting a wait-and-see attitude in certain non-severe cases [21]. Corticosteroids A randomized placebo-controlled clinical trial utilizing prednisone for the treatment of TB-associated IRIS was recently reported [82]. Several parameters were reduced after a 4-week course of prednisone, including the duration of hospitalization or the need for therapeutic procedures. The authors described significantly greater improvements in the disease symptoms, Karnofsky score and quality of life at 2 and 4 weeks (but not at 8 -- 12 weeks). Antibiotic resistance was detected in 12 of the 110 patients (10.9%) included in this study after controlled trial enrollment, including 7 multidrug-resistant cases, 2 isolated rifampicin-resistant cases, 2 isoniazid monoresistant cases and 1 rifampicin-resistant case, but other drugs were not tested, highlighting the need to investigate potential 4.1
drug-resistant TB before diagnosing IRIS and initiating corticosteroid treatments [82]. The mechanisms explaining the benefits of corticosteroids in TB-associated IRIS are not well characterized. A recent study demonstrated that corticosteroid treatment was mediated through the suppression of predominantly proinflammatory cytokine responses of innate immune origin but not via a reduction of the numbers of antigen-specific T cells in peripheral blood [83]. To our knowledge, for the other bacterial infections associated with IRIS, regardless of the HIV status of the patients, no evidence-based studies exist concerning the role of corticosteroids, except for case reports or case series [9,76,84].
Thalidomide Thalidomide was initially used as an antiemetic agent during pregnancy [85], but severe embryologic defects occurred on its use. The resurgence of thalidomide was initially associated with its paradoxical effects on erythema nodosum leprosum [38] but its immunomodulatory, anti-inflammatory and antiangiogenic properties allowed its use in multiple myeloma and other cancer, sarcoidosis and other immune-related diseases [86,87]. Major side effects are peripheral neuropathy and leukopenia [86]. Different case reports of the effectiveness of thalidomide in IRIS have been reported, including cases of two children with neurotuberculosis [88]. A randomized study evaluating an adjunctive thalidomide therapy in children with TB meningitis was terminated in an untimely fashion because of the high rate of side effects. However, in this study, a high dose of thalidomide was used (24 mg/kg/day) in all of the TB meningitis cases, regardless of association with IRIS [89]. Thalidomide was also proposed as an alternative treatment for steroid-dependent IRIS during AIDS [90] or in many cases of IRIS associated with Whipple’s disease [19,79,91], but the mechanisms underlying the antiinflammatory effects of thalidomide remain elusive. The modulation of inflammatory cytokines, particularly the downregulation of TNF-a appears essential [38,43]. Nevertheless, this immunomodulatory effect on the cytokine level should be specific in patients developing IRIS, as two randomized studies, including HIV-infected patients with oral aphthous ulcers and Kaposi’s sarcoma, treated with placebo or thalidomide, revealed a paradoxical increase in the serum levels of TNF [92,93]. 4.2
Limited anecdotal report Case studies using anti-inflammatory or immunomodulatory drugs, including pentoxifylline, hydroxychloroquine, montelukast, nonsteroidal anti-inflammatory drugs, aspirin, mycophenolate mofetil or TNF-a inhibitors, such as infliximab, have been reported [84,88,94-96]. These can sometimes represent a therapeutic alternative in second line. 4.3
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Antibiotics Or Antiretroviral treatment
Bacterial species belonging to Actinobacteria phylum
93 88 65 26 21 28
38 28
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Immune restoration
38 Macrophage
M. genavense X60070 M. simiae X52931 M. parascrofulaceum AY337273 M. xenopi AJ536033 M. scrofulaceum AF480604 M. kansasii AJ536035 M. avium AJ536037 M. malmoense X52930 M. ulcerans AB548725 M. leprae X53999 M. tuberculosis NCTC7416 T. whipplei AF483651
Cytokine storm
Corticosteroids TNF-α and IFN-γ
Down-expression
Lymphocytes
Or Thalidomide
Figure 1. Summary of the macrophage role in immune reconstitution inflammatory syndrome is shown. M. genavense: Mycobacterium genavense; T. whipplei: Tropheryma whipplei.
5.
Conclusion
Twenty years after the seminal description of this disease, IRIS still remains poorly understood. Strict consensus definitions are difficult to establish because of the broad spectrum of clinical manifestations. In addition, except for TB-associated IRIS, the evidence-based management of patients is difficult because of low numbers and the heterogeneity of cases to design randomized studies. In our opinion, thalidomide, the reference drug for the management of erythema nodosum leprosum reactions occurring during lepromatous leprosy, could be used as a first-line treatment for IRIS associated with Whipple’s disease and as a second-line treatment for TB or M. aviumintracellulare complex-associated IRIS.
6.
Expert opinion
IRIS and lepromatous leprosy are two similar clinical manifestations involving macrophages [26,29]. The clinical manifestations occurring during tuberculoid and lepromatous leprosy 346
reactions result from variations in the cellular immune response to M. leprae. Lepromatous leprosy is characterized by the absence of specific cellular immunity [26]. Therefore, the uncontrolled proliferation of leprosy bacilli occurs, with multiple lesions and extensive nerve and skin infiltration. High levels of IL-4 and IL-10 in skin, nerve lesions and peripheral blood T cells are detected [26]. Foamy macrophages, unable to kill M. leprae, are present in the dermis and are consequently filled with numerous bacilli. A redirection of cytokine production is observed between Th2- and Th1-like cells in patients with lepromatous leprosy, with a consequent loss of immune response control [37]. In addition, erythema nodosum leprosum, which occurs most often after the initiation of treatment in multibacillary patients, is characterized by a cytokine storm, including high serum concentrations of TNF-a [13]. A parallel can be drawn with IRIS observed in HIVinfected patients [1]. TB and M. avium-intracellulare are the main bacterial disease associated with IRIS in HIV-infected patients [3]. The macrophage lung infiltrates obtained from a HIV-infected patient who died of TB-IRIS demonstrated the central role of macrophages in this clinical entity [35].
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IRIS associated with bacterial infections
The precise physiopathology remains still debated and partially unknown. Nevertheless, Ruhwald and Ravn suggested that the immune restoration of the host following the ART initiation causes deleterious and disproportionate reactions due to a massive release of cytokines, including both IFN-g and TNF-a [30]. Interestingly, many viruses and eukaryotes associated with IRIS in HIV-infected patients, such as cytomegalovirus, herpes virus, HHV8 and C. neoformans, may have a close relationship with macrophages [1,97]. In addition to the clinical manifestations associated with the host response restoration after the initiation of ART, the sudden decrease in bacterial load following treatment with antibiotics could explain the inflammatory signs observed during IRIS in non-HIV-infected patients [41]. T. whipplei, the causative agent of Whipple’s disease, is the prototype bacterial species associated with IRIS [43]. IRIS is observed in approximately 10% of patients [9] and most frequently occurs in patients previously treated with immunosuppressive drugs because of misdiagnosed inflammatory rheumatism [80]. Whipple’s disease is characterized by the massive infiltration of intestinal foamy macrophages responsible for the secretion of numerous cytokines, including TNF-a [42]. The bacterial Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Declaration of interest The authors have no competing interests to declare and have received no funding in preparation of the manuscript.
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Affiliation
Jean-Christophe Lagier1 & Didier Raoult†2 † Author for correspondence 1 Aix-Marseille Universite´, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte´ de Me´decine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France 2 Professor, Aix-Marseille Universite´, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte´ de Me´decine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France Tel: +33 491 38 55 17; Fax: +33 491 83 03 90; E-mail: [email protected]
Immune reconstitution inflammatory syndrome associated with bacterial infections
1.
Introduction
2.
Methods
3.
Immune reconstitution
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inflammatory syndrome 4.
Therapeutic management
5.
Conclusion
6.
Expert opinion
Jean-Christophe Lagier & Didier Raoult† Aix-Marseille Universite´, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte´ de Me´decine, Marseille, France
Introduction: Immune reconstitution inflammatory syndrome (IRIS) is defined by various clinical manifestations following the initiation of antiretroviral treatment (ART) in HIV patients primarily infected with Mycobacteria. IRIS has clinical similarities with lepromatous reactions in patients with leprosy following antibiotic initiation. Areas covered: Tuberculosis and more rarely lepromatous leprae and Whipple’s disease are the main diseases caused by actinobacteria associated with IRIS, regardless of HIV status. The pathogenesis of this syndrome remains complex and partially understood. The treatment for IRIS is non-evidencebased, except for corticosteroids in tuberculosis-IRIS. Thalidomide and other immunomodulatory drugs have been successfully used in case series. Expert opinion: IRIS is mainly observed during infections (viral, fungal or bacterial) which involve inefficient macrophages for the clearance of bacteria, namely Actinobacteria such as Mycobacterium leprae, M. tuberculosis and Tropheryma whipplei. The restoration of macrophage competence after ART or antibiotic initiation results from a complex mechanism, probably involving a sudden and violent immune reaction with a cytokine storm, such as TNF-a and IFN-g. This overreaction might be controlled using corticosteroids and thalidomide. Keywords: corticosteroids, human immunodeficiency virus, immune reconstitution inflammatory syndrome, lepromatous leprosy, macrophages, thalidomide, Tropheryma whipplei Expert Opin. Drug Saf. (2014) 13(3):341-350
1.
Introduction
Immune reconstitution inflammatory syndrome (IRIS) involves a broad range of heterogeneous clinical manifestations caused by an excessive and deregulated immune response due to modifications of immune status [1]. A similar clinical entity results from a lerpomatous reaction during Mycobacterium leprae infections. IRIS was first described in 1992 by French et al. [2] and has emerged as a frequent complication of antiretroviral therapy (ART), notably in patients with tuberculosis [3,4]. In HIV-infected patients, IRIS is also mainly associated with M. aviumintracellulare, Cryptococcus neoformans, Cytomegalovirus, Pneumocystis jirovecii, human herpes virus-8 (HHV8) (associated with Kaposi’s sarcoma) and herpes simplex virus [5]. This syndrome is also observed during many cases of autoimmune and inflammatory diseases [6], and exacerbations of IRIS have been described during pregnancy [7,8]. Notably, most of the bacterial species associated with IRIS are Actinobacteria, namely, Mycobacterium spp. in HIV or non-HIV infected patients or Tropheryma whipplei in non-HIV patients [9,10]. Regarding the pathogenesis and treatment target, it also seems to be essential to note that 10.1517/14740338.2014.887677 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . . . .
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.
Immune reconstitution inflammatory syndrome (IRIS) can cause large range of clinical manifestations. Lepromatous reaction during leprosy and IRIS has similarities. Mycobacterium tuberculosis is the main pathogen associated with IRIS in HIV-infected patient. Corticosteroids are the recommended first line treatment in IRIS associated with Mycobacterium spp. infections. Thalidomide, probably thanks to a TNF-a downregulation, can be a treatment for IRIS associated with Whipple’s disease.
This box summarizes key points contained in the article.
Mycobacterium spp. Infections, including leprosy and tuberculosis, and Whipple’s disease have been associated with macrophages infections [11-13]. The prognosis of IRIS can be serious with sometimes a fatal outcome after the initiation of anti-infective treatments, such as ART [14-17] or antibiotics [9,18]. In addition, clinical deterioration during anti-infective treatment might be interpreted as a treatment failure, leading clinicians to change or prolong anti-infective treatment or resort to unnecessary surgery in rare cases [19,20]. Consequently, as different definitions exist [5,21-23] and no diagnostic test available [24], diagnosis is key to the clinical understanding of this entity. This review will describe the different aspects of IRIS, including classic cases involving ART, and the use of antibiotics. 2.
Methods
To comprehensively describe cases of IRIS, we first conducted a literature search using the MEDLINE database, without time limits, cross-referencing the following terms: ‘immune reconstitution inflammatory syndrome’, ‘immune restoration disease’, ‘immune reconstitution disease’ and ‘bacterial infections’, ‘treatment’, ‘antibiotics’, ‘management’, ‘corticosteroids’ and ‘thalidomide’. Only studies published in English were considered relevant for this review. A reference list of the more relevant articles has been assessed. All article categories, including major articles, reviews, brief reports, case reports and letters to the editor, were included.
Immune reconstitution inflammatory syndrome 3.
Definition ‘Immune reconstitution inflammatory syndrome’, also referred as ‘immune reconstitution disease’ or ‘immune restoration disease’, generally results from the rapid restoration of pathogen-specific immune responses to opportunistic infections [3], which can complicate ART initiation. A lack of 3.1
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consensus regarding the definition cases exists (Table 1). Typically, IRIS occurs during the initial months of ART (typically within 1 week to 3 months and occasionally up to 6 months [25]), and a wide spectrum of clinical manifestations caused by a broad range of pathogens has been described [24]. IRIS includes two main syndromes, including a paradoxical reaction in the first weeks after the initiation of ART (named ‘paradoxical-associated IRIS’), with a worsening of clinical signs or the appearance or new manifestations in patients with a known infection. More rarely, in ‘unmasking IRIS’, the opportunistic infection preexists before ART treatment but was clinically latent [3,25]. Nevertheless, because of a lack of clinical definition, the frequency of unmasking IRIS has never been accurately determined. A recent meta-analysis, analyzing 54 cohort studies, including 13,103 patients with a median CD4 count of 57/mm3 (ranging from 17 to 174 CD4/mm3), starting ART for HIV infection, revealed an IRIS incidence of 12.9%. Most of the pathogens associated with IRIS were M. tuberculosis, M. avium-intracellulare, cytomegalovirus and C. neoformans. Other clinical manifestations included Kaposi’s sarcoma, herpes zoster infections and progressive multifocal leukoencephalitis caused by John Cunningham virus [4]. Physiopathology of IRIS IRIS associated with AIDS pathogenesis remains incompletely understood. Nevertheless, evidence exist regarding a higher risk of IRIS in HIV-infected patients with lower CD4 counts, particularly those with < 50 CD4/mm3 [4]. The increase of CD4 that occurs generally in the first 15 days after ART initiation results in a large redistribution of CD45 Ro memory cells. Most of the IRIS associated with mycobacteria occurs during this phase [26]. In addition, genetic studies have detected polymorphisms in the genes encoding IL-6 and TNF-a associated with mycobacterial IRIS [27]. Mycobacterial IRISs are characterized by a granulomatous inflammation [28], but both innate and adaptive immunity are potentially involved during IRIS [29]. The release of numerous cytokines, including IFN- and TNF-a and elevated T-helper cell-1 (Th1) and inflammatory cytokine and chemokine levels, but not Th2 cytokines [23,30], have been associated with tuberculosis-IRIS (TB-IRIS). Conversely, Meintjes et al. showed that patients with TB-IRIS had greater T-cell expansions in response to mycobacterial antigens; nevertheless, in both controls and patients, the responses were heterogeneous [31]. Conesa-Botella et al. observed that IL-6, IL-8, IL-12p40, IL-18, interferon g-induced protein 10 and TNF-a increased at 2 weeks after the initiation of ART [32]. The role of the innate system in IRIS is poorly understood, but as in M. leprae infections [26], a central role of macrophages in TB-IRIS has been strongly suggested [33,34]. This hypothesis is supported by the histological necropsy of a patient who died of TB-IRIS revealing for the first time lesions characteristics of bronchiolitis obliterans organizing pneumonia with macrophage lung infiltrates [35]. Finally, 3.2
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IRIS associated with bacterial infections
Table 1. Case definition of immune reconstitution inflammatory syndrome associated with HIV infection.
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French et al. [5]: diagnosis requires either one major criteria or one major criteria + two minor criteria Major criteria Atypical presentation of opportunistic infections or tumors in patients under ART Decrease in plasma HIV RNA concentration by > 1 log copies per ml Minor criteria Increase in CD4 cell counts after ART Increase in an immune response specific to the relevant pathogen Spontaneous resolution of disease without specific antimicrobial treatment or chemotherapy with continued ART Shelburne et al. [22]: criteria for diagnosis HIV-infected patients Treated effectively with ART with decrease of HIV RNA concentration from baseline or increase of CD4 cell count from baseline Clinical symptoms of systemic inflammation Not expected clinical course or new opportunistic infection Additional criteria for cryptococcal meningitis Decrease in CSF antigen concentration Negative CSF fungal cultures Increased of white blood cell count in CSF ART: Antiretroviral treatment; CSF: Cerebrospinal fluid.
TB-IRIS likely reflects a rapid change in the innate response with consequent influence on the acquired response [29]. The host response in lepromatous leprosy represents the prototype of the IRIS [26,36]. Lepromatous leprosy is characterized by the absence of cellular immunity. This disease is characterized by a systemic inflammatory storm following the deposition of extravascular immune complexes, with neutrophils infiltration and activation of the complement as consequence in several clinical sites. Macrophages play a central role in this disease because they are unable to kill M. leprae [13]. Foamy macrophages containing numerous leprae bacilli are detected in histological lesions, and high level of cytokines, such as IL-4 and IL-10, have been detected [26]. The histological examination of erythema nodosum leprosum lesions reveals inflammatory infiltration caused by macrophages and neutrophils rarely associated with vasculitis or panniculitis [36], and the clinical entity is primarily associated with the release of TNF-a [37,38], explaining why thalidomide is considered as the first-line treatment of choice [36]. Several dysregulated T-cell functions have been detected in patients with classic Whipple’s disease, including the persistent deficiency of a T. whipplei-specific Th1 response in patients [39]. In contrast, the T. whipplei-specific Th2 answer increases in lymphocytes from the duodenal mucosa and the peripheral blood [40]. The cytokine profile of Whipple’s disease patients
is modified toward Th2 and regulatory T-cell responses with an increasing secretion of IL-10 and IL-4, which are inefficient against intracellular pathogens [40]. The impairment of antigen-presenting cells, with an alternative activation of macrophages, and the lack of an anti-inflammatory answer against T. whipplei also inadequately stimulate T cells [40-42]. In vitro, T. whipplei is multiplied in monocytes sampled from patients with Whipple’s disease but not from those of healthy individuals [41]. Moreover, the replication in macrophages is associated with an apoptosis that might facilitate bacterial dissemination. Replication is correlated with the expression and release of IL-16. T. whipplei IRIS pathogenesis was recently well described by Moos et al. Twenty-four patients with IRIS were compared with healthy individuals and patients with classic Whipple’s disease without IRIS. The findings revealed that IRIS is primarily mediated through the non-specific activation of CD4 T cells and suggested an increase in TNF-a expression [43]. 3.3
Bacterial infections in AIDS patients Mycobacterium tuberculosis
3.3.1
Mycobacterium tuberculosis is the main bacterium associated with IRIS in HIV-infected patients. The frequency of tuberculosis-associated IRIS is difficult to precisely assess because of the definition heterogeneity, but the incidence of this disease ranges from approximately 10 to 40%. Indeed, a lack of consensus in case definition exists (Table 2) [24]. A broad range of clinical manifestations have been described, including fever; night sweats; weight loss; new or enlarging lymph nodes; new respiratory symptoms, such as cough or dyspnea; and cold abscesses [21,24,44]. Neurological TB-IRIS occurs in 12% of the TB-IRIS cases in one center in a TB endemic area [45]. A recent prospective study included 34 TB meningitis cases in the analysis, with 16 patients who developed IRIS. The clinical manifestations, developed after a median of 14 days after ART initiation, included worsening headaches, generalized tonic--clonic seizures or neurological focalized defects. The prognosis was poor, with 13% of death resulting from TB meningitis IRIS. Interestingly, the combination of a high level of TNF-a and a low level of IFN-g in cerebrospinal fluid at the time of diagnosis might predict TB meningitis IRIS [45]. Non-tuberculous Mycobacteria Mycobacterium avium-intracellulare complexes are the more frequently detected non-tuberculous Mycobacteria (NTM) species associated with IRIS [10]. The patients commonly present fever and lymphadenopathy. The second clinical manifestation is pulmonary involvement with parenchymal lesions or rare endobronchial tumors as recently reported in a 33-year-old woman [46]. Other unusual manifestations, including pericarditis [47], arthritis or osteomyelitis [48,49], pyomyositis or psoas abscess [50,51], skin lesions [2,51,52], otomastoiditis [53] or parotitis [54], or enteritis sometimes mistaken with Whipple’s disease [55], have also been observed. 3.3.2
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Table 2. Definition of immune reconstitution inflammatory syndrome-associated with TB. Wendel et al. 2001 [99]: paradoxical worsening of tuberculosis Worsening of fever, cough or adenopathy or exacerbation of the disease at other extrapulmonary sites despite an appropriate treatment Radiographic worsening on chest radiograph or CT scan
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Meintjes et al. 2008 [24]: tuberculosis-associated cases in resource-poor setting Antecedents TB diagnosed before ART initiation Clinical criteria (major) New lymph nodes New or worsening radiological signs of TB New or worsening CNS TB New or worsening serositis Clinical criteria (minor) New or worsening symptoms such as fever, night sweats or weight loss New or worsening respiratory symptoms such as cough or dyspnea New or worsening abdominal pain with peritonitis, lymph nodes, hepatomegaly or splenomegaly Excluded criteria Drug resistance Poor adherence to treatment Another opportunistic infection of neoplasm Drug toxicity Adapted from [4] and [98]. ART: Antiretroviral treatment; CT: Computed tomography.
the clinical and histological spectrum of leprosy [71]. This idea is intriguing because M. leprae is a closely related bacteria of M. tuberculosis, which, conversely, has profound interactions with HIV and IRIS [3]. Leprosy associated with IRIS is similar to a leprosy type 1 reaction, with an unexplained and sudden switch in the Th1 type responses to M. leprae antigens [69]. The host granulomatous response to M. leprae is maintained in HIV-infected patients. Nevertheless, differences between the immunological activation of M. tuberculosis and M. leprae granulomas are suspected [69]. In addition, compared with M. leprae, M. tuberculosis has a greater capacity to induce the secretion of TNF-a [73], potentially explaining the difference in the prevalence of IRIS associated with these mycobacterial species.
3.4
Bacterial infections in non-AIDS patients Mycobacterium leprae
3.4.1
Mycobacterium leprae causes chronic granulomatous inflammation in the skin and peripheral nerves, depending on the leprosy type (tuberculoid disease or lepromatous leprosy) [13]. Few lesions, an adequate cell-mediated response and the absence of detected mycobacteria characterize tuberculoid disease, whereas in lepromatous leprosy, patients exhibit multiple skin lesions with frequent fever and malaise and a poor cell-mediated response [36]. Erythema nodosum leprosum occurs in ~ 50% of patients with lepromatous after the initiation of therapy [13,38] and is characterized by the systemic inflammation of the skin, nerves and eyes. Mycobacterium spp. Paradoxical reactions after the initiation of treatment with antibiotics in M. tuberculosis infections are observed among 2 -- 23% of non-HIV-infected patients, leading to various clinical manifestations, such as fever, lymphadenitis or severe pulmonary or neurological involvement [74,75]. These reactions have been associated with an intense cell-mediated immune response and an increase in TNF-a serum levels resulting from macrophage activation [10]. Mycobacterium ulcerans causes Buruli ulcer, which is safely and efficiently treated through both limited surgical debridement and antibiotics. In a group of 163 Buruli ulcer patients followed in a reference center (Victoria, Australia), 31 patients (19%) developed paradoxical effects at 2 -- 13 weeks after the initiation of antibiotic treatment. It is important to know this entity because the outcome is classically spontaneously favorable without supplementary treatment and avoids unnecessary antibiotics switch or extensive surgery [20]. Whereas the histopathology of Buruli ulcer reveals a poor inflammatory response, paradoxical histological lesions were observed in IRIS, with ulceration, necrosis, inflammatory infiltrate with neutrophils and negative mycobacterial cultures [76]. Among the 31 patients, 5 patients needed corticosteroids because of severe lesions [76]. 3.4.2
Disseminated infections, including central nervous system involvement, have also been rarely described [56,57]. Among other NTM species associated with IRIS, patients with lung involvement caused by M. simiae [58] and disseminated disease with cerebrospinal fluid involvement [59] have been previously described. M. kansasii causes cutaneous lesions, such as pustule, followed by small-healing ulcers [60], cutaneous abscesses [61] or pulmonary involvement [62]. Most of the cases caused by M. xenopi involved pulmonary or pleural manifestations [10,63,64]. The other observed NTM species were anecdotal, causing more or less severe manifestations, as in cases of acute bilateral parotitis caused by M. scrofulaceum [54], infrapatellar bursitis associated with M. malmoense [65], cervical lymphadenitis caused by M. genavense [66], pulmonary infection caused by M. parascrofulaceum [67] or disseminated infection caused by M. sherrisii [68]. In Brazil, India and South and Southeast Asia, fewer cases of leprosy, as a manifestation of IRIS after the initiation of ART, have been described compared with M. tuberculosis and M. avium-complex infections [26,69-72]. A paradox exists because although a shift in the clinical spectrum of leprosy from the tuberculoid form to lepromatous involvement was predicted in AIDS patients, HIV infection does not modify 344
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3.4.3
Tropheryma whipplei
Whipple’s disease is a chronic infectious disease caused by T. whipplei, typically involving middle-aged Caucasian male patients with arthralgia and diarrhea [77]. Specific immune defects are strongly suspected, explaining how ubiquitous bacteria cause rare diseases and why re-infections with genetically different strains are possible [78,79]. IRIS can occur in a few weeks after antibiotic initiation and might be fatal [9,80]. Treatment with immunosuppressive therapies has been frequently prescribed because of misdiagnosed inflammatory diseases, thereby increasing the risk of developing IRIS [80]. The clinical manifestations, including fever, erythema nodosum leprosum-like lesions and arthritis, are varied [9,19,81]. A supplementary parallel can be drawn with M. leprae because these diseases are caused by Actinobacteria bacteria, and macrophages play a key role in the host defense [19]. Indeed, although treatment is typically based on corticosteroids, we propose that thalidomide, which is the best treatment proposed in erythema nodosum leprosum reactions, should be considered as a first-line treatment in patients with IRIS cause by T. whipplei [9,19]. 4.
Therapeutic management
It is fundamental to know the IRIS entity to avoid unnecessary and unsuitable antibiotic changes. Nevertheless, the use of corticosteroids, commonly considered as a reasonable alternative in IRIS, should be cautiously prescribed. Indeed, the lack of evidence-based treatment in IRIS patients presents a challenge in the management of these patients. Recently, a retrospective study reported the management of TB-associated IRIS in 34 HIV-infected patients. IRIS was defined according to a previously described reasonable definition [5,24]. Four treatment groups were designed: no treatment and nonsteroidal anti-inflammatory drugs, ART interruption, ART interruption and corticosteroids or corticosteroids [21]. The outcome was favorable, regardless of the treatment choice, suggesting a wait-and-see attitude in certain non-severe cases [21]. Corticosteroids A randomized placebo-controlled clinical trial utilizing prednisone for the treatment of TB-associated IRIS was recently reported [82]. Several parameters were reduced after a 4-week course of prednisone, including the duration of hospitalization or the need for therapeutic procedures. The authors described significantly greater improvements in the disease symptoms, Karnofsky score and quality of life at 2 and 4 weeks (but not at 8 -- 12 weeks). Antibiotic resistance was detected in 12 of the 110 patients (10.9%) included in this study after controlled trial enrollment, including 7 multidrug-resistant cases, 2 isolated rifampicin-resistant cases, 2 isoniazid monoresistant cases and 1 rifampicin-resistant case, but other drugs were not tested, highlighting the need to investigate potential 4.1
drug-resistant TB before diagnosing IRIS and initiating corticosteroid treatments [82]. The mechanisms explaining the benefits of corticosteroids in TB-associated IRIS are not well characterized. A recent study demonstrated that corticosteroid treatment was mediated through the suppression of predominantly proinflammatory cytokine responses of innate immune origin but not via a reduction of the numbers of antigen-specific T cells in peripheral blood [83]. To our knowledge, for the other bacterial infections associated with IRIS, regardless of the HIV status of the patients, no evidence-based studies exist concerning the role of corticosteroids, except for case reports or case series [9,76,84].
Thalidomide Thalidomide was initially used as an antiemetic agent during pregnancy [85], but severe embryologic defects occurred on its use. The resurgence of thalidomide was initially associated with its paradoxical effects on erythema nodosum leprosum [38] but its immunomodulatory, anti-inflammatory and antiangiogenic properties allowed its use in multiple myeloma and other cancer, sarcoidosis and other immune-related diseases [86,87]. Major side effects are peripheral neuropathy and leukopenia [86]. Different case reports of the effectiveness of thalidomide in IRIS have been reported, including cases of two children with neurotuberculosis [88]. A randomized study evaluating an adjunctive thalidomide therapy in children with TB meningitis was terminated in an untimely fashion because of the high rate of side effects. However, in this study, a high dose of thalidomide was used (24 mg/kg/day) in all of the TB meningitis cases, regardless of association with IRIS [89]. Thalidomide was also proposed as an alternative treatment for steroid-dependent IRIS during AIDS [90] or in many cases of IRIS associated with Whipple’s disease [19,79,91], but the mechanisms underlying the antiinflammatory effects of thalidomide remain elusive. The modulation of inflammatory cytokines, particularly the downregulation of TNF-a appears essential [38,43]. Nevertheless, this immunomodulatory effect on the cytokine level should be specific in patients developing IRIS, as two randomized studies, including HIV-infected patients with oral aphthous ulcers and Kaposi’s sarcoma, treated with placebo or thalidomide, revealed a paradoxical increase in the serum levels of TNF [92,93]. 4.2
Limited anecdotal report Case studies using anti-inflammatory or immunomodulatory drugs, including pentoxifylline, hydroxychloroquine, montelukast, nonsteroidal anti-inflammatory drugs, aspirin, mycophenolate mofetil or TNF-a inhibitors, such as infliximab, have been reported [84,88,94-96]. These can sometimes represent a therapeutic alternative in second line. 4.3
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Antibiotics Or Antiretroviral treatment
Bacterial species belonging to Actinobacteria phylum
93 88 65 26 21 28
38 28
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Immune restoration
38 Macrophage
M. genavense X60070 M. simiae X52931 M. parascrofulaceum AY337273 M. xenopi AJ536033 M. scrofulaceum AF480604 M. kansasii AJ536035 M. avium AJ536037 M. malmoense X52930 M. ulcerans AB548725 M. leprae X53999 M. tuberculosis NCTC7416 T. whipplei AF483651
Cytokine storm
Corticosteroids TNF-α and IFN-γ
Down-expression
Lymphocytes
Or Thalidomide
Figure 1. Summary of the macrophage role in immune reconstitution inflammatory syndrome is shown. M. genavense: Mycobacterium genavense; T. whipplei: Tropheryma whipplei.
5.
Conclusion
Twenty years after the seminal description of this disease, IRIS still remains poorly understood. Strict consensus definitions are difficult to establish because of the broad spectrum of clinical manifestations. In addition, except for TB-associated IRIS, the evidence-based management of patients is difficult because of low numbers and the heterogeneity of cases to design randomized studies. In our opinion, thalidomide, the reference drug for the management of erythema nodosum leprosum reactions occurring during lepromatous leprosy, could be used as a first-line treatment for IRIS associated with Whipple’s disease and as a second-line treatment for TB or M. aviumintracellulare complex-associated IRIS.
6.
Expert opinion
IRIS and lepromatous leprosy are two similar clinical manifestations involving macrophages [26,29]. The clinical manifestations occurring during tuberculoid and lepromatous leprosy 346
reactions result from variations in the cellular immune response to M. leprae. Lepromatous leprosy is characterized by the absence of specific cellular immunity [26]. Therefore, the uncontrolled proliferation of leprosy bacilli occurs, with multiple lesions and extensive nerve and skin infiltration. High levels of IL-4 and IL-10 in skin, nerve lesions and peripheral blood T cells are detected [26]. Foamy macrophages, unable to kill M. leprae, are present in the dermis and are consequently filled with numerous bacilli. A redirection of cytokine production is observed between Th2- and Th1-like cells in patients with lepromatous leprosy, with a consequent loss of immune response control [37]. In addition, erythema nodosum leprosum, which occurs most often after the initiation of treatment in multibacillary patients, is characterized by a cytokine storm, including high serum concentrations of TNF-a [13]. A parallel can be drawn with IRIS observed in HIVinfected patients [1]. TB and M. avium-intracellulare are the main bacterial disease associated with IRIS in HIV-infected patients [3]. The macrophage lung infiltrates obtained from a HIV-infected patient who died of TB-IRIS demonstrated the central role of macrophages in this clinical entity [35].
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IRIS associated with bacterial infections
The precise physiopathology remains still debated and partially unknown. Nevertheless, Ruhwald and Ravn suggested that the immune restoration of the host following the ART initiation causes deleterious and disproportionate reactions due to a massive release of cytokines, including both IFN-g and TNF-a [30]. Interestingly, many viruses and eukaryotes associated with IRIS in HIV-infected patients, such as cytomegalovirus, herpes virus, HHV8 and C. neoformans, may have a close relationship with macrophages [1,97]. In addition to the clinical manifestations associated with the host response restoration after the initiation of ART, the sudden decrease in bacterial load following treatment with antibiotics could explain the inflammatory signs observed during IRIS in non-HIV-infected patients [41]. T. whipplei, the causative agent of Whipple’s disease, is the prototype bacterial species associated with IRIS [43]. IRIS is observed in approximately 10% of patients [9] and most frequently occurs in patients previously treated with immunosuppressive drugs because of misdiagnosed inflammatory rheumatism [80]. Whipple’s disease is characterized by the massive infiltration of intestinal foamy macrophages responsible for the secretion of numerous cytokines, including TNF-a [42]. The bacterial Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Affiliation
Jean-Christophe Lagier1 & Didier Raoult†2 † Author for correspondence 1 Aix-Marseille Universite´, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte´ de Me´decine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France 2 Professor, Aix-Marseille Universite´, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte´ de Me´decine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France Tel: +33 491 38 55 17; Fax: +33 491 83 03 90; E-mail: [email protected]
