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HIV/AIDS • CID 2009:48 (1 January) • 101

HIV/AIDSINVITED ARTICLE

Section Editor, Kenneth H. Mayer

Immune Reconstitution Inﬂammatory Syndrome:

A Reappraisal

Martyn A. French

Department of Clinical Immunology and Immunogenetics, Royal Perth Hospital, and PathWest Laboratory Medicine School of Pathology and Laboratory Medicine,

University of Western Australia, Perth, Australia

Individuals with human immunodeﬁciency virus infection who commence antiretroviral therapy when they are very im-

munodeﬁcient are susceptible to immune reconstitution disorders. The most common disorders are the various forms of

immune restoration disease (IRD) that appear to result from the restoration of a dysregulated immune response against

pathogen-speciﬁc antigens. Essentially, any pathogen that can cause an opportunistic infection as a result of cellular im-

munodeﬁciency can provoke IRD when pathogen-speciﬁc immune responses recover during antiretroviral therapy.In resource-

poor countries, Mycobacterium tuberculosis and Cryptococcus neoformans are the most signiﬁcant pathogens, because the

former causes substantial morbidity and the latter causes substantial mortality. IRD associated with these pathogens is

characterized by severe inﬂammatory responses and is often referred to as immune reconstitution inﬂammatory syndrome.

Prevention and treatment strategies for IRD are being developed, but preliminary data have demonstrated the efﬁcacy of

corticosteroid therapy in severe cases. Immune reconstitution after antiretroviral therapy may also be associated with au-

toimmune disease or sarcoidosis, both of which appear to have an immunopathogenesis that is different from that of IRD.

Contemporary antiretroviral therapy (ART) is both potent and

tolerable for long periods. Consequently, a majority of indi-

viduals with HIV infection who achieve optimal adherence to

ART will experience at least partial reversal of HIV-induced

immune defects and reconstitution of the immune system (ta-

ble 1). It remains unclear whether complete immune recon-

stitution ever occurs, but it is clear is that patients who com-

mence ART when they are very immunodeﬁcient are susceptible

to immune reconstitution disorders [1]. A group of these dis-

orders is characterized by inﬂammatory and/or autoimmune

disease and is commonly referred to as immune reconstitution

inﬂammatory syndrome (IRIS) [2]. It has become apparent

that IRIS consists of several distinct disorders that appear to

result from dysfunction of those aspects of immune reconsti-

tution that affect restoration of pathogen-speciﬁc immune re-

sponses and/or immune regulation. Although it is acknowl-

Received 27 May 2008; accepted 29 August 2008; electronically published 24 November

2008.

Reprints or correspondence: Dr. Martyn French, Dept. of Clinical Immunology, Royal Perth

Hospital, GPO Box X2213, Perth, WA 6847, Australia (martyn.french@health.wa.gov.au).

Clinical Infectious Diseases 2009;48:101–7

1058-4838/2009/4801-0016$15.00

DOI: 10.1086/595006

edged that there are still uncertainties about the immuno-

pathogenesis of IRIS, sufﬁcient information has been obtained

from clinicopathological and immunological studies to permit

a discussion of the etiology of the different components. There-

fore, in this review, the components of IRIS will be considered

separately as immune restoration disease (IRD), which is a

consequence of the restoration of an immune response against

pathogen-speciﬁc antigens that results in immunopathology,

and immune reconstitution–associated autoimmune disease

and sarcoidosis; these are also adverse outcomes of immune

reconstitution but are not directly related to the restoration of

pathogen-speciﬁc immune responses.

With respect to IRD in patients with HIV infection, this

review will particularly focus on 3 aspects. First, it will focus

on the immunopathogenesis of IRD in patients with HIV in-

fection, because studies of the immunopathogenesis have the

potential to not only improve diagnostic methods and treat-

ment but also provide novel insights into the characteristics of

pathogen-speciﬁc immune responses and their regulation. This

information might also be applicable to other situations in

which immune reconstitution disorders occur, such as in pa-

tients who have undergone haematopoietic stem cell trans-

plantation and/or in those who receive intensive immunosup-

1 2 3 4 5 6 7

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Strany 1 - A Reappraisal

HIV/AIDS • CID 2009:48 (1 January) • 101HIV/AIDSINVITED ARTICLESection Editor, Kenneth H. MayerImmune Reconstitution Inﬂammatory Syndrome:A Reappraisa

Strany 2

102 • CID 2009:48 (1 January) • HIV/AIDSTable 1. Immune reconstitution in patients with HIV infection.CharacteristicReplenishment of immune cells depl

Strany 3

HIV/AIDS • CID 2009:48 (1 January) • 103Table 2. Differing characteristics of immune restoration disease and immunodeﬁciency disease in patients with

Strany 4

104 • CID 2009:48 (1 January) • HIV/AIDSFigure 1. Postulated disease mechanisms in immune reconstitutiondiseasebeen a small number of reports of HIV e

Strany 5

HIV/AIDS • CID 2009:48 (1 January) • 105tients is ∼20 times higher than that among HIV-infected pa-tients from resource-rich countries [28, 45]. Tuber

Strany 6 - References

106 • CID 2009:48 (1 January) • HIV/AIDSuse of IL-2 or IFN-a therapy in both HIV-infected patients[62] and HIV-uninfected persons [66]. Therefore, it

Strany 7

HIV/AIDS • CID 2009:48 (1 January) • 10727. Puthanakit T, Oberdorfer P, Punjaisee S, Wannarit P, Sirisanthana T,Sirisanthana V. Immune reconstitution

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