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Bioscience Hypotheses (2009) 2, 282e285

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Could adrenal insufficiency serve as a predictor

of immune reconstitution inflammatory syndrome
(IRIS) in HIV disease?
Palanisamy Jayakumar a,*, Esaki Muthu Shankar b,
Sundaramoorthy Ezhilnambi b, Murugesan Karthikeyan c

ART Medical Centre, Government Rajaji Hospital, Madurai 625 020, India
Department of Infectious Diseases, YRG Centre for AIDS Research and Education, Voluntary Health Services Hospital
Campus, Taramani, Chennai 600 113, India
Department of Psychiatry, Government Rajaji Hospital, Madurai 625 020, India

Received 18 June 2009; accepted 24 June 2009

KEYWORDS Abstract Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory manifesta-

AIDS; tion that occurs subsequent to initiation of highly active antiretroviral therapy in terminal (HAART)
HAART; HIV infection, mainly due to the restoration of robust immune responses directed against latent
Hypothalamo-pituitary- microbial antigens. IRIS is believed to be multifactorial and less studied. Herein, we postulate that
adrenal axis; hypothalamoepituitaryeadrenal (HPA) dysregulation, a well-documented manifestation in HIV/
IRIS AIDS, could possibly disturb the balance between pro-inflammatory and anti-inflammatory cyto-
kines leading to clinical IRIS. Drugs, opportunistic infections, stress and numerous intrinsic and
extrinsic factors have been described to be the possible causes of IRIS in HIV illness.
ª 2009 Elsevier Ltd. All rights reserved.

Introduction paradoxical reaction that occurs generally during the first

3 months after initiation of HAART is known as immune
Highly active antiretroviral therapy (HAART) improves the reconstitution inflammatory syndrome (IRIS) or immune
quality of life of persons living with human immunodeficiency reconstitution disease (IRD) [1]. IRIS is also closely associated
virus (HIV) infection. However, a significant proportion of with certain other infectious (mycobacteria, varicella zos-
HIV infected persons living in developing countries experi- ter, herpesviruses, and cytomegalovirus) and non-infectious
ence a temporary worsening of their clinical status after (autoimmune) conditions. While the exact immunological
starting HAART despite immunological improvement and this mechanism behind the development of IRIS is still ambig-
uous, recent literatures have described the possible role of
altered immune attributes. Furthermore, identification of
* Corresponding author. Tel.: þ91 44 22542929; fax: þ91 44 predictive factors of IRIS in HIV disease has remained a key
22542939. goal of research for almost a decade. Shankar and others
E-mail address: (P. Jayakumar). have suggested the possible involvement of gram negative

1756-2392/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved.
Author's personal copy

Adrenal insufficiency and IRIS 283

bacterial lipopolysaccharides (LPS) during the immune

depletion of the gut in HIV disease [1]. The role of defective
CD4 þ CD25 þ FoxP3þ cells (regulatory T cells or Tregs) in
IRIS has also been suggested [1,2]. Recent studies have also
outlined the importance of performing functional testing of
vitamin D enzymes to find out whether an increase in vitamin
D catabolism or a decrease of its production contributed to
low 1,25-(OH)2D concentrations at the site of inflammation,
which possibly could lead to clinical IRIS [3]. We propose
a newer pathophysiological mechanism relating to hypo-
thalamoepituitaryeadrenal (HPA) dysregulation, which has
been postulated as one of the possible means of development
of IRIS.


Every individual undergoes continuous stress [4e6] since

a diagnosis of HIV infection is made along with other ‘usual’
disease-related psycho-mental disturbances namely,
stigma, stress and discrimination (social), pill burden and
load of opportunistic infection (OI). Some studies have
shown adrenal excess among HIV infected individuals and
others have described steroid resistance in AIDS [7,18].
Similar to the over-trained syndrome noticed among over-
trained athletes, continuous activation of the adrenal gland
might lead to exhaustion, especially at a later stage when
the gland almost goes uncontrollable to such an extent
that the adrenal secretions become inadequate (adrenal
insufficiency) to maintain the homeostasis between the
pro-inflammatory and anti-inflammatory mediators of in-
flammation. Furthermore, hypothalamoepituitaryeadrenal
(HPA) dysregulation is a well-documented manifestation in
HIV/AIDS and corticosteroid supplements appear to restore
the balance between pro-inflammatory and anti-inflam-
matory mediators that have their impact on HPA axis and
dysregulation. It is apparent that high burden of inflam-
matory mediators and HPA axis dysregulation could result in
inadequate control of inflammation leading to clinical IRIS
[8e13]. Lately, a defective FoxP3þ gene suspected to be
one amongst the factors of IRIS [2] has also been linked to
adrenal insufficiency. Studies have shown altered FoxP3þ
receptors on CD4þ cells of patients on dehydroepian-
drosterone (DHEA) therapy for adrenal insufficiency.
Figure 1 Factors leading to adrenal insufficiency directly or
Normal FoxP3þ gene, which is believed to confer anergy or
indirectly could contribute to the development of IRIS. A series
tolerance appears to be associated with normal adrenal
of disease-related psycho-mental disturbances namely, stigma,
function [2,14]. Also, clinical AIDS is characterized by the
stress and discrimination (social), drugs, steroid use and
onset of numerous OIs and neoplasms. Most of these OIs
opportunistic infections lead to steroid resistance which
reportedly afflict the adrenal gland and therefore could
subsequently leads to a disturbance in cytokine homeostasis.
lead to adrenal insufficiency. Notably, HIV infection by
Pro-inflammatory cytokines (IL-1, IL-2, TNF-a, IFN-g, IL-6,
itself is reported to cause HPA dysregulation [11,15e17]. In
IL-15) act on the hypothalamus and induce an acute-phase
particular, subtle sub-clinical adrenal insufficiency is a key
response and fever, the initial hallmark of IRIS.
factor, which is often under reported, and therefore,
sensitive and easily available methods to identify the sub-
clinical adrenal insufficiency status seem lacking [19,39]. or steroid resistance [29e34,46,47]. Drugs used in the
More interestingly, most of the microorganisms believed to treatment and prophylaxis of OIs can induce adrenal
cause adrenal insufficiency are also often associated with insufficiency. Unfortunately, some antiretrovirals also
IRIS with a high incidence [20e28,42e45]. Hyperpigmen- appear to cause adrenal insufficiency. Drugs causing
tation, a common dermatological manifestation in AIDS, endocrine abnormalities are ketoconazole, itraconazole,
appears to be attributed to HPA dysregulation. Hyperpig- rifampin, vidarabine, pentamidine, trimethoprim-sulfame-
mentation in papular pruritic eruption (PPE) is believed to thoxazole, didanosine, and ganciclovir [35e37]. Irrational
be due to either HPA dysregulation or adrenal inadequacy prescription of steroids and improper use of steroids by
Author's personal copy

284 P. Jayakumar et al.

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