Leishmaniasis as a Manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected Patients

Abstract

Introduction:

After the onset of highly active antiretroviral therapy (HAART), some HIV-infected patients present a severe inflammation in response to a latent or a previously treated opportunistic pathogen termed immune reconstitution inflammatory syndrome (IRIS). Few reports of tegumentary and visceral leishmaniasis have been described in association with IRIS.

Methods:

A systematic literature review of IRIS in association with leishmaniasis identified 34 reported cases.

Results and Discussion:

The majority of these occurred in males 4 months following the onset of HAART. The mean CD4 count before HAART was 94 ± 77 cells/mm³, increasing to 5 times the initial value between the onset of HAART and IRIS presentation. Visceral leishmaniasis and post–kala-azar dermal leishmaniasis were the most commonly reported clinical manifestations, followed by tegumentary leishmaniasis and uveitis.

Conclusions:

Commonly found characteristics included cutaneous involvement, regardless of Leishmania species; appearance of lesions unrelated to time of probable Leishmania infection; rapid recovery of CD4 count following HAART; and rapid progression.

Keywords

HIV/AIDS immune reconstitution inflammatory syndrome IRIS leishmaniasis

Introduction

Highly active antiretroviral therapy (HAART) has dramatically changed the natural course of HIV infection by decreasing the occurrence of opportunistic infections and, consequently, the mortality associated with AIDS. However, after the onset of HAART, some patients experience clinical deterioration following an increase in CD4 count and a decrease in HIV viral load. This worsening is usually due to the clinical manifestation of a latent or a previously treated opportunistic pathogen that paradoxically presents as a severe clinical manifestation. The immune response against these types of pathogens results in severe inflammation as a consequence of the restored immune response termed as immune reconstitution inflammatory syndrome (IRIS).^1
–3

The majority of IRIS cases are associated with nonparasitic infections, including (a) bacteria (Mycobacterium tuberculosis, the Mycobacterium avium complex, and other nontuberculous mycobacteria); (b) viruses (cytomegalovirus, varicella zoster virus, herpes simplex virus, human herpes virus 8, JC virus, and hepatitides B and C); (c) fungi (Pneumocystis jirovecii, Cryptococcus neoformans, and Histoplasma spp).^4,5 However, other parasitic infections associated with IRIS, such as Strongyloides stercoralis and Schistosoma mansoni, have also been previously described.^5,6 The risk of IRIS is mainly associated with severe immunosuppression at the start of HAART.⁵

To date, very few reports of tegumentary and visceral leishmaniasis (PL), as well as post–kala-azar dermal leishmaniasis (PKDL), have been described in association with IRIS in HIV-infected patients from several countries.^{7

–17} Furthermore, many cases may remain underreported due to the difficulty in diagnosing leishmaniasis in association with IRIS because of the absence of universal criteria. The present study conducts a review of the international literature pertaining to cases of leishmaniasis in association with IRIS.

Methods

The literature considering the cases of leishmaniasis as a manifestation of IRIS in HIV-infected individuals was analyzed. The search was performed in MEDLINE and BIREME, the Brazilian regional library of medicine, using the following key words: immune reconstitution inflammatory syndrome, cutaneous leishmaniasis, mucocutaneous leishmaniasis (MCL), PKDL, VL, and ocular leishmaniasis. No restrictions were placed with regard to the time of publication or language of publication. Articles were selected if all of the following criteria were met: the patient serology for HIV was positive, there was evidence of a decrease in viral load and an increase in the CD4 count following the onset of HAART, leishmaniasis presented with an inflammatory or atypical manifestation, and Leishmania parasites were detected in lesions. All other literature reviews were excluded.

Literature Review

To date, 34 cases of leishmaniasis as a manifestation of IRIS have been described worldwide (Table 1). Males (77%) predominated among the cases described. The mean age of patients was 39 (ranging from 28 to 60 years). The most frequent clinical presentation was VL (19 cases),^{7
–9,12,20,26} followed by PKDL (10 cases).^{7,13,15,17,19,22

–26} In 2 cases, VL and PKDL were diagnosed simultaneously.^7,26 Tegumentary leishmaniasis was reported in 5 cases^10,11,14,16, and MCL was reported in 2 of the 5 cases,¹⁴ while diffuse cutaneous leishmaniasis (DCL) was reported in 2 others.^10,16 Uveitis as a consequence of leishmaniasis was reported in 3 cases,^13,18,21 wherein 1 was found to be associated with PKDL.¹³ The mean time between the onset of HAART and the occurrence of IRIS manifestations was 4 months (range: 6 days-111 months). Mean CD4 counts were 94 ± 77 cells/mm³, ranging from 4 to 256 cells/mm³ (Table 2). Sixteen patients had an increase in CD4 count following HAART, with an average gain of 235 ± 198 cells/mm³ (57-40 cells/mm³), corresponding to a 5-fold rise. The elapsed time between onset of HAART and manifestation of IRIS was not related to the degree of CD4 boost and viral load before therapy.

Table 1.

Reported Characteristics of HIV-Infected Patients with Leishmaniasis in Association with IRIS in the Literature.

Author, year	Country	N	Age/Gender	Leishmaniasis IRIS	Primary Manifestation	Leishmania Species	Treatment
Ridolfo et al, 2000¹⁷	Italy	1	36/F	PKDL	VL	L infantum	LAmphB
Gilad et al, 2001¹⁵	Ethiopia	1	32/M	PKDL	VL	L sp	SSG
Blanche et al, 2002¹⁸	Burkina Faso	1	34/M	Uveitis	DCL and ganglionic	L major	Corticosteroid, LAmphB, INF-γ, Enucleation, Sbv
Bittencourt et al, 2003¹⁹	Brazil	1	28/M	PKDL	VL	NR	Sbv
Berry et al, 2004²⁰	France	2	45/F 36/M	LV	Asymptomatic Asymptomatic	L infantum, L infantum	AmphB AmphB
Meenken et al, 2004²¹	Netherlands	1	NR / M	Uveitis	VL	L donovani	Corticosteroid, SSG, Flu, Enucleation
Posada-Vergara et al, 2005¹⁴	Brazil	2	52/M 46/M	MCL MCL	Asymptomatic DCL	L sp, L brasilienses	AmphB, Sbv
Alsina-Gibert et al, 2006²²	Spain	1	48/M	PKDL	VL	L sp	LAmphB, Sbv, allopurinol
Kerob et al, 2006¹¹	Senegal	1	55/M	CL	CL	L major	Flu
Rihl et al, 2006²⁶	Germany/Spain	1	42/M	PKDL and VL	VL	L sp	SSG, miltefosine
Stark et al, 2006²⁴	Australia/Greece	1	45/M	PKDL	VL	L infantum	LAmphB
Antinori et al, 2007¹³	Italy	1	46/M	PKDL and uveitis	VL	L infantum	Pentamidine, miltefosine
Guffanti et al, 2008²⁵	Italy	1	40/F	PKDL	VL	L sp	Miltefosine
Sinha et al, 2008¹⁰	Nicaragua	1	39/M	DCL	Asymptomatic	L chagasi	LAmphB
ter Horst et al, 2008⁸	Ethiopia	13	33^a/NR	VL	VL	L sp	NR
Chrusciak-Talhari et al, 2009¹⁶	Brazil	1	32/M	DCL	CL	L guyanensis	Sbv, prednisone
Patel et al, 2009¹²	India/Kuwait	1	35/M	VL	Asymptomatic	L sp	AmphB, antibiotic
Tadesse et al, 2009²³	Ethiopia	1	25/M	PKDL	VL	NR	SSG
Auyeung et al, 2010⁹	Australia/Cyprus	1	60/M	VL	Asymptomatic	L donovani	Corticosteroid, LAmphB
Gelanew et al, 2010⁷	Ethiopia	1	38/M	PKDL and VL	Asymptomatic	L donovani	Sbv

Abbreviations: PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis, MCL, mucocutaneous leishmaniasis, CL, cutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; INF-γ, interferon gamma; F, female; M, male; NR, not reported; Flu, fluconazol; SSG, sodium stibogluconate; Sbv, pentavalent antimonial; LAmphB, lipisomal amphotericin B; AmphB, amphotericin B; IRIS, immune reconstitution inflammatory syndrome.

^aMean age.

Table 2.

CD4 Counts and Viral Loads before and after HAART.

Author, year	CD4 Count prior to HAART	CD4 Count after HAART	% Increase in CD4 Count	Viral Load prior to HAART	Viral Load after HAART	Leishmaniasis IRIS	Time of HAART, Months
Ridolfo et al, 2000¹⁷	35	157	348	NR	<50	PKDL	8
Blanche et al, 2002¹⁸	4	91	2175	381 000	<50	Uveitis	4
Berry et al, 2004²⁰	186	226	21	1 700 000	NR	VL	10 days
Berry et al, 2004²⁰	15	66	340	354 000	NR	VL	6 days
Meenken et al, 2004²¹	60	740	1133	NR	NR	Uveitis	26
Posada-Vergara et al, 2005¹⁴	38	65	71	750 000	NR	MCL	1
Posada-Vergara et al, 2005¹⁴	24	283	1179	NR	400	MCL	1
Alsina-Gibert et al, 2006²²	69	158	128	578	<200	PKDL	11
Rihl et al, 2006²⁶	28	116	314	<50	NR	PKDL and VL	22
Stark et al, 2006²⁴	176	374	112	NR	NR	PKDL	84
Antinori et al, 2007¹³	71	321	352	73 000	<50	PKDL and uveitis	111
Guffanti et al, 2008²⁵	200	584	192	NR	<50	PKDL	2
Sinha et al, 2008¹⁰	115	200	74	700	<400	DCL	6
Chrusciak-Talhari et al, 2009¹⁶	16	184	1050	NR	NR	CL	10
Auyeung et al, 2010⁹	55	75	36	>100 000	562	VL	5

Abbreviations: HAART, highly active antiretroviral therapy; PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis; MCL, mucocutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; NR, not related; IRIS, immune reconstitution inflammatory syndrome.

In the 2 cases reported by Berry et al,²⁰ the diagnosis of VL in association with IRIS was inconclusive, as manifestations appeared shortly after the onset of HAART (6-10 days). In addition, both patients had leukopenia and thrombocytopenia prior to the onset of HAART, which may be due to the natural course of VL instead of IRIS. The largest series of cases of VL in association with IRIS was reported in Ethiopia; however, scarce clinical data were presented regarding these patients. In these cases, IRIS was diagnosed 3 months after the onset of HAART, based solely on positive serology for Leishmania, or due to the presence of Leishmania spp in splenic aspirate. All these patients previously had negative serology for Leishmania.⁸ It is known²⁷ that 50% of HIV/Leishmania co-infected individuals have negative serology for Leishmania, especially those with CD4 counts of less than 100 cells/mm³. Therefore, perhaps VL as a manifestation of IRIS was an uncertain diagnosis in this series of cases reported in Ethiopia. Moreover, in a prospective study conducted by de la Rosa et al,²⁸ VL in association with IRIS was not observed in 11 patients with the subclinical form of the disease, who were treated with HAART during 29 months of follow-up. Four patients with active VL who started HAART during the clinical manifestation of VL presented a regression of symptoms.

A total of 10 cases of PKDL were reported in association with IRIS.^{7,13,15,17,19,22

–26} Post–kala-azar dermal leishmaniasis was diagnosed between 1 and 111 months after the onset of HAART. In only 1 patient, the previous diagnosis of VL was unconfirmed. Following the onset of antiretroviral treatment (ART), CD4 counts increased in all 10 cases. Furthermore, skin lesions appeared only after HAART was initiated, characterizing a new event related to a preexisting Leishmania infection. Taken together, these findings suggest a stronger association between PKDL and IRIS compared to VL in association with IRIS.

Regarding the 5 reported cases of cutaneous leishmaniasis associated with IRIS, Leishmania infection was commonly disseminated. In 1 case in Brazil, the dissemination of lesions occurred during CD4 count recovery,¹⁶ whereas in the case described by Kerob et al,¹¹ several nodules containing Leishmania appeared following combined ART and amphotericin B treatment.

Sinha et al¹⁰ reported a case of DCL in association with IRIS in 1 HIV-positive individual on ART. In contrast to classical DCL, which is an anergic form of leishmaniasis characterized by disseminated non ulcerating skin lesions, this patient had fever, weight loss, diarrhea and splenomegaly. In addition, Leishmania chagasi was isolated from this patient’s lesions, which had not been previously reported in cases with DCL. In this case, PKDL should have been considered as a possible diagnosis due to the patient’s clinical presentation.

Two cases of cutaneous leishmaniasis with mucosal involvement have been previously described.¹⁴ In both patients, mucosal damage occurred shortly after immune recovery following HAART in contrast to the classical course observed in uninfected individuals wherein mucosal damage occurs later. Moreover, the species isolated in these 2 cases was Leishmania braziliensis, which is commonly associated with the mucosal form of leishmaniasis. Treatment with pentavalent antimony and amphotericin B resulted in the resolution of lesions in the 2 cases, although the authors did not specify the use of corticosteroids.

Uveitis as a manifestation of IRIS, resulting from Leishmania infection, was reported in 3 HIV-infected patients undergoing HAART. One patient had uveitis concomitantly with PKDL and was treated successfully with miltefosine.¹³ In 2 patients, uveitis resulted in blindness in the affected eye, despite treatment with high doses of corticosteroids.^18,21 In these cases, as well as in the patient reported herein, the isolated species was L braziliensis, which is commonly associated with the mucosal form of leishmaniasis.

Discussion

The present study reviewed cases of severe leishmaniasis in HIV-infected individuals as a manifestation of IRIS. Common characteristics found in these patients were cutaneous involvement regardless of the Leishmania species isolated, onset of disease regardless of when the patients were infected with Leishmania, as well as a rapid progression to severe forms of the disease in association with a rapid CD4 count recovery following ART. The median CD4 count before the onset of HAART was over 50 cells/mm³ in almost all cases, in comparison with lower CD4 counts found in patients with other infectious diseases in association with IRIS.^5,29 In the majority of the reviewed cases, the length of time between the onset of HAART and occurrence of IRIS was 6 months, similar to what was observed in other infectious diseases associated with IRIS. The only exception was a patient who developed PKDL and uveitis as a manifestation of IRIS 9 years after the onset of HAART. However, this patient was unsuccessfully treated¹³ during this period, and IRIS occurred following rescue therapy, when the CD4 count rose from 71 to 321 cells/mm³. This finding suggests that leishmaniasis as a manifestation of IRIS occurs largely as a result of immune response recovery, despite the length of the recovery period or the initial CD4 count. Gelanew et al⁷ reported on 3 HIV-infected patients with PKDL, in which a definitive IRIS diagnosis was impossible due to the absence of standardized clinical and laboratory criteria.⁷ However, PKDL in association with IRIS could be considered in one of these cases, since the onset of symptoms was concomitant with an increase in CD4 (from 40 to 93 cell/mm³) following HAART. A diagnosis of IRIS would be conceivable in several notable cases detailed in the literature, involving an aggressive co-infection with HIV/Leishmania.^30,31 Yet, in most of these reports, the length of time between the initiation of HAART and the occurrence of leishmaniasis is incomplete or absent, and relevant information regarding CD4 counts and viral load, before and after HAART, is missing.

Two cases of patients infected with HIV and MCL as a manifestation of IRIS have been described.¹⁴ Common finding are dissemination of lesions, frequently found on the arms, lower limbs, and feet. In addition, lesions are also observed in the nasal, oropharyngeal, and genital mucosa in these patients. Moreover, in the 2 patients reported by Posada-Vergara et al,¹⁴ the onset of leishmaniasis, in one case, and the worsening of leishmaniasis, in the other, occurred 1 month after the onset of HAART. It has been well established that mucosal damage in individuals with leishmaniasis who are not HIV positive is usually associated with an exacerbation of the cellular immune response and elevated production of proinflammatory cytokines. In this form of leishmaniasis, the Montenegro skin test is positive, indicating a positive delayed-type hypersensitivity response to Leishmania antigens.^32,33

In several reports, patients experienced rapid healing of lesions in response to combined amphotericin B and corticosteroid treatments.^9,12 From an immunological point of view, a parallel could be established between IRIS and type 2 leprosy reactions. Leprosy is the prototype of granulomatous disease in which the immune response can result in a paradoxical exacerbation of a patient’s lesions, which are typically characterized as erythema nodosum leprosum.³⁴ Treatment with anti-inflammatory immunomodulatory drugs, such as thalidomide, is required to control the exacerbation of leprosy.^35,36 Further studies should be conducted to evaluate the effectiveness of combined ART and corticosteroid therapy during the first 6 months of treatment in HIV-infected individuals with severe immunosuppression, who are at potential risk for life-threatening immune restoration disease.

ART results in a decreased incidence of opportunistic infections and longer patient survival.¹ Viral loads markedly decrease in tandem with an increase in CD4 counts, resulting in the restoration of immune function in more than 70% of the affected individuals.^1,6 Restoration of CD4 counts seems to take place in 2 phases: the first phase occurs 2 weeks after treatment and lasts for 3 months. There is a relatively rapid redistribution of sequestered memory T lymphocytes (CD4+CD45RO+) from the lymphoid tissues into the bloodstream following a decrease in viral load.^37,38 The second phase starts 6 months after viremia control and is characterized by less profuse and more gradual expansion of naive T cells (CD45RA+CD62L+), persisting for 1 to 2 years.³⁸ The swift restoration of the T-cell repertoire may contribute to the development of IRIS, especially in individuals with high amounts of antigens caused by either the presence of killed microorganisms during previous infections or prior subclinical opportunistic infections.⁶ The immunological mechanisms involved in IRIS development remain unclarified. Elevated production of proinflammatory cytokines is frequently found during the course of IRIS, most notably high levels of interleukin 6, interferon gamma, and tumor necrosis factor-α.^39
–41 The recovery of pathogen-specific T cells may play a role in the intensity of the inflammatory response, as evidenced by several reports which found an increase in T cells specific to M tuberculosis, M avium, and Cryptococcus neoformans in patients who developed IRIS in association with these diseases.^42,43 However, the importance of specific T cells warrants further investigation, as other studies found no association between the recovery of M tuberculosis–specific T cells and tuberculosis in association with IRIS.^44,45 To date, the literature contains no reports linking the recovery of Leishmania-specific T cells with IRIS-associated leishmaniasis. It is also possible that other mechanisms could contribute to the intensity of inflammatory responses during IRIS, such as the excessive activation of innate immune cells³ or the impairment of a regulatory T-cell response.^44,46

In conclusion, leishmaniasis as a manifestation of IRIS may present as a new disease or as the progression of latent disease following the introduction of HAART and consequent restoration of immunity. Further studies should be conducted to clarify the immunological aspects involved in IRIS development as well as to establish relevant criteria to aid in the definitive and prompt diagnosis of IRIS.

Footnotes

Acknowledgment

We thank Andris K. Walter for his assistance in English revision.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported by UCSD Center for AIDS Research, NIH (grant P30AI036214).

References

Shelburne

3rd Hamill

Rodriguez-Barradas

. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore). 2002;81 (3):213–227.

Shelburne

3rd Hamill

. The immune reconstitution inflammatory syndrome. AIDS Rev. 2003;5 (2):67–79.

Barber

Andrade

Sereti

Sher

. Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. Nat Rev Microbiol. 2012;10 (2):150–156.

Murdoch

Venter

Van Rie

Feldman

. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther. 2007;4:9.

Muller

Wandel

Colebunders

Attia

Furrer

Egger

. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10 (4):251–261.

Lawn

Wilkinson

. Immune reconstitution disease associated with parasitic infections following antiretroviral treatment. Parasite Immunol. 2006;28 (11):625–633.

Gelanew

Amogne

Abebe

Kuhls

Hailu

Schonian

. A clinical isolate of Leishmania donovani with ITS1 sequence polymorphism as a cause of para-kala-azar dermal leishmaniasis in an Ethiopian human immunodeficiency virus-positive patient on highly active antiretroviral therapy. Br J Dermatol. 2010;163 (4):870–874.

ter Horst

Collin

Ritmeijer

Bogale

Davidson

. Concordant HIV infection and visceral leishmaniasis in Ethiopia: the influence of antiretroviral treatment and other factors on outcome. Clin Infect Dis. 2008;46 (11):1702–1709.

Auyeung

French

Hollingsworth

. Immune restoration disease associated with Leishmania donovani infection following antiretroviral therapy for HIV infection. J Microbiol Immunol Infect. 2010;43 (1):74–76.

10.

Sinha

Fernandez

Kapila

Lambert

Schwartz

. Diffuse cutaneous leishmaniasis associated with the immune reconstitution inflammatory syndrome. Int J Dermatol. 2008;47 (12):1263–1270.

11.

Kerob

Bouaziz

Sarfati

. First case of cutaneous reconstitution inflammatory syndrome associated with HIV infection and leishmaniasis. Clin Infect Dis. 2006;43 (5):664–666.

12.

Patel

Sarda

Shah

Ranjan

. Immune reconstitution visceral leishmaniasis presented as hemophagocytic syndrome in a patient with AIDS from a nonendemic area: a case report. J Int Assoc Physicians AIDS Care (Chic). 2009;8 (4):217–220.

13.

Antinori

Longhi

Bestetti

. Post-kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient with acquired immune deficiency syndrome. Br J Dermatol. 2007;157 (5):1032–1036.

14.

Posada-Vergara

Lindoso

Tolezano

Pereira-Chioccola

Silva

Goto

. Tegumentary leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome in 2 patients with AIDS. J Infect Dis. 2005;192 (10):1819–1822.

15.

Gilad

Borer

Hallel-Halevy

Riesenberg

Alkan

Schlaeffer

. Post-kala-azar dermal leishmaniasis manifesting after initiation of highly active anti-retroviral therapy in a patient with human immunodeficiency virus infection. Isr Med Assoc J. 2001;3 (6):451–452.

16.

Chrusciak-Talhari

Ribeiro-Rodrigues

Talhari

. Tegumentary leishmaniasis as the cause of immune reconstitution inflammatory syndrome in a patient co-infected with human immunodeficiency virus and Leishmania guyanensis. Am J Trop Med Hyg. 2009;81 (4):559–564.

17.

Ridolfo

Gervasoni

Antinori

. Post-kala-azar dermal leishmaniasis during highly active antiretroviral therapy in an AIDS patient infected with Leishmania infantum. J Infect. 2000;40 (2):199–202.

18.

Blanche

Gombert

Rivoal

Abad

Salmon

Brezin

. Uveitis due to Leishmania major as part of HAART-induced immune restitution syndrome in a patient with AIDS. Clin Infect Dis. 2002;34 (9):1279–1280.

19.

Bittencourt

Silva

Straatmann

Nunes

Follador

Badaro

. Post-kala-azar dermal leishmaniasis associated with AIDS. Braz J Infect Dis. 2003;7 (3):229–233.

20.

Berry

Abraham

Dereure

Pinzani

Bastien

Reynes

. Two case reports of symptomatic visceral leishmaniasis in AIDS patients concomitant with immune reconstitution due to antiretroviral therapy. Scand J Infect Dis. 2004;36 (3):225–227.

21.

Meenken

van Agtmael

Ten Kate

van den Horn

. Fulminant ocular leishmaniasis in an HIV-1-positive patient. AIDS. 2004;18 (10):1485–1486.

22.

Alsina-Gibert

Lopez-Lerma

Martinez-Chamorro

Herrero-Mateu

. Cutaneous manifestations of visceral leishmaniasis resistant to liposomal amphotericin B in an HIV-positive patient. Arch Dermatol. 2006;142 (6):787–789.

23.

Tadesse

Hurissa

. Leishmaniasis (PKDL) as a case of immune reconstitution inflammatory syndrome (IRIS) in HIV-positive patient after initiation of anti-retroviral therapy (ART). Ethiop Med J. 2009;47 (1):77–79.

24.

Stark

Pett

Marriott

Harkness

. Post-kala-azar dermal leishmaniasis due to Leishmania infantum in a human immunodeficiency virus type 1-infected patient. J Clin Microbiol. 2006;44 (3):1178–1180.

25.

Guffanti

Gaiera

Bossolasco

. Post-Kala-Azar dermal leishmaniasis in an HIV-1-infected woman: recovery after amphotericin B following failure of oral miltefosine. Am J Trop Med Hyg. 2008;79 (5):715–718.

26.

Rihl

Stoll

Ulbricht

Bange

Schmidt

. Successful treatment of post-kala-azar dermal leishmaniasis (PKDL) in a HIV infected patient with multiple relapsing leishmaniasis from Western Europe. J Infect. 2006;53 (1):e25–e27.

27.

Houghton

Petrescu

Benson

. A cloned antigen (recombinant K39) of Leishmania chagasi diagnostic for visceral leishmaniasis in human immunodeficiency virus type 1 patients and a prognostic indicator for monitoring patients undergoing drug therapy. J Infect Dis. 1998;177 (5):1339–1344.

28.

de la Rosa

Pineda

Delgado

. Influence of highly active antiretroviral therapy on the outcome of subclinical visceral leishmaniasis in human immunodeficiency virus-infected patients. Clin Infect Dis. 2001;32 (4):633–635.

29.

Dhasmana

Dheda

Ravn

Wilkinson

Meintjes

. Immune reconstitution inflammatory syndrome in HIV-infected patients receiving antiretroviral therapy: pathogenesis, clinical manifestations and management. Drugs. 2008;68 (2):191–208.

30.

Cavalcanti

Medeiros

Lopes

. Diagnosing visceral leishmaniasis and HIV/AIDS co-infection: a case series study in Pernambuco, Brazil. Rev Inst Med Trop Sao Paulo. 2012;54 (1):43–47.

31.

Ngouateu

Kollo

Ravel

. Clinical features and epidemiology of cutaneous leishmaniasis and Leishmania major/HIV co-infection in Cameroon: results of a large cross-sectional study. Trans R Soc Trop Med Hyg. 2012;106 (3):137–142.

32.

Goto

Lindoso

. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther. 2010;8 (4):419–433.

33.

Lindoso

Barbosa

Posada-Vergara

. Unusual manifestations of tegumentary leishmaniasis in AIDS patients from the New World. Br J Dermatol. 2009;160 (2):311–318.

34.

Eickelmann

Steinhoff

Metze

Tomimori-Yamashita

Sunderkotter

. Erythema leprosum--after treatment of Lepromatous Leprosy. J Dtsch Dermatol Ges. 2010;8 (6):450–453.

35.

Vieira

Valente Mdo

. Thalidomide levels in patients with erythema nodosum leprosum. Ther Drug Monit. 2009;31 (5):602–603.

36.

Villahermosa

Fajardo

Jr Abalos

. A randomized, double-blind, double-dummy, controlled dose comparison of thalidomide for treatment of erythema nodosum leprosum. Am J Trop Med Hyg. 2005;72 (5):518–526.

37.

Autran

Carcelain

. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997;277 (5322):112–116.

38.

Carcelain

Debre

Autran

. Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol. 2001;13 (4):483–488.

39.

Stone

Price

Keane

Murray

French

. Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART. HIV Med. 2002;3 (1):21–27.

40.

Antonelli

Mahnke

Hodge

. Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome. Blood. 2010;116 (19):3818–3827.

41.

Morlese

Orkin

Abbas

. Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection. AIDS. 2003;17 (9):1411–1413.

42.

Bourgarit

Carcelain

Martinez

. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS. 2006;20 (2):F1–F7.

43.

Tan

Yong

Tan

. Immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis. HIV Med. 2008;9 (5):307–316.

44.

Meintjes

Wilkinson

Rangaka

. Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome. Am J Respir Crit Care Med. 2008;178 (10):1083–1089.

45.

Tieu

Ananworanich

Avihingsanon

. Immunologic markers as predictors of tuberculosis-associated immune reconstitution inflammatory syndrome in HIV and tuberculosis coinfected persons in Thailand. AIDS Res Hum Retroviruses. 2009;25 (11):1083–1089.

46.

Lim

D'Orsogna

Price

French

. Imbalanced effector and regulatory cytokine responses may underlie mycobacterial immune restoration disease. AIDS Res Ther. 2008;5:9.