Tag Archives: MAC

Atypical Mycobacteriosis

– Christian Hoffmann –

Atypical mycobacterioses are usually synonymous for infections with Mycobacterium avium complex (MAC). Although MAC is by far the most frequent pathogen, numerous other atypical mycobacterioses exist that cause a similar disease pattern, such as M. celatum, M. kansasii, M. xenopi or M. genavense. MAC bacteria are ubiquitous and can be found in diverse animal species, on land, in water and in food. Exposure prophylaxis is therefore not possible. Consequently, isolation of infected patients is not necessary. While MAC may be detectable in the sputum or stool of asymptomatic patients (colonization), only patients with massive immunodeficiency and less than 50 CD4 T cells/µl develop disease (Horsburgh 1999). This used to include up to 40% of AIDS patients in the pre-HAART era (Nightingale 1992).

The infection has now become very rare in industrialized countries (Karakousis 2004). However, it remains important, as it has developed into a completely new disease in the ART era. It previously occurred mainly with a chronic, disseminated course of disease, often in patients with wasting syndrome. MAC infections under ART are now almost always localized and related to an immune reconstitution inflammatory syndrome. The disease now occurs with manifestations that were previously never seen (see below).

Signs and symptoms

The symptoms of disseminated MAC infection are unspecific. When the CD4 count is less than 100 cells/µl, fever, weight loss and diarrhea should always lead to consideration of atypical mycobacteriosis. Abdominal pain may also occur. As described above, disseminated MAC infection has now become rare.

Localized forms of atypical mycobacterioses are far more frequent. These include, above all, lymph node abscesses, which may occur practically everywhere. We have seen abscesses in cervical, inguinal and also abdominal lymph nodes, some of which developed fistulae and resolved only slowly even after surgical intervention. Any abscess appearing whilst on ART (with severe immunosuppression) is highly suspicious of MAC! In addition to skin lesions, localized forms include osteomyelitis, particularly of the vertebrae, and septic arthritis (observed: knee, hand, fingers).

Diagnosis

Diagnosis of the disseminated form is difficult. Blood cultures (heparinized blood) should always be sent to a reference laboratory. Although atypical mycobacteria usually grow more rapidly than TB bacteria, the culture and differentiation from TB may take weeks. In cases presenting with anemia, bone marrow aspiration is often successful. If atypical mycobacteria are detected in the stool, sputum or even BAL, it is often difficult to distinguish between infection requiring treatment and mere colonization. In such cases, treatment should not be initiated if general symptoms are absent. This is also true for Mycobacterium kansasii (Kerbiriou 2003).

Laboratory evaluations typically show elevated alkaline phosphatase (AP) – a raised AP in severely immunosuppressed patients is always suspicious of MAC. Similarly, MAC infection should be considered in any cases of anemia and constitutional symptoms. Cytopenia, particularly anemia, often indicates bone marrow involvement. Ultrasound reveals enlargement of the liver and spleen. Lymph nodes are often enlarged, but become apparent due to their number rather than their size (Gordin 1997). Here, differential diagnoses should always include TB or malignant lymphoma.

Direct specimens should always be obtained for localized forms, as identification of the organism from material drained from the abscess is usually successful.

Treatment

Treatment of MAC infection detected from culture is complex. Similarly to TB, monotherapy does not suffice. Since 1996, many clinicians prefer the combination of a macrolide (clarithromycin or azithromycin) with ethambutol and rifabutin (Shafran 1996). In the past, this treatment was given lifelong; today it is generally considered sufficient to treat for at least six months and until a ART-induced increase in the CD4 T cell count to above 100 cells/µl has been achieved. After publication of data indicating that rifabutin may be omitted from the regimen (Dunne 2000), the multicenter, randomized ACTG 223 Study demonstrated survival benefit with the triple combination C+R+E compared to C+E and C+R – mortality rates were halved in the triple combination arm (Benson 2003).

Due to the high potential for interactions, however, rifabutin can be discontinued after several weeks when clinical improvement is observed. The clarithromycin dose should not exceed 500 mg bid. In at least two randomized studies, there was a significantly higher number of deaths in treatment arms with a higher clarithromycin dose, for reasons that remain unclear (Chaisson 1994, Cohn 1999). Instead of clarithromycin, azithromycin can also be given, which is cheaper and interacts less with cytochrome P450 enzymes. Azithromycin and clarithromycin have comparable efficacy in combination with ethambutol (Ward 1998).

In disseminated illnesses, treatment should be monitored through regular blood cultures. Cultures must be negative after eight weeks, at the latest. In the localized from, the response can be assessed better clinically. Every MAC therapy has a high potential for side effects and drug interactions. The concomitant medications, including ART, should be carefully examined – dose adjustments are frequently required and there may be contraindications (see Drugs section).

Reserve drugs such as amikacin, quinolones or clofazimine are only required in rare cases today. It is important to perform resistance testing for all atypical mycobacterial infections with species other than M. avium complex.

We have generally stopped treatment of localized MAC infections when the abscess has healed – this usually takes several months. In individual cases, steroids may be helpful temporarily. However, there are no specific guidelines for treatment of local MAC infections.

Prophylaxis

In the US, large placebo-controlled trials have shown that the macrolides, clarithromycin and azithromycin, as well as rifabutin, significantly reduce MAC morbidity and mortality when used for primary prophylaxis in severely immunocompromised patients (Havlir 1996, Nightingale 1992, Pierce 1996, Oldfield 1998). Prophylaxis also saves costs (Sendi 1999). However, MAC infections are more rare in Europe. As a result, and because of concerns over compliance and development of resistance, few patients in Europe receive primary MAC prophylaxis (Lundgren 1997).

For patients failing currently available ART regimens and without new treatment options, prophylaxis with a macrolide should be considered at low CD4 T cell counts (below 50 cells/µl). Weekly dosing with azithromycin is convenient for patients and has comparable efficacy to daily rifabutin (Havlir 1996).

Primary prophylaxis and maintenance therapies can be discontinued quite safely at CD4 T cell counts above 100/µl (Currier 2000, El Sadr 2000, Shafran 2002, Aberg 2003). It is possible that even partial viral suppression suffices for MAC-specific immune reconstitution (Havlir 2000). Complete recovery as a result of immune reconstitution is possible (Aberg 1998).

Treatment/prophylaxis of MAC (daily doses, if not specified otherwise)
Acute therapy    
Treatment of choice Clarithromycin +ethambutol +

possibly rifabutin

Clarithromycin 1 tbl. at 500 mg bid plusethambutol 3 tbl. at 400 mg qd plus

rifabutin 2 tbl. at 150 mg qd

Alternative Azithromycin +ethambutol +

possibly rifabutin

Azithromycin 1 tbl. at 600 mg qd plusethambutol 3 tbl. at 400 mg qd plus

rifabutin 2 tbl. at 150 mg qd

Maintenance therapy As for acute therapy, but without rifabutinDiscontinue if > 100 CD4 T cells/µl > 6 months
Primary prophylaxis Consider for CD4 cells below 50/µlDiscontinue if > 100 CD4 T cells /µl > 3 months
Treatment of choice Azithromycin Azithromycin 2 tbl. at 600 mg/week
Alternative Clarithromycin Clarithromycin 1 tbl. at 500 mg bid

References

Aberg JA, Williams PL, Liu T, et al. A study of discontinuing maintenance therapy in HIV-infected subjects with disseminated Mycobacterium avium complex. J Infect Dis 2003; 187: 1046-52.

Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with HAART. J Infect Dis 1998, 178:1446-9.

Benson CA, Williams PL, Currier JS, et al. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons. Clin Infect Dis 2003; 37:1234-43.

Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med 1994, 121:905-11.

Cohn DL, Fisher EJ, Peng GT, et al. A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose clarithromycin. Clin Infect Dis 1999, 29:125-33.

Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. Ann Intern Med 2000, 133:493-503.

Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with HIV. Clin Infect Dis 2000, 31:1245-52.

El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to ART. N Engl J Med 2000, 342:1085-92.

Gordin FM, Cohn DL, Sullam PM, et al. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997, 176:126-32.

Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996, 335:392-8.

Havlir DV, Schrier RD, Torriani FJ, et al. Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in HIV-infected subjects. J Infect Dis 2000, 182:1658-63.

Horsburgh CR Jr. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS. J Infect Dis 1999, Suppl 3:S461-5.

Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis 2004, 4:557-65.

Kerbiriou L, Ustianowski A, Johnson MA, Gillespie SH, Miller RF, Lipman MC. HIV type 1-related pulmonary Mycobacterium xenopi infection: a need to treat? Clin Infect Dis 2003; 37: 1250-4.

Lundgren JD, Phillips AN, Vella S, et al. Regional differences in use of antiretroviral agents and primary prophylaxis in 3122 European HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1997, 16:153-60.

Nightingale SD, Byrd LT, Southern PM, et al. Incidence of Mycobacterium avium-intracellulare complex bacteremia in HIV-positive patients. J Infect Dis 1992, 165:1082-5.

Oldfield EC 3rd, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multicenter trial. Clin Infect Dis 1998, 26:611-9.

Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced AIDS. N Engl J Med 1996, 335:384-91.

Sendi PP, Craig BA, Meier G, et al. Cost-effectiveness of azithromycin for preventing Mycobacterium avium complex infection in HIV-positive patients in the era of HAART. J Antimicrob Chemother 1999, 44:811-7.

Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996, 335:377-83.

Shafran SD, Mashinter LD, Phillips P, et al. Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy. Ann Intern Med 2002;137:734-7.

Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with HIV infection. Clin Infect Dis 1998, 27:1278-85.

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Filed under 11. Opportunistic Infections, Atypical Mycobacteriosis, Part 3 - AIDS

Immune reconstitution inflammatory syndrome (IRIS)

– Christian Hoffmann –

For the first time, in mid-1997 and early 1998, two groups described atypical manifestations of CMV retinitis (Jacobsen 1997) and MAC disease with abscess formation (Race 1998) in HIV patients within a few weeks of initiation of ART. Although the pathogens, pathogenesis and localization were very different, all these illnesses had a distinct inflammatory component and were associated with significant immune reconstitution in these patients. Consequently, suspected early on that these presentations could constitute a syndrome during which a latent infection present at initiation of therapy is fought more effectively by the recovering immune system (Overview: French 2009). Infections are not the only cause of an IRIS. Malignancies and other diseases have also been decribed as IRIS-related (see below).

The International Network for the Study of HIV-associated IRIS (INSHI, http://www.med.umn.edu/inshi/) has established the following consensus criteria for diagnosis of IRIS:

1. Response to ART (at least one log10 copies/mL decrease in HIV RNA)

2. Clinical deterioration of an infectious or inflammatory condition temporally related to ART initiation.

3. Symptoms cannot be explained by expected clinical course of a previously recognized and successfully treated infection, medication side effect or toxicity, treatment failure or complete non-adherence.

One must differentiate between subclinical infections first appearing on ART (“unmasking IRIS”) and clinically evident infections already existing at therapy initiation, which often paradoxically become worse during therapy (”paradoxical IRIS”).

IRIS in many publications today is often a collection of bizarre, sometimes grotesque case reports, which have actually only one common ground: an unexpected, usually clinically impressing infection, differing significantly from the courses of diseases seen during the pre-HAART era. Nevertheless, IRIS has three rules:

  1. Anything is possible.
  2. Nothing is as it was in the pre-HAART era.
  3. IRIS does not mean that ART has failed. In addition, the patients usually have a good prognosis.

How frequently does IRIS occur? Due to the lack of a definition in the early years of ART, the data vary substantially. In our experience, a frequency of 5-10% in patients with less than 200 CD4 T cells/µl is realistic. Very low CD4 T cells, a high viral load before initiation of therapy or a rapid drop of HIV RNA on ART seem to be important predictive factors for IRIS. If one focus on the patients who were already infected with mycobacteria or cryptococcus neoformans before ART was started, IRIS rates of 30% are reached (Müller 2010).

Mycobacterial IRIS. For MAC, the number of published cases with grotesque, fistular lymphadenitis, cutaneous or muscular abscesses, osteomyelitis, nephritis or meningitis is too large to be cited here. After a total of 83 patients started ART with a CD4 T cell count of less than 200/µl, only six mycobacterioses, among these four MAC infections were observed within the first weeks of beginning therapy (Hoffmann 1999). Lymph node abscesses usually occur during the first weeks on ART. IRIS cases with Mycobacterium xenopi or kansasii have also been described (Chen 2004, Phillips 2005).

There are now also numerous reports on tuberculosis (John 1998, Chien 1998), which are reminiscent of the “paradox” reactions to TB treatment known since the 1950s. All of these patients similarly suffered an initial deterioration under sufficient tuberculostatic treatment and ART-induced immune reconstitution. By the same token, meningitis as well as marked lymphadenopathy with unspecific histology can complicate the course of disease, yet both respond astonishingly rapidly and well to steroids. Prednisolone was very effective in a recent placebo-controlled trial (Meintjes 2010).

It is still not clear whether an early or immediate start of ART in therapy naïve patients facilitates the occurrance of an IRIS. In at least two large randomized trials (STIDE and SAPIT) the risk of an IRIS increased when ART was started immediately in patients with TB. In both studies, however, the increased risk did not lead to an increased mortality (Abdool 2011, Havlir 2011). A randomized study in patients with tuberculous meningitis contradicts these results showing less favorable effects for an early ART (Torok 2009).

CMV IRIS. In addition to mycobacteriosis, numerous cases of unusual CMV infections under ART have been published. In patients with previously diagnosed CMV retiniotis, IRIS developed in 38% (Müller 2010). Inflammatory CMV retinitis with vitritis that may lead to visual impairment, papillitis and macular edema, can now be described as a distinct syndrome, differing significantly from the course of CMV retinitis seen in the pre-HAART era (Jacobson 1997, Karavellas 1999). Neovascularization endangers vision even after resolution (Wright 2003). As with MAC disease, in vitro studies have shown that the CMV-specific immune response is improved most significantly in those patients developing vitritis (Mutimer 2002, Stone 2002). Inflammatory CMV manifestations are not limited to the retina and may involve other organs.

PML IRIS. The course of inflammatory PML that occurs during an IRIS is different from the infaust prognosis seen during the pre-HAART era (Collazos 1999, Kotecha 1998, Cinque 2001, Miralles 2001). Clinical symptoms are often more fulminant initially, and on radiology, there is a contrast enhancement which is otherwise atypical for PML, that may resolve over time. Patients have a better prognosis, and PML seems to even resolve completely (Hoffmann 2003, Du Pasquier 2003). It appears that a number of patients with inflammatory PML, who have been asymptomatic for years, live without any residual symptoms. However, fatal cases of inflammatory PML have also been reported (Safdar 2002). Previously documented experiences indicate that steroids are ineffective, although there have been accounts of positive results (Nuttall 2004, Tan 2009).

Cryptococcal IRIS. Numerous cases with inflammatory courses of disease have been described (Overview: Haddow 2010). Together with MAC/TBC and CMV, cryptococci are probably the most influential pathogens that contribute to an IRIS. In particular, severely immunocompromised patients who start with ART after cryptococcal therapy should be watched closely for the first few weeks and months. Newer studies show that 10-20% of patients with co-infections develop a cryptococcal IRIS (Sungkanuparph 2009, Müller 2010). The MRI usually shows choriomeningitis with significant enhancement in the choroid plexus. Cryptococcal antigen in the CSF is positive, although culture remains negative (Boelaert 2004). The intracranial pressure is often particularly high (Shelbourne 2005). As well as meningitis, lymphadenitis can also occur (Skiest 2005).

IRIS, induced by other infections. A variety of contemporary case studies have documented the induction of IRIS by the following infections: leishmaniasis (Jiménez-Expósito 1999), penicillosis (Ho 2010), histoplasmosis (De Lavaissiere 2008), pneumocystosis (Barry 2002, Koval 2002, Godoy 2008, Jagannathan 2009, Mori 2009), or herpes (Fox 1999). Herpes zoster and hepatitis B or C episodes also seem to occur on ART, particularly during the first weeks (Behrens 2000, Chung 2002, Manegold 2001, Martinez 1998, Domingo 2001). HHV-8-associated Kaposi’s sarcoma can worsen significantly on ART in the presence of an IRIS (Bower 2005, Leidner 2005, Feller 2008). Increasing dermatological problems such as exacerbation of pre-existing folliculitis or skin disease have also been reported (Handa 2001, Lehloenyia 2006, Pereira 2007, Iarikov 2008). There are even reports about parvovirus and leprosy (Nolan 2003, Couppie 2004, Bussone 2010, Watanabe 2011).

IRIS and other diseases. Diseases other than OIs are now recognized to occur under IRIS. These include autoimmune diseases such as Graves’ disease, lupus, Sweet’s and Reiter’s syndromes, Guillain-Barré syndrome, acute porphyria, gout and sarcoidosis, to name but a few (Bevilacqua 1999, Behrens 1998, Fox 1999, Gilquin 1998, Makela 2002, Mirmirani 1999, Neumann 2003, Piliero 2003, Sebeny 2010). Even two cases of Peyronie’s disease, a fibrosis of the penis, were reported (Rogers 2004). These reports do raise the question of whether all of these manifestations are truly induced by immune reconstitution or perhaps merely chance occurrences. While most reports initially offered little information on the etiology beyond purely hypothetical discussions, it has recently become apparent that changes in the cytokine profile are involved in the pathogenesis of IRIS, together with an activation of the cellular immune response. However, it seems that the mechanisms differ according to disease and genetic profile (Price 2001, Shelbourne 2005).

Consequences

Patients starting ART with less than 200 CD4 T cells/µl and particularly those who have a high viral load require close clinical monitoring during the first weeks. Close attention should be give especially in cases where very immunocompromised patients who have previously declined antiretroviral treatment, suddenly feel physically “affected,” express subfebrile conditions, and want to start ART “after thinking about it for a long time.” Latent infections are often present in such cases and rapidly become apparent as immune reconstitution occurs – the poorer the immune status and the longer its duration, the greater the danger of IRIS. Although newer studies prove that infection parameters such as CROP, D-dimer or cytokines such as IL-6 or IP-7 are predictive for an IRIS or OI (Rodger 2009, Antonelli 2010, Porter 2010) it is not generally practiced in routine diagnosis.

However chest radiography, abdominal ultrasound and fundoscopy should be included in routine investigations of such patients before beginning treatment. Moreover, clinical examination which nowadays are often gladly overlooked should be taken seriously. Some authors suggest that MAC prophylaxis start even before ART in severely immunocompromised patients seems problematic, even though prophylaxis cannot prevent MAC IRIS (Phillips 2002+2005). Still, prospective clinical studies have yet to prove whether administration of IL-2 or GM-CSF is worthwhile, as was recently postulated (Pires 2005).

Mycobacterioses in particular should be treated generously with steroids. This has been confirmed in a randomized trial (Meintjes 2010). One should always be prepared for atypical localizations, findings and disease courses of opportunistic infections. Generally speaking, prognosis of IRIS usually is good. Mortality of patients developing IRIS is reportedly not higher than that of patients without IRIS (Park 2006).

References

Aberg JA, Chin-Hong PV, McCutchan A, et al. Localized osteomyelitis due to Mycobacterium avium complex in patients with HIV receiving HAART. Clin Infect Dis 2002, 35:E8-E13.

Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010, 362:697-706.

Aberg JA, Chin-Hong PV, McCutchan A, et al. Localized osteomyelitis due to Mycobacterium avium complex in patients with HIV receiving HAART. Clin Infect Dis 2002, 35:E8-E13.

Antonelli L, Yolanda Mahnke Y, Hodge J, et al. Elevated serum IL-7 levels, expansion of memory CD4+ T cells, augmented t cell activation and inflammation in patients developing IRIS after ART initiation. Abstract 336, 17th CROI 2010, San Francisco.

Barry SM, Lipman MC, Deery AR, Johnson MA, Janossy G. Immune reconstitution pneumonitis following Pneumocystis carinii pneumonia in HIV-infected subjects. HIV Med 2002, 3:207-11.

Behrens G, Knuth C, Schedel I, Mendila M, Schmidt RE. Flare of SLE following HAART. Lancet 1998, 351:1057-8.

Behrens GM, Meyer D, Stoll M, Schmidt RE. Immune reconstitution syndromes in HIV infection following effective antiretroviral therapy. Immunobiology 2000, 202:186-93.

Bevilacqua S, Hermans P, Van Laethem Y, Demaubeuge J, Clumeck N. Sweet’s syndrome in an HIV-infected patient. AIDS 1999, 13: 728-9.

Boelaert JR, Goddeeris KH, Vanopdenbosch LJ, Casselman JW. Relapsing meningitis caused by persistent cryptococcal antigens and immune reconstitution after the initiation of highly active antiretroviral therapy. AIDS 2004, 18:1223-4.

Bower M, Nelson M, Young AM, et al. Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol 2005, 23:5224-8.

Bussone G, Charlier C, Bille E, et al. Unmasking leprosy: an unusual immune reconstitution inflammatory syndrome in a patient infected with human immunodeficiency virus. Am J Trop Med Hyg 2010, 83:13-4.

Chen F, Sethi G, Goldin R, Wright AR, Lacey CJ. Concurrent granulomatous Pneumocystis carinii and Mycobacterium xenopi pneumonia: an unusual manifestation of HIV immune reconstitution disease. Thorax 2004, 59:997-999.

Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998, 114: 933-6.

Chung RT, Evans SR, Yang Y, et al. Immune recovery is associated with persistent rise in HCV RNA, infrequent liver test flares, and is not impaired by HCV in co-infected subjects. AIDS 2002, 16:1915-1923.

Cinque P, Pierotti C, Vigano MG, et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol 2001, 7:358-63.

Collazos J, Mayo J, Martinez E, Blanco MS. Contrast-enhancing progressive multifocal leukoencephalopathy as an immune reconstitution event in AIDS patients. AIDS 1999, 13: 1426-1428.

Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol. 2004, 140:997-1000.

De Lavaissière M, Manceron V, Bourée P, et al. Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection. J Infect 2008 Dec 16. [Epub ahead of print]

Domingo P, Torres OH, Ris J, Vazquez G. Herpes zoster as an immune reconstitution disease after initiation of combination antiretroviral therapy in patients with HIV-1 infection. Am J Med 2001, 110:605-9.

Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003, 9 Suppl 1:25-31.

Feller L, Anagnostopoulos C, Wood NH, et al. Human immunodeficiency virus-associated Kaposi sarcoma as an immune reconstitution inflammatory syndrome: a literature review and case report. J Periodontol 2008;79:362-8.

Fox PA, Barton SE, Francis N, et al. Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease. HIV Med 1999, 1:10-8.

Fox PA, Boag FC, Hawkins DA, Francis N. Acute porphyria following commencement of indinavir. AIDS 1999, 13: 622-3.

French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with HAART. HIV Med 2000, 1:107-15.

French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009, 48:101-7.

Ghosn J, Paris L, Ajzenberg D, et al. Atypical toxoplasmic manifestation after discontinuation of maintenance therapy in a HIV type 1-infected patient with immune recovery. Clin Infect Dis 2003; 37: E112-4.

Gilquin J, Viard JP, Jubault V, Sert C, Kazatchkine MD. Delayed occurrence of Graves’ disease after immune restoration with HAART. Lancet 1998, 352:1907-8.

Godoy MC, Silva CI, Ellis J, Phillips P, Muller NL. Organizing pneumonia as a manifestation of Pneumocystis jiroveci immune reconstitution syndrome in HIV-positive patients: report of 2 cases. J Thorac Imaging 2008;23:39-43.

Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010, 10:791-802.

Haddow LJ, Easterbrook PJ, Mosam A, et al.  Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. Clin Infect Dis 2009, 49:1424-32.

Handa S, Bingham JS. Dermatological immune restoration syndrome: does it exist? J Eur Acad Dermatol Venereol 2001, 15:430-2.

Havlir D, Ive P, Kendall M, et al. International Randomized Trial of Immediate vs Early ART in HIV+ Patients Treated for TB: ACTG 5221 STRIDE Study. Abstract 38, 18th CROI 2011, Boston.

Ho A, Shankland GS, Seaton RA. Penicillium marneffei infection presenting as an immune reconstitution inflammatory syndrome in an HIV patient. Int J STD AIDS 2010, 21:780-2.

Hoffmann C, Degen O, Horst HA, van Lunzen J, Stellbrink HJ. Immune reconstitution in severely immunocompromised patients initiating HAART – the critical first months. 7. Deutscher AIDS-Kongress 1999, Essen, F1088.

Hoffmann C, Horst HA, Albrecht H, Schlote W. Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 2003, 74:1142-4.

Hoffmann C, Horst HA, Degen O, van Lunzen J, Stellbrink HJ. Manifestation of Mycobacterial Lymphadenitis after Initiating of HAART. Abstract 22172, 12th World AIDS Conference 1998, Geneva, Suisse.

Iarikov D, Duke W, Skiest D. Extensive development of flat warts as a cutaneous manifestation of immune reconstitution syndrome. AIDS Read 2008, 18:524-7.

Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of HAART. Lancet 1997, 349:1443-5.

Jagannathan P, Davis E, Jacobson M, Huang L. Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis neumonia: a cautionary case series. AIDS 2009, 23:1794-6.

Jiménez-Expósito MJ, Alonso-Villaverde C, Sardà P, Masana L. Visceral leishmaniasis in HIV-infected patients with non-detectable HIV-1 viral load after HAART. AIDS 1999, 13:152-3.

John M, French MA. Exacerbation of the inflammatory response to mycobacterium tuberculosis after antiretroviral therapy. Med J Aust 1998, 169: 473-4.

Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful HAART. J Infect Dis 1999, 179: 697-700.

Koval CE, Gigliotti F, Nevins D, Demeter LM. Immune reconstitution syndrome after successful treatment of Pneumocystis carinii pneumonia in a man with HIV type 1 infection. Clin Infect Dis 2002, 35:491-3.

Lehloenya R, Meintjes G. Dermatologic manifestations of the immune reconstitution inflammatory syndrome. Dermatol Clin 2006, 24:549-70.

Leidner RS, Aboulafia DM. Recrudescent Kaposi’s sarcoma after initiation of HAART: a manifestation of immune reconstitution syndrome. AIDS Patient Care STDS 2005, 19:635-44.

Makela P, Howe L, Glover S, Ferguson I, Pinto A, Gompels M. Recurrent Guillain-Barre Syndrome as a complication of immune reconstitution in HIV. J Infect 2002, 44:47-9.

Manegold C, Hannoun C, Wywiol A, et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving HAART. Clin Infect Dis 2001, 32: 144-8.

Martinez E, Gatell J, Moran Y, et al. High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors. Clin Infect Dis 1998, 27:1510-3.

Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010, 24:2381-90.

Miralles P, Berenguer J, Lacruz C, et al. Inflammatory reactions in progressive multifocal leukoencephalopathy after HAART. AIDS 2001, 15:1900-2.

Mirmirani P, Maurer TA, Herndier B, et al. Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome. J Am Acad Dermatol 1999, 41:285-6.

Mori S, Polatino S, Estrada-Y-Martin RM. Pneumocystis-associated organizing pneumonia as a manifestation of immune reconstitution inflammatory syndrome in an HIV-infected individual with a normal  CD4+ T-cell count following antiretroviral therapy. Int J STD AIDS 2009, 20:662-5.

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