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Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection
Journal of Infection (2009) 58, 245e247
www.elsevierhealth.com/journals/jinf
CASE REPORT
Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection `re a, Ve ´ronique Manceron b, Patrice Boure ´e c, Marc De Lavaissie Loı¨c Garc ¸on d, Francine Bisaro c, Jean-Franc ¸ois Delfraissy a,e, ´cile Goujard a,e,* Olivier Lambotte a,e, Ce a
Service de Me´decine Interne, Hoˆpital Biceˆtre, AP-HP, Le Kremlin Biceˆtre, France Service de Me´decine Interne, Hoˆpital Louis Mourier AP-HP, Colombes, France c Laboratoire de Parasitologie et Mycologie, Hoˆpital Biceˆtre, AP-HP, Le Kremlin Biceˆtre, France d Laboratoire d’He´matologie, Hoˆpital Biceˆtre, AP-HP, Le Kremlin Biceˆtre, France e INSERM U802, Faculte´ de Me´decine Paris-Sud 11, Le Kremlin Biceˆtre, France b
Accepted 15 November 2008 Available online 17 December 2008
KEYWORDS HIV; Histoplasmosis; Immune reconstitution; Hemophagocytic syndrome
Summary Immune reconstitution after initiation of antiretroviral therapy may unmask a latent infection. We report a case of disseminated Histoplasma capsulatum capsulatum infection associated with a hemophagocytic syndrome in an HIV-infected patient, three weeks after initiation of antiretroviral therapy. The immune reconstitution inflammatory syndrome might be a risk factor for hemophagocytosis. ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
The advent of protease inhibitor-based combined antiretroviral therapy (cART) sharply reduced the incidence of opportunistic infections in HIV-infected patients. However, cART-induced recovery of specific immunity to opportunistic pathogens can be detrimental in some circumstances. Exaggerated responses to previously treated infections or
* Correspondence to: Ce ´cile Goujard, Service de Me ´decine Interne, Ho ˆpital Bice ˆtre, AP-HP, 78 rue du Ge ´ne ´ral Leclerc, 94275 Le Kremlin Bicetre Cedex, France. Tel.: þ33 145212577; fax: þ33 145212741. E-mail address: [email protected] (C. Goujard).
to latent/subclinical infections after cART initiation are known collectively as the immune reconstitution inflammatory syndrome (IRIS). Histoplasma capsulatum capsulatum is able to cause IRIS and has also been implicated in the hemophagocytic syndrome (HS) in HIV-infected patients.1 We describe the first reported case of histoplasmosis associated with HS and IRIS.
Case report The patient, a 33-year-old man born in French Guyana, had been living in the Paris region for ten years. He had not
0163-4453/$36 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.11.010
246 travelled to South America or Africa since moving to Paris. HIV infection had been diagnosed 15 years previously but the patient had declined treatment. He presented to an emergency department with fever, headache and a focal neurological disorder. Cerebral toxoplasmosis was diagnosed on computed tomography. The plasma HIV RNA level was 5.4 log10 copies/mL and the CD4þ T cell count was 13/mm3. He was treated for six weeks with pyrimethamine and sulfadiazine and showed a major clinical and radiological improvements. He then started combined antiretroviral therapy with zidovudine, lamivudine and boosted lopinavir. Three weeks after cART initiation, he presented with high-grade fever, confusion and dizziness, for which onset had occurred rapidly. The blood pressure was 130/80 mmHg, the heart rate 120/min and the respiratory rate 28/min. No headache, neck stiffness or focal neurological signs were found. Physical examination showed moderate painless ulcerative gingivitis. Polyadenopathy and hepatosplenomegaly were confirmed by whole-body CT. Cerebral CT was normal. Laboratory tests showed pancytopenia (hemoglobin, 79 g/L; hematocrit, 23%; white blood cell count, 1 109/L; platelet count, 28 109/L) and coagulation activation (fibrinogen, 0.8 g/L; fibrinogen degradation products >40 mg/mL (normal value < 5 mg/mL); prothrombin time, 54% (normal value > 70%)). He also had acute hepatitis with cytolysis (alanine aminotransaminase, 72 U/L (normalrange, 10e45 U/L); aspartate aminotransaminase, 166 U/L (normal range, 10e40 U/L)), and cholestasis (alkaline phosphatase, 191 U/L (normal range, 40e130 U/L); g-glutamyl transferase, 154 U/L (normal range, 10e60 U/L) and bilirubin, 106 mmol/L (normal value < 17 mmol/L)). Other laboratory abnormalities included decreased sodium (120 mmol/L) and albumin levels (26 g/L), elevated levels of C-reactive protein (176 mg/L, normal value < 5 mg/L), lactate dehydrogenase (3169 U/L, normal range, 240e480 U/L) and serum triglycerides (4.44 mmol/L, normal range, 0.6e1.7 mmol/L) and raised ferritin (102,000 ng/mL, normal range, 30e350 ng/mL). At that time, the CD4þ T cell count had increased to 59/mm3 and the HIV RNA level had fallen to 2.2 log10 copies/mL. Biochemical, cytological and microbiological analyses of cerebrospinal fluid (CSF) were normal, including fungal culture for Cryptococcus. Mycobacterial cultures of blood, bone marrow and CSF were negative. Other etiological investigations, including tests for herpes virus infection, were negative. The bone marrow aspirate (Fig. 1) contained mainly granulocytic cells, with 6% monocytes, and revealed active hemophagocytosis with prominent phagocytosis of erythroid precursors. MayeGru ¨nwaldeGiemsa (MGG) staining of blood and mouth ulcer stabs revealed ovoid yeast cells. One hyphal phase was observed in a mouth sample. MGG staining of the marrow aspirate revealed intracellular budding yeast cells. This dimorphic fungus was identified as Histoplasma capsulatum capsulatum, and all cultures were positive at 27 C. Treatment began with intravenous immunoglobulin (1000 mg/kg daily for two days) and a deoxycholate formulation of amphotericin B (0.8 mg/kg daily) to treat the HS and histoplasmosis, respectively. CART was not discontinued or modified. Amphotericin B was switched to
M. De Lavaissie `re et al.
Figure 1 Bone marrow aspirate (MGG stain 100) showing hemophagocytosis of a basophilic premature marrow precursor (black arrow) and an intracellular yeast cell (white arrow) in an activated monocytic cell.
itraconazole after four weeks (200 mg TID for three days and then BID). The patient gradually improved, becoming afebrile after five days. The LDH level had returned to normal at discharge, one month after admission. The CRP level fell to 50 mg/L and 9 mg/L after one and two months of antifungal therapy, respectively. The CD4þ T cell count was 74/mm3, 140/mm3 and 217/mm3 at 6, 12 and 18 months of ART, respectively. The HIV RNA level remained below the detection threshold (<40 copies/mL) after the sixth month of cART. Itraconazole blood levels were monitored to detect interactions with protease inhibitors, and the antifungal drug dose was reduced to 100 mg daily after one month. Itraconazole was discontinued at six months, once stable immune recovery had been achieved, with CD4þ T cell counts consistently above 200/mm3. No clinical relapse of histoplasmosis occurred during 18 months of follow-up.
Discussion In HIV-infected patients, IRIS results from a disproportionate inflammatory response of the immune system to various antigens often inducing atypical clinical manifestations, and occurring weeks to months after cART initiation.2 One of the main diagnostic criteria for IRIS3 is a fall in HIV viral load and an increase in the CD4þ T cell count after cART initiation. IRIS has been linked to a variety of pathogens, including mycobacteria, cryptococci, herpes viruses, and JC virus. Histoplasmosis-associated IRIS has rarely been described although a recent retrospective study showed a substantial increase in the incidence of disseminated histoplasmosis after cART initiation in an endemic region, with reactivation of latent Histoplasma infection up to ten years after the primary infection.4,5 In addition, histoplasmosis was associated in our patient with a hemophagocytic syndrome, as occasionally reported in patients both with and without HIV infection.1,6 The main manifestations of HS were present, namely acute high-grade
Histoplasmosis in HIV infection fever, hepatosplenomegaly, pancytopenia, and hemophagocytosis on a bone marrow smear. Typical laboratory markers were also present, as well as disseminated intravascular coagulation.7 Secondary HS may be related to various infections, and particularly to herpes viruses and intracellular pathogens.8 The prognosis is poor and treatment may be difficult, depending on the underlying disease. Impaired cytotoxicity of natural killer cells and cytotoxic T cells, associated with excessive production of interferon gamma, is probably key determinants of HS.9 These abnormalities lead to uncontrolled macrophage activation and abundant secretion of proinflammatory cytokines.10 In our patient, the rapid virological response to cART (the HIV RNA level fell to 1 log10 copies/ml) and the acute onset following cART initiation both pointed to IRIS. Furthermore, IRIS probably contributed to the onset of HS in this patient. During the immune reconstitution that follows cART initiation, there is an early rise in the CD4þ T cell count, reflecting a redistribution of memory T cells from lymphoid tissues,11 together with a proinflammatory cytokine storm. IRIS was recently studied in patients with tuberculosis, a disease also associated with HS.12 A prominent Th-1 inflammatory response was observed, with increased production of cytokines and chemokines (IFN-g, IL-2, IL-12, TNF-a, IL-6, IL-10 and RANTES), some of which are also involved in the pathophysiology of HS.10 Disseminated histoplasmosis has already been reported in association with either HS or IRIS. In contrast, this is the first reported case in which histoplasmosis, HS and IRIS were present simultaneously in an HIV-infected patient. As the main pathogens and cytokines involved in HS are the same as those involved in IRIS, IRIS may facilitate HS onset in HIV-infected patients. HS may be overlooked during IRIS but should be suspected, especially in the most serious cases.13 The causative agent may be a quiescent opportunistic pathogen that infected the patient many years ago. This case also underlines the importance of considering the patient’s travel history and habits before initiating antiretroviral therapy.
247
References 1. Koduri PR, Chundi V, DeMarais P, Mizock BA, Patel AR, Weinstein RA. Reactive hemophagocytic syndrome: a new presentation of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis 1995;21:1463e5. 2. French MA, Price P, Stone SF. Immune reconstitution disease after antiretroviral therapy. AIDS 2004;18:1615e27. 3. Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White Jr AC, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;19:399e406. 4. Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 2006;20:119e21. 5. Nacher M, Sarazin F, El Guedj M, Vaz T, Alvarez F, Nasser V, et al. Increased incidence of disseminated histoplasmosis following highly active antiretroviral therapy initiation. J Acquir Immune Defic Syndr 2006;41:468e70. 6. Rouphael NG, Talati N, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007;7:814e22. 7. Kaito K, Kobayashi M, Katayama T, Otsubo H, Ogasawara Y, Sekita T, et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol 1997;59:247e53. 8. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601e8. 9. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8þ T cells and interferon gamma are essential for the disorder. Blood 2004;104:735e43. 10. Larroche C, Mouthon L. Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun rev 2004;3:69e75. 11. Carcelain G, Debre P, Autran B. Reconstitution of CD4þ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol 2001;13:483e8. 12. Bourgarit A, Carcelain G, Martinez V, Lascoux C, Delcey V, Gicquel B, et al. Explosion of tuberculin-specific Th1-responses induces immune reconstitution syndrome in tuberculosis and HIV co-infected patients. AIDS 2006;20:F1e7. 13. Huang DB, Wu JJ, Hamill RJ. Reactive hemophagocytosis associated with the initiation of highly active antiretroviral therapy (HAART) in a patient with AIDS. Scand J Infect Dis 2004;36:516e9.
www.elsevierhealth.com/journals/jinf
CASE REPORT
Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection `re a, Ve ´ronique Manceron b, Patrice Boure ´e c, Marc De Lavaissie Loı¨c Garc ¸on d, Francine Bisaro c, Jean-Franc ¸ois Delfraissy a,e, ´cile Goujard a,e,* Olivier Lambotte a,e, Ce a
Service de Me´decine Interne, Hoˆpital Biceˆtre, AP-HP, Le Kremlin Biceˆtre, France Service de Me´decine Interne, Hoˆpital Louis Mourier AP-HP, Colombes, France c Laboratoire de Parasitologie et Mycologie, Hoˆpital Biceˆtre, AP-HP, Le Kremlin Biceˆtre, France d Laboratoire d’He´matologie, Hoˆpital Biceˆtre, AP-HP, Le Kremlin Biceˆtre, France e INSERM U802, Faculte´ de Me´decine Paris-Sud 11, Le Kremlin Biceˆtre, France b
Accepted 15 November 2008 Available online 17 December 2008
KEYWORDS HIV; Histoplasmosis; Immune reconstitution; Hemophagocytic syndrome
Summary Immune reconstitution after initiation of antiretroviral therapy may unmask a latent infection. We report a case of disseminated Histoplasma capsulatum capsulatum infection associated with a hemophagocytic syndrome in an HIV-infected patient, three weeks after initiation of antiretroviral therapy. The immune reconstitution inflammatory syndrome might be a risk factor for hemophagocytosis. ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
The advent of protease inhibitor-based combined antiretroviral therapy (cART) sharply reduced the incidence of opportunistic infections in HIV-infected patients. However, cART-induced recovery of specific immunity to opportunistic pathogens can be detrimental in some circumstances. Exaggerated responses to previously treated infections or
* Correspondence to: Ce ´cile Goujard, Service de Me ´decine Interne, Ho ˆpital Bice ˆtre, AP-HP, 78 rue du Ge ´ne ´ral Leclerc, 94275 Le Kremlin Bicetre Cedex, France. Tel.: þ33 145212577; fax: þ33 145212741. E-mail address: [email protected] (C. Goujard).
to latent/subclinical infections after cART initiation are known collectively as the immune reconstitution inflammatory syndrome (IRIS). Histoplasma capsulatum capsulatum is able to cause IRIS and has also been implicated in the hemophagocytic syndrome (HS) in HIV-infected patients.1 We describe the first reported case of histoplasmosis associated with HS and IRIS.
Case report The patient, a 33-year-old man born in French Guyana, had been living in the Paris region for ten years. He had not
0163-4453/$36 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.11.010
246 travelled to South America or Africa since moving to Paris. HIV infection had been diagnosed 15 years previously but the patient had declined treatment. He presented to an emergency department with fever, headache and a focal neurological disorder. Cerebral toxoplasmosis was diagnosed on computed tomography. The plasma HIV RNA level was 5.4 log10 copies/mL and the CD4þ T cell count was 13/mm3. He was treated for six weeks with pyrimethamine and sulfadiazine and showed a major clinical and radiological improvements. He then started combined antiretroviral therapy with zidovudine, lamivudine and boosted lopinavir. Three weeks after cART initiation, he presented with high-grade fever, confusion and dizziness, for which onset had occurred rapidly. The blood pressure was 130/80 mmHg, the heart rate 120/min and the respiratory rate 28/min. No headache, neck stiffness or focal neurological signs were found. Physical examination showed moderate painless ulcerative gingivitis. Polyadenopathy and hepatosplenomegaly were confirmed by whole-body CT. Cerebral CT was normal. Laboratory tests showed pancytopenia (hemoglobin, 79 g/L; hematocrit, 23%; white blood cell count, 1 109/L; platelet count, 28 109/L) and coagulation activation (fibrinogen, 0.8 g/L; fibrinogen degradation products >40 mg/mL (normal value < 5 mg/mL); prothrombin time, 54% (normal value > 70%)). He also had acute hepatitis with cytolysis (alanine aminotransaminase, 72 U/L (normalrange, 10e45 U/L); aspartate aminotransaminase, 166 U/L (normal range, 10e40 U/L)), and cholestasis (alkaline phosphatase, 191 U/L (normal range, 40e130 U/L); g-glutamyl transferase, 154 U/L (normal range, 10e60 U/L) and bilirubin, 106 mmol/L (normal value < 17 mmol/L)). Other laboratory abnormalities included decreased sodium (120 mmol/L) and albumin levels (26 g/L), elevated levels of C-reactive protein (176 mg/L, normal value < 5 mg/L), lactate dehydrogenase (3169 U/L, normal range, 240e480 U/L) and serum triglycerides (4.44 mmol/L, normal range, 0.6e1.7 mmol/L) and raised ferritin (102,000 ng/mL, normal range, 30e350 ng/mL). At that time, the CD4þ T cell count had increased to 59/mm3 and the HIV RNA level had fallen to 2.2 log10 copies/mL. Biochemical, cytological and microbiological analyses of cerebrospinal fluid (CSF) were normal, including fungal culture for Cryptococcus. Mycobacterial cultures of blood, bone marrow and CSF were negative. Other etiological investigations, including tests for herpes virus infection, were negative. The bone marrow aspirate (Fig. 1) contained mainly granulocytic cells, with 6% monocytes, and revealed active hemophagocytosis with prominent phagocytosis of erythroid precursors. MayeGru ¨nwaldeGiemsa (MGG) staining of blood and mouth ulcer stabs revealed ovoid yeast cells. One hyphal phase was observed in a mouth sample. MGG staining of the marrow aspirate revealed intracellular budding yeast cells. This dimorphic fungus was identified as Histoplasma capsulatum capsulatum, and all cultures were positive at 27 C. Treatment began with intravenous immunoglobulin (1000 mg/kg daily for two days) and a deoxycholate formulation of amphotericin B (0.8 mg/kg daily) to treat the HS and histoplasmosis, respectively. CART was not discontinued or modified. Amphotericin B was switched to
M. De Lavaissie `re et al.
Figure 1 Bone marrow aspirate (MGG stain 100) showing hemophagocytosis of a basophilic premature marrow precursor (black arrow) and an intracellular yeast cell (white arrow) in an activated monocytic cell.
itraconazole after four weeks (200 mg TID for three days and then BID). The patient gradually improved, becoming afebrile after five days. The LDH level had returned to normal at discharge, one month after admission. The CRP level fell to 50 mg/L and 9 mg/L after one and two months of antifungal therapy, respectively. The CD4þ T cell count was 74/mm3, 140/mm3 and 217/mm3 at 6, 12 and 18 months of ART, respectively. The HIV RNA level remained below the detection threshold (<40 copies/mL) after the sixth month of cART. Itraconazole blood levels were monitored to detect interactions with protease inhibitors, and the antifungal drug dose was reduced to 100 mg daily after one month. Itraconazole was discontinued at six months, once stable immune recovery had been achieved, with CD4þ T cell counts consistently above 200/mm3. No clinical relapse of histoplasmosis occurred during 18 months of follow-up.
Discussion In HIV-infected patients, IRIS results from a disproportionate inflammatory response of the immune system to various antigens often inducing atypical clinical manifestations, and occurring weeks to months after cART initiation.2 One of the main diagnostic criteria for IRIS3 is a fall in HIV viral load and an increase in the CD4þ T cell count after cART initiation. IRIS has been linked to a variety of pathogens, including mycobacteria, cryptococci, herpes viruses, and JC virus. Histoplasmosis-associated IRIS has rarely been described although a recent retrospective study showed a substantial increase in the incidence of disseminated histoplasmosis after cART initiation in an endemic region, with reactivation of latent Histoplasma infection up to ten years after the primary infection.4,5 In addition, histoplasmosis was associated in our patient with a hemophagocytic syndrome, as occasionally reported in patients both with and without HIV infection.1,6 The main manifestations of HS were present, namely acute high-grade
Histoplasmosis in HIV infection fever, hepatosplenomegaly, pancytopenia, and hemophagocytosis on a bone marrow smear. Typical laboratory markers were also present, as well as disseminated intravascular coagulation.7 Secondary HS may be related to various infections, and particularly to herpes viruses and intracellular pathogens.8 The prognosis is poor and treatment may be difficult, depending on the underlying disease. Impaired cytotoxicity of natural killer cells and cytotoxic T cells, associated with excessive production of interferon gamma, is probably key determinants of HS.9 These abnormalities lead to uncontrolled macrophage activation and abundant secretion of proinflammatory cytokines.10 In our patient, the rapid virological response to cART (the HIV RNA level fell to 1 log10 copies/ml) and the acute onset following cART initiation both pointed to IRIS. Furthermore, IRIS probably contributed to the onset of HS in this patient. During the immune reconstitution that follows cART initiation, there is an early rise in the CD4þ T cell count, reflecting a redistribution of memory T cells from lymphoid tissues,11 together with a proinflammatory cytokine storm. IRIS was recently studied in patients with tuberculosis, a disease also associated with HS.12 A prominent Th-1 inflammatory response was observed, with increased production of cytokines and chemokines (IFN-g, IL-2, IL-12, TNF-a, IL-6, IL-10 and RANTES), some of which are also involved in the pathophysiology of HS.10 Disseminated histoplasmosis has already been reported in association with either HS or IRIS. In contrast, this is the first reported case in which histoplasmosis, HS and IRIS were present simultaneously in an HIV-infected patient. As the main pathogens and cytokines involved in HS are the same as those involved in IRIS, IRIS may facilitate HS onset in HIV-infected patients. HS may be overlooked during IRIS but should be suspected, especially in the most serious cases.13 The causative agent may be a quiescent opportunistic pathogen that infected the patient many years ago. This case also underlines the importance of considering the patient’s travel history and habits before initiating antiretroviral therapy.
247
References 1. Koduri PR, Chundi V, DeMarais P, Mizock BA, Patel AR, Weinstein RA. Reactive hemophagocytic syndrome: a new presentation of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis 1995;21:1463e5. 2. French MA, Price P, Stone SF. Immune reconstitution disease after antiretroviral therapy. AIDS 2004;18:1615e27. 3. Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White Jr AC, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;19:399e406. 4. Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 2006;20:119e21. 5. Nacher M, Sarazin F, El Guedj M, Vaz T, Alvarez F, Nasser V, et al. Increased incidence of disseminated histoplasmosis following highly active antiretroviral therapy initiation. J Acquir Immune Defic Syndr 2006;41:468e70. 6. Rouphael NG, Talati N, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007;7:814e22. 7. Kaito K, Kobayashi M, Katayama T, Otsubo H, Ogasawara Y, Sekita T, et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol 1997;59:247e53. 8. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601e8. 9. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8þ T cells and interferon gamma are essential for the disorder. Blood 2004;104:735e43. 10. Larroche C, Mouthon L. Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun rev 2004;3:69e75. 11. Carcelain G, Debre P, Autran B. Reconstitution of CD4þ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol 2001;13:483e8. 12. Bourgarit A, Carcelain G, Martinez V, Lascoux C, Delcey V, Gicquel B, et al. Explosion of tuberculin-specific Th1-responses induces immune reconstitution syndrome in tuberculosis and HIV co-infected patients. AIDS 2006;20:F1e7. 13. Huang DB, Wu JJ, Hamill RJ. Reactive hemophagocytosis associated with the initiation of highly active antiretroviral therapy (HAART) in a patient with AIDS. Scand J Infect Dis 2004;36:516e9.