Immune reconstitution syndrome in a child with TB and HIV
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《美国医学杂志》
1 Tuberculosis Research Centre, Chetput, India
2 Govt. Hospital of Thoracic Medicine, Tambaram Sanatorium, Chennai, India
Abstract
Immune reconstitution syndrome (IRS) is the transient worsening or appearance of new signs, symptoms, or radiological manifestation of an opportunistic infection occurring after the initiation of Highly active antiretroviral therapy (HAART) and is not due to treatment failure or new infection. We describe a case of a HIV infected child with tubercular (mediastinal) lymphadenitis with worsening of clinical and radiological features on starting HAART.
Keywords: HAART; IRS; TB; Paradoxical reaction
Synonyms: Immune reconstitution syndrome (IRS), immune reconstitution inflammatory syndrome (IRIS), Paradoxical reaction, "HAART attack"
Immune reconstitution can occur in infectious as well as autoimmune conditions. The common infectious organisms are Mycobacterium t uberculosis , Pneumocystitis jirovecii , hepatitis B and C , cytomegalovirus , varicella and Cryptococcus neoformans . Rarer causes include papillomavirus , Epstein-Barr virus, and human herpes virus type VIII. The non-infectious causes include sarcoidosis, rheumatoid arthritis, systemic lupus erythematosis, and polymyositis. Relapsing polychondritis and Graves' disease have also been reported.[1] In Mycobacterium tuberculosis -TB) infection, immune reconstitution should be considered in patients with (i) emergence or worsening of the clinical/radiological manifestations of tuberculosis with or without positive acid -fast bacilli smear results obtained from the involved organs. (ii) Exclusion of other potential causes of the symptoms and signs after an extensive diagnostic evaluation, particularly drug fever and other related infection. (iii) Exclusion of drug resistant tuberculosis or other causes that could explain the persistence or relapse of tuberculosis.[2] These reactions are due to augmentation and restoration of immunological response by inflammatory mediators due to increased CD4 cell counts. The syndrome can be managed by anti-inflammatory and steroid therapy. Rarely temporary discontinuation of HAART is indicated.
Case report
A 12-year-old boy was admitted in a hospital with history of fever and weight loss for a period of 2 months. Quantitative buffy coat analysis for malaria, Widal's test and urine culture were negative. Patient was found to be reactive for human immunodeficiency virus (HIV) antibody. A chest skiagram revealed mediastinal lymphadenopathy Figure1. His investigations were as follows; Hb-5.8 gms%, RBC-2.82millions /cu.mm. TLC- 12,000/cu.mm. DLC - P 84 , L 10 , M 6. LFT - Serum Alkaline Phosphatase alone elevated. His CD4 was 3 %(51 cells), CD8-26%(442 cells). CD4/CD8 ratio was 0.12. Mantoux test was negative as well as three sputum smears for AFB were negative. One of the pretreatment smears was culture positive for AFB and sensitive to INH, rifampicin and ethambutol. He was treated with antituberculous drugs (ATT) (INH, rifampicin, ethambutol, pyrazinamide) daily for 2 months. Child gained weight, and was asymptomatic. His chest skiagram revealed that the nodes had decreased in size Figure2 and CD4 at the end of 2 months was 4%(72 cells). He continued with rifampicin and INH in the continuation phase. At the end of 4 months, due to his low CD4 counts, he was started on antiretroviral therapy (ART) with efavirenz 300 mg once daily along with stavudine 30 mg and lamivudine 150 mg twice daily. Patient developed fever on the third day of ART. He was treated with antimalarials and cefotaxime and gentamicin for 5 days. Widal test was negative. A check x-ray taken (on the 9th day of HAART) showed enlarged mediastinal nodes Figure3. Blood investigations revealed that CD4 was 225 cells (19%). A clinical diagnosis of immune reconstitution syndrome was made. He was started on 1mg/kg/day of prednisolone in divided doses, which was tapered in the next 6 weeks. Patient's fever subsided. ATT was continued. At the end of steroid therapy, a repeat chest X-ray was normal. Figure4. A diagnosis of immune reconstitution syndrome with paradoxical worsening of lymph nodal tuberculosis on starting HAART was thus confirmed.
Discussion
Immune reconstitution syndrome (IRS) tends to occur in about 7% of HIV infected cases being treated for TB and 20% or more in patients started on HAART.[2], [3] Even though effective highly active antiretroviral therapy (HAART) can result in beneficial immune reconstitution for patients with advanced HIV disease, some have exuberant inflammatory responses to opportunistic pathogens that can lead to troublesome immune reconstitution syndromes (IRS). Effective HAART that durably suppresses HIV replication results in rapid and sustained rises in absolute CD4 T-cell counts.
Typically, a 2-phase increase in CD4 T cells occurs after effective ART is initiated; a rapid initial rise in the first few months, primarily due to increase in memory T cells, followed by a slow, steady increase in naive T-cell counts that can continue for years with sustained suppressive antiretroviral therapy (ART). The increased levels of CD4 cell with their inflammation mediating cytokines such as interferon-gamma (IFN-g) and interleukin-2 are responsible for the reaction. There is proliferation of peripheral blood mononuclear cells, antigen specific CD4 lymphocytes and IFN-g response to M-TB antigens after initiation of HAART in HIV-infected patients.[4]
Tuberculosis is the most commonly occurring IRS worldwide.[2], [3] Paradoxical enlargement of lymph nodes is the commonest manifestation.[2] Even though paradoxical reactions were known to occur during treatment of TB in the pre-HIV era, it is considerably more common in HIV-infected persons, especially those on anti-retroviral treatment.[2], [3], [4] It nearly always presents with fever. Other clinical findings may include worsening infiltrates or new pleural effusion on chest x-ray, mediastinal and/or peripheral lymphadenopathy, skin or visceral abscesses, arthritis, and osteomyelitis.[1] Onset is 1 to 6 weeks after ART is initiated. Risk factors for IRS include the presence of extra pulmonary/disseminated tuberculosis, lower pre-ART CD4 T-cell count, pre-ART plasma viral load >100,000 copies/mL, and earlier initiation of ART after beginning antimycobacterial therapy.[6] Diagnosis is one of exclusion. Treatment failure, other opportunistic infections and drug reactions are the differential diagnosis.[2] It is important to note that most reported IRS cases have resolved within several weeks simply by continuing ART and treatment of the opportunistic pathogen. Unless clinical presentation of the IRS is immediately life threatening, there is no rationale for discontinuing ART. Occurrence of IRS does not require reinitiating antimicrobial treatment, or changing existing maintenance therapy, for the infection in question. Invasive diagnostic procedures can be avoided if this condition is recognized. In several reports, a brief course of systemic prednisolone (e.g., 1 mg/kg/day for 1-2 weeks followed by a slow tapering) appeared to be beneficial, especially if symptoms are severe.[5],[7]
References
1. French M A, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18(12): 1615-1627.
2. Narita M, Ashkin D, Hollender E S, and Pitchenik A E. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158 : 157-161.
3. Wendel K A, Alwood K S, Gachuhi R, Chaisson R E, Bishai W R and Sterling T R. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001; 120(1): 193-197.
4. Swaminathan S, Padmapriya C, Narendran G, Beena Thomas, Anand S, Rajalakshmi A. Immune reconstitution syndrome following initiation of antiretroviral therapy in HIV and multidrug resistant tuberculosis. Ind J Chest Dis Allied Sci 2005;47: 299-304.
5. Burman WJ and Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001; 164 : 7-12.
6. Breen R A M, Smith C J, Bettinson H, Dart S, Bannister B, Johnson MA et al. Paradoxical reactions during tuberculosis treatment in patients with and without coinfection. Thorax 2004; 59 : 704-707.
7. Kumarasamy N, Chataguru S, Mayer KH, Solomon S, Yepthomi HT, Balakrishnan P, Flanigan TP. Incidence of immune reconstitution syndrome in HIV/tuberculosis coinfected patients after initiation of generic antiretroviral therapy in India. Acquir Immune Defic Syndr 2004; 37(5): 1574-1576.(Narendran G, Swaminathan )
2 Govt. Hospital of Thoracic Medicine, Tambaram Sanatorium, Chennai, India
Abstract
Immune reconstitution syndrome (IRS) is the transient worsening or appearance of new signs, symptoms, or radiological manifestation of an opportunistic infection occurring after the initiation of Highly active antiretroviral therapy (HAART) and is not due to treatment failure or new infection. We describe a case of a HIV infected child with tubercular (mediastinal) lymphadenitis with worsening of clinical and radiological features on starting HAART.
Keywords: HAART; IRS; TB; Paradoxical reaction
Synonyms: Immune reconstitution syndrome (IRS), immune reconstitution inflammatory syndrome (IRIS), Paradoxical reaction, "HAART attack"
Immune reconstitution can occur in infectious as well as autoimmune conditions. The common infectious organisms are Mycobacterium t uberculosis , Pneumocystitis jirovecii , hepatitis B and C , cytomegalovirus , varicella and Cryptococcus neoformans . Rarer causes include papillomavirus , Epstein-Barr virus, and human herpes virus type VIII. The non-infectious causes include sarcoidosis, rheumatoid arthritis, systemic lupus erythematosis, and polymyositis. Relapsing polychondritis and Graves' disease have also been reported.[1] In Mycobacterium tuberculosis -TB) infection, immune reconstitution should be considered in patients with (i) emergence or worsening of the clinical/radiological manifestations of tuberculosis with or without positive acid -fast bacilli smear results obtained from the involved organs. (ii) Exclusion of other potential causes of the symptoms and signs after an extensive diagnostic evaluation, particularly drug fever and other related infection. (iii) Exclusion of drug resistant tuberculosis or other causes that could explain the persistence or relapse of tuberculosis.[2] These reactions are due to augmentation and restoration of immunological response by inflammatory mediators due to increased CD4 cell counts. The syndrome can be managed by anti-inflammatory and steroid therapy. Rarely temporary discontinuation of HAART is indicated.
Case report
A 12-year-old boy was admitted in a hospital with history of fever and weight loss for a period of 2 months. Quantitative buffy coat analysis for malaria, Widal's test and urine culture were negative. Patient was found to be reactive for human immunodeficiency virus (HIV) antibody. A chest skiagram revealed mediastinal lymphadenopathy Figure1. His investigations were as follows; Hb-5.8 gms%, RBC-2.82millions /cu.mm. TLC- 12,000/cu.mm. DLC - P 84 , L 10 , M 6. LFT - Serum Alkaline Phosphatase alone elevated. His CD4 was 3 %(51 cells), CD8-26%(442 cells). CD4/CD8 ratio was 0.12. Mantoux test was negative as well as three sputum smears for AFB were negative. One of the pretreatment smears was culture positive for AFB and sensitive to INH, rifampicin and ethambutol. He was treated with antituberculous drugs (ATT) (INH, rifampicin, ethambutol, pyrazinamide) daily for 2 months. Child gained weight, and was asymptomatic. His chest skiagram revealed that the nodes had decreased in size Figure2 and CD4 at the end of 2 months was 4%(72 cells). He continued with rifampicin and INH in the continuation phase. At the end of 4 months, due to his low CD4 counts, he was started on antiretroviral therapy (ART) with efavirenz 300 mg once daily along with stavudine 30 mg and lamivudine 150 mg twice daily. Patient developed fever on the third day of ART. He was treated with antimalarials and cefotaxime and gentamicin for 5 days. Widal test was negative. A check x-ray taken (on the 9th day of HAART) showed enlarged mediastinal nodes Figure3. Blood investigations revealed that CD4 was 225 cells (19%). A clinical diagnosis of immune reconstitution syndrome was made. He was started on 1mg/kg/day of prednisolone in divided doses, which was tapered in the next 6 weeks. Patient's fever subsided. ATT was continued. At the end of steroid therapy, a repeat chest X-ray was normal. Figure4. A diagnosis of immune reconstitution syndrome with paradoxical worsening of lymph nodal tuberculosis on starting HAART was thus confirmed.
Discussion
Immune reconstitution syndrome (IRS) tends to occur in about 7% of HIV infected cases being treated for TB and 20% or more in patients started on HAART.[2], [3] Even though effective highly active antiretroviral therapy (HAART) can result in beneficial immune reconstitution for patients with advanced HIV disease, some have exuberant inflammatory responses to opportunistic pathogens that can lead to troublesome immune reconstitution syndromes (IRS). Effective HAART that durably suppresses HIV replication results in rapid and sustained rises in absolute CD4 T-cell counts.
Typically, a 2-phase increase in CD4 T cells occurs after effective ART is initiated; a rapid initial rise in the first few months, primarily due to increase in memory T cells, followed by a slow, steady increase in naive T-cell counts that can continue for years with sustained suppressive antiretroviral therapy (ART). The increased levels of CD4 cell with their inflammation mediating cytokines such as interferon-gamma (IFN-g) and interleukin-2 are responsible for the reaction. There is proliferation of peripheral blood mononuclear cells, antigen specific CD4 lymphocytes and IFN-g response to M-TB antigens after initiation of HAART in HIV-infected patients.[4]
Tuberculosis is the most commonly occurring IRS worldwide.[2], [3] Paradoxical enlargement of lymph nodes is the commonest manifestation.[2] Even though paradoxical reactions were known to occur during treatment of TB in the pre-HIV era, it is considerably more common in HIV-infected persons, especially those on anti-retroviral treatment.[2], [3], [4] It nearly always presents with fever. Other clinical findings may include worsening infiltrates or new pleural effusion on chest x-ray, mediastinal and/or peripheral lymphadenopathy, skin or visceral abscesses, arthritis, and osteomyelitis.[1] Onset is 1 to 6 weeks after ART is initiated. Risk factors for IRS include the presence of extra pulmonary/disseminated tuberculosis, lower pre-ART CD4 T-cell count, pre-ART plasma viral load >100,000 copies/mL, and earlier initiation of ART after beginning antimycobacterial therapy.[6] Diagnosis is one of exclusion. Treatment failure, other opportunistic infections and drug reactions are the differential diagnosis.[2] It is important to note that most reported IRS cases have resolved within several weeks simply by continuing ART and treatment of the opportunistic pathogen. Unless clinical presentation of the IRS is immediately life threatening, there is no rationale for discontinuing ART. Occurrence of IRS does not require reinitiating antimicrobial treatment, or changing existing maintenance therapy, for the infection in question. Invasive diagnostic procedures can be avoided if this condition is recognized. In several reports, a brief course of systemic prednisolone (e.g., 1 mg/kg/day for 1-2 weeks followed by a slow tapering) appeared to be beneficial, especially if symptoms are severe.[5],[7]
References
1. French M A, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18(12): 1615-1627.
2. Narita M, Ashkin D, Hollender E S, and Pitchenik A E. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158 : 157-161.
3. Wendel K A, Alwood K S, Gachuhi R, Chaisson R E, Bishai W R and Sterling T R. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001; 120(1): 193-197.
4. Swaminathan S, Padmapriya C, Narendran G, Beena Thomas, Anand S, Rajalakshmi A. Immune reconstitution syndrome following initiation of antiretroviral therapy in HIV and multidrug resistant tuberculosis. Ind J Chest Dis Allied Sci 2005;47: 299-304.
5. Burman WJ and Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001; 164 : 7-12.
6. Breen R A M, Smith C J, Bettinson H, Dart S, Bannister B, Johnson MA et al. Paradoxical reactions during tuberculosis treatment in patients with and without coinfection. Thorax 2004; 59 : 704-707.
7. Kumarasamy N, Chataguru S, Mayer KH, Solomon S, Yepthomi HT, Balakrishnan P, Flanigan TP. Incidence of immune reconstitution syndrome in HIV/tuberculosis coinfected patients after initiation of generic antiretroviral therapy in India. Acquir Immune Defic Syndr 2004; 37(5): 1574-1576.(Narendran G, Swaminathan )