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Clinical Investigations: INFECTION |

Paradoxical Worsening of Tuberculosis in HIV-Infected Persons* FREE TO VIEW

Karen A. Wendel, MD; Karla S. Alwood, CRNP; Regina Gachuhi, MS; Richard E. Chaisson, MD; William R. Bishai, MD, PhD; Timothy R. Sterling, MD
Author and Funding Information

*From the Division of Infectious Diseases (Drs. Wendel, Chaisson, Sterling, and Ms. Alwood), Johns Hopkins University School of Medicine; Baltimore City Health Department Eastern Chest Clinic (Drs. Gachuhi and Sterling); and Department of International Health (Dr. Bishai), Johns Hopkins University School of Public Health, Baltimore, MD.

Correspondence to: Karen A. Wendel, MD, Division of Infectious Diseases, 1830 E. Monument St, Room 401, Baltimore, MD 21287; e-mail: kwwendel@mail.jhmi.edu



Chest. 2001;120(1):193-197. doi:10.1378/chest.120.1.193
Text Size: A A A
Published online

Objective: To determine the incidence of paradoxical worsening of tuberculosis (TB) in HIV-infected persons.

Design: Observational cohort study.

Setting: Public, urban TB clinic.

Patients: HIV-infected persons treated for TB between January 1, 1996, and December 31, 1999, and followed through June 30, 2000.

Intervention: Patients received standard anti-TB therapy. Antiretroviral therapy was provided by primary medical providers. Patients receiving antiretroviral therapy were given nucleoside reverse transcriptase inhibitors alone or highly active antiretroviral therapy (HAART; nucleoside reverse transcriptase inhibitors in combination with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor).

Main outcome measure: Paradoxical worsening of TB.

Results: There were 82 TB cases in 76 patients. Paradoxical worsening was identified in 6 of 82 cases (7%; 95% confidence interval, 3 to 15%). Paradoxical worsening occurred in 3 of 28 cases (11%) in patients receiving HAART and in 3 of 44 cases (7%) in patients not receiving antiretroviral therapy (p = 0.67). Cases complicated by paradoxical worsening were more likely to have both pulmonary and extrapulmonary disease at initial diagnosis than cases without paradoxical worsening (83% vs 24%; p = 0.006). TB relapse occurred in 2 of 6 cases (33%) in patients with paradoxical worsening and in 4 of 76 cases (5%) in patients without paradoxical worsening (p = 0.06).

Conclusions: Paradoxical worsening of TB occurred less frequently than in previous reports and was not associated with HAART. Paradoxical worsening also appeared to be associated with an increased risk of TB relapse. Further studies are warranted to better characterize the risk factors for paradoxical worsening and the appropriate duration of anti-TB therapy in patients in whom it occurs.

Treatment of HIV infection, particularly with highly active antiretroviral therapy (HAART), results in suppression of viral replication and partial restoration of cell-mediated immunity. Several case reports of paradoxical worsening of tuberculosis (TB) in the setting of immune reconstitution have been described.15 In the only study6 of the incidence of paradoxical worsening of TB in HIV-infected persons published to date and to our knowledge, 36% of patients who received treatment for both TB and HIV developed paradoxical worsening compared with 7% of historical control patients who received TB treatment alone. The mean time to onset of paradoxical worsening was 15 days after initiation of antiretroviral therapy. However, all patients in the study received inpatient care, most received combination nucleoside reverse transcriptase inhibitor therapy (NRTI), and few patients received HAART. Since most TB treatment occurs in the outpatient setting and the use of HAART is increasing, the generalizability of this study may be limited. The purpose of this study was to describe the incidence of paradoxical worsening of TB in the outpatient setting, in HIV-infected patients receiving a variety of antiretroviral regimens

An observational cohort study was conducted among all HIV-infected patients treated for active TB through the Baltimore City Health Department between January 1, 1996, and December 31, 1999. The follow-up period was through June 30, 2000. Demographic and clinical data were obtained by chart review. Patients received TB treatment through the Baltimore City Health Department TB Clinic and HIV treatment through primary medical providers. Details of paradoxical worsening of TB were compiled from TB and HIV clinic charts and hospital records.

Patients were included if they had a positive serologic test result for HIV-1 infection and a new diagnosis of definite or probable TB treated with standard anti-TB therapy. TB relapses were counted as separate TB episodes. Exclusion criteria included TB diagnosed at death or receipt of < 3 weeks of anti-TB therapy.

Definitions

Definite TB was defined as a clinical illness consistent with TB accompanied by a culture-positive finding for Mycobacterium tuberculosis. TB was considered probable if histopathology and acid-fast staining results were consistent with TB, or the patient had a clinical history consistent with active TB and symptoms that responded to anti-TB therapy.7Paradoxical worsening was defined as documented worsening of signs or symptoms of TB (eg, fever, cough, shortness of breath, or adenopathy) or exacerbation of disease at other extrapulmonary sites during appropriate anti-TB treatment after an initial response to treatment. Worsening of pulmonary infiltrates on chest radiograph or chest CT scan without other etiology was also considered paradoxical worsening. Clinical or radiographic worsening in the setting of treatment noncompliance was not considered paradoxical worsening. Treatment failure was defined as culture findings persistently positive for M tuberculosis for at least 5 months despite anti-TB treatment.8 HAART was defined as antiretroviral therapy that included NRTIs plus either an HIV-1 protease inhibitor or non-NRTI. Relapse was defined as a new positive culture finding for M tuberculosis or histopathologic and acid-fast stain findings compatible with TB after completing a course of anti-TB treatment with documented negative culture findings.9

Laboratory Techniques

Baseline mycobacterial cultures were performed at local hospital clinical microbiology laboratories using liquid culture medium (BACTEC 12B; Becton-Dickinson; Sparks, MD) and/or Lowenstein-Jensen medium. Follow-up cultures were performed at the Maryland Department of Health and Mental Hygiene Mycobacteriology Laboratory using BACTEC 12B and Lowenstein-Jensen media. Susceptibility testing was performed using BACTEC 12B vials and Middlebrook 7H11 agar medium. HIV diagnosis was established by a positive enzyme-linked immunosorbent assay for HIV-1, with a confirmatory Western blot. Flow cytometry was used to determine CD4+ lymphocyte levels.

Restriction fragment length polymorphism (DNA fingerprinting) analysis was performed as previously described.10Briefly, M tuberculosis isolates were cultivated on Lowenstein-Jensen medium, harvested, and heat-killed. Genomic DNA was isolated, and PvuII-IS6110 restriction fragment length polymorphism analysis was performed according to a standard method.11 Isolates with six or fewer IS6110 bands were analyzed further with the probe specific for the M tuberculosis polymorphic GC-rich repetitive sequence. A 3.8-kb EcoRI-HindIII fragment from plasmid pTBN12 was used to probe AluI-cleaved genomic DNA.14 For questionable IS6110 or polymorphic GC-rich repetitive sequence matches, Southern blots were repeated side-by-side on the same gel for direct comparison. Isolates were considered to match only if they produced the same number of bands after testing with the IS6110 or pTBN12 probes.

Treatment and Follow-up

All patients with M tuberculosis isolates susceptible to first-line anti-TB agents who received directly observed therapy (DOT) were treated with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months followed by 4 months of twice-weekly isoniazid and rifampin.9 Treatment was extended if conversion of sputum culture findings to negative required > 3 months of treatment or if there was a delay in clinical improvement. Patients with drug-resistant disease were treated with at least two drugs to which the organism was susceptible. DOT was provided by the Baltimore City Health Department staff throughout the entire course of treatment. Patients who did not receive DOT were treated with the same drugs as above, but on a daily basis. Rifabutin was used in place of rifampin in patients receiving an HIV-1 protease inhibitor or non-NRTI.

The time of initiation of antiretroviral therapy in relation to anti-TB therapy varied within the cohort. Of the 38 cases in which patients were receiving antiretroviral therapy, antiretroviral therapy was initiated prior to the diagnosis of TB in 21 cases, antiretroviral and TB treatment were initiated simultaneously in 5 cases, and antiretroviral therapy was initiated after TB treatment in 12 cases. In these 12 cases, the median time to starting antiretroviral therapy was 8 weeks (range 2 weeks to 24 weeks) after initiating TB treatment.

Statistical Analysis

Fisher’s Exact Test (two tailed) was used to compare categorical variables. For comparison of continuous variables, the Mann-Whitney U test or Kruskal-Wallis test was used. Statistical analysis was performed using software (Epi Info Version 6.04; Centers for Disease Control and Prevention; Atlanta, GA).

There were 84 HIV-infected patients in whom 90 cases of TB were diagnosed during the study period. Three cases of TB were diagnosed at death, and five patients received < 3 weeks of anti-TB therapy and were excluded. A total of 82 TB cases were included in the study, of which 61 cases (74%) had a positive culture result. Of these 61 M tuberculosis isolates, 56 were susceptible to first-line TB drugs. TB therapy was administered as DOT to patients in 79 of 82 cases (96%).

Overall, in 28 of 82 cases (34%), patients received HAART and in 10 cases (12%), they received NRTI therapy alone while receiving anti-TB therapy; patients in 44 cases (54%) received no antiretroviral therapy during TB treatment. Data on adherence to antiretroviral therapy were not available. Among those cases in which CD4+ counts were known, the initial median CD4+ level in those who received HAART was 73/μL (n = 21), compared to 130/μL (n = 33) in those who did not receive antiretroviral therapy (p = 0.21; Table 1 ).

Of the patients in 28 TB cases that received concomitant HAART and TB therapy, patients in 3 of 28 cases (11%) developed paradoxical worsening, compared to patients in 3 of 44 cases (7%) who did not receive antiretroviral therapy (p = 0.67). The three patients who developed paradoxical worsening while receiving HAART were all receiving stavudine, lamivudine, and nelfinavir. One patient was also receiving nevirapine. The initial median CD4+ level among cases complicated by paradoxical worsening was 69/μL compared to 154/μL among cases without paradoxical worsening (p = 0.17). Both pulmonary and extrapulmonary TB were present at initial evaluation in 5 of 6 cases (83%) in patients in whom paradoxical worsening subsequently developed, compared to only 18 of 76 cases (24%) in patients in whom paradoxical worsening did not develop (p = 0.006; Table 2 ).

The three episodes of paradoxical worsening that occurred in patients receiving TB therapy alone occurred 4 to 10 weeks after initiating therapy and were characterized by new or worsening lymphadenopathy. The lymphadenopathy in these patients did not cause significant compressive symptoms or require incision and drainage. The three episodes of paradoxical worsening in patients receiving HAART all occurred within 4 weeks of starting antiretroviral therapy. These episodes were more severe and of greater duration than those in patients who did not receive HAART. These three patients all developed fever, weight loss, and severe lymphadenopathy. The lymphadenopathy required recurrent incision and drainage in one patient and caused compression of the trachea to < 1 cm in another patient. Two of these patients also developed psoas abscesses requiring external drainage. All three patients with paradoxical worsening while receiving HAART required hospitalization for evaluation and stabilization and received extended courses of anti-TB treatment due to their slow response to therapy.

Death during treatment was less common in patients receiving antiretroviral therapy, though the difference was not statistically significant (2 of 24 patients [8%] receiving HAART vs 1 of 10 patients [10%] receiving NRTI vs 12 of 42 patients [29%] receiving no HIV therapy; p = 0.09). Of the 15 deaths, 8 deaths were attributed to TB. These eight patients all received < 2.5 months of anti-TB therapy. The other seven deaths were primarily due to complications of HIV infection and/or injection drug use.

There were six cases of TB relapse; all occurred within 1 year of treatment completion. The DNA fingerprint was available for four of the six relapse isolates, and all four were identical to the original isolate. All relapses occurred in patients who were not receiving antiretroviral therapy. Two TB relapses occurred among the six TB cases complicated by paradoxical worsening (33%) compared to four relapses in the 76 TB cases without paradoxical worsening (5%; p = 0.06). In the two patients with paradoxical worsening who subsequently suffered relapses, the initial episode of TB was notable for worsening lymphadenopathy in the setting of improving pulmonary infiltrates, weight gain, and conversion of sputum acid-fast bacilli cultures to negative. The lymphadenopathy subsequently improved, and both patients completed a standard 6-month course of therapy. These patients did not have evidence of treatment failure. Relapse occurred 6 months and 11 months after completion of initial TB therapy in these two patients, respectively.

We found that paradoxical worsening occurred in 7% of HIV-infected patients being treated for active TB. Paradoxical worsening was similarly frequent in patients who were and were not receiving antiretroviral therapy. Patients with paradoxical worsening were more likely to have concurrent pulmonary and extrapulmonary TB at presentation, and CD4+ counts were somewhat lower in these individuals. The proportion of patients with paradoxical worsening in this study was lower than previously reported by Narita et al,6 and this may be due in part to differences in the study populations. The previous study was conducted among inpatients hospitalized for treatment of TB; such patients may have had more severe forms of TB, and also may have been more likely to receive the prescribed antiretroviral therapy. In this study, patients received most of their treatment as outpatients. Although TB therapy was directly observed in almost all patients, antiretroviral therapy was not; therefore, adherence may have been lower. Decreased adherence to antiretroviral therapy may have also contributed to the lack of a difference in the rate of paradoxical worsening between persons who did or did not receive HAART in this study. This contrasts with the study by Narita et al,6 in which the risk of paradoxical worsening was higher among patients receiving concomitant antiretroviral therapy. Of note, however, the episodes of paradoxical worsening that occurred in persons receiving HAART were more severe than in persons who were not receiving HAART.

All three patients in whom paradoxical worsening of TB developed while receiving HAART were receiving stavudine, lamivudine, and nelfinavir. However, it is unlikely that paradoxical worsening is associated with specific antiretroviral therapy, but rather is due to immune reconstitution regardless of its etiology. This line of reasoning is supported by the three cases of paradoxical worsening that occurred in persons who did not receive antiretroviral therapy. Nevertheless, future studies should assess the risk of paradoxical worsening according to the antiretroviral regimen used.

TB cases complicated by paradoxical worsening tended to be associated with a higher rate of TB relapse than cases not complicated by paradoxical worsening. The reason for this is unclear, but could be related to differences in the bacillary burden or in the host immune response to M tuberculosis. The increased risk of relapse in patients with paradoxical worsening suggests that standard 6-month rifamycin-based treatment may be insufficient in these patients.

The pathogenesis of paradoxical worsening is unclear but is believed to be related to the development of improved M tuberculosis-specific immune responses during the course of anti-TB treatment.1516 Paradoxical worsening has been described in both HIV-seronegative1718 and HIV-seropositive persons.16,1923 Recent work24has demonstrated increased proliferation of peripheral blood mononuclear cells and interferon-γ production in response to M tuberculosis antigens after initiation of HAART in HIV-infected patients. Antigen-specific CD4 + lymphocyte responses have also been shown27 to improve in HIV-infected persons receiving HAART. This has also been demonstrated25,28 in paradoxical worsening of other opportunistic infections, such as Mycobacterium avium complex disease and cytomegalovirus infection.

There are several limitations of this study. Data collection was conducted by chart review. This may have underestimated the actual occurrence of paradoxical worsening. The number of patients studied was small, and CD4+ lymphocyte data after initiation of anti-TB therapy were limited. This precluded a detailed comparison of the level of immune function in persons with and without paradoxical worsening.

This study identifies several areas for further study. Risk factors for paradoxical worsening need to be better characterized so that interventions can be introduced to decrease its incidence. In addition, if larger studies confirm that the risk of relapse is increased in patients with paradoxical worsening, the optimal duration of TB therapy in these patients will also need to be assessed.

Abbreviations: DOT = directly observed therapy; HAART = highly active antiretroviral therapy; NRTI = nucleoside reverse transcriptase inhibitor; TB = tuberculosis

Presented in part at the American Thoracic Society International Conference, April 23–28, 1999, San Diego, CA.

Supported by funds from the Baltimore City Health Department, the Centers for Disease Control and Prevention (Cooperative Agreement U300466–10), and the National Institutes of Health grants R01 AI 40605, K23 AI 01654, and K24 AI 01637.

Table Graphic Jump Location
Table 1. Characteristics of the 82 TB Cases*
* 

Data are presented as No. of cases (%) unless otherwise indicated. ART = antiretroviral therapy.

 

Data available on 33 cases.

 

Data available on 7 cases.

§ 

Data available on 21 cases; p = 0.21, CD4 count. No antiretroviral therapy vs HAART.

Table Graphic Jump Location
Table 2. Features of Paradoxical Worsening*
* 

Data are presented as No. of cases (%) unless otherwise indicated.

 

Data available on 4 cases.

 

Data available on 57 cases.

We are indebted to the staff of the Baltimore City Health Department TB Clinic. We thank Nancy Hooper, BA, of the Maryland Department of Health and Mental Hygiene, and Susan Harrington, MPH, of the Johns Hopkins University School of Medicine, for their assistance.

Chien, JW, Johnson, JL (1998) Paradoxical reactions in HIV and pulmonary TB.Chest114,933-936. [PubMed] [CrossRef]
 
Crump, JA, Tyrer, MJ, Lloyd-Owen, SJ, et al Military tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy.Clin Infect Dis1998;26,1008-1009. [PubMed]
 
Furrer, H, Malinverni, R Systemic inflammatory reaction after starting highly active antiretroviral therapy in AIDS patients treated for extrapulmonary tuberculosis.Am J Med1999;106,371-372. [PubMed]
 
John, M, French, MA Exacerbation of the inflammatory response toMycobacterium tuberculosisafter antiretroviral therapy.Med J Aust1998;169,473-474. [PubMed]
 
Kunimoto, DY, Chui, L, Nobert, E, et al Immune mediated ‘HAART’ attack during treatment for tuberculosis: highly active antiretroviral therapy.Int J Tuberc Lung Dis1999;3,944-947. [PubMed]
 
Narita, M, Ashkin, D, Hollender, ES, et al Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med1998;158,157-161. [PubMed]
 
Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000; 161(4 pt 1):1376–1395.
 
Bass, JB, Jr, Farer, LS, Hopewell, PC, et al Treatment of tuberculosis and tuberculosis infection in adults and children: American Thoracic Society and the Centers for Disease Control and Prevention.Am J Respir Crit Care Med1994;149,1359-1374. [PubMed]
 
Sterling, TR, Alwood, K, Gachuhi, R, et al Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons.AIDS1999;13,1899-1904. [PubMed]
 
Bishai, WR, Graham, NM, Harrington, S, et al Molecular and geographic patterns of tuberculosis transmission after 15 years of directly observed therapy.JAMA1998;280,1679-1684. [PubMed]
 
van Embden, JD, Cave, MD, Crawford, JT, et al Strain identification ofMycobacterium tuberculosisby DNA fingerprinting: recommendations for a standardized methodology.J Clin Microbiol1993;31,406-409. [PubMed]
 
Burman, WJ, Reves, RR, Hawkes, AP, et al DNA fingerprinting with two probes decreases clustering ofMycobacterium tuberculosis.Am J Respir Crit Care Med1997;155,1140-1146. [PubMed]
 
Ross, BC, Raios, K, Jackson, K, et al Molecular cloning of a highly repeated DNA element fromMycobacterium tuberculosisand its use as an epidemiologic tool.J Clin Microbiol1992;30,942-946. [PubMed]
 
Yang, Z, Chaves, F, Barnes, PF, et al Evaluation of method for secondary DNA typing ofMycobacterium tuberculosiswith pTBN12 in epidemiologic study of tuberculosis.J Clin Microbiol1996;34,3044-3048. [PubMed]
 
Dannenberg, AM, Jr Immune mechanisms in the pathogenesis of pulmonary tuberculosis.Rev Infect Dis1989;11(suppl 2),S369-S378. [PubMed]
 
Ellner, JJ, Wallis, RS Immunologic aspects of mycobacterial infections.Rev Infect Dis1989;11(suppl 2),S455-S459. [PubMed]
 
Campbell, IA, Dyson, AJ Lymph node tuberculosis: a comparison of various methods of treatment.Tubercle1977;58,171-179. [PubMed]
 
Chambers, ST, Hendrickse, WA, Record, C, et al Paradoxical expansion of intracranial tuberculomas during chemotherapy.Lancet1984;2,181-184. [PubMed]
 
Hernandez-Albujar, S, Arribas, JR, Royo, A, et al Tuberculous radiculomyelitis complicating tuberculous meningitis: case report and review.Clin Infect Dis2000;30,915-921. [PubMed]
 
Hill, AR, Mateo, F, Hudak, A Transient exacerbation of tuberculous lymphadenitis during chemotherapy in patients with AIDS.Clin Infect Dis1994;19,774-776. [PubMed]
 
Minguez, C, Roca, B, Gonzalez-Mino, C, et al Superior vena cava syndrome during the treatment of pulmonary tuberculosis in an HIV-1 infected patient.J Infect2000;40,187-189. [PubMed]
 
Mofredj, A, Guerin, JM, Leibinger, F, et al Paradoxical worsening in tuberculosis during therapy in an HIV-infected patient [letter].Infection1996;24,390-391. [PubMed]
 
Ramdas, K, Minamoto, GY Paradoxical presentation of intracranial tuberculomas after chemotherapy in a patient with AIDS [letter].Clin Infect Dis1994;19,793-794. [PubMed]
 
Perez, D, Liu, Y, Jung, T, et al Reconstitution of host immunity toM tuberculosisin HIV-infected individuals [abstract].Am J Respir Crit Care Med2000;161,A224
 
DeSimone, JA, Pomerantz, RJ, Babinchak, TJ Inflammatory reactions in HIV-1–infected persons after initiation of highly active antiretroviral therapy.Ann Intern Med2000;133,447-454. [PubMed]
 
Foudraine, NA, Hovenkamp, E, Notermans, DW, et al Immunopathology as a result of highly active antiretroviral therapy in HIV-1–infected patients.AIDS1999;13,177-184. [PubMed]
 
Wendland, T, Furrer, H, Vernazza, PL, et al HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responsesin vitrois correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia.AIDS1999;13,1857-1862. [PubMed]
 
Race, EM, Adelson-Mitty, J, Kriegel, GR, et al Focal mycobacterial lymphadenitis following initiation of protease- inhibitor therapy in patients with advanced HIV-1 disease.Lancet1998;351,252-255. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Characteristics of the 82 TB Cases*
* 

Data are presented as No. of cases (%) unless otherwise indicated. ART = antiretroviral therapy.

 

Data available on 33 cases.

 

Data available on 7 cases.

§ 

Data available on 21 cases; p = 0.21, CD4 count. No antiretroviral therapy vs HAART.

Table Graphic Jump Location
Table 2. Features of Paradoxical Worsening*
* 

Data are presented as No. of cases (%) unless otherwise indicated.

 

Data available on 4 cases.

 

Data available on 57 cases.

References

Chien, JW, Johnson, JL (1998) Paradoxical reactions in HIV and pulmonary TB.Chest114,933-936. [PubMed] [CrossRef]
 
Crump, JA, Tyrer, MJ, Lloyd-Owen, SJ, et al Military tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy.Clin Infect Dis1998;26,1008-1009. [PubMed]
 
Furrer, H, Malinverni, R Systemic inflammatory reaction after starting highly active antiretroviral therapy in AIDS patients treated for extrapulmonary tuberculosis.Am J Med1999;106,371-372. [PubMed]
 
John, M, French, MA Exacerbation of the inflammatory response toMycobacterium tuberculosisafter antiretroviral therapy.Med J Aust1998;169,473-474. [PubMed]
 
Kunimoto, DY, Chui, L, Nobert, E, et al Immune mediated ‘HAART’ attack during treatment for tuberculosis: highly active antiretroviral therapy.Int J Tuberc Lung Dis1999;3,944-947. [PubMed]
 
Narita, M, Ashkin, D, Hollender, ES, et al Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med1998;158,157-161. [PubMed]
 
Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000; 161(4 pt 1):1376–1395.
 
Bass, JB, Jr, Farer, LS, Hopewell, PC, et al Treatment of tuberculosis and tuberculosis infection in adults and children: American Thoracic Society and the Centers for Disease Control and Prevention.Am J Respir Crit Care Med1994;149,1359-1374. [PubMed]
 
Sterling, TR, Alwood, K, Gachuhi, R, et al Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons.AIDS1999;13,1899-1904. [PubMed]
 
Bishai, WR, Graham, NM, Harrington, S, et al Molecular and geographic patterns of tuberculosis transmission after 15 years of directly observed therapy.JAMA1998;280,1679-1684. [PubMed]
 
van Embden, JD, Cave, MD, Crawford, JT, et al Strain identification ofMycobacterium tuberculosisby DNA fingerprinting: recommendations for a standardized methodology.J Clin Microbiol1993;31,406-409. [PubMed]
 
Burman, WJ, Reves, RR, Hawkes, AP, et al DNA fingerprinting with two probes decreases clustering ofMycobacterium tuberculosis.Am J Respir Crit Care Med1997;155,1140-1146. [PubMed]
 
Ross, BC, Raios, K, Jackson, K, et al Molecular cloning of a highly repeated DNA element fromMycobacterium tuberculosisand its use as an epidemiologic tool.J Clin Microbiol1992;30,942-946. [PubMed]
 
Yang, Z, Chaves, F, Barnes, PF, et al Evaluation of method for secondary DNA typing ofMycobacterium tuberculosiswith pTBN12 in epidemiologic study of tuberculosis.J Clin Microbiol1996;34,3044-3048. [PubMed]
 
Dannenberg, AM, Jr Immune mechanisms in the pathogenesis of pulmonary tuberculosis.Rev Infect Dis1989;11(suppl 2),S369-S378. [PubMed]
 
Ellner, JJ, Wallis, RS Immunologic aspects of mycobacterial infections.Rev Infect Dis1989;11(suppl 2),S455-S459. [PubMed]
 
Campbell, IA, Dyson, AJ Lymph node tuberculosis: a comparison of various methods of treatment.Tubercle1977;58,171-179. [PubMed]
 
Chambers, ST, Hendrickse, WA, Record, C, et al Paradoxical expansion of intracranial tuberculomas during chemotherapy.Lancet1984;2,181-184. [PubMed]
 
Hernandez-Albujar, S, Arribas, JR, Royo, A, et al Tuberculous radiculomyelitis complicating tuberculous meningitis: case report and review.Clin Infect Dis2000;30,915-921. [PubMed]
 
Hill, AR, Mateo, F, Hudak, A Transient exacerbation of tuberculous lymphadenitis during chemotherapy in patients with AIDS.Clin Infect Dis1994;19,774-776. [PubMed]
 
Minguez, C, Roca, B, Gonzalez-Mino, C, et al Superior vena cava syndrome during the treatment of pulmonary tuberculosis in an HIV-1 infected patient.J Infect2000;40,187-189. [PubMed]
 
Mofredj, A, Guerin, JM, Leibinger, F, et al Paradoxical worsening in tuberculosis during therapy in an HIV-infected patient [letter].Infection1996;24,390-391. [PubMed]
 
Ramdas, K, Minamoto, GY Paradoxical presentation of intracranial tuberculomas after chemotherapy in a patient with AIDS [letter].Clin Infect Dis1994;19,793-794. [PubMed]
 
Perez, D, Liu, Y, Jung, T, et al Reconstitution of host immunity toM tuberculosisin HIV-infected individuals [abstract].Am J Respir Crit Care Med2000;161,A224
 
DeSimone, JA, Pomerantz, RJ, Babinchak, TJ Inflammatory reactions in HIV-1–infected persons after initiation of highly active antiretroviral therapy.Ann Intern Med2000;133,447-454. [PubMed]
 
Foudraine, NA, Hovenkamp, E, Notermans, DW, et al Immunopathology as a result of highly active antiretroviral therapy in HIV-1–infected patients.AIDS1999;13,177-184. [PubMed]
 
Wendland, T, Furrer, H, Vernazza, PL, et al HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responsesin vitrois correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia.AIDS1999;13,1857-1862. [PubMed]
 
Race, EM, Adelson-Mitty, J, Kriegel, GR, et al Focal mycobacterial lymphadenitis following initiation of protease- inhibitor therapy in patients with advanced HIV-1 disease.Lancet1998;351,252-255. [PubMed]
 
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