Risk Factors for Development of Paradoxical Response During Antituberculosis Therapy in HIV-Negative Patients

  • V. C. C. Cheng
  • W. C. Yam
  • P. C. Y. Woo
  • S. K. P. Lau
  • I. F. N. Hung
  • S. P. Y. Wong
  • W. C. Cheung
  • K. Y. YuenEmail author


The risk factors for development of paradoxical response were studied in a cohort of 104 patients with culture-documented Mycobacterium tuberculosis infection. Paradoxical deterioration occurred in 16 (15.4%) patients (case group) during antituberculosis therapy, involving lungs and pleura (n=4), spine and paraspinal tissue (n=5), intracranium (n=3), peritoneum (n=2), bone and joint (n=1), and lymph node (n=1). The median time from commencement of treatment to paradoxical deterioration was 56 days (range, 20–109 days). Compared with 53 patients without clinical deterioration after antituberculosis therapy (control group), patients with paradoxical response were more likely to have extrapulmonary involvement (62.5% vs. 17.0%; P<0.05) at initial diagnosis, to have lower baseline lymphocyte counts (672±315 cells/μl vs. 1,328±467 cells/μl; P<0.001), and to exhibit a greater surge in lymphocyte counts (627±465 cells/μl vs. 225±216 cells/μl; P<0.05) during paradoxical response. Further studies on lymphocyte subsets and cytokine levels would be useful in understanding the exact immunological mechanisms involved in immunorestitution.


Tuberculosis Isoniazid Mycobacterium Tuberculosis Lymphocyte Count Absolute Lymphocyte Count 
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  1. 1.
    Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, Lau SK, Yuen KY (2002) Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 21:803–809CrossRefPubMedGoogle Scholar
  2. 2.
    Al-Majed SA (1996) Study of paradoxical response to chemotherapy in tuberculous pleural effusion. Respir Med 90:211–214PubMedGoogle Scholar
  3. 3.
    Campbell IA, Dyson AJ (1977) Lymph node tuberculosis: a comparison of various methods of treatment. Tubercle 58:171–179PubMedGoogle Scholar
  4. 4.
    Memish ZA, Mah MW, Mahmood SA, Bannatyne RM, Khan MY (2000) Clinico-diagnostic experience with tuberculous lymphadenitis in Saudi Arabia. Clin Microbiol Infect 6:137–141PubMedGoogle Scholar
  5. 5.
    Mofredj A, Guerin JM, Leibinger F, Masmoudi R (1996) Paradoxical worsening in tuberculosis during therapy in an HIV-infected patient. Infection 24:390–391PubMedGoogle Scholar
  6. 6.
    Chien JW, Johnson JL (1998) Paradoxical reactions in HIV and pulmonary TB. Chest 114:933–936PubMedGoogle Scholar
  7. 7.
    Narita M, Ashkin D, Hollender ES, Pitchenik AE (1998) Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 158:157–161Google Scholar
  8. 8.
    Wendel KA, Alwood KS, Gachuhi R, Chaisson RE, Bishai WR, Sterling TR (2001) Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 120:193–197PubMedGoogle Scholar
  9. 9.
    John M, French MA (1998) Exacerbation of the inflammatory response to Mycobacterium tuberculosis after antiretroviral therapy. Med J Aust 1998 169:473–474Google Scholar
  10. 10.
    Furrer H, Malinverni R (1999) Systemic inflammatory reaction after starting highly active antiretroviral therapy in AIDS patients treated for extrapulmonary tuberculosis. Am J Med 106:371–372CrossRefPubMedGoogle Scholar
  11. 11.
    Ramdas K, Minamoto GY (1994) Paradoxical presentation of intracranial tuberculomas after chemotherapy in a patient with AIDS. Clin Infect Dis 19:793–794PubMedGoogle Scholar
  12. 12.
    Crump JA, Tyrer MJ, Lloyd-Owen SJ, Han LY, Lipman MC, Johnson MA (1998) Miliary tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy. Clin Infect Dis 26:1008–1009PubMedGoogle Scholar
  13. 13.
    Eyer-Silva WA, Pinto JF, Arabe J, Morais-De-Sa CA (2002) Paradoxical reaction to the treatment of tuberculosis uncovering previously silent meningeal disease. Rev Soc Bras Med Trop 35:59–61PubMedGoogle Scholar
  14. 14.
    Orlovic D, Smego RA Jr (2001) Paradoxical tuberculous reactions in HIV-infected patients. Int J Tuberc Lung Dis 5:370–375PubMedGoogle Scholar
  15. 15.
    Navas E, Martin-Davila P, Moreno L, Pintado V, Casado JL, Fortun J, Perez-Elias MJ, Gomez-Mampaso E, Moreno S (2002) Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med 162:97–99CrossRefPubMedGoogle Scholar
  16. 16.
    Ramos A, Asensio A, Perales I, Montero MC, Martin T (2003) Prolonged paradoxical reaction of tuberculosis in an HIV-infected patient after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 22:374–376PubMedGoogle Scholar
  17. 17.
    Cheng VC, Woo PC, Lau SK, Cheung CH, Yung RW, Yam LY, Yuen KY (2003) Peripartum tuberculosis: a form of immunorestitution disease. Eur J Clin Microbiol Infect Dis 22:313–317PubMedGoogle Scholar
  18. 18.
    Valdez LM, Schwab P, Okhuysen PC, Rakita RM (1997) Paradoxical subcutaneous tuberculous abscess. Clin Infect Dis 24:734Google Scholar
  19. 19.
    Cheng VC, Yuen KY, Chan WM, Wong SS, Ma ES, Chan RM (2000) Immunorestitution disease involving the innate and adaptive response. Clin Infect Dis 30:882–892PubMedGoogle Scholar
  20. 20.
    Cheng VC, Yuen KY, Wong SS, Woo PC, Ho PL, Lee R, Chan RM (2001) Immunorestitution diseases in patients not infected with HIV. Eur J Clin Microbiol Infect Dis 20:402–406PubMedGoogle Scholar
  21. 21.
    Espinal MA, Laszlo A, Simonsen L, Boulahbal F, Kim SJ, Reniero A, Hoffner S, Rieder HL, Binkin N, Dye C, Williams R, Raviglione MC (2001) Global trends in resistance to antituberculosis drugs. N Engl J Med 344:1294–1303PubMedGoogle Scholar
  22. 22.
    Kam KM, Yip CW, Tse LW, Leung OC, Sin LP, Chan MY, Wong WS (2002) Trends in multidrug-resistant Mycobacterium tuberculosis in relation to sputum smear positivity in Hong Kong, 1989–1999. Clin Infect Dis 34:324–329CrossRefPubMedGoogle Scholar
  23. 23.
    Ohno H, Koga H, Kuroita T, Tomono K, Ogawa K, Yanagihara K, Yamamoto Y, Miyamoto J, Tashiro T, Kohno S (1997) Rapid prediction of rifampin susceptibility of Mycobacterium tuberculosis. Am J Respir Crit Care Med 155:2057–2063PubMedGoogle Scholar
  24. 24.
    Torres MJ, Criado A, Palomares JC, Aznar J (2000) Use of real-time PCR and fluorimetry for rapid detection of rifampin and isoniazid resistance-associated mutations in Mycobacterium tuberculosis. J Clin Microbiol 38:3194–3199PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • V. C. C. Cheng
    • 1
  • W. C. Yam
    • 1
  • P. C. Y. Woo
    • 1
  • S. K. P. Lau
    • 1
  • I. F. N. Hung
    • 1
  • S. P. Y. Wong
    • 1
  • W. C. Cheung
    • 1
  • K. Y. Yuen
    • 1
    Email author
  1. 1.Division of Infectious Diseases, Center of Infection, University Pathology BuildingThe University of Hong Kong, Queen Mary HospitalHong Kong

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