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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 771-772, (2004)
© 2004 American Thoracic Society

Correspondence

TB Chemotherapy

Antagonism between Immunity and Sterilization

To the Editor:

The study by Johnson and colleagues (1) of adjunctive interleukin (IL)-2 in the treatment of pulmonary tuberculosis (TB) is important because it illustrates the potential antagonism between immunity and sterilization. Available evidence indicates that human antimycobacterial immunity is bacteristatic rather than bactericidal. Its expression would thus expand a bacillary subpopulation against which current chemotherapeutics are relatively inactive. Antagonism between immunity and sterilization can be shown in vitro using a whole blood model of intracellular infection in which the influence of immunity on chemotherapy is evident (2, 3). In this model, the effect of a bactericidal drug such as ofloxacin is markedly reduced in cells of patients with TB (see Figure 1) , in whom immune antimycobacterial mechanisms are activated.



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  		Figure 1. Survival of Mycobacterium tuberculosis H37Rv in whole blood cultures of healthy purified protein derivative–negative volunteers and patients with tuberculosis (TB), with and without ofloxacin. Positive values indicate growth. The effect of ofloxacin was significantly reduced in the patients with TB (p < 0.001).

 
We completed two prospective controlled clinical trials of immunosuppressive treatment in TB that support this hypothesis. The first (in which Dr. Johnson also participated) examined the effects of soluble tumor necrosis factor receptor (etanercept) during the first month of TB chemotherapy in 16 patients and 42 control subjects (4). The mean time to sputum culture conversion was 60.5 ± 24 days in etanercept-treated subjects versus 71.7 ± 33 in control subjects (p = 0.2). Etanercept-treated subjects also tended to show superior change from baseline to Month 6 in the number of involved lung zones (-2.5 versus -1.9 lung zones, p = 0.2), closure of cavities (55% versus 34%, p = 0.3), weight gain (2.18 versus 1.73 kg, p = 0.4), and Karnofsky performance score (9.1 versus 5.1, p = 0.2). In the second study, high-dose methylprednisolone (2.75 mg/kg per day) or placebo was administered to 189 subjects for the first month of TB treatment. Sputum culture conversion rates after 1 month were 62 and 37% in treated subjects and control subjects, respectively (p < 0.001) (5).

These findings suggest that until nonreplicating bacilli can be specifically targeted by new chemotherapeutics, it may be wise to wait until after completion of chemotherapy before attempting augmentation of antimycobacterial immunity in future clinical trials.

Robert S. Wallisa, Ho-Yeon Songa, Christopher Whalenb and Alphonse Okwerac

a UMDNJ–New Jersey Medical School Newark, New Jersey
b Case Western Reserve University Cleveland, Ohio
c Makerere University Kampala, Uganda

FOOTNOTES

Conflict of Interest Statement: R.S.W., H-Y.S., C.W., and A.O. have no declared conflict of interest.

Dr. Johnson was given the opportunity to respond to this letter but declined to do so.

REFERENCES

  1. Johnson JL, Ssekasanvu E, Okwera A, Mayanja H, Hirsch CS, Nakibali JG, Jankus DD, Eisenach KD, Boom WH, Ellner JJ, et al., for the Uganda–Case Western University Research Collaboration. Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis. Am J Respir Crit Care Med 2003;168:185–191.[Abstract/Free Full Text]
  2. Cheon SH, Kampmann B, Hise AG, Phillips M, Song HY, Landen K, Li Q, Larkin R, Ellner JJ, Silver RF, et al. Bactericidal activity in whole blood as a potential surrogate marker of immunity after vaccination against tuberculosis. Clin Diagn Lab Immunol 2002;9:901–907.[Abstract/Free Full Text]
  3. Wallis RS, Vinhas SA, Johnson JL, Ribeiro FC, Palaci M, Peres RL, Sa RT, Dietze R, Chiunda A, Eisenach K, et al. Whole blood bactericidal activity during treatment of pulmonary tuberculosis. J Infect Dis 2003;187:270–278.[CrossRef][Medline]
  4. Wallis RS, Kyambadde P, Johnson JL, Horter L, Kittle R, Pohle M, Ducar C, Millard M, Mayanja-Kizza H, Whalen C, et al. A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis. AIDS (In press).
  5. Jones-Lopez EC, Mayanja-Kizza H, Namale A, Yun H, Newell K, Ferguson LE, Okwera A, Mugerwa R, Whalen C. Phase II clinical trial of immunoadjuvant therapy for HIV-associated tuberculosis with prednisolone [abstract]. Infectious Disease Society of America Annual Meeting 2001.



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