0 M O N T H

CorrespondenceLack of a Therapeutic Role forInterferon γ in Patients WithTuberculosis

TO THE EDITOR—I read with interest therecent article by Wong and Jacobs on theeffects of interferon γ (IFN-γ) on Myco-bacterium tuberculosis–infected macro-phages [1]. I believe their findings are animportant contribution to our under-standing of the human biology of M. tu-berculosis infection. However, I must takeissue with their speculation that theirwork is likely to enable future therapeutictrials of IFN-γ for tuberculosis.

As the authors noted, the first trial oftherapeutic IFN-γ in patients with tuber-culosis without overt defects in IFN-γproduction or responsiveness was report-ed by Condos et al in 1997 [2]. In that un-controlled study, aerosolized IFN-γ 500µg thrice weekly was added to the currenttherapy for 5 patients with multidrug-resis-tant tuberculosis. The study found thatresults of sputum smears became negativeand that the number of colony-formingunits tended to decrease. However, noneof 2 small uncontrolled and 2 adequatelypowered controlled subsequent trials hasbeen successful in replicating those results(Table 1). The most rigorous trial, con-ducted by InterMune, compared aerosol-ized IFN-γ 500 µg thrice weekly for 6months to placebo in 80 patients withmultidrug-resistant tuberculosis, all ofwhom also received standardized therapywith second-line drugs [6]. The studydesign included an aerosolized placebo.The study was halted prematurely by itsexternal safety monitoring board becauseof a trend toward increased mortality inthe experimental arm (10 deaths, com-pared with 5 in the control arm; P = .14),with no beneficial effect on sputum smearor culture results or chest radiography

findings. The study findings have neverbeen formally published but are describedin an online supplement that accompaniesthe article by Dawson et al [5].The only published randomized con-

trolled trial of adjunctive IFN-γ in tuber-culosis compared the effects of standardtherapy plus IFN-γ 200 µg given thriceweekly for 4 months by aerosol or bysubcutaneous injection with the effects ofstandard therapy alone in 77 evaluablepatients with drug-susceptible pulmo-nary tuberculosis [5]. All subjects also re-ceived standard 4-drug tuberculosistherapy. The study design did not includea subcutaneous or aerosolized placebo.The analysis of the study’s primary endpoints (ie, times to sputum smear andculture conversion) as it was reported dif-fered from that described in the study’sstatistical analysis plan, because results ofthe subcutaneous IFN-γ and control armswere merged and because the plannedintent-to-treat analysis was abandoned.Sputum smear findings were reportedout to 120 days. A transient beneficialeffect of aerosolized treatment on sputumsmear results was noted at 4 weeks, but itwas absent at all subsequent time points.A sputum culture conversion rate of 32%was reported at 4 weeks in the aerosol-ized IFN-γ arm, compared with 18% inthe other arms combined (P = .15), butno subsequent data were provided. Spu-tum culture status at 2 months has recog-nized prognostic value in the evaluationof new tuberculosis regimens [7]. In con-trast, sputum smear has no recognizedprognostic value, nor does any sputumparameter at 1 month [8, 9].Subsequent research has found that

most IFN-γ–induced genes are alreadyupregulated in the lung during tubercu-losis and that therapeutic aerosolized

IFN-γ has relatively little additional effect[10]. These findings indicate it is very un-likely that IFN-γ will have any futuretherapeutic role in patients with tubercu-losis without overt defects in its produc-tion.

Note

Potential conflict of interest. Author certi-fies no potential conflicts of interest.The author has submitted the ICMJE Form for

Disclosure of Potential Conflicts of Interest. Con-flicts that the editors consider relevant to thecontent of the manuscript have been disclosed.

Robert S. Wallis

Old Lyme, Connecticut

References

1. Wong KW, Jacobs WR Jr.Mycobacterium tu-berculosis exploits human interferon γ tostimulate macrophage extracellular trap for-mation and necrosis. J Infect Dis 2013; 208:109–19.

2. Condos R, Rom WN, Schluger NW. Treat-ment of multidrug-resistant pulmonary tu-berculosis with interferon-gamma via aerosol.Lancet 1997; 349:1513–5.

3. Suarez-Mendez R, Garcia-Garcia I, Fernan-dez-Olivera N, et al. Adjuvant interferongamma in patients with drug-resistant pulmo-nary tuberculosis: a pilot study. BMC InfectDis 2004; 4:44.

4. Koh WJ, Kwon OJ, Suh GY, et al. Six-monththerapy with aerosolized interferon-gammafor refractory multidrug-resistant pulmonarytuberculosis. J Korean Med Sci 2004;19:167–71.

5. Dawson R, Condos R, Tse D, et al. Immuno-modulation with recombinant interferon-gamma1b in pulmonary tuberculosis. PLoSOne 2009; 4:e6984.

6. InterMune enrolls first patient in phase IIItrial in multidrug-resistant tuberculosis.Business Wire. 2000. http://www.thefreelibrary.com/InterMune+Enrolls+First+Patient+in+Phase+III+Trial+in...-a063778269. Accessed22 October 2013.

7. Wallis RS, Wang C, Doherty TM, et al. Bio-markers for tuberculosis disease activity,

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Table 1. Clinical Trials of Adjunctive Interferon γ (IFN-γ) in Pulmonary Tuberculosis

Study

Experimental Arm(s) Control Arm

Microbiologic OutcomesSubjects, no. IFN-γ Regimen Subjects, no. Regimen

Condos et al [2] 5 500 µg aerosol 3 times/wkfor 1 mo

Not applicable Not applicable Improved sputum smears; trendtoward reduced number ofcolony-forming units

Suarez-Mendez et al [3] 5 1 MU intramuscularly daily,then 3 times/wk for 6 mo

Not applicable Not applicable Not evaluable, because ofsimultaneous change inchemotherapy

Koh et al [4] 6 2 MU aerosol 3 times/wkfor 6 mo

Not applicable Not applicable No microbiologic effect

InterMunea 40 500 µg aerosol 3 times/wkfor 6 mo

40 Aerosolized placebo No microbiologic effect

Dawson et al [5] Arm 1, 28

Arm 2, 23

Arm 1, 200 µg aerosol3 times/wk for 4 mo

Arm 2, 200 µgsubcutaneously3 times/wk for 4 mo

26 No aerosolized or subcutaneouslyadministered placebo

No effect on sputum culture;Improved sputum smear findingsin the aerosol group at 1 mo butnot at 2 mo

a The InterMune study was halted prematurely by its safety monitoring board because of a trend in the experimental arm toward excess deaths without corresponding microbiologic benefit. Its findings have beenpublished only as an online supplement to the article by Dawson et al [5].

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cure, and relapse. Lancet Infect Dis 2010; 10:68–9.

8. Horne DJ, Royce SE, Gooze L, et al. Sputummonitoring during tuberculosis treatmentfor predicting outcome: a systematic reviewand meta-analysis. Lancet Infect Dis 2010;10:387–94.

9. Phillips PP, Fielding K, Nunn AJ. An evalua-tion of culture results during treatment for

tuberculosis as surrogate endpoints for treat-ment failure and relapse. PLoS One 2013; 8:e63840.

10. Raju B, Hoshino Y, Kuwabara K, et al. Aerosol-ized gamma interferon (IFN-gamma) inducesexpression of the genes encoding the IFN-gamma-inducible 10-kilodalton protein but notinduciblenitricoxidesynthaseinthelungduringtuberculosis. Infect Immun 2004; 72:1275–83.

Received 23 June 2013; accepted 3 September 2013.Correspondence: Robert S. Wallis, MD, FIDSA (rswallis@

gmail.com).

The Journal of Infectious Diseases© The Author 2013. Published by Oxford University Presson behalf of the Infectious Diseases Society of America. Allrights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/infdis/jit555

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