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PULMONARY, SLEEP, ANDCRITICAL CARE UPDATE

Update in Tuberculosis and Nontuberculous Mycobacterial

Infections 2013

Randall Reves1,2 and Neil W. Schluger3,4

1Department of Medicine, University of Colorado, Denver, Colorado; 2Denver Public Health Department, Denver, Colorado; 3Departmentof Medicine, Columbia University College of Physicians and Surgeons, New York, New York; and 4Departments of Epidemiology andEnvironmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York

The past year saw incremental progressrather than dramatic breakthroughs inmycobacterial disease research. Researchin nontuberculous mycobacteria publishedin the Journal focused on host factors thatmay underlie or predispose to infection.

Tuberculosis (TB) research touched onepidemiology, basic immunology, diagnostics,and clinical trials, as well as murine studies ofantibiotic regimens. Researchers from theUniversity of California, San Francisco addedto their impressive 20-year body of work witha description of the molecular epidemiologyof TB in immigrant communities. Furtherelucidation of the usefulness of IFN-greleaseassays used in health-care workers pointedtoward renement in our understanding ofthe optimal use of IFN-g release assays inclinical settings. Several papers added to ourknowledge of the immunology of TB, and

this work seems especially important in lightof a disappointing late phase 2b vaccinetrial. Finally, several papers in the mousemodel pointed toward important trialsusing existing TB drugs in novel ways toachieve durable cures in patients with drug-susceptible and drug-resistant active disease.This review focuses on work published in theJournaland highlights important advancesin other publications.

Nontuberculous

Mycobacterial Disease

The Journalpublished two clinical studiesin 2013 of patients in the United States with

nontuberculous mycobacterial (NTM) lungdisease. Although the study populationsevaluated include similar populations ofpredominately white female patients, thelines of investigation were distinctlydifferent. Kartalija and colleagues at

National Jewish Health compared 103patients with NTM lung disease with 110age-matched control subjects and founda distinct body morphotype (patients withNTM were taller, thinner and more likely tohave skeletal abnormalities such as scoliosisand pectus excavatum), altered adipokinebody fat relationships, and lower stimulatedwhole-blood IFN-g and IL-10 levels (1).These ndings conrmed that there isa predisposing immunophenotype to NTM,and they suggest avenues for furtherinvestigation. Fowler and colleagues andthe National Institutes of Health compared

the abnormal nasal nitric oxideproduction, ciliary beat frequency, and toll-like receptor responses in epithelium of 58patients with NTM lung disease comparedwith 40 healthy control subjects (2). Theyfound that patients with NTM had lownasal nitric oxide production and lowciliary beat frequency as well as abnormalresponses to agonists of several toll-likereceptors important for normal immuneresponses.

Both studies pose questions for furtherinvestigation into mechanisms for

susceptibility to NTM lung disease and alsoraise question about how the very differentndings of the studies may be related.Perhaps the challenges of identifying

effective treatment for NTM lung diseaseare to a greater extent attributable tohost-related factors rather than specicantimicrobial drug regimens.

TBBasic Science

Four articles published in the Journal in2013 drew attention to important aspectsof TB pathogenesis and host immuneresponses. They paint a picture of a verycomplex puzzle, and certainly we shouldremember that despite all manner ofimmune dysregulation in individualpatients, chemotherapy remains the mosteffective therapeutic modality. These papersadd considerably to our understanding ofdisease pathology and especially provide

important insights for vaccinedevelopment.

Semple and colleagues studied therole of T regulatory cells (T-Regs) ininhibiting the growth and metabolism ofMycobacterium tuberculosis in alveolar andblood-derived macrophages recovered frompatients with TB (3). In general, T-Regsare known to down-regulate effectorfunctions of CD41 and CD81 T cells, andthey have been shown to have a role inautoimmunity. In this experiment,investigators sampled blood and alveolar

macrophages from patients with TB andhealthy control subjects. They infected themacrophages with a virulent laboratorystrain ofM. tuberculosis, H37Rv, and

(Received in original form February 3, 2014; accepted in final form March 7, 2014)

Correspondence and requests for reprints should be addressed to Neil W. Schluger, M.D., Columbia University Medical Center, 622 West 168th Street,New York, NY 10032. E-mail: [email protected]

Am J Respir Crit Care Med Vol 189, Iss 8, pp 894898, Apr 15, 2014

Copyright 2014 by the American Thoracic Society

DOI: 10.1164/rccm.201402-0210UP

Internet address:www.atsjournals.org

894 American Journal of Respiratory and Critical Care Medicine Volume 189 Number 8 | April 15 2014
mailto:[email protected]://10.0.4.140/rccm.201402-0210UPhttp://www.atsjournals.org/http://www.atsjournals.org/http://10.0.4.140/rccm.201402-0210UPmailto:[email protected]


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cocultured the cells with autologous T-Regsand PPD-primed T-Regdepleted effectorcells. They found that T-Regs were present inhigher numbers in blood and bronchoalveolarlavage samples from patients with TB ascompared with those with latent TB infection.

Furthermore, they demonstrated thatrestriction of mycobacterial growth withinmacrophages was signicantly diminished inthe presence of T-Regs cocultured with thePPD-primed effector cells. Notably, the lungswere enriched for CD41 T-Regs as comparedwith blood, and the authors concluded thatCD41 CD251 FoxP31 T-Regs inhibitadaptive immune responses to mycobacteria inthe lungs and thus are permissive for bacterialreplication. This study is particularly notablefor having been performed in humans,a difcult task indeed, but one that adds great

strength to the

ndings and their implicationsfor understanding host immune responsesto TB.

A related investigation describedsuppression of T-cell function in patients withactive TB and recently acquired latentinfection through the actions of myeloid-derived suppressor cells. Nelita Du Plessis andcolleagues took blood samples from SouthAfrican patients with TB and their infectedhousehold contacts and analyzed the numberof myeloid-derived suppressor cells at thesites of disease (4). As controls, they usedsamples from patients with lung cancer and

from uninfected (tuberculin skin test [TST]-negative) household contacts. In blood andpleuraluid samples from patients with TB,increased numbers of myeloid-derivedsuppressor cells were found, and these cellshad considerable ability to inhibit T-cellfunction, as assessed in an allogeneic mixedlymphocyte reaction. In fact, myeloid-derivedsuppressor cells from both patients with TBand their TST-positive household controlsubjects impaired CD41 T-cell function,although this effect was more pronouncedin cells taken from patients with TB than

in those from their infected householdcontacts. Cytokines associated with thesefunctions included IL-1, IL-6, IL-8,granulocyte colonystimulating factor,and monocyte chemoattractant protein-1,whereas production of granulocytemacrophage colonystimulating factor andmacrophage inammatory protein-1 wasreduced. The implications of this are thatlocal immune dysregulation can beresponsible for disease manifestations.(One cannot help noting that VerdisoperaLa Traviata, in which the heroine of

course tragically dies of TB, was based onthe life of Marie Du Plessis!).

The mechanism of tissue destructionin active TB was investigated by RadhaGopal and a large group of collaboratorsin a study that demonstrated an important

role for S100 proteins in TB pathogenesis(5). These investigators showed that lunginammation and destruction are mediatedthrough accumulation of neutrophils thatproduce S100A8/A9 proteins locally.Functional granulomas that maintainthe latent state of infection were notcharacterized by the elaboration of S100proteins, but the inammatory granulomasfrom patients with active disease were.Perhaps most intriguing in this study wasthe nding that S100 protein levels wereelevated in the blood of patients with TB

as compared with control subjects with latentinfection, suggesting that this measurementcould be useful in distinguishing activedisease from latent infection. Furthermore,levels of serum S100 proteins seemed tocorrelate with lung pathology, indicatingthat this could be a useful marker of diseaseseverity. Interestingly, S100 proteinsseemed to have no role in controlling thebacterial population, suggesting thatinhibition of S100 could limit lungpathology without impairing hostantibacterial responses. However, it wouldbe intriguing to consider whether S100

could be used as a biomarker of diseaseseverity in clinical trials, as extensivecavitary disease is known to be a risk factorfor relapse after treatment completion.

A group of investigators from severalexperienced vaccine development groups(South Africa Tuberculosis Vaccine Initiative,GlaxoSmithKline, and Aeras Global TBVaccine Foundation) conducted a phase1 trialof a TB vaccine called M72/AS01 in SouthAfrican adults and demonstrated that thisvaccine induced high frequencies of T cellsbelieved to be important in the adaptive

immune response (6). In this experiment,the M72/AS01 vaccine, a recombinant fusionprotein vaccine made with several potentimmunostimulatory adjuvants, was testedin healthy South Africa adults forimmunogenicity and safety. The fusionproteins in the vaccine are found in bothM. tuberculosisand bacillus Calmette-Guerin(BCG) and are capable of inducing T-cellresponses in healthy TST-positive but not-negative adults. In the present experiment,the vaccine was safe and induced robust andlong-lasting Th1 cytokine responses. The

T-cell responses induced by the vaccine werequite complex, and, importantly, theyincluded stimulation of Th17 cells, which arebelieved to be important in protection fromTB disease through their ability to recruitIFN-gproducing cells to the lungs, where

they can inhibit mycobacterial growth.The positive results and encouraging

immune response generated in theM72/AS01 trial just discussed are temperedby the disappointing results of the phaseIIb MVA85 trial this year, published in JuneinThe Lancet(7). In this highly anticipated,large phase 2 trial, healthy infants aged4 to 6 months who had previously receivedBCG vaccine received a dose of MVA85Aor a placebo, and the cohort was followedevery 6 months for up to 3 years. A totalof 2,797 infants were vaccinated. The

number of systemic and/or serious adverseevents between the experimental andplacebo groups was not different. However,the incidence of TB in the follow-up periodwas nearly identical in the vaccinatedand control groups: 2% of the experimentallyvaccinated group developed TB in thefollow-up period, and 3% of the controlvaccinated infants did. The calculatedvaccine efcacy was only 17.3%, far belowthe level of protection needed to prevent TBdisease. Although the vaccine did induceMVA85A-specic T-cell responses, theseresponses were not as robust as had been

seen in the preclinical animal studies or insome human trials. The results of this trialcall into question the whole enterprise ofselecting vaccine candidates based on currentassumptions about immune correlates ofprotection against either initial infection withM. tuberculosisor from progression fromlatent infection to active disease.

It has been well established that thetype II interferons (particularly IFN-g arecritical in host defense against TB. Animportant insight into the regulation ofIFN-g responses was contributed by Teles

and colleagues, who demonstrated thattype I interferons (IFN-a and IFN-b),which are commonly produced duringviral infections as an important hostdefense mechanism, can inhibit productionof IFN-g, leading to loss of control againstTB (and leprosy [8]).

Epidemiology

Three articles published in the Journal in2013 further our understanding of theepidemiologic features of TB transmissionusing unique and very different approaches.

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In the latest of a series of successively largercommunity-wide epidemiologic studies ofTB conducted among residents of SanFrancisco, Suwanpimolkul and colleaguesdescribe use of molecular epidemiologictechniques to describe the more rapid

decline of the case rates due to secondarytransmission from 1991 to 2009 amongthose born in the United States comparedwith foreign-born persons (9). Beginning in2000, population-based analysis wasfeasible for the U.S.-born and the threelargest foreign-born populations (fromChina, the Philippines, and Mexico)revealing unique clinical, microbiological,and epidemiologic differences that mayinform specic TB control measures. Thehigher rates due to secondary transmissionfor cases among U.S.-born individuals in

the San Francisco study were also observedin a large multicenter study of thetransmission of multidrug-resistant (MDR)TB published by Moonan and colleagues inThe Lancet Infectious Diseasesin 2013 (10).Consent for interviews was obtained in92 of 168 patients with MDR TB reportedin eight centers during 2007 to 2009,of whom 86% were foreign born.Approximately one-fth of cases wereconsidered imported cases owing todiagnosis in foreign-born persons within3 months of arrival in the United States(three with extensively drug-resistant TB)

and another one-fth due to transmissionwithin the United States. The majority wereattributed to reactivation of infection withMDR TB acquired years before U.S. entry.The frequency of transmission was 2.9-foldhigher from cases among U.S.-born thanforeign-born persons, but because of thegreater number of cases among the latter,half of secondary cases resulted fromtransmission from foreign-born cases. TheWorld Health Organization estimates thatnot even 20% of the 500,000 new MDR TBcases globally each year are diagnosed,

much less effectively treated. Ongoingtransmission of MDR TB can be expectedin both developed and developing countriesuntil safe and effective short-courseregimens are developed and made available.In contrast to the San Francisco study,results of which were largely driven bythe arrival of individuals infected withM. tuberculosisin their country of birth, theother two articles seek to address theimportant topic of ongoing transmission ofTB in high-burden countries. Jones-Lopezand colleagues conducted contact

investigations for household members of 96patients diagnosed in Kampala, Ugandawith acid-fast bacillus (AFB)-positivesputum specimens (11). This was the rststudy to show the value of the coughaerosol sampling system (CASS) in

stratifying the risk of transmission, denedas baseline to 6-week conversion to positiveresults by TST and/or IFN-g releaseassay (IGRA). The CASS category of highaerosol production, present in only 25(26%) of the patients, was associated witha 5- to 10-fold higher rate of transmission,independent of AFB smear grading.Whether CASS can be implemented asa tool in TB control is yet to be determined,but these data help us understand whysome AFB-positive patient are efcienttransmitters and similar ones are not.

Dowdy and colleagues modeled therelative effectiveness of strategies forreducing the transmission and thus thefuture incidence of TB in high-burden TBcommunities where most of the 1.4million global TB deaths occur each year.Of the three strategies evaluated, twoinvolve improvements applicable toindividuals with symptoms of TB,specically more accurate and rapiddiagnostics and reducing delays inreceiving evaluation and treatment. Themodeling suggests that the third strategyof active case nding (including in part

the process of contact investigations) fordetection and treatment of subclinicalcases of TB could be more effectivethan the rst two, depending on anunknownthe relative infectiousness ofsubclinical cases (12).

Related to this topic, the results ofthe large, randomized community andhousehold intervention trial in southernAfrica (ZAMSTAR) were also reported in2013 and disappointingly showed nosignicant reduction in the incidence of TBor TB infection in schoolchildren in the

study arms of enhanced community accessto AFB microscopy or interventions toimprove TB-HIV services for householdmembers of individuals with new TB cases(13). Perhaps the data from this studywill help inform further evaluation ofintervention strategies for TB, whether inthe form of future community interventiontrials or modeling studies.

Diagnostics

In 2010, the United States Centers forDisease Control and Prevention published

recommendations that IGRA could be usedinstead of the Mantoux TST for thediagnosis of latent TB infection, especiallyfor those with prior vaccination withBCG or unlikely to return for the TSTinterpretation. Over a decade later, IGRA is

increasingly being used, although thechallenges in interpreting the results remainto be completely understood. Three articlesand an editorial on the topic of IGRApublished in the Journalin 2013 improveour understanding of some of theremaining puzzles, including the meaningof the high frequency (60% or more) ofreversion of positive IGRA test results inrepeat testing and the use of IGRA tomeasure the effectiveness of treatment forlatent TB infection. The two studies of theQuantiFERON-TB Gold assay both involve

largely low-risk populations in theUnited States, although both studies lackindividual-level data on risk of prior TBexposure, vaccination with BCG, and TSTresults. The study reported by Slater andcolleagues of more than 9,000 health-careworkers undergoing annual repeat testingfound a 4% rate of conversion to a positivetest result that was interpreted as falsepositive based on comparison with thehistorical TST conversion rate of 0.4%, anda reversion from a positive to negativeresult in more than 60% at a 60-day follow-up (14). Even after accounting for

reversions, however, there was still a higherapparent rate of infection as measured byIGRA compared with TST. These resultsare not easily explained and highlight thedifculty of developing new assays forlatent infection in the absence of a true goldstandard.

The study by Metcalfe and colleaguesexamined one of the potential componentsof the variability in results by merelyrepeating the ELISA assay on the residualstimulated plasma for a subset of individualswhose assay responses were at least

0.25 IU/ml (15). Discordant results wereobserved in the repeat ELISA for 9% ofrepeats with initial negative results and 7%when the initial result was positive. AsMancuso and colleagues point out in theeditorial, the predictive value of a positivetest result will be diminished whenapplied in a low-risk population, a problemnot resolved by the introduction of theIGRA (16).

The article by Adetifa demonstrates thevalue of a well-designed randomized clinicaltrial in answering an important question:




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Can the IGRA responses be used asa biomarker for response to treatment oflatent TB infection (17)? The answer isclearly no: about 20% of contacts witha positive TST and a positive IFN-genzyme-linked immunospot assay had

reversion to a negative IGRA response at1 month in both the placebo and 6-monthisoniazid arms without decline at a 1-yearfollow-up. Screening for study eligibilitydid show the apparent improvedspecicity of the IGRA in this populationin Gambia. Positive TSTs were detected in39% of 1,659 household contacts, butonly 33% of the TST-positive contacts hada positive IGRA, presumably reecting theeffect of prior BCG vaccination on theTST.

Clinical TrialsTwo studies published in the Journalin2014 examined the role of quinoloneantibiotics in the treatment of TB. Ina trial of levooxacin as compared withmoxioxacin in patients with MDR TB inSouth Korea, levooxacin seemed toperform just as well as moxioxacin,although moxioxacin is known to havea more favorable minimal inhibitoryconcentration against M. tuberculosisin vivo as compared with levooxacin (18).An editorial that accompanied that studypointed out several potential shortcomings

in the conduct of the trial but concludedthat overall, based on present publisheddata, there seems to be rough equivalencebetween the two drugs in actual clinicaluse (19).

A murine study further examined therole of moxioxacin and levooxacin insecond-line regimens for TB. In this study,moxioxacin-containing regimens andlevooxacin-containing regimensperformed similarly in initial phases oftreatment, but the moxioxacin-basedregimens were associated with better

bacterial killing 4 and 5 months afterinitiation of therapy (20). Interestingly, thisadvantage for moxioxacin was largelyeliminated if pyrazinamide was included inthe regimen. This may in part explain theresults of the South Korean trial in humans,as 82% of the patients in the levooxacinarm and 69% of patients in themoxioxacin arm were also receivingpyrazinamide.

Other murine studies ofantituberculosis drugs focused on optimal

use of existing medications. Over the pastseveral years, there has been a growingappreciation that the most potent class ofantituberculosis drugs, the rifamycins, havenot been used to maximum advantage,primarily because they have been used at the

lower end of their effective dosing range(21). A number of ongoing clinical trials inhumans are examining higher doses ofseveral members of this class, includingrifampin and rifapentine. Using the mousemodel of TB, a Dutch group led by Jurriande Steenwinkel showed that themaximum tolerated dose of rifampin wasan astounding 160 mg/kg/d (in humans,treatment doses are generally 10 mg/kg/d)(22). At that very high dose, importantpharmacokinetic parameters such as Cmaxand AUC0-24 were substantially higher

than those achieved with conventionaldosing. Rifampin given to the mice ata dose of 80 mg/kg/d in combination withisoniazid resulted in complete sterilizationwithout relapse after only 9 weeks oftreatment. These results will surely bolsterthose examining the role of higher doses ofrifamycins in humans.

The potential role of clofazimine,another old and by now infrequently usedantituberculosis drug, was assessed ina murine trial conducted by Jacques Grossetand colleagues (23). This drug has generallybeen regarded as less potent than many

of the other second-line agents, andproblems with skin hyperpigmentationhave further limited its use. However,because of the emergence of MDR TB andthe shallow pipeline of new agents inclinical development, interest has beenrekindled. In this study, Grosset andcolleagues (23) treated mice infected withTB with a second-line regimen ofmoxioxacin, ethambutol, pyrazinamide,and (for the initial 2 months) amikacinwith or without clofazimine. All mice thatreceived clofazimine were culture negative

after 5 months (with an ultimate relapserate of 7%), whereas mice that did notreceived clofazimine remained culturepositive through 9 months of treatment.

A fascinating study from WilliamBishai and his group working in Baltimoreand Durban examined the potential roleof verapamil as adjunctive therapy for TB(24). A prior study from another group haddemonstrated a novel mechanism of drugtolerance in mycobacteria that involved anefux pump that could be inhibitedin vitro

by addition of verapamil (25). Efux pumpslower intracellular drug concentrationsand make error-prone replication morelikely, increasing the chance of a minimalinhibitory concentrationchangingmutation. In the study by Gupta and

colleagues (24), researchers tested the effectof adjunctive verapamil in a murine model,using C3HeB/FeJ mice, which are capableof forming necrotizing granulomas.Addition of verapamil accelerated bacterialclearance, allowed for treatment shortening,and lowered relapse rates. Althoughwidespread use of verapamil (especially inthe higher doses needed to overcome theinduction of metabolism caused byrifampin) may be unrealistic in TB, the useof efux inhibitors in general will be anintriguing avenue to pursue in clinical trials

in the future.In a different vein, an importantimplementation science study was publishedthat examined the role of the GenXpertMTB/RIF technology in affecting betteroutcomes for patients (26). Thisrandomized trial conducted in South Africademonstrated positive effects of thetechnology as manifested by more patientsstarting same-day treatment, more culture-positive patients starting therapy, anda shorter time to treatment. However, therewas no overall effect on TB mortality.This study points out the challenges of

integrating this important new technologyinto TB control programs in a manner thataffects overall morbidity and mortality.

TB Research Funding

In some ways, the most importantpublication related to TB research this pastyear was the 2013 Report on TuberculosisResearch Funding Trends, 20052012published by Treatment Action Group (27).This report demonstrated the dramaticunderfunding of TB research globally (forbasic science, diagnostics, drugs, andvaccines) compared with other similarpublic health crises, such as HIV.Furthermore, and most worrying, TBresearch funding globally actually declinedin 2013. If this trend continues, the chancefor signicant progress in controlling oneof the worlds great public health challengeswill remain unlikely. n

Author disclosuresare available with the textof this article at www.atsjournals.org.


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