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Speaker was diagnosed in early Mayto Greece for his wedding later that month.Tracked down in Rome on his honeymoon,he was told he had extensively drug-resis-tant tuberculosis (XDR-TB) and was askedto stay put.

to Prague and Montreal and then drove

from the Centers for Disease Control andPrevention directed Speaker to report toBellevue Hospital, where he was servedwith a federal warrant that isolated him fororder issued in 44 years.

Bellevue is no stranger to TB. The hos-pitals Chest Service, established in 1903to treat the disease, has contributed a greatdeal of knowledge about its pathophysiol-ogy, clinical behavior, and treatment. Inthe late 1980s and early 1990s, Bellevueendured a long bout with this familiar foe,grappling with nearly 4,000 cases in NewYork City, many of them homeless people

addicted to drugs and infected with HIV.I came here and I found everything was

M.D., M.P.H., director of the Chest Service.He came to NYU in 1989 after a long stintat the Rocky Mountain Center for Occupa-tional and Environmental Health, wherehis primary experience had been with coalminers and asbestos workers. Dr. Rom,the Sol and Judith Bergstein Professor ofMedicine and professor of environmentalmedicine, quickly discovered that TB treat-ment and care had barely changed since

the 1960s, and that the available drugswere powerless against some new strainsofM.Tb.

Multi-drug resistant (MDR) TB developswhen patients dont complete the pre-scribed six-month course of isoniazid andrifampicin. About one in 20 new cases of TB

-counterM. tb and that the bacteria live andmultiply in these macrophages. But somebacteria, such asM. tb, have devised ways toright, says Dr. Ernst.

Dr. Ernst and graduate student Andrea

M. tb -cent green label to allow them to trackthe bacterias progress through the body.They found that, in fact, the bacteriainfect different kinds of cells and that thepredominant type of cell infected changesover time. At the earliest point there isa three-way tie in the cell types infectedwithM. tb: macrophages, dendritic cells,arrive at a site of infection). By the thirdweek, dendritic cells, not macrophages,are the cell type predominantly infectedwithM. tb, they reported. That certainlycalls into question the TB dogma that mac-

rophages are the only cells that harborM.tb, says Dr. Ernst. It says TB immunityis in line with the rest of contemporarycellular immunology.

The researchers also found the bacteriain lung-draining lymph nodes, but up to 80percent of the bacteria were once again inof infection, Dr. Ernst explains, a largenumber of infected dendritic cells carry thebacteria from the lung to the lymph nodes.Its only after the bacteria appear in theselymph nodes that T cells are activated. TheT cells then have to be transported back tothe lung, the main site of infection.M. tb

takes advantage of this lost time, multiply-ing to overwhelming numbers. I thinkthats one of the reasons TB wins, says Dr.Ernst. It rigs the system so that by the timethe T cells are recruited into the lung, thereare a million bacteria.

Getting the bacteria to the lymph nodes,which has to happen before the immuneresponse kicks into gear, appears to be thetime-dependent step that slows down thewhole process. Dr. Ernst says the bacteriamay have evolved to survive in a part ofthe lung from which they cant easily bemoved to the lymph nodes. Some peoplesbodies may be able to get around this bet-

ter than others, which potentially explainswhy not everyone exposed to TB developsa full-blown infection. Unfortunately,even the infected cells in the lymph nodesare rather inept at inducing an adequateimmune response.-

plications for vaccine development. If theinfection, vaccines designed to activate im-mune cells may prove powerless at leastwithout additional methods to foilM. tbsevasive tactics.

NYU PHYSICIAN+ SUMMER 2008

FOR A FEW WEEKS LAST SUMMER,Americans were riveted by news that Andrew Speaker,on commercial airplanes, exposing hundreds of peopleto a virtually untreatable type of tuberculosis (TB).They could be forgiven for having thought of TB as strict-ly a third-world disease. In 2006, 13,767 people in the U.S.had TB the lowest prevalence in the country recordedsince 1953 while else-where 1.5 million peopledied of the disease.

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Fighting Drug-Resistant TB inNew York City

BY:APOORVAMANDAVILLI

Dr. Will iam Rom stands at theentrance of the Chest Serviceon Bellevues 7th floor.A Bellevue security officer standsguard in the foreground.

DOCTOR:WILLIAM ROM

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accounting for nearly 500,000 of the 9million new TB cases reported each year, ac-

Treating these strains is even moregrueling and expensive: at least fourdrugs taken daily for up to two years. Notsurprisingly, many patients miss dosesor abandon treatment entirely, putting

themselves and others at risk of develop-ing the deadlier XDR-TB. It can take weeksto identify the few drugs to which a par-ticular strain is still sensitive. These haveto be drugs the patient has never takenbefore, explains Dr. Rom, so you can besure that theyre not resistant.

Bellevue was one of only two hospitalsin New York City with facilities to isolatethose who failed to take their medicinesregularly. Between 1993 and 1998, the cityscourts allowed Bellevue and GoldwaterMemorial Hospital, which closed its TBward in 2001, to detain more than 250patients for the duration of their treatment.

Dr. Rom took the important step of mod-negative air pressure, and UV lights to killairborne bacteria.

Bellevue also instituted hospital-basedDirectly Observed Therapy (DOT), inwhich patients took their TB drugs inthe presence of a hospital worker. DOT is

RESEARCHER:SUMAN LAAL

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credited with turning the tide, slashingthe number of cases from 3,800 in 1992 toroughly one-third that number today.

Ironically, the citys epidemic affordeddoctors the opportunity to apply advancedtechnology to an age-old disease.

Dr. Rom and his colleagues quicklybecame TB experts, leading rigorous stud-

ies on the epidemiology of the disease andthe treatment of drug-resistant strains. Ofthe 173 patients with MDR-TB admittedby Bellevue between 1983 and 1994, 72 per-cent were cured with second-line drugs. Inthose also infected with HIV, however, thecure rate was only 20 percent.

More recently, researchers have madeinroads into understanding the immunesystems response toM. tb, the effective-ness of linelazid and aerosolized interfer-on-gamma on XDR-TB patients, and theinteraction between HIV and TB.

After only 72 hours at Bellevue, Andrew-

ical Center in Denver. His diagnosis, basedon tests conducted there and at Bellevue,was later downgraded to MDR-TB. Thecity he left behind is home to nearly 1,300people infected with TB, and Bellevue seesmore than its fair share, including somewith MDR-TB. TB is a disease of povertyand immigrants, says Dr. Rom. Theresplenty of both in New York City.

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TO CONFIRM THAT YOUhave TB, the doctor willask you to cough upat least a teaspoonfulof phlegm, or sputum.Youll have to come

back to the hospitaltwice more to provide samples, andtechnicians will painstakingly culture theslow-growing bacteria from the sputum.A few weeks after that third visit by whichpoint you may have exposed others thedoctor should be able to tell you whetheryou have TB.

HopeGrows forFaster

TBTest

This crude sputumdiagnostic test is100 years old. Thesituation is fairlyhorrendous, says Dr.Suman Laal, Ph.D.,associate professorof pathology andmircrobiology.

There are afew expensivealternatives:fluorescentmicroscopy,automated culturesystems, and testsfor the bacterialDNA. But 90 percentof the disease isconcentrated in thepoorest parts of theworld, where theseoptions are notfeasible.

Clinically, TBsymptoms can bedifficult to distinguishfrom those ofother bacterial orfungal infections,

pneumonia, orcertain tumors.Diagnosis withX-rays is subjectiveand all but uselessin people who areHIV-positive, anda commonly usedskin test gives falsepositives in anyonewho has beenimmunized with theBCG vaccine orhas been infectedwith the TB bugsbacterial cousins.

The ideal test forTB would be fast,cheap, and woulddeliver a simple Yes

or No answer much like a dipstickpregnancy test. Butdeveloping a testlike that has provedchallenging.

The DNA of thebacterium thatcauses TB twistsand coils into astructure that wasdifficult to unravelwith old-fashionedsequencingtechniques. In 1998,when researchersfinally decoded its

enormous genome,they found thatsome 500 of thebacterias 4,000genes belongedto a previouslyunknown geneticfamily.

Applying whattheyve sincelearned about thebacteriums proteins,several teams aretrying to developsimple TB tests. Dr.Laal and otherresearchers acrossthe U.S. and in Indiahave been workingto develop a urine-or serum-based testthat would detectone or more of thebacteriums proteins,even in someoneinfected with HIV.Her quest has takenDr. Laal back to hernative India at leastonce every year. The

country has sizableepidemics of both TBand HIV.

The combinationof proteins madeby the bacteriachange as theinfection progresses,so researchers havetried to find onesthat are expressedthroughout thecourse of thedisease. From apromising list of12 proteins, theyfound two inparticular thatsignal active TBinfection well before

symptoms becomeobvious andirrespective of HIVinfection.

Researchersare now trying toidentify a smallpiece of eachprotein that wouldbe cheaper andeasier to produceen masse. I thinkwere pretty closeto having a set ofpeptides that canreplace the smeartest, says Dr. Laal.