肺结核进展

Copyrig New and improved tuberculosis diagnostics: evidence, policy, prac Madh ga Introduction In 2010, poor diagnosis remains a major obstacle to global tuberculosis (TB) control. In most high-burden countries, TB is still diagnosed using tools such as direct sputum microscopy and chest radiographs. Fortunately, the past few years have seen an unprecedented level of interest, funding support, and activity focused on the development of new tools for TB diagnosis, and the new diagnostics pipeline for TB is rapidly expanding. In parallel, there have been several new policy recommendations on TB diagnostics by the WHO. Because recent publications [1�,2,3�,4] have exhaustively reviewed thecurrent pipeline of new diagnostics and the expanding evidence base for their use, we focus our attention on how evidence is translated into policy, limitations of the existing evidence base, deficiencies in the current diagnostics pipeline, and challenges involved in translating policies into practice and impact. What is the evidence base for tuberculosis diagno The ev derived individual studies are seldom sufficient to inform policy and guideline development, the totality of available evidence must be synthesized. Thus, systematic reviews and meta-analyses are often necessary to summarize the evidence on a given diagnostic test. In the past decade, there have been over 35 systematic reviews published on TB diagnostics, on topics ranging from smear microscopy to molecular diagnostics and in-vitro assays for latent TB infection (LTBI). All of these systematic reviews have been made available on a new website ‘Evidence-based Tuberculosis Diagnosis’ (www.tbevidence.org) compiled by the Stop TB Partnership’s New Diagnostics Working Group, in collaboration with several agencies [5�]. While the key findings of published systematic reviews and meta-analyses on TB diagnostics have been reviewed elsewhere [6�], Table 1 provides a brief overview of the evidence base for TB diagnosis, essentially synthesizing the evidence from several systematic reviews [7–37]. What is lacking in current evidence base? aDepartme Occupation Canada, bF Center, Un California, U WHO Spec Tropical Di Geneva, Sw Correspond Professor, and Occup Avenue We Tel: +1 51 e-mail: mad Current O 16:271–28 ev ostics, and discuss issues such as how evidence is ons pa be vel xpa s. H test ura diag act nd de ge ep diagnostics, evidence, impact, policy, tuberculosis Curr Opin Pulm Med 16:271–284 � 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1070-5287 1070-528 stics? idence base for TB diagnostics is ultimately from a large body of original research. Because Although a large number of systematic reviews have been published on TB diagnostics, almost all focus on test accuracy (i.e. sensitivity and specificity). This is in part 7 � 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MCP.0b013e328338094f tice, and impact ukar Paia, Jessica Miniona, Karen Stein nt of Epidemiology, Biostatistics and al Health, McGill University, Montreal, rancis J. Curry National Tuberculosis iversity of California, San Francisco, SA and cUNICEF/UNDP/World Bank/ ial Programme for Research and Training in seases (TDR), World Health Organization, itzerland ence to Madhukar Pai, MD, PhD, Assistant Department of Epidemiology, Biostatistics ational Health, McGill University, 1020 Pine st, Montreal, QC H3A 1A2, Canada 4 398 5422; fax: +1 514 398 4503; hukar.pai@mcgill.ca pinion in Pulmonary Medicine 2010, 4 Purpose of review The aim is to summarize the recent policies on TB diagn translated into policy, limitati in translating policies into im Recent findings Case detection continues to due to an unprecedented le pipeline for TB has rapidly e guidelines on TB diagnostic (e.g. lack of a point-of-care research studies of test acc Summary With the availability of new is translation of policy into pr extent of their introduction a itself depend in part on policy TB programs. With the enga evidence-based policies into Keywords ht © Lippincott Williams & Wilkins. Unauthorized of the existing evidence base, and challenges involved ct. a major obstacle to global TB control. Fortunately, of interest, funding, and activity, the new diagnostics nded. There have been several new policies and owever, there are major gaps in the existing pipeline ) and the evidence base is predominantly made up of cy. nostics and supporting policies, the next major step ice. The impact of new tests will depend largely on the acceptance into the global public sector. This will cisions by international technical agencies and national ment of all key stakeholders, we will need to translate idemiological and public health impact. rtb and Andrew Ramsayc idence base for tuberculosis (TB) diagnostics, review reproduction of this article is prohibited. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 272 Infectious diseases T a b le 1 S u m m a ry o f fi n d in g s fr o m sy st e m a ti c re vi e w s o n tu b e rc u lo si s d ia g n o st ic te st s D ia g no st ic te st D es cr ip tio n D is ea se /s ite M aj o r fin d in g s/ re su lts o f sy st em at ic re vi ew s M aj o r re fe re nc es D ia g n o si s o f a ct iv e T B S p ut um sm ea r m ic ro sc o p y M ic ro sc o p ic o b se rv at io n o f st ai ne d ac id fa st b ac ill i P ul m o na ry T B F lu o re sc en ce m ic ro sc o p y (F M ) is o n av er ag e 1 0 % m o re se ns iti ve th an co nv en tio na l m ic ro sc o p y. S p ec ifi ci ty o f b o th flu o re sc en ce an d co nv en tio na l m ic ro sc o p y is si m ila r. F lu o re sc en t m ic ro sc o p y is as so ci at ed w ith im p ro ve d tim e ef fic ie nc y. [7 – 9 ] LE D F M p er fo rm s eq ui va le nt ly to co nv en tio na l F M , w ith ad d ed b en efi ts o f lo w co st , d ur ab ili ty , an d ab ili ty to us e w ith o ut a d ar kr o o m . C en tr ifu g at io n an d o ve rn ig ht se d im en ta tio n, p re ce d ed w ith an y o f se ve ra l ch em ic al m et ho d s (in cl ud in g b le ac h) is sl ig ht ly m o re se ns iti ve (6 – 9 % ) th an d ire ct m ic ro sc o p y; sp ec ifi ci ty m ay b e sl ig ht ly d ec re as ed (1 – 3 % ) b y sp ut um p ro ce ss in g m et ho d s. W he n se ria l sp ut um sp ec im en s ar e ex am in ed , th e m ea n in cr em en ta l yi el d an d /o r in cr ea se in se ns iti vi ty fr o m ex am in at io n o f th ird sp ut um sp ec im en ra ng es b et w ee n 2 an d 5 % . N uc le ic ac id am p lifi ca tio n te st s (N A A T s) Is o la tio n, re p lic at io n, an d d et ec tio n o f nu cl ei c ac id se q ue nc es sp ec ifi c fo r M yc o b ac te ri u m tu b er cu lo si s P ul m o na ry an d ex tr ap ul m o na ry T B N A A T s ha ve hi g h sp ec ifi ci ty an d p o si tiv e p re d ic tiv e va lu e. N A A T s, ho w ev er , ha ve re la tiv el y lo w er (a nd hi g hl y va ria b le ) se ns iti vi ty an d ne g at iv e p re d ic tiv e va lu e fo r al l fo rm s o f T B , es p ec ia lly in sm ea r- ne g at iv e an d ex tr ap ul m o na ry d is ea se . In -h o us e (‘ ho m e b re w ’) N A A T s p ro d uc e hi g hl y in co ns is te nt re su lts as co m p ar ed w ith co m m er ci al , st an d ar d iz ed N A A T s. [1 0 – 1 5 ] C o m m er ci al se ro lo g ic al an tib o d y d et ec tio n te st s D et ec tio n o f ho st an tib o d y re sp o ns e to M yc o b ac te ri u m tu b er cu lo si s an tig en s P ul m o na ry an d ex tr ap ul m o na ry T B S er o lo g ic al te st s fo r b o th p ul m o na ry an d ex tr ap ul m o na ry T B p ro d uc e hi g hl y in co ns is te nt es tim at es o f se ns iti vi ty an d sp ec ifi ci ty ; no ne o f th e cu rr en t as sa ys p er fo rm w el l en o ug h to re p la ce m ic ro sc o p y. [1 2 ,1 6 ,1 7 ] N o nc o m m er ci al (in -h o us e) se ro lo g ic al an tib o d y d et ec tio n te st s D et ec tio n o f ho st an tib o d y re sp o ns e to M yc o b ac te ri u m tu b er cu lo si s an tig en s P ul m o na ry T B S ev er al p o te nt ia l ca nd id at e an tig en s fo r in cl us io n in an an tib o d y d et ec tio n- b as ed d ia g no st ic te st fo r p ul m o na ry T B in H IV -in fe ct ed an d -u ni nf ec te d in d iv id ua ls w er e id en tifi ed . [1 8 ] C o m b in at io ns o f se le ct an tig en s p ro vi d e hi g he r se ns iti vi tie s th an si ng le an tig en s. A d en o si ne d ea m in as e (A D A ) D et ec tio n o f ho st ce llu la r en zy m e re le as ed b y ly m p ho cy te s in re sp o ns e to liv e in tr ac el lu la r p at ho g en s T B p le ur iti s, p er ic ar d iti s, p er ito ni tis M ea su re m en t o f A D A le ve ls in p le ur al , p er ic ar d ia l, an d as ci tic flu id is a us ef ul ad ju nc t te st fo r T B p le ur iti s, p er ic ar d iti s, an d p er ito ni tis . S ys te m at ic re vi ew s ha ve re p o rt ed p o o le d se ns iti vi ty es tim at es b et w ee n 8 8 an d 1 0 0 % , an d sp ec ifi ci ty es tim at es b et w ee n 8 3 an d 9 7 % . [1 9 ,2 0 ] In te rf er o n- g am m a (I F N -g ) M ea su re m en t o f IF N -g T B p le ur iti s P le ur al flu id IF N -g d et er m in at io n ap p ea rs to b e a us ef ul d ia g no st ic fo r T B p le ur iti s, w ith sy st em at ic re vi ew s re p o rt in g p o o le d se ns iti vi ty es tim at es b et w ee n 8 9 an d 9 6 % , an d sp ec ifi ci ty es tim at es b et w ee n 9 6 an d 9 7 % . [1 9 ,2 1 ] P ha g e am p lifi ca tio n as sa ys D et ec tio n o f M yc o b ac te ri u m tu b er cu lo si s- sp ec ifi c p ha g e vi ru se s, af te r th ei r in fe ct io n an d am p lifi ca tio n o f liv e M T B P ul m o na ry T B D es p ite hi g h- ac cu ra cy es tim at es , cu rr en t p ha g e- b as ed as sa ys ar e lim ite d b y hi g h ra te s o f in d et er m in at e re su lts (u p to 3 6 % ). [2 2 ] A ut o m at ed liq ui d cu ltu re s A ut o m at ed d et ec tio n o f ch an g es in o xy g en , ca rb o n d io xi d e, o r p re ss ur e re su lti ng fr o m b ac te ria l g ro w th P ul m o na ry T B A ut o m at ed liq ui d cu ltu re s ar e m o re se ns iti ve th an so lid cu ltu re s; tim e to d et ec tio n is m o re ra p id th an so lid cu ltu re s. [1 2 ,2 3 ] D ia g n o si s o f la te n t T B T ub er cu lin sk in te st (T S T ) M ea su re m en t o f in d ur at io n as a re su lt o f ex p o su re to in tr ad er m al tu b er cu lin La te nt T B in fe ct io n In d iv id ua ls w ho ha ve re ce iv ed B C G va cc in at io n ar e m o re lik el y to ha ve a p o si tiv e T S T ; th e ef fe ct o f B C G o n T S T re su lts is le ss af te r 1 5 ye ar s; p o si tiv e T S T w ith in d ur at io ns o f > 1 5 m m ar e m o re lik el y to b e th e re su lt o f T B in fe ct io n th an o f B C G va cc in at io n. [2 4 ,2 5 ] T he ef fe ct o n T S T o f B C G re ce iv ed in in fa nc y is m in im al , es p ec ia lly 1 0 ye ar s af te r va cc in at io n. B C G re ce iv ed af te r in fa nc y p ro d uc es m o re fr eq ue nt , m o re p er si st en t, an d la rg er T S T re ac tio ns . N o nt ub er cu lo us m yc o b ac te ria l (N T M ) in fe ct io n is no t a cl in ic al ly im p o rt an t ca us e o f fa ls e- p o si tiv e T S T , ex ce p t in p o p ul at io ns w ith a hi g h p re va le nc e o f N T M se ns iti za tio n an d a ve ry lo w p re va le nc e o f T B in fe ct io n. T -c el l-b as ed in te rf er o n- g re le as e as sa ys (I G R A s) M ea su re m en t o f IF N -g re le as ed fr o m ly m p ho cy te s w he n st im ul at ed b y M yc o b ac te ri u m tu b er cu lo si s- sp ec ifi c an tig en s La te nt T B in fe ct io n IG R A s ha ve ex ce lle nt sp ec ifi ci ty (h ig he r th an th e tu b er cu lin sk in te st ) an d ar e un af fe ct ed b y p rio r B C G va cc in at io n. [1 2 ,2 6 – 2 9 ] IG R A s ca nn o t d is tin g ui sh b et w ee n LT B I an d ac tiv e T B an d ha ve no ro le fo r ac tiv e T B d ia g no si s in ad ul ts . U se d as an ad ju nc tiv e d ia g no st ic , IG R A s m ay ai d in th e in ve st ig at io n o f p ed ia tr ic T B . IG R A s co rr el at e w el l w ith m ar ke rs o f T B ex p o su re in lo w -in ci d en ce co un tr ie s. IG R A p er fo rm an ce ap p ea rs to d iff er in hi g h- en d em ic vs . lo w -e nd em ic co un tr ie s. IG R A se ns iti vi ty va rie s ac ro ss p o p ul at io ns an d te nd s to b e lo w er in hi g h- en d em ic co un tr ie s an d in H IV -in fe ct ed in d iv id ua ls . Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. New and improved tuberculosis diagnostics Pai et al. 273 D ia g n o si s o f d ru g re si st a n ce P ha g e am p lifi ca tio n as sa ys D et ec tio n o f M yc o b ac te ri u m tu b er cu lo si s- sp ec ifi c p ha g e vi ru se s, af te r th ei r in fe ct io n an d am p lifi ca tio n o f liv e M T B þ in hi b iti o n o f g ro w th in p re se nc e o f an tit ub er cu lo us d ru g s R ap id d et ec tio n o f rif am p ic in re si st an ce W he n us ed o n cu ltu re is o la te s, p ha g e as sa ys ha ve hi g h se ns iti vi ty , b ut va ria b le an d lo w er sp ec ifi ci ty . In co nt ra st , ev id en ce is la ck in g o n th e ac cu ra cy o f th es e as sa ys w he n th ey ar e d ire ct ly ap p lie d to sp ut um sp ec im en s. R ec en t st ud ie s ha ve ra is ed co nc er ns ab o ut co nt am in at io n, fa ls e- p o si tiv e re su lts , an d te ch ni ca l as sa y fa ilu re s. [3 0 ,3 1 ] Li ne p ro b e as sa ys : IN N O -L iP A R if. T B [L iP A ] an d G en o T yp e M T B D R as sa y D et ec tio n o f g en et ic se q ue nc es as so ci at ed w ith re si st an ce (a ft er ex tr ac tio n an d am p lifi ca tio n) us in g im m o b ili ze d p ro b es an d co lo rim et ric d ev el o p m en t R ap id d et ec tio n o f rif am p ic in re si st an ce Li P A is a hi g hl y se ns iti ve an d sp ec ifi c te st fo r th e d et ec tio n o f rif am p ic in re si st an ce in cu ltu re is o la te s. T he te st ha s re la tiv el y lo w er se ns iti vi ty w he n us ed d ire ct ly o n cl in ic al sp ec im en s. T he G en o T yp e M T B D R as sa ys ha ve ex ce lle nt se ns iti vi ty an d sp ec ifi ci ty fo r rif am p ic in re si st an ce ev en w he n d ire ct ly us ed o n cl in ic al sp ec im en s. [3 2 – 3 4 ] C o lo rim et ric re d o x in d ic at o rs (C R Is ) D et er m in at io n o f M IC us in g m ic ro d ilu tio n, fo llo w ed b y ad d iti o n o f re ag en t w hi ch w ill b ec o m e re d uc ed in th e p re se nc e o f ac tiv el y g ro w in g M T B re su lti ng in a co lo r ch an g e R ap id d et ec tio n o f rif am p ic in an d is o ni az id re si st an ce C o lo rim et ric m et ho d s ar e se ns iti ve an d sp ec ifi c fo r th e d et ec tio n o f rif am p ic in an d is o ni az id re si st an ce in cu ltu re is o la te s. C R Is us e in ex p en si ve no nc o m m er ci al su p p lie s an d eq ui p m en t an d ha ve a ra p id tu rn ar o un d tim e (7 d ay s) . [3 5 ] N itr at e re d uc ta se as sa ys (N R A s) D ire ct o r in d ire ct in o cu la tio n o f d ru g -f re e an d d ru g -c o nt ai ni ng m ed ia co nt ai ni ng K N O 3 . A d d iti o n o f G re is s re ag en t d et ec ts ea rly g ro w th b y re ac tin g w ith en zy m at ic b yp ro d uc t an d re su lti ng in a co lo r ch an g e. R ap id d et ec tio n o f rif am p ic in an d is o ni az id re si st an ce N R A ha s hi g h ac cu ra cy w he n us ed to d et ec t rif am p ic in an d is o ni az id re si st an ce in cu ltu re is o la te s. Li m ite d d at a ar e av ai la b le o n its us e w he n d ire ct ly ap p lie d to cl in ic al sp ec im en s, b ut re su lts ar e p ro m is in g . T he N R A is si m p le , us es in ex p en si ve no nc o m m er ci al su p p lie s an d eq ui p m en t, an d ha s a ra p id tu rn ar o un d tim e (7 – 1 4 d ay s) co m p ar ed to co nv en tio na l m et ho d s. [3 6 ] M ic ro sc o p ic o b se rv at io n d ru g su sc ep tib ili ty (M O D S ) D ire ct o r in d ire ct in o cu la tio n o f d ru g -f re e an d d ru g -c o nt ai ni ng liq ui d m ed ia , fo llo w ed b y ex am in at io n us in g an in ve rt ed m ic ro sc o p e to d et ec t ea rly g ro w th R ap id d et ec tio n o f rif am p ic in an d is o ni az id re si st an ce M O D S ha s hi g h ac cu ra cy w he n te st in g fo r rif am p ic in re si st an ce , b ut sh o w s sl ig ht ly lo w er se ns iti vi ty w he n d et ec tin g is o ni az id re si st an ce . M O D S ap p ea rs to p er fo rm eq ua lly w el l us in g d ire ct p at ie nt sp ec im en s an d cu ltu re is o la te s. M O D S us es no nc o m m er ci al su p p lie s an d eq ui p m en t, an d ha s a ra p id tu rn ar o un d tim e (1 0 d ay s) co m p ar ed w ith co nv en tio na l m et ho d s. [3 7 ] T hi n la ye r ag ar (T LA ) D ire ct o r in d ire ct in o cu la tio n o f d ru g -f re e an d d ru g -c o nt ai ni ng so lid m ed ia , fo llo w ed b y ex am in at io n us in g a m ic ro sc o p e to d et ec t ea rly g ro w th R ap id d et ec tio n o f rif am p ic in an d is o ni az id re si st an ce T he re is a p au ci ty o f d at a ev al ua tin g T LA fo r th e d et ec tio n o f d ru g su sc ep tib ili ty ; ho w ev er , al l st ud ie s to d at e ha ve fo un d 1 0 0 % co nc o rd an ce w ith th ei r re fe re nc e st an d ar d s. T LA us es in ex p en si ve no nc o m m er ci al su p p lie s an d eq ui p m en t, an d ha s a ra p id tu rn ar o un d tim e (1 1 d ay s) co m p ar ed w ith co nv en tio na l m et ho d s. [3 7 ] B C G ,b ac ill us C al m et te -G ue´ rin ;L E D ,l ig ht em itt in g d io d e; LT B I, la te nt T B in fe ct io n; M IC ,m in im al in hi b ito ry co nc en tr at io n; M T B ,M yc o b ac te ri u m tu b er cu lo si s; T B ,t ub er cu lo si s. A d ap te d fr o m [6 � ] .( O p en A cc es s un d er C re at iv e C o m m o ns A tt rib ut io n Li ce ns e) . Copyrigh because a large proportion of TB diagnostic research studies are focused on measuring test accuracy. Findings from systematic reviews suggest that even relatively straightforward studies of test accuracy are often poorly designed and reported [38,39]. Both researchers of primary TB diagnostic studies and authors of systematic reviews and meta-analyses need to make efforts to follow published guidelines for conducting and reporting their work [40,41], to make the most of their contribution to a useful and unbiased literature base. Although the quality of diagnostic studies measuring test accuracy is important, evidence about test accuracy is only one link in a long chain of activities that make up the pathway to developing and implementing a new TB diagnostic. In 2009, the Stop TB Partnership’s New Diagnostics Working Group published a scientific blue- print for development of new TB diagnostics [42��]. This publication provides a comprehensive, well referenced plan to guide researchers, clinicians, industry partners, academics, and TB controllers in all sectors in all aspects of TB �� needs’ a to test d scale-up impact. As show but poli test acc to consi outcom sophisti [43,44], diagnos relevant outcom increased number of patients detected and receiving appropriate treatment, fewer patients defaulting from the dia