Started by shobha luxmi on 15 Jun 2012
It means no precautions are required to prevent transmission as soon as one start ATT.Dr. ShobhaID specialistKarachi,Pakistan
Please be very very clear on what I have said. The existing data for drugsusceptible TB is very, very clear that infectiousness ends well before thesmear and culture turns negative. Riley's guinea pig data indicates thatpatients started on therapy the same day as they entered his experimentalfacility were 98% less infectious than those who did not start therapy. However, treatment must be effective treatment - not just any treatment. So you cannot say that no precautions are necessary as soon as you startATT (antituberculosis therapy) unless you know the drug susceptibilitypattern of the patient's isolate, which is only possible with rapiddiagnostics. If you do not know the drug susceptibility pattern, thepatient could be drug resistant, not on EFFECTIVE therapy, and may beinfectious, so the usual precautions are necessary. I will provide thisdata on line here as soon as I am situated in a place with reliable email -am travelling.Edward Nardell, MD
7:23 AM, 15 Jun 2012 | Permalink
Totally agree. Precautions remain in place for two weeks for sensitive TB in S Africa but less so in the UK. MDR-TB should have airborne precautions during hospital admission unless cleared.ShaheenSent via my BlackBerry from Vodacom - let your email find you!
8:05 AM, 15 Jun 2012 | Permalink
Dear Shaheen,You are reflecting current, widely held policy. I am suggesting that therehas been excellent evidence for more that 50 years that infectiousness ofdrug susceptible patients ceases much sooner than 2 weeks, regardless ofsmear or culture status - on EFFECTIVE therapy. There is some evidencethat the same holds for MDR-TB, and I will elaborate on this shortly. Although sputum culture colony counts decrease rapidly on effectivetherapy (early bacteriocidal activity), they do not convert to negativeuntil 2 months on average. Therefore, we as a community in applying the"two week rule" we have long accepted the notion that sputum smear is not areliable indicator of infectiousness. That is, many patients are smearpositive when they are considered non-infectious. It is true that we alsosay that patients should be clinically responding to treatment withdecreasing cough, etc, but these are simply additional indicators ofEFFECTIVE therapy. Now, with the advent of rapid DSTs, we have theopportunity to avoid INEFFECTIVE therapy from the beginning, allowing us tohave greater certainty (when rapid DSTs are available) that patients areon effective therapy.I will post a more complete version of my argument shortly.Ed Nardell ...
Dear Shaheen,You are reflecting current, widely held policy. I am suggesting that therehas been excellent evidence for more that 50 years that infectiousness ofdrug susceptible patients ceases much sooner than 2 weeks, regardless ofsmear or culture status - on EFFECTIVE therapy. There is some evidencethat the same holds for MDR-TB, and I will elaborate on this shortly. Although sputum culture colony counts decrease rapidly on effectivetherapy (early bacteriocidal activity), they do not convert to negativeuntil 2 months on average. Therefore, we as a community in applying the"two week rule" we have long accepted the notion that sputum smear is not areliable indicator of infectiousness. That is, many patients are smearpositive when they are considered non-infectious. It is true that we alsosay that patients should be clinically responding to treatment withdecreasing cough, etc, but these are simply additional indicators ofEFFECTIVE therapy. Now, with the advent of rapid DSTs, we have theopportunity to avoid INEFFECTIVE therapy from the beginning, allowing us tohave greater certainty (when rapid DSTs are available) that patients areon effective therapy.I will post a more complete version of my argument shortly.Ed Nardell, MD
2:39 PM, 16 Jun 2012 | Permalink
In response to several comments asking for more information on my assertionthat the EFFECTIVE treatment of drug susceptible TB, and probably drugresistant TB, occurs almost immediately, I am posting a summary of a talkgiven at a TB IC subcommittee meeting in Berlin, November, 2010. I haveedited it to remove data that might be considered a barrier to publishingthis work in a peer-reviewed journal.Some have asked how rapid is rapid? All I can say is that, as you willsee, Richard Riley started patients on therapy the same day that theyentered his experimental ward and we have done the same. The 98% reductionin infectiousness to sentinel guinea pigs that Riley reported was not dueto 2 wks or even 2 days treatment, but somewhat less than 24 hrs, concedingthat there is a time lag in the process of transmission. That is, evenuntreated patients may not infect guinea pigs on their first day ofexposure. The point is that the effect is rapid and profound, toparaphrase Riley - quoted in the text, below. My apologies for the lengthof this post.To reiterate one more time, I am not saying that no ...
In response to several comments asking for more information on my assertionthat the EFFECTIVE treatment of drug susceptible TB, and probably drugresistant TB, occurs almost immediately, I am posting a summary of a talkgiven at a TB IC subcommittee meeting in Berlin, November, 2010. I haveedited it to remove data that might be considered a barrier to publishingthis work in a peer-reviewed journal.Some have asked how rapid is rapid? All I can say is that, as you willsee, Richard Riley started patients on therapy the same day that theyentered his experimental ward and we have done the same. The 98% reductionin infectiousness to sentinel guinea pigs that Riley reported was not dueto 2 wks or even 2 days treatment, but somewhat less than 24 hrs, concedingthat there is a time lag in the process of transmission. That is, evenuntreated patients may not infect guinea pigs on their first day ofexposure. The point is that the effect is rapid and profound, toparaphrase Riley - quoted in the text, below. My apologies for the lengthof this post.To reiterate one more time, I am not saying that no TB IC precautions areneeded once treatment is started. There are several limitations with thatnotion: 1) there are inherent delays in suspecting and diagnosing TB, 2)there are major delays in diagnosing drug resistance, and 3) there aredelays in initiating effective therapy even when drug susceptibility isknown. Because these logistical delays exist and because rapid, reliablemolecular testing are not widely available, usual TB IC precautions arestill needed. Since there will always be a pre-diagnostic period,conventional TB IC will always be needed. I am suggesting a changein priorities to !) active case finding, 2) rapid molecular diagnostics,including DSTs, and 3) rapid institution of DST-based effective therapy. Wecall this approach, F-A-S-T: Find cases Actively, Separate safely, andTreat effectively.Ed Nardell, MDTB Infection Control Sub-Working GroupBerlin, November, 2010*Impact of Treatment on MDR-TB TransmissionPreliminary Data from the Airborne Infections Research (AIR) Facility*Edward A. Nardell, MDHarvard Medical School/PIHBrigham & Women’s HospitalAccording to the WHO, of the estimated 500,000 new MDR-TB cases per year,more than half result from transmission* *Multidrug and extensivelydrug-resistant TB (M/XDR-TB). Most MDR cases are treated in hospitals forfirst 6 months – until culture conversion. In some high incidence areas ofMDR TB, such as South Africa, there is a growing appreciation of the gapbetween the growing need for MDR treatment and the availability of hospitalbeds. South Africa is therefore planning to switch to community-basedtreatment, as practiced in many sites around the world, but there islingering concern about transmission in the community by MDR-TB patients ontherapy.Exactly how long MDR-TB patients remain infectious on therapy is notknown. A recent CDC task force reviewed the medical literature and foundlittle or no evidence to support any policy on treatment duration andinfectivity of MDR-TB. Most national policies on TB treatment of drugsusceptible TB indicate that infectiousness ends after about 2 weeks ofeffective treatment. However, during the 1985-1992 outbreaks of MDR-TB inNYC, transmission was associated with undiagnosed MDR-TB patients who werereleased from isolation after 2 weeks therapy. In response, many nationalprograms recommend treatment until smear or culture conversion – at least 6months, as previously noted.In examining the evidence base for the 2-week treatment recommendation fordrug susceptible TB, the following citations were reviewed:• Andrews RH. Bull WHO. 1960 (Madras, India)• Crofton J. Bull IUAT. 1962 (Edinburg, Scotland)• Brooks S. Am Rev Resp Dis. 1973 (Ohio)• Riley R. Am Rev Resp Dis. 1974 (Baltimore)• Gunnels J. Am Rev Resp Dis. 1974 (Arkansas)• Rouillon A. Tubercle. 1976 (Review)The latter review of the literature indicated that it appeared that smearand culture correlate with infectivity only in untreated cases, and thatthere appeared to be a discordance between the effect of treatment on smearand culture on the one hand and infectivity. The primary evidence is thatsmear and culture positive TB patients on therapy generally do not infectskin test negative close contacts. However, Menzies reviewed the effect oftreatment on the contagiousness of patients with active pulmonarytuberculosis (Infect Control Hops Epidemiol 1997; 18:582-586) and foundmethodological flaws in several of these studies. He questioned, forexample, whether there might have been selection bias in the householdcontact studies. Perhaps the sickest patients remained in the hospitalwhile less infectious patients were sent home.Despite these reservations, Rouillon concluded the following about theimpact of effective treatment on transmission:“There is an ever-increasing amount of evidence in support of the idea thatabolition of the patient’s infectiousness *– a different matter from‘cure,’ which takes months and from negative results of bacteriologicalexaminations, direct and culture, which may take weeks –* is very probablyobtained after less than 2 weeks of treatment”.“These facts seem to indicate very rapid and powerful action by the drugson infectivity…”These studies greatly influenced official isolation policies by CDC, ATS,and other national and international agencies until the mid 70’s, such as:• 1969 ATS – Guidelines for the general hospital for the admissionand care of tuberculosis patients.• 1970 ATS – Bacteriologic standards for discharge of patients• 1973 ATS – Guidelines for work for patients with tuberculosis• 1974 CDC – Recommendation for health department supervision oftuberculosis patientsHowever, more direct evidence on the impact of treatment on TB transmissionwas obtained by the classic experimental studies by Riley and colleaguesusing air sampling by sentinel guinea pigs on a 6-bed experimentaltuberculosis ward at the Baltimore VA Hospital between 1958 and 1962 (Am JHyg 1959; 70:185-196, reprinted as “classic” Am J Epidemiol 1995; 142:3-14)Riley reported that although an average of 3 guinea pigs were infected permonth, infections were highly variable. During one 4-month periodinfections ceased completely. In investigating the reasons, it wasdiscovered that during that period only drug susceptible cases had beenadmitted to the ward. Prior to that time, and afterwards, when drugresistant cases were again admitted to the ward, transmission to guinearesumed.Recognizing the importance of treatment to transmission, Riley exposedguinea pigs to patients with and without treatment during the second 2 yearstudy. The result was a direct comparison of the relative effects oftreatment on drug susceptible and drug resistant TB. Note that there wasno MDR TB at the time, since this was many years before the introduction ofrifampin. On the other hand, please keep in mind that the remarkableeffects on transmission shown before were accomplished with just INH, PAS,and SM, and in the case of DR disease, just one or two of these drugs.Finally, and most importantly*, Riley started therapy on the day that thepatients were admitted to the ward, so these results represent very, verylittle treatment*.*Relative infectivity of patients*:*– Susceptible TB• 61 *Untreated* (29 GPs) *100%*• 29 Treated (1 GP)*2%*– Drug-resistant TB• 6 *Untreated * (14 GPs) *28%*• 11 Treated (6 GPs) *5%** **all smear positive patients, relative to the amount of time on the wardRiley concluded (Am Rev Resp Dis 1962; 85:511-525):“The treated patients were *admitted to the ward at the time treatment wasinitiated* and were generally removed before the sputum became completelynegative. Hence the decrease in infectiousness preceded the elimination ofthe organisms from the sputum, indicating that *the effect was prompt aswell as striking.” ** **“Drug therapy appeared to be effective in reducing the infectivity ofpatients with drug resistant (H, SM, PAS only) organisms, but the data donot permit detailed analysis of the problem”. *In another similar, more recent study of the infectivity of TB patientsusing guinea pig air sampling in Lima, Peru, Escombe (Plos Medicine 2008;5:e188) noted that virtually all transmission was from inadequately treateddrug resistant strains. In that study, 97 HIV+ pulmonary TB patientsexposed 292 guinea pigs over 505 days. Of these patients, 66 cult wereculture positive and 35 smear were sputum smear positive. Of 125 infectedguinea pigs, 122 (98%) were due to 9 MDR patients who were inadequatelytreated or who’s treatment was delayed. It should be noted that 108 orthe 125 infections were due to just 1 MDR patient. Three drug susceptiblepatients infected one guinea pig each – two had had delayed treatment andone had had treatment stopped for side effects.Finally, in South Africa, in yet another contemporary facility designed forsentinel guinea pig air sampling, researchers from the South African MRC,CDC, and Harvard University have studied the transmission of MDR TB and theeffects of various interventions, such as ultraviolet air disinfection andmasks on patients. The, as yet unpublished, studies mentioned here werenot intended to examine the effects of treatment on transmission, althoughsuch investigations were planned. However, observations made in the courseof a pilot study and 3 subsequent intervention studies independently shedlight on the impact of treatment on MDR and XDR TB transmission.Because these data are being prepared for publication, I cannot report themin detail here. Suffice it to say that cohorts of patients caused highlyvariable rates of transmission in 6 separate experiments including 109patients and groups of 90 – 360 guinea pigs. In an already publishedpilot study (Dharmadhikari AS, Basaraba RJ, Van Der Walt ML, Weyer K,Mphahlele M, Venter K, Jensen PA, First MW, Parsons S, McMurray, DN, OrmeIM, *Nardell EA*. *Natural infection of guinea pigs exposed to patientswith highly drug-resistant tuberculosis.* *Tuberculosis*, 2011. *91*(4): p.329-38.) , 26 patients referred with MDR-TB (selected for pos smear,coughing, cavitary) treated with standard South African regimen (started onadmission) infected 74% of 360 sentinel guinea pigs over a 4 monthexposure. In contrast, 27 patients selected for the same criteria infectedjust 1 of 90 exposed guinea pigs over a 3 month exposure. As indicated inthe above publication, isolates from guinea pigs in the first study matchedby spoligotype with 3 XDR patients among the 26 who occupied the ward.These XDR patients were unsuspected and not being treated for XDR TB. Incontrast, in the unpublished study where only 1 guinea pig was infected,there were no XDR patients by MIGIT or LPA among the patient isolates. Toreinterate, 27 patients slected for cough, lung cavitation, smearpositivity, and not on MDR treatment (until they were admitted to thehospital) infected only 1 of 90 exposed guinea pigs. In 4 otherexperiments XDR patients retrospectively identified and transmissionoccurred to guinea pigs at rates varying from 10 to 77% of exposedanimals. These data appear to substantiate the observations of Riley andcolleagues some 60 years earlier. Effective treatment appears to have anextremely rapid and profound effect on transmission from humans to sentinelguinea pigs. The mechanism of this phenomenon has been considered.Writing about the rapid effects of treatment on transmission based on earlyhousehold contact and experimental data in the 60’s, Loudon and colleagues(Am Rev Resp Dis 1969; 100:172-176) had speculated that as largerrespiratory droplets evaporated into droplet nuclei, drug concentrationssurrounding airborne organisms increased dramatically, blockingtransmission to animal (or human) hosts armed with some innate immunity,whereas organisms in sputum could easily contain organisms that are visibleon concentrated smear and which might grow under culture conditions. Incollected sputum there is no aerosolization damage to organisms and noconcentration of antibiotic. Recall also Roullion’s conviction, quotedearlier, of the discordance between culture and smear on the one hand andinfectivity in the treated patient.We conclude that airborne transmission may be the weak link in TBpropagation. Only about 1/3 of untreated pulmonary TB patients infect anyclose contacts. In Fennelly’s cough aerosol studies, *Mtb* is culturedfrom only approximately 1/3 of smear positive patients. Based on both thehistorical and recent animal data, we suggest that it may be possible thatvery little *effective* treatment may tip the balance against transmission.We further conclude a restatement of the dogma that effective treatment isthe best form of TB infection control. However, in the era of MDR and XDRTB, this implies the need for a rapid, point of care diagnostic that canidentify drug resistance and lead to proper treatment within hours ofpresentation. The advent of Gene Xpert is rapidly making this goalpossible. Together with cough-based, active case finding in hospital andclinic admission areas, a diagnostic with a 2 hour turn-around time could,in theory, assure that almost all TB patients will be identified and placedon effective therapy, thereby stopping transmission.Some questions for further research are apparent. What is the mechanism forthe rapid effect of treatment on transmission? The escalating drugconcentration hypothesis should be proven or disproven. The effects ofspecific antimicrobials on transmission should be explored, including thelikelihood that the *fluoroquinolones (rather than the injectable drugs)account for the effectiveness of MDR treatment on transmission. *
3:26 PM, 16 Jun 2012 | Permalink
colleagues of other problems related to the infectiousness of MDR-TB patients is the malabsorption syndromes are so frequent in HIV + patients and keeping their infectivity for longer. Given that the monitoring of all these aspects is fundamenrtal with DOT
9:38 AM, 27 Jun 2012 | Permalink
Thanks Elizabeth for raising that issue. About 60+% of our MDRpatients are co-infected with HIV at the Mpumalanga MDR TreatmentCenter in South Africa, but still effective therapy in a cohort of 27mostly smear positive, coughing, mostly cavitary MDR-TB cases appearedto almost completely suppress transmission to guinea pigs at the AIRFacilty over a 3 month period (1 gp infected). Additional confirmatorystudies are needed and planned for the near future.Ed
9:59 AM, 27 Jun 2012 | Permalink
I may be grossly wrong but can we think about inhalation therapy as wellfor the infectiousness to become less? Has it been tried ?Thanks
6:39 PM, 27 Jun 2012 | Permalink
You are right on, Dr. Ghatak. We are about to begin a trial in SouthAfrica of a dry-powder inhaled antibiotic specifically to reduce TBtransmission, including a novel drug never used for TB that hasanti-mycobacterial activity and may be effective in reducing XDRtransmission.There is one study in the literature showing that inhaledaminoglycosides resulted in sputum conversion in chronic patients, butthey did not have the ability to measure transmission that we havewith the guinea pig model. Presumably, any effective inhaled drugshould help, although for drug susceptible TB, systemic therapy isamazingly fast.Ed Nardell, MD
6:48 PM, 27 Jun 2012 | Permalink
Can we have a control subgroup of COPD patients as well? More and moredeaths are occuring in adult males who have healed TB lesions but have notsurvived the lung damage by COPD .And there is no national level control program for COPD anywhere? The WHOalso has not been very proactive about COPDs and in truth with all theenvironmental /pollution /air particulate screenings .....bottomlineremains they are dying from COPD. Just a thought .....Thanks !
7:53 PM, 27 Jun 2012 | Permalink
and inhalation would be faster in reducing the infectiousness and spread ofthe disease.thats what matters more ?
7:57 PM, 27 Jun 2012 | Permalink
transmissibility of XDR is less ? because of the morphological fragility ?Is this based on hard evidence? This was being discussed by a lab expert ?How much truth is there it is hard to verify but it is evident thatwithout injudicious use of drugs, XDR wouldn't have emerged this way.blame game is on DOT , government , private sector ...OTC sales....butonly POOR DRUG USAGE has given us the XDR
8:08 PM, 27 Jun 2012 | Permalink
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