Accurate and affordable TB diagnosis in private sector becoming a reality

Bobby Ramakant *

Tuberculosis (TB) care and control does not end with an accurate and confirmed diagnosis, but that is a good start point. It needs to be followed with initiating standard and effective anti-TB treatment (without delay), supporting the person with TB to adhere to the treatment regimen and get cured. Dr Madhukar Pai, Associate Director of McGill International TB Centre, addressed private TB healthcare providers including physicians and laboratory experts in New Delhi before the World TB Day 2014.

Dr Pai stressed: "Good diagnosis alone is not enough. TB treatment and completion is as important as diagnosis. TB control needs a complete solution. Diagnosis, treatment, adherence, notification, completion, cure..."

Dr RS Gupta, Deputy Director General, Central TB Division, Ministry of Health and Family Welfare, Government of India, said while opening this continuing medical education (CME): "Indian public sector had notified 1.9 million TB patients last year but we are still missing one-third of people who need TB care services. We need to accurately diagnose these 'missing' one third patients too, provide them standard anti-TB treatment and ensure these get cured." - Dr RS Gupta

TB NOTIFICATION FROM PRIVATE SECTOR REMAINS LOW
Indian government had made TB a notifiable disease in May 2012. Public healthcare sector was already notifying TB cases to the Revised National TB Control Programme (RNTCP) but since May 2012 even private healthcare sector is also supposed to notify every TB case. However the uptake of TB notification has been far from satisfactory. "There are over 50,000 registered private hospitals but only 40,000 or so TB case notifications came in from the private sector since May 2012" said Dr RS Gupta.

Dr Gupta also stressed on the role of balanced nutrition in TB treatment and said "Many TB patients are malnourished. We are presently talking to the concerned ministries and government departments to help TB patients get extra supplies of food grains through public distribution system."

DIAGNOSING TB EARLY, ACCURATELY
But are we diagnosing people with presumptive TB early enough? Data suggests otherwise. "An average TB patient is diagnosed with TB after a delay of 2 months and has consulted till then at least 3 physicians or healthcare providers before getting diagnosis" said Dr Pai. Nearly 50% TB patients seek healthcare in private sector so role of private sector in TB care and control cannot be ignored.

If we really want to control TB and achieve the formidable targets of 'zero new TB infection' we have to ensure that every TB patient gets diagnosed accurately and is provided standard treatment without delay – regardless of whether the patient is seeking care in private or public sector. It is vital that every physician or any other healthcare provider, whether in public or private healthcare sector, is following the Standards of TB Care in India (STCI, 2014) released on World TB Day which are on the lines of the latest edition of the International Standards for TB Care (ISTC, 2014).

INNOVATION IN ADDRESSING SUBOPTIMAL TB DIAGNOSIS
"Accurate diagnosis is absolutely essential to drug-resistant TB" said Dr Pai who is part of the path-breaking innovative initiative called IPAQT (Initiative for Promoting Affordable and Quality TB Tests).

Tests used in private sector to diagnose TB are often not the WHO recommended ones. Not only WHO but also the Indian government had to ban such ineffective tests to diagnose active TB disease such as blood serological tests (banned in India since June 2012). But as half of TB patients are estimated to seek care in private sector, it was an important challenge to arm the private laboratories with WHO recommended diagnostic capacities. Another challenge was to make these WHO approved diagnostic tests for TB and anti-TB drug resistance affordable. This is how IPAQT was born on 24th March 2013 to respond to these challenges of not only making WHO approved diagnostics for TB available in the private sector but also to make these tests affordable than the market price.

It is important to underline that these WHO approved latest TB diagnostic tests are available free of cost in public sector laboratories across the country. The challenge was to make these WHO approved TB diagnostic tests available in accredited private laboratories as well, at an affordable price.

What made IPAQT a good practice example is that it helped WHO approved diagnostic manufacturers and accredited private laboratories in India to come to an agreement that was important to address the issue of suboptimal diagnosis of TB in private sector. Diagnostic manufacturers agreed to provide WHO recommended TB diagnostic equipment such as Gene Xpert, Line Probe Assays (LPAs), Liquid Culture or Fluoroscent Microscope and requisite supplies to private accredited laboratories at public sector pricing. Private accredited laboratories that are part of IPAQT network agreed to pass on the same financial benefit to the patient who is seeking test for TB and agreed at a maximum price they can charge for such tests (which was broadly half of market price). Private laboratories also agreed to notify TB cases they were testing to the RNTCP. "Diagnostic manufacturers benefited because their sale volumes went up as they had made their products more affordable. Laboratories benefited because they now had a replacement for [banned] serology that is affordable to the patients. Central TB Division benefited because of greater TB notification from private sector, awareness and effective partnerships with these private laboratories" said Dr Pai.

Maximum prices agreed by private laboratories that are part of IPAQT network were as follows: Gene Xpert INR 2000 (market price is INR 4000); HAIN LPA INR 1600 (market price is INR 3500); and MGIT Liquid Culture 900.

As a result of IPAQT, TB diagnosis using WHO recommended diagnostic tests shot up in private sector. Number of TB cases getting diagnosed using Gene Xpert in private sector went up from 500 to 22,210 after roll out of IPAQT. Similarly as LPA was not available in private sector before roll out of IPAQT, the number of cases diagnosed with TB using LPA till February 2014 was 13,278.

"Any private laboratory in India can join IPAQT provided they are accredited, agree to notify cases to RNTCP, and agree to be part of external quality assurance programme. IPAQT has partnered with 64 laboratories in a year" said Dr Pai to Citizen News Service (CNS).

OPT FOR CORRECT TEST TO DIAGNOSE TB
Gene Xpert, LPAs, Liquid and Solid Cultures are some of the WHO recommended standard tests for accurately diagnosing TB, and anti-TB drug resistance as well. Fluroscent microscope is another WHO recommended test for TB. Dr Pai said that "LED Fluoroscent Microscope picked up 20% more TB cases than conventional microscope."

GENE XPERT
"If resources were not a problem then Gene Xpert is the top start test for TB. But resources are a problem so that is why we prioritize two groups for getting TB diagnosed using Gene Xpert: 1) those with presumptive multidrug-resistant TB (MDR-TB) and 2) those with HIV. Roll out of a Gene Xpert has crossed five million cartridges now. Gene Xpert picks up 88% of all culture positive TB with has a specificity as high as 99%. It practically picks up every smear positive case and also picks up almost 70% of smear negative TB. If used for Drug Susceptibility Testing (DST is used to test anti-TB drug resistance) then it picks up 95% of rifampicin resistance with specificity of 98%. Recent publication by Central TB Division and Foundation for Innovative New Diagnostics (FIND) colleagues show that it is possible to use this technology even at a decentralized level. It has been put up in microscopy centres in 18 cities across India and gave 99% valid results with very low failure rates. Data also shows substantial increase in case detection of bacteriologically confirmed TB and increase in rifampicin resistance case detection" said Dr Pai.

For diagnosing presumptive extra pulmonary TB (EPTB), appropriate samples from the suspected site of involvement should be obtained for microbiological and histological examination, as per the latest edition of ISTC.

Private physicians have to suspect EPTB to start with. Then sending the right sample from the suspected site of involvement for confirmed diagnosis is no less important. "I cannot emphasize more how critical is to take the right sample from the site of involvement of presumptive EPTB. The myth in India is that EPTB can be magically picked up by peripheral veinous blood. Nobody in the world has come up with a biomarker that magically tells you where EPTB is in the body. There is no role for any blood test for diagnosing EPTB [or pulmonary TB]. We have to put a needle or other appropriate methods to collect right sample from site of the disease, get a tissue or aspirate from this site and send that for microbiological confirmation. So smear sputum examination should be done in presumptive EPTB cases although without much hope but nucleic acid amplification test (NAAT) or Gene Xpert should definitely be done with right samples. Cultures are extremely helpful in EPTB and it is worth waiting for extra two weeks [if choice of test is liquid culture] as it adds value. Histopathology is very helpful too if a trained pathologist is available" said Dr Pai.

Gene Xpert is also the preferred recommended TB test for presumptive TB meningitis because for the need of rapid diagnosis. "Within 90 minutes we get to know whether TB meningitis diagnosis is right or not. As we know TB meningitis is a medical emergency and there is no time to waste. Gene Xpert has a sensitivity of 81% and specificity of 98% for samples of cerebro spinal fluid (CSF)" said Dr Pai.

WHO has reviewed the evidence of using Gene Xpert in diagnosing childhood TB. "It seems that Gene Xpert works fairly well in gastric juice aspirates samples. Paediatric TB is officially included in WHO Gene Xpert policy" informed Dr Pai.

WHO also recommends Gene Xpert as an initial test for diagnosing TB of the lymph nodes and some other tissues too. "For diagnosing TB of the lymph nodes, sensitivity of Gene Xpert is 83% and specificity is 94%. Pleural fluid is one specimen in which Gene Xpert unfortunately does not pick up TB a lot. Pleural biopsy could add value to confirm TB" said Dr Pai.

LIQUID CULTURE
Liquid culture is the gold standard and most sensitive test we have which will not only diagnose TB but also pick up anti-TB drug resistance. "This is the only technology we have that can assay all anti-TB drugs that are critically important. It is an ideal test for smear negative and EPTB. Two weeks is the usual turnaround time which is the only real negative factor and is now much more affordable than in the past" said Dr Pai.

"Drug resistance testing is critical. ISTC says that anyone who has been previously treated for TB or anyone who is not responding to standard TB treatment must receive drug susceptibility testing (DST). Solid culture which unfortunately has a long turnaround time of 2-3 months and is often too late for the patient, is widely available in India and is a reliable option for DST too. Liquid cultures are significantly underused in India. If we look at the number of liquid cultures done in private sector in India then we realize how underutilized this good test is. Liquid culture is the only technology we have that can generally give us a complete anti-TB drug susceptibility profile without which we really cannot treat drug resistant TB" said Dr Pai.

LINE PROBE ASSAYS (LPAs)
Line Probe Assays are excellent rapid molecular tests that WHO approved in 2008. "LPAs have 98% sensitivity and 99% specificity for rifampicin resistance, Isoniazid (INH) sensitivity always tends to be lower 84% and specificity is 99%. If LPA is positive for TB and rifampicin resistance then one can confidently begin MDR-TB treatment while waiting for culture and DST reports to come [and modify treatment if required]" said Dr Pai.

"We know that INH mono-resistance is a problem in India but by and large if Rifampicin resistance test is positive then clinicians should accept it as a [surrogate] marker for MDR-TB and begin treatment BUT wait for culture reports and DST to come back and modify the treatment if required" cautioned Dr Pai.

Dr Pai summarized: "No molecular test is an end in itself. Molecular tests are the start point and one has to wait for culture reports and DST to come back and finally decide what the right regimen is for a particular patient."

DO NOT USE BLOOD SEROLOGICAL TEST OR IGRAs FOR DIAGNOSING ACTIVE TB DISEASE
Immunological blood tests are not confirmatory test for active TB disease. Similarly Mantoux Skin Test is not a confirmatory test for active TB disease. Likewise IGRAs (such as Quantiferon Gold or Platinum) is also not a confirmatory test for active TB disease. Mantoux Skin Test or IGRAs are tests only for LATENT TB infection. "In children Mantoux Skin Test or IGRAs could be helpful as an indication for TB along with chest x-rays, symptoms and history of contact. WHO has recommended against using immunological blood tests and IGRAs and same has been done by RNTCP" said Dr Pai.

TREATMENT, ADHERENCE, CURE, SOCIAL SECURITY AND SUPPORT
Dr Pai emphasized that accurate diagnosis of TB is as important as providing standard treatment and care to every person with TB. With RNTCP aspiring to achieve universal access to TB care and global thrust to find, treat and cure every patient of TB as per the International Standards for TB Care (ISTC 2014), it is undoubtedly important to do every step right: diagnose TB early and accurately, provide standard anti-TB treatment without delay, help achieve cure and help those in need access social security benefits.