We need to early diagnose TB and treat with drugs that work


No other way out: We need to early diagnose TB and treat with drugs that work

Bobby Ramakant, Citizen News Service – CNS

Photograph of Dr Madhukar Pai is online at: http://3.bp.blogspot.com/-pgWQbXW9l_4/VUHYfxcS50I/AAAAAAAAOxM/tQPEAL7lA6Y/s1600/IMG_6363.JPG

(CNS): It may sound rhetorical but some of the 'absolute must' steps for progressing towards ending tuberculosis (TB) are to early and accurately diagnose TB and treat with the standard combination of drugs that are sensitive and work for a particular patient. Although sounds simplistic yet these are 'easier said than done' steps! Agrees globally-noted expert on TB diagnosis: "Early diagnosis is a huge problem in India. Not only it is critical to diagnose TB early but also drug-resistant forms of TB, otherwise it is going to be a phenomenal problem! This is what is happening in places like Mumbai where delayed TB diagnosis and even-further delayed drug susceptibility testing (DST) have proved catastrophic" said Dr Madhukar Pai, Director, McGill Global Health Programs, who was speaking at the centenary celebrations of Lady Hardinge Medical College in New Delhi on 24th April 2015.


Dr Pai shared: "In a study we published last year we found that an average TB patient has to wait for almost two months before a TB diagnosis is made and they have to see at least three different doctors before a doctor tests the person for TB, and then starts the anti-TB therapy. We really do not know what this two months of delay in TB diagnosis can mean in terms of actual numbers of transmission events [of TB] as it can only be modelled in a study but our guesstimate is that it is an important driver of the TB epidemic in the country."

India accounts for 25% TB burden in the world, and despite enormous efforts of India's national TB programme (formally called Revised National TB Control Programme - RNTCP) there is no indication that TB incidence is significantly declining in India. "Transmission is continuing, people are getting infected" said Dr Pai.


"A scientific paper published earlier in April 2015 by us showed what is the quality of TB care in India – what an average TB patient gets in terms of diagnosis and treatment in India. Anyone living in countries like India with 2-3 weeks of cough with fever, weight loss and other symptoms must be screened for TB ideally with sputum test - this is the baseline knowledge we expect our doctors to have! This is also what International Standards of TB Care and Indian Standards of TB Care say too! We found in the study review that only half of doctors in India were actually aware when they should be screening someone for TB (if she or he has 2-3 weeks of cough with other symptoms). In the same study we also looked at how many doctors were actually aware of correct management of TB: only one third of doctors were aware of the correct management of TB."

Dr Pai rightly stressed that "This means that even if people with classic TB symptoms go to a doctor there is no guarantee they will get tested for TB, and even if they do get tested for TB and get confirmed and early diagnosis, there is no guarantee they will get correct treatment as per guidelines and standards of care. This is what is happening in cities like Mumbai otherwise we would not have so much of multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and other severe forms of drug-resistant TB. So TB is consistently being missed and mismanaged in Indian settings. Early TB diagnosis is not the norm usually, it is an exception!"




Dr Pai shared another study outcome to underline public sector DOTS (Directly Observed Treatment Shortcourse) is not the first choice for lot of people with presumptive TB. "This is a study done in Delhi when researchers went to DOTS clinics and asked patients how did they end up in DOTS centres. The study found that public DOTS system is not the first choice for lot of TB patients in India. Patients usually go to public DOTS system only when they are broke and/ or not able to afford private care any longer. Most TB patients went first to local pharmacists, chemists, ‘vaid’ (traditional healers), non-qualified practitioners, AYUSH practitioners, these are the people who first see people with cough."


"This means that we are constantly missing patients with presumptive TB when instead they get broad-spectrum antibiotics, steroids, broncho-dilators, etc. We need to end this delay of few weeks or months so that every patient with presumptive TB gets tested and receives standard care without delay. In reality, by the time 'TB cascade' begins it is weeks and months down the line. By the time MDR-TB gets detected it is several months down the line. MDR in this country is not detected at the start of the TB treatment routinely but it is detected only if the patient fails one round of anti-TB therapy."




Obviously yes! TB is curable and therefore we need to treat every patient with confirmed accurate diagnosis of TB, with standard combination of drugs that work for a particular patient. Giving drug or drugs that do not work for a patient (because patient may be resistant to one or more drugs already) will not have desired treatment outcomes, rather can have alarming public health and social justice consequences!


So ideally, every presumptive case of TB should get accurate confirmatory diagnosis for TB, and also get a DST so that doctors know which drugs are sensitive for a given patient (and which are the drugs patient is already resistant to). But it is seldom happening right now in reality.


Dr Mario Raviglione, Director of Global TB Programme of the World Health Organization (WHO) had said earlier last week when "Call To Action For A TB-Free India" was launched that it is a "clinical malpractice" if DST is not done on day-1 when a patient contacts a health system (public or private).


Dr Pai shared with Citizen News Service (CNS): "Usually a patient has to take six months of standard anti-TB therapy before DST is even done for a patient. Most people never know if they have drug resistance early on - they only get to know when they fail one round of anti-TB therapy or have recurrence or relapse."




A challenge which is puncturing efforts to diagnose TB early and accurately is use of diagnostic tests that are not WHO-approved for active TB disease. A part of private health sector in India has been using tests that are not meant to be used for diagnosing active TB disease: such as antibody blood serology, or QuantiFERON Gold or Platinum. QuantiFERON Gold or Platinum may be a test for diagnosis LATENT TB, but not active TB disease.


The government of India had banned antibody blood serology for TB diagnosis in June 2012. We need WHO-approved standard tools for diagnosing active TB disease.




Government of India made it mandatory in May 2012 that every single private practitioner or private laboratory must notify all TB cases to the RNTCP through its user-friendly electronic portal called NIKSHAY. "But TB notification from private health sector is hardly happening in India" said Dr Pai.


Public health community needs to worry because not only private health sector is not always notifying TB cases but use of non-evidence based tests is still occurring. If ending TB is a goal in sight, then every TB case has to be diagnosed early, treated with drugs that work for her/him, and adherence needs to be ensured too - among other components of TB care and control.


"We have 1 million missing TB cases in India – we have no idea of what’s happening to them - how are they being diagnosed in private (if they are being diagnosed at all!), what drugs are they being treated with, how treatment is being monitored, how adherence is being ensured, etc."




"If we go around India we see one-room small laboratories –what is the quality of any of the test being done there? RNTCP has a nationwide network of sputum microscopy and has taken it years to develop a strong robust system for External Quality Assurance (EQA). Private sector has very little in terms of EQA. What to talk of quality of sophisticated tests, we cannot even trust the quality of sputum smear microscopy done in a laboratory that does not have EQA."


"All 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 and affordable in accredited private laboratories as well. 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 LED 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."


As of now,  95 private laboratories across India are offering WHO approved tests at 50% lesser price at least than the market price. More than 100,000 tests have been done in the last two years in these laboratories, said Dr Pai.




"RNTCP is heavily relying on conventional sputum smear microscopy (done by Ziehl-Neelsen staining) which is not as sensitive as LED microscopy. We need to upgrade microscopy centres across the country to at least use LED fluoroscence microscopy (done by auramine-rhodamine staining). Also we need to scale up capacity in the country to increasingly provide DST along with TB testing."


"Even if we do best job of smear microscopy we will only pick up 60-70% of TB. Its sensitivity cannot go up anymore than that. If smear microscopy has to be done then at least laboratory should be equipped with LED fluoroscence microscope, trained technician, and EQA programme also have to be in place. Studies show that LED fluoroscence microscope picked up 20% more cases than conventional microscopy done in India" said Dr Pai.




Gene Xpert, a cartridge-based nucleic acid amplification test (CB-NAAT), is indeed one of the major game changers in TB diagnostics globally. "Novelty is not that it is polymerase chain reaction (PCR) technology based test, as PCR is not new and has been around for long time. But since it is completely automated PCR, that is why it is novel and perhaps the single biggest advancement in TB diagnostics!"


Gene Xpert gives results within 100 minutes whether a person has TB or not, and if so, then whether a person is resistant (or sensitive) to Rifampicin.


"The WHO policy says that Gene Xpert should be number-one choice for TB diagnostics if affordable. If we cannot afford it then priority for doing Gene Xpert goes to anyone at risk of MDR-TB or people living with HIV (PLHIV)."


10 million Gene Xpert tests have been done globally with South Africa accounting for half of them. India is increasingly doing Gene Xpert tests. Private sector did over 100,000 Gene Xpert tests. Public health sector has 119 Gene Xpert machines under RNTCP and there are plans to buy another 300! "We did a Cochrane systematic review on Gene Xpert and found that compared to 'culture test' (which is a gold standard WHO approved test), Gene Xpert picks up about 88% of TB. Even if smear is negative, Gene Xpert picks up 70% cases of TB. So that is the advantage"emphasized Dr Pai.


"In a study published in The Lancet, Gene Xpert shows good sensitivity of 62% and specificity of 98% in samples of paediatric induced sputum or expectorate. With gastric juise aspiration Gene Xpert picks up 66% of all TB in children. This is an important finding because in children sputum smear microscopy is rarely positive as it is so difficult to get sputum samples from them."


Dr Pai shared that "One of the largest studies getting published soon has assessed 115,000 Gene Xpert tests done in 18 districts of India. Gene Xpert tests were done on all patients with presumptive TB. Researchers did not wait till the end of first-line anti-TB therapy to do DST. This is not RNTCP policy yet to do DST on 'day-1' when a patient contacts a health system with presumptive TB, but researchers did it to show what will happen if we do DST right at the start of diagnostic process. Results are very impressive with 39% increase in notification rates of bacteriologically-confirmed TB and five fold increase in rifampicin resistance case detection." Rifampicin-resistance case detection has increased eight fold in Mumbai with introduction of Gene Xpert upfront testing. So when we test for drug resistance we find more than we had estimated for!




If we diagnose more drug-resistant TB then it makes public health sense only if all the confirmed cases of drug-resistant TB get treated by sensitive drugs. It is a widely known fact that cost of treating drug-resistant TB is hundreds of times more than what it costs to treat drug-sensitive TB!


So as number of those who are getting diagnosed shoots up, drug supplies and other logistical and programmatic preparations have to be in place to ensure continuum of care. "This is the irony as MDR-TB treatment alone could account for 40% of RNTCP budget. So drug supply has to match diagnostic potential. That is why Government of India is being careful of how they roll the technology."




One-fifth of all TB is extra-pulmonary TB (EPTB). "Unless doctors send samples of wherever they think EPTB is, microbiologists cannot really help - pathologists cannot help. No one technology is sensitive enough for EPTB so we have to use all what we have. If everything fails then we need to start anti-TB therapy and hope for a positive clinical response" said Dr Pai.


"At times gynaecologists send wrong samples for presumptive cases of genital TB, such as menstrual blood. Blood is not a sample for TB. Unless someone is seriously septic it is not possible to detect TB in a blood sample. We need to send tissue from site of the presumptive EPTB" emphasized Dr Pai.


Gene Xpert works well to diagnose EPTB in lymph node with 83% sensitivity and TB meningitis with 80% sensitivity. "But samples have to be good quality and from site of suspected EPTB: for lymph node TB, sample should be a tissue from lymph node, and for TB meningitis, cerebro-spinal fluid (CSF) is the right sample. TB meningitis is a medical emergency - if we suspect it then the child has to be put on anti-TB therapy right then - we cannot wait for confirmatory TB tests. Gene Xpert provides 80% sensitivity for TB meningitis with CSF as sample – highest sensitivity anyone has ever seen for TB meningitis!". Gene Xpert does not work on some samples to diagnose EPTB such as of pleural fluid. A study done by Dr SK Sharma of All India Institute of Medical Sciences (AIIMS) re-validates these findings.




"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 TB and EPTB. Two weeks is the usual turnaround time for test results. Despite decent availability of liquid culture systems across the country in private and public health sector, these tests are significantly underused in India" said Dr Pai.


Line Probe Assays (LPAs) have 98% sensitivity and 99% specificity for rifampicin resistance, Isoniazid (INH) sensitivity always tends to be lower 84% and specificity is 99%. LPAs are also widely available in DST laboratories across the country.




Universal DST is a component of the WHO's post-2015 End TB Strategy. "Everybody deserves a DST. In cities like Mumbai, one-in-five new TB cases are of MDR-TB. So we have to do DST right in the beginning. Noted TB expert Dr Zarir Udwadia had pointed out that it just takes one or two prescription errors to convert regular TB into MDR or MDR into XDR or XDR to further serious drug-resistant forms. We have to get DST done upfront and figure out the right combination of drugs sensitive for a particular patient" said Dr Pai.




Indian government has committed to routinely diagnose every TB patient with DST by 2019 when universal DST will become a reality in India. Central TB Division is already progressing towards achieving this vision with rapidly scaled up world-class accredited laboratories across the country - fully-equipped with WHO-approved tests such as liquid and solid culture testing, LPAs, Gene Xperts, etc.


Dr Pai summarised that ideally a patient with presumptive TB should get WHO-approved test for TB and DST both at first point of contact with a health system (public or private). If the patient has TB and drug resistance to Rifampicin, then a sample from the patient has to be sent for culture profiling - but meantime standard MDR-TB treatment should commence. When culture profile test results come forth then treatment can be adjusted to ensure patient is taking all the drugs he or she is sensitive to. Adhering to effective anti-TB treatment and successfully getting cured is indeed critical to progress towards ending TB.




"The best time to plant a tree was twenty years ago. The second best time is today" goes the old gold adage, which perfectly sums up the fight against TB. We need to solve the riddle: find every missing case of TB, correctly and early diagnose every presumptive case of TB with WHO approved tools and tests, get to know which drugs a particular patient is sensitive or resistant to so that effective standard anti-TB therapy can commence without any delay, ensure adherence, ensure infection control, contact tracing, treatment monitoring, and doing everything we already know is critically important component of TB care and control. There is no other way out to reach the ambitious goal of ending TB.


Bobby Ramakant, Citizen News Service – CNS


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