Breaking the drug-resistant TB transmission cycle important


Nearly two months after the Health Ministry set a highly ambitious target of working towards elimination of tuberculosis by 2025, a study published in The Lancet Infectious Diseases indicates that India’s TB crisis is all set to snowball by 2040 when one in 10 cases could be drug-resistant. What is even more alarming is that the increased number of drug-resistant cases — both multidrug-resistant TB (resistant to more than one of the first-line drugs) and extensively drug-resistant TB (additionally resistant to fluoroquinolones and at least one of the second-line injectable drugs) — will come from direct transmission from infected people to others rather than by strains acquiring resistance to TB drugs during treatment due to inappropriate treatment or discontinuation of treatment midway. The study found that “most incident” MDR cases are “not caused” by acquired drug resistance, and that acquired drug resistance will become a “decreasing cause” of drug-resistant TB. The increased availability of drugs to fight drug-sensitive TB has led to the emergence of MDR-TB strains. With increasing number of MDR-TB cases, there has been a shift in the way people get infected with drug-resistant TB — from strains acquiring drug resistance during treatment to direct transmission of MDR-TB strains from an infected person. The same trend is seen in the case of XDR-TB too. As a result, in high MDR-TB burden countries such as India, improved treatment outcomes in people might only reduce and not eliminate drug-resistant TB. Till 2015, only about 93,000 people with MDR-TB have been diagnosed and put on treatment.

The study, based on a mathematical model to forecast how TB is likely to progress in the four most-affected countries (Russia, the Philippines and South Africa, India), suggests that the number of new MDR-TB cases in a year in India will touch 12.4% by 2040, up from 7.9% in 2000. In the case of XDR-TB, the incident cases will rise to 8.9%, up from 0.9% in 2000. In 2015, the four countries accounted for about 40% (more than 230,000) of all drug-resistant TB cases in the world. Besides increasing the number of people who are diagnosed early and successfully treated, India’s TB control programme has come up with enhanced interventions to break the transmission cycle of the bacteria in the community. One of the ways this can be achieved is by carrying out immediate screening of all family members of a patient who has been diagnosed with the disease. Contact screening of family members and preventive treatment of all children below the age of five years who have not developed TB disease are already a part of the Revised National Tuberculosis Control Program (RNTCP) but is rarely done. Another important strategy that has to be adopted is making drug susceptibility testing universal and mandatory. Developing more accurate, cheaper and effective diagnostic tests and improved treatment regimens that are less expensive and of shorter duration will also go a long way in winning the war against the disease.

Published in The Hindu on May 12, 2017

Depression: The fault lies in classification


The World Health Organization estimates that more than 300 million people across the world are living with depression. “But that does not mean that all the 300 million people would need medical intervention,” says Vikram Patel from Harvard Medical School and the Delhi-based Public Health Foundation of India. The reason: the current binary classification of depression that distinguishes people as either “well” or “sick” is fundamentally flawed. The binary model is “unsuitable” for depression as there is no clear line that differentiates the miseries of daily life from the disorder that can be treated through medical intervention.

Levels of depression

In the absence of a biomarker that neatly distinguishes healthy and depressed people, the binary model relies on symptoms of emotional well-being — feeling miserable, losing interest in things, unable to sleep, idea of self-harm and feeling profoundly fatigued — and assesses the duration and impact of these symptoms to arrive at a diagnosis.

“The binary model uses the answers to a list of questions and then applies a complicated set of rules to arrive at a diagnosis for depression,” says Prof. Patel. “It uses a set of symptoms without recognising that there might be stages through which the symptoms graduate to a full medical disorder.”

In an essay published in PLOS Medicine on April 4, Prof. Patel proposes a continuum of stages to define depression. At one end of the spectrum are people who are well and do not have any distressing emotional experiences. “But many people have depression-like symptoms in reaction to the trials of everyday life, for example when there is the death of a dear one,” he says. A significant proportion of people now diagnosed as suffering from depression have only mild to moderate symptoms and most often do not need clinical intervention. What such people need is advice on how to help themselves recover and support from friends, community-based workers or the Internet.

IMG_0488When to step in

The next stage is when the distressing experience lasts longer — at least two to four weeks — and severely impacts day-to-day social functioning. This condition needs medical intervention — antidepressants, brief psychological treatments or both, though most of this can be provided through primary care physicians and community health workers. At the extreme stage are the recurrent or refractory depressive episodes where patients do not respond to existing treatments or suffer from relapse. “This constitutes only a small fraction and they need to see a psychiatrist or clinical psychologist,” he says.

Since the model of various stages would dramatically reduce the number of people with depressive symptoms who need medical intervention, the focus of specialists can be to treat severe cases.

Staged model in India

There is a body of evidence to show that with appropriate training and supervision, front-line community health workers can effectively deliver psychological treatments for moderately severe to severe depression, such as the Healthy Activity Program, a six- to eight-session treatment; the results of the study were published in December 2016 in The Lancet.

In the VISHRAM (the Vidarbha Stress and Health ProgRAM) programme in 30 villages in the Amravati district in Vidarbha, central India, the staged model was implemented by providing care for mild stages by community agents, while more severe stages were treated by lay counsellors working in collaboration with primary care physicians and visiting psychiatrists. This led to a huge reduction in treatment gap for depression, according to a paper published in January this year in The Lancet Psychiatry.

Following the study, all the 30 villages have a community health worker “who is trained to detect depression, provide low-intensity psychosocial interventions, and refer the patient to the public health system for further management”.

Published in The Hindu on April 8, 2017

Lancet gets in touch with Current Science authors on litchi disease ethics issue


The paper in Current Science where Dr. Jacob John and others accuse the Lancet paper authors for not crediting their papers published in 2014.

In response to an article I wrote on February 3 about Dr. Jacob John raising ethics issues about the way the authors of the Lancet Global Health paper had failed to properly acknowledge his team’s work on Muzaffarpur mystery disease, the journal has got in touch with Dr. Mukul Das, one of the authors of the Current Science papers, for more details.

Dr. John, Dr. Das and others had published two papers in 2014 (May and August) and another one in December 2015 in Current Science wherein they report clinical similarity between ackee poisoning in Jamaicans and the Muzaffarpur illness. At a time when the Lancet authors were looking for a viral cause, Dr. John’s team had correctly zeroed in on methylenecyclopropylglycine (MCPG) toxin in litchi as the likely reason for illness and reported the findings. The team found consumption of litchi and skipping the evening meal as likely reasons for children exhibiting dangerously low blood glucose level and acute encephalopathy early in the morning leading to death in many cases. They also found the presence of MCPG toxin in litchi through chemical analysis and recommended infusing 10% dextrose within four hours of disease onset to save lives.

While the January 30 paper in the Lancet Global Health has acknowledged and cited all three papers, it does not give due credit to the work done by Dr. John’s team. “They quote our study but don’t honestly say what we have found. They have borrowed all important information connected with the illness from us,” Dr. John had told me.

litchi1“Dr. John and I would jointly be sending our response on Monday or Tuesday [February 6 or 7],” says Dr. Das. “It is very decent of the Lancet to have got in touch with us and seek our clarification on this issue. That shows Lancet is careful of its credibility, careful that any such issue is immediately sorted out. I admire Lancet. This is what we want from every journal publisher, every investigator and every paper. Caesar’s wife must be above suspicion,” says Dr. John. “We never complained to Lancet or the media. It is the media that got in touch with us as they knew about our work. That makes us happy.”


The authors from Centres for Disease Control and Prevention (CDC) and Delhi’s National Centre for Disease Control, India (NCDC) have indulged in scientific misconduct in a paper published in January 2015 in the Morbidity and Mortality Weekly Report (MMWR), the authors of the Lancet paper cite the possibility of exposure to MCPG, a toxin in litchi, as a likely cause of acute hypoglycemia and encephalopathy in some children. The paper does not even cite the May and August 2014 papers in Current Science by Dr. John’s team.

Dr. John and Dr. Das had exposed the “scientific misconduct” by the authors in a correspondence published in Current Science. “They were creating a precedent by publishing in MMWR, which is a CDC in-house publication. It gave us a clue to their mind and now it is an extension of that mentality by citing us so we don’t complain but not giving us the credit that we deserve,” says Dr. John.

Published in The Hindu on February 5, 2017

Renal failure deaths nearly double in a decade in India

Sugar test

Poorly treated diabetes is the leading risk factor for renal failure deaths among Indians.

Deaths from renal failure among Indian adults now outstrip deaths from HIV/AIDS, signalling a major shift in causes of mortality in the country over the past decade — away from infectious disease causes to non-communicable disease causes. These are the results of a study published recently in The Lancet.

As per a National AIDS Control Organization (NACO) annual report 2015-16, in 2015, an estimated 67,600 people died of AIDS-related causes nationally. In the same year, renal failure accounted for an estimated three per cent of all premature deaths in India. The proportion of renal failure deaths has been steadily rising from 2.1 per cent in 2001-03 to 2.9 per cent in 2010-13. Compared with 86,000 renal failure deaths in 2003, the number has increased to 136,000 in 2015.

“What is more important than the absolute change in the number of deaths (which will reflect the increasing population and changing population structure in India over the past decade) is the changing age-standardised rates of renal failure death, which have significantly increased over the study time period, especially for the age group 45-69 years,” Prof. Prabhat Jha from the University of Toronto, Canada, and the corresponding author of the paper, tells me.

Renal failure is a growing cause of premature deaths in southern and eastern States in India.The rate of deaths due to renal failure at ages 15-69 years was 13 per 100,000 in 2001-03 but has since increased to 17 per 100,000 in 2010-13. Among 45 to 69 year olds, the rate has shot up from 30 per 100,000 in 2001-03 to 40 per 100,000 in 2010-13.

While the total number of deaths was more in rural areas, the death rate was higher in urban areas; the increase in deaths in urban areas increased from 27 per cent in 2001-03 to 32 per cent in 2010-13. And for reasons not known, the southern and eastern States recorded the highest number of premature renal failure deaths.

In the east (Assam, West Bengal, Odisha and Jharkhand), the death rate doubled to 50 per 100,000 population between the two time periods. In the south, Tamil Nadu had the highest death rate and it increased more than Kerala, Andhra Pradesh and Karnataka. In contrast to south and east India, the renal death rate in both north and west India remained nearly static during this time period.

“We are not able to definitely explain the reasons for the different rates of renal failure deaths in the south and east in this study. It seems likely it is due to differences in risk factors such as diabetes, including the prevalence of diabetes, how early it is diagnosed and how well controlled it is. These factors will all influence the progression of diabetes complications including renal failure,” Prof. Jha says.

While hypertension and cardiovascular disease are significantly associated with increased risk of renal failure deaths, diabetes is the leading risk factor for Indians. “Most people” with diabetes in India have poor glycaemic control.

Pointer to diagnosis

“Untreated or poorly controlled diabetes is well recognised to cause kidney complications, including progression to end-stage renal failure and death from renal failure,” he says. “Renal failure is usually a late complication of diabetes, developing many years after the onset of the disease, but among Indian adults with diabetes, we saw a substantial number of deaths in people in their fourth and fifth decade of life. This suggests that diabetes in Indian adults has been going under-diagnosed or under-treated, resulting in [an] acceleration of renal failure complications.”

Besides causing death due to renal failure, chronic kidney disease can also significantly increase the risk of premature cardiovascular death. So the total number of deaths caused by kidney disease will be much higher than those attributed to renal failure alone.

Published in The Hindu on December 18, 2016

Non-communicable diseases killed more Indians in 2015



Cardiovascular diseases were the leading cause of deaths in males and females in India in 2015. And high systolic blood pressure was the number one risk factor.

In 2015, India, like other developed countries, had more number of deaths caused by non-communicable diseases. In the case of males, deaths due to non-communicable diseases (3.6 million) were more than double that caused by communicable diseases (1.5 million), while it was nearly double in females (2.7 million due to non-communicable diseases and nearly 1.4 million deaths due to communicable diseases, neonatal, and nutritional diseases). Globally, 70 per cent (40 million) of deaths in 2015 were due to non-communicable diseases.

Cardiovascular diseases were the leading cause of death in both sexes in India — 1.6 million in males and 1.1 million in females. The next biggest cause of deaths was chronic respiratory diseases — 0.68 million in males and 0.5 million in females.

These are some of the Global Burden of Diseases results (here, here, here, here, here, here,  and here) published in seven papers in The Lancet on October 6.

Injuries killed 0.6 million males and 0.3 million females in 2015 alone. India had the highest number of suicide deaths in the world last year, with nearly 132,000 deaths in men and over 76,000 deaths in women. At 0.36 and 0.31 million, neonatal disorders killed nearly equal number of males and females. The other leading causes of deaths last year in both sexes were ischemic stroke, haemorrhagic stroke, TB, lower respiratory infections and diarrhoea.

India had the highest number of suicide deaths in the world in 2015.

Slower reduction in MMR

Along with Nepal and Bhutan, India has registered a slower reduction in maternal mortality rate (MMR). The MMR was reduced by a little over 50 per cent in 25 years (1990 to 2015), from over 130,000 deaths in 1990 to nearly 64,000 deaths in 2015.

In 2015 alone, the number of under-5 deaths in India was 1.26 million. The number of stillbirths alone was 0.53 million. “India recorded the largest number of under-5 deaths in 2015, at 1.3 million (1.2–1.3 million), followed by Nigeria (726,600) and Pakistan (341,700),” says a paper in The Lancet. Neonatal pre-term birth complications, lower respiratory infections, diarrhoeal diseases and measles were some of the leading causes of under-5 mortality.

The rate of under-5 deaths was 48.9 deaths per 1,000 live births. For every 1,000, live births there were 29.06 neonatal deaths (0-27 days after birth), 20.25 stillbirths, 11.74 post-neonatal (28 days to 1 year) deaths, and 8.80 deaths during the 1-4 years.

The Janani Suraksha Yojana conditional cash transfer programme was established when increasing number of women sought reproductive health services. “[The programme] has been successful at increasing reproductive health-care services, but even despite its popularity this programme has not been as effective at reaching poor rural women, the sociodemographic group that is already at highest risk of adverse pregnancy outcomes,” a paper notes.

Leading risk factors

For both sexes, the leading risk factors are high systolic blood pressure, fasting plasma glucose, ambient particulate matter, household air pollution, and unsafe water. According to The Lancet, smoking is a bigger risk factor for Indians than even cholesterol and iron deficiency. Childhood under-nutrition and lack of whole grains figure in the list.

Iron-deficiency anaemia is the leading cause for years lived with disability in the case of India, followed by lower back and neck pain, sense organ diseases, and depression.

Published in The Hindu on October 6, 2016

Indian private sector bears 2-3 times higher TB burden than estimated


A major revision of the TB burden estimates might be required both for India and the world.

A study has found that in 2014 there were 2.2 million TB patients treated in India’s private sector alone. This is 2-3 times higher than current estimates.

In all probability, the higher TB burden in the private sector might still be an underestimation as drug-resistant TB cases were not taken into account. Thus, the private sector is treating an enormous number of patients for TB, appreciably higher than has been previously recognised. In contrast, the State-run Revised National Tuberculosis Control Programme (RNTCP) treated 1.42 million TB patients in 2014.

According to a 2015 WHO report, six million new TB cases were reported to WHO from across the world in 2014. And India’s TB contribution accounted for 26 per cent of these reported cases. But based on the results of the study, a major revision of the TB burden estimates in India and worldwide might be required. Under-reporting of TB cases could be significantly fuelling drug resistance and have implications for patients across the globe.

More importantly, the results of a study published on August 25 in the journal The Lancet suggests that TB incidence is considerably higher than previously recognised, Prof. Nimalan Arinaminpathy, the first author of the paper from the School of Public Health, Imperial College London, says in an email to me.

India has to redouble efforts to reach patients being treated in the private sector.

Lack of systematic data

Despite the private sector treating more patients than the public sector, systematic data on the private sector was lacking. So the study by Prof. Arinaminpathy looked at the sales of anti-TB drugs containing rifampicin by pharmacists across the country in 2013 and 2014. The team then used this figure to calculate the number of cases. The authors adjusted for TB overdiagnosis in the private sector. There was much variance in the number of patients treated in the private and public sector in different States. For instance, the public sector in Orissa had 1.5-2.8 times the volume of TB medicines prescribed than the private sector but Bihar had three times the volume of TB medicines prescribed in the private sector than public sector. But on a national level, there was nearly twice as much TB treatment in the private sector as in public sector in 2013 and 2014.

The 2.2 million cases treated in 2014 in the private sector was arrived at by considering that TB patients underwent four months of treatment on average and only 50 per cent of TB diagnosis in the private sector was correct. The number of patients treated in the private sector increases when higher accuracy of positive TB diagnosis and shorter average treatment duration were considered.

The results of the study have major implications for TB strategy for India. The disorganised private sector poses several challenges to TB control. Since free TB care is assured even to patients opting for private sector, India has to “redouble efforts to reach patients being treated in the private sector and to deliver the highest possible standards of TB care.”


Indians spent $59 million for TB drugs alone in the private sector in 2014.

Second, surveillance of TB in the private sector has to be strengthened. In 2014, as against 2.2 million cases, only a little over 100,000 cases were notified by doctors in the private sector. “But the government has been making strong progress in engaging with providers in the private sector. There has been a rapid increase of private-sector notifications in the last two years (there were essentially zero in 2011). These are encouraging first steps, and our results show the scale of the challenge ahead,” he says.

 Finally, there is a compelling need to find the true TB burden in the country. “TB burden is typically measured through TB prevalence surveys, the most recent of which was in Gujarat. We may soon see the opportunity to conduct these surveys more broadly across the country, which would cast critical light on the TB burden in India as a whole,” says Prof. Arinaminpathy.

There is an economic cost attached to the disease. Since TB treatment in private sector is met primarily by out-of-pocket expenditure, as no medical insurance in India covers treatment cost, a six-month treatment course for first-line TB drugs would cost $20. The 2.2 million patients seeking care in the private sector would have therefore spent $59 million for drugs alone.

Published in The Hindu on August 25, 2016

The yawning gap in tuberculosis care in India


The doctors showed low adherence to established standards of TB care in clinical practice despite having markedly high levels of knowledge.

The dismal state of tuberculosis (TB) care in the private sector in India has been exposed by a November 2015 study (The Lancet) that employed a novel strategy of using standardised TB patients — healthy individuals trained to pose as TB patients and interact with health-care providers. Standardised patient method has been widely used in India for several other conditions such as asthma, angina, diarrhoea, and pneumonia.

“Relative to other methods [questionnaire surveys, recall-based patient surveys, analysis of prescription and patients’ medical records], data from standardised patients yield an assessment of provider practice free from observation bias, less vulnerable to recall bias, and more complete than medical records. Furthermore, standardised patients permit estimates of case detection rates since illnesses are fixed by design. Finally, because cases are standardized, the methodology allows for quality comparisons across different care providers (public and private practitioners),” Dr. Madhukar Pai, the senior author of the paper from McGill University, Montreal, Canada, says in an email to me.

Seventeen healthy individuals who were trained to pose as TB patients made 250 interactions with 100 doctors who had consented to the study. The 17 individuals interacted with doctors as either patient 1 or patient 2 (presumed TB — suspected but not already diagnosed to have TB), patient 3 (confirmed TB) or patient 4 (suspected MDR-TB). The doctors practising in low- and middle-income settings in Delhi had a MBBS degree (29 numbers), a degree in alternative medicine (40 doctors) or were informal health-care providers with no qualification. All the interactions took place between April 1 and April 23, 2014.

The standardised patients were correctly managed for their respective TB conditions only in 21 per cent (52 of 250) interactions.  The ones who presented with confirmed TB were the most correctly managed ones — 14 per cent for treatment and 26 per cent for referral to DOTS centre or qualified providers. In contrast, correct case management was seen in only 12-13 per cent in the case of standardised patients with presumed TB.

In the case of suspected MDR-TB, referral to a DOTS centre or a qualified provider was only 20 per cent, indicating a “low use of drug-susceptibility testing”.  Contrary to the general notion, MBBS doctors were less likely to correctly treat those with suspected MDR-TB as they started treatment without seeking drug-susceptibility testing.

MBBS doctors were more likely to correctly manage patients and more likely to ask for sputum tests and chest X-rays than others.Like earlier studies that revealed private practitioners’ tendency to initially treat TB patients with antibiotics, the current study found this practice to be widely prevalent. While fluoroquinolones were given to all the four standardised patients in 10-16 per cent of cases, broad-spectrum antibiotics were widely given to those who presented with presumed TB.  Even in the case of standardised patient 2 who had presumed TB but had already finished a round of antibiotic treatment, the doctors were less inclined to ask for sputum test or chest X-ray; steroids were given to them in at least 13 per cent of all interactions.

Microbiological confirmation is the gold standard for TB diagnosis. In spite of having such a microbiological confirmation, standardised patients with confirmed TB and suspected MDR-TB were asked to take a chest X-ray by a large proportion of the doctors. Chest X-ray is a screening tool and has less relevance when microbiological confirmation is already available.

The study revealed that MBBS doctors were more likely to correctly manage “patients” and more likely to ask for sputum tests and chest X-rays than others. Yet, they were “equally likely” to prescribe antibiotics and “more likely” to prescribe fluoroquinolones than others.

Deviations and delay

Incidentally, the study found a major gap in provider knowledge and practice. While doctors showed low adherence to established standards of TB care in clinical practice, they had “markedly high levels of knowledge”.

The private sector is the first point of contact for nearly 80 per cent of TB patients in India, and it offers TB care to nearly 50 per cent. Yet, the deviation from the established standards of TB care in clinical practice, as seen in this study, is the reason why TB patients most often encounter a delay of nearly two months before a correct diagnosis is made and are subjected to high levels of treatment failure and drug resistance.

The doctors were able to detect the standardised patients only in 11 of 232 (five per cent) instances though they were informed before hand that they might come across “patients” who were not real.

“Our study was a pilot because we ourselves did not know whether they [standardised TB patients] would go undetected. We were told that standardised patient method will not work for TB because patients need to have fever and appear sick. But that is not true — unlike malaria or pneumonia, TB fever comes and goes, and is often low grade (night sweats). And TB patients do not look very sick (unless they have advanced TB or MDR-TB). So, we were happy that the detection rate was [only] about 5 per cent,” says Dr. Pai. “Now that we know it works, we are doing much larger studies.”

Related story and link:

Trials with antibiotics lead to TB diagnosis delay


Published in The Hindu on July 31, 2016