Indian researchers use a novel approach to kill TB bacteria

Bergenin-Optimized

The compound isolated from Shayla tree does not directly target the TB bacteria but modulates the immune system to kill the bacteria.

A team of Indian researchers has been able to achieve 100-fold reduction in TB bacterial load in lungs of mice after 60 days of treatment using bergenin — a phytochemical isolated from tender leaves of sakhua or shala tree (Shorea robusta). Unlike the regularly used antibiotic drugs that target the TB bacteria, the bergenin compound modulates the immune system to kill the bacteria found inside the macrophages (a type of white blood cells). The results were published in the journal Frontiers in Cellular and Infection Microbiology.

“Our studies show that the bergenin compound can be used to clear the bacteria, and when used in combination with other TB drugs can produce good results,” says Gobardhan Das from the Special Centre for Molecular Medicine at Jawaharlal Nehru University (JNU), a corresponding author of the paper. “Since the compound does not target the bacteria directly but modulates the immune system to kill the bacteria, it can be used against drug-resistant TB too.”

The researchers undertook several studies to understand the mode of action of the compound. The compound was unable to directly kill TB bacteria when treated with the compound. However, in the case of in vitro studies, the compound was able to kill the bacteria found inside infected cells. In mice infected with TB and treated with the compound, there was significant reduction in the bacterial load in the lungs. Unlike in the case of in vitro studies, in mice the compound was found to activate not only the macrophages but also other cell types (T cells) that led to effective killing of the bacteria. A significant reduction in the number of granulomatic lesions was seen in animals treated with the compound. Also, the bacterial load was 100-fold lower in mice treated with the compound compared with controls (animals that were not treated with bergenin). “These findings strongly suggest that the immune response enhanced by the compound is able to increase the capacity to clear the TB bacteria,” Prof. Das says.

The levels of nitric oxide and a cytokine (TNF-alpha) were found to be enhanced. “We found the bergenin compound was selectively enhancing the frequency of interferon-gamma and interleukin-17-producing T cells in the TB infected animals,” says Dhiraj K. Singh from ICGEB and a co-author of the paper. Interferon-gamma promotes bacteria-killing nitric oxide inside macrophages thus promoting the generation of protective immune responses against TB bacteria.

Previous studies have shown that T helper 1 (Th1) cells play a key role in protecting the host against TB bacteria, while Th2 cells oppose the protection offered by Th1 cells. “There is a dynamic balance between the Th1 and Th2,” says Ved P. Dwivedi from ICGEB and the first author of the paper. “While TB bacteria prevents Th1 response and facilitates Th2 response, the bergenin compound promotes the expression of Th1 and Th17 responses.”

Beats conventional drugs

The compound has been shown to heal wounds faster than conventional drugs. Dr. Debprasad Chattopadhyay, Director of the ICMR-National Institute of Traditional Medicine (ICMR-NITM) in Belgaum, Karanataka, and the other corresponding author of the paper, had isolated the compound. He had seen tribals using the leaves of shala tree for wound-healing.

“The stage is now set to test many more Ayurvedic and plant-derived natural products for their potency against pathogenic diseases,” says Dr. Anand Ranganathan from the Special Centre for Molecular Medicine at JNU and one of the authors of the paper.

Prof. Das with the help of ICMR-NITM plans to carry out further tests in larger animals. If used in combination with other TB drugs the compound can shorten the duration of treatment and prevent the emergence of drug-resistance, the authors write.

Published in The Hindu on May 19, 2017

Euro VI diesel emission norms can avert nearly 174,000 premature deaths

pollution

Under the current diesel emission norms, there is a wide gap between on-road NOx emissions and certification limits.

Despite tighter nitrogen oxides (NOx) emission norms for diesel cars, buses and trucks in several countries, the actual amount of NOx emitted by diesel vehicles is far more during on-road driving conditions than under laboratory testing carried out at the time of certification. As a result, the excess NOx emitted over certification limits caused nearly 38,000 premature deaths in 2015 in the European Union, China and India; India alone had 9,400 deaths due to excess NOx emissions. Over and above the deaths caused by excess NOx emissions, increased air pollution from diesel NOx caused 107,600 premature deaths globally in 2015.

Diesel vehicles in the 11 major markets (Australia, Brazil, Canada, China, the EU, India, Japan, Mexico, Russia, South Korea, and the U.S.) emitted 13.2 million tonnes of NOx under on-road driving conditions, which is 4.6 million tonnes more than the vehicles’ performance under official laboratory testing. Compared with certification testing, the average on-road NOx emission is 2.3 times higher for light-duty diesel vehicles and 1.45 times the limit for heavy-duty diesel vehicles. Diesel vehicles sold in the 11 markets account for about 80% of global sales.

Adopting and enforcing the stricter Euro VI emission norms could “nearly eliminate” on-road diesel-related NOx emissions and avoid nearly 174,000 premature deaths in 2040, says a study published in Nature on May 15. NOx is a key contributor to outdoor air pollution in the forms of ground-level ozone and fine particulate matter of less than 2.5 micrometre size (PM2.5).

Under the current Euro IV diesel emission norms, there is a wide gap between on-road NOx emissions and certification limits. The excess NOx emissions coming from diesel vehicles gained worldwide attention when 11 million Volkswagen vehicles that contained defeat devices that controlled emissions only at the time of emission testing became known. But what is less known is that the current certification procedure adopted for diesel cars, buses and trucks “legally permits higher” vehicle emissions under normal driving conditions than the certification limits.

Euro VI emission norms have in-service testing, in-use emission monitoring, expanded driving conditions and independent verification.

Heavy diesel vehicles accounted for 86% of on-road emissions and over 75% of excess on-road diesel NOx emissions in 2015, about 90% of which is from China and India, the EU, Brazil and the U.S. In the case of diesel cars, the on-road emissions were 130% more than the certification limits.

Breaking the drug-resistant TB transmission cycle important

GeneXpert

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

Preterm babies don’t gain growth by early initiation of complementary food

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Babies started early on complementary food tend to suffer more due to diarrhoea and lower tract infections.

Babies born preterm (before 37 completed weeks of gestation) have a higher energy requirement than babies born full term and therefore fail to gain weight adequately. Parents of preterm babies and doctors alike are not sure whether breast milk or formula milk alone will meet the energy requirements after the first four months and whether preterm babies should be started on complementary food. While normal babies are given solids and semi-solids only from six months of age, early initiation of complementary food, which has a higher calorie density, in preterm babies appears to be a good idea to meet their energy needs and improve their growth (weight and length).

Till recently there was little evidence of whether earlier introduction of complementary feeding (prior to six months of corrected age) would improve growth of preterm babies.

No gain in growth

A study published a few days ago in The Lancet Global Health has found an answer to this vexatious issue — early initiation of complementary feeding in preterm babies born before 34 weeks of gestation does not improve growth.

Doctors from the All India Institute of Medical Sciences (AIIMS), Safdarjung Hospital and Kasturba Hospital, all in New Delhi, enrolled 403 babies born before 34 weeks of gestation and randomly assigned them to two groups — one in which they were started on complementary feeding at four months of corrected age and the other group of babies where complementary feeding was initiated at six months of corrected age. The corrected age refers to age that is corrected for the period of prematurity — for a baby born at 32 weeks of gestation, which is approximately two months earlier than the normal gestation period, the corrected age is 10 months at the end of one year of birth.

Complementary feeding was standardised in both the groups in terms of frequency, consistency, type of food, preparing food hygienically, and ways of feeding. Complementary foods were given in addition to breastfeeding/other milk feeding.

“Even though one group of babies was started on complementary feeding at an earlier age of four months of corrected age, there was no difference in growth compared with babies who were started on complementary feeding at six months of corrected age,” says Dr. Ramesh Agarwal from the Department of Paediatrics at AIIMS, one of the corresponding authors of the paper.

Some health risks

On the other hand, the study indicates that early initiation of complementary feeding had some negative fallout. “There were more hospitalisations in the group that started on complementary feeding at four months of corrected age,” he says. Though overall hospital admission in both the groups was low, babies in the four-month group were at increased risk of hospital admission due to diarrhoea and lower respiratory tract infections. “There could be several reasons for this increased risk, including potential contamination of complementary foods due to inadequate hygiene or having less breast milk,” he says.

“Our study shows that there is no difference in growth whether complementary feeding is started at four or six months of corrected age. But there are more infections when complementary feeding is started earlier. So it is advisable that complementary feeding is started only at six months of corrected age in preterm babies less than 34 weeks of gestation,” says Dr. Agarwal. However, studying the difference in growth and not infection was the primary objective of the study.

Published in The Hindu on May 7, 2017

India to treat all HIV positive people irrespective of CD4 count

AIDS

Lakhs of HIV deaths can now be averted as India follows the WHO’s recommendation.

Two years after the World Health Organisation recommended that antiretroviral therapy (ART) be initiated in people living with HIV irrespective of the CD4 cell (a type of white blood cell) count, India has aligned its policy with the guideline. In a major shift in the HIV treatment guidelines, Union Health Minister J.P. Nadda had recently said that any person who tests positive for HIV will be provided ART “as soon as possible and irrespective of the CD4 count or clinical stage”. By expanding the provision of ART, about 0.45 million deaths can be averted.

It was in 2002 that the WHO first issued its ART guidelines. In the absence of AIDS-defining illnesses, the WHO set CD4 count less than 200 cells per cubic millimetre as the threshold to begin ART treatment. Over time, the WHO changed its guidelines and, in 2013, increased the threshold to CD4 count less than 500 cells per cubic millimetre. But for certain populations — HIV positive people who also have TB disease, pregnant and breastfeeding women, children below five years — ART was to be initiated regardless of the CD4 count.

The recommendation was based on the evidence that earlier initiation of ART will help people with HIV live longer, remain healthier and “substantially reduce” the risk of transmitting the virus to others. The availability of safer, affordable and easy-to-manage medicines that could help to lower the amount of virus in the blood played a key role in WHO’s decision to increase the threshold. Earlier initiation could avert an “additional three million deaths and prevent 3.5 million more new HIV infections between 2013 and 2025,” the WHO noted in 2013.

The biggest challenge will be to identify half a million who have been infected but have not been diagnosed.In 2015, the WHO once again changed its guidelines. Based on evidence from clinical trials and observational studies since 2013, it became clear that earlier use of ART, irrespective of the CD4 count, results in better clinical outcomes compared with delayed treatment. Accordingly, it recommended that ART be initiated in HIV positive people at any CD4 cell count. Early start of treatment has the potential to “significantly reduce the number of people acquiring HIV infection and dying from HIV-related causes and significantly impact global public health” it said.

As per 2015 estimates, India has 2.1 million HIV positive people, of which only 1.6 million have been diagnosed and about a million are on treatment. But half a million people are not even aware of their HIV status. With the government changing its treatment guidelines, 0.6 million who have been diagnosed but not been on treatment are now eligible for treatment. Of the 0.6 million, about 0.25 million have been enrolled for pre-ART care and can be started on treatment almost immediately. But the biggest challenge will be to identify the 0.5 million who have been infected but have not been diagnosed and about 80,000 people who become infected each year.

Even as efforts are on to expand the 1,600 treatment delivery sites that are currently operational, there should be greater focus now on identifying people with HIV. The government has plans to start community-based testing to bring HIV testing closer to those in need, and target special groups that are more vulnerable to infection such as partners of people who are HIV positive.

Despite the WHO releasing the guidelines for self-testing in December last year to improve access to testing, India has refused to approve it on the grounds that pre- and post-testing counselling will not be possible. Self-testing could have increased the number of people who would have got themselves tested. However, the OraQuick self-test is not highly sensitive and any positive test should be reconfirmed with conventional testing.

Published in The Hindu on May 3, 2017

Number of wild poliovirus cases drop in Pakistan, Afghanistan

polio

Several vaccine-derived poliovirus cases have been detected in the environment in Nigeria in 2017.

In the last six months, there have been only eight wild-type poliovirus (type 1 and type 3) cases reported in Afghanistan and Pakistan, down from 32 cases during the same period last year. “The overall situation in Afghanistan and Pakistan has significantly improved in common corridors of transmission,” says a summary report of a April meeting of the Strategic Advisory Group of Experts (SAGE) on immunisation. Except for Pishin and Quetta, children 6-11 months old showed 95% ‘seroprotection’ in all districts during a recent ‘serosurvey’ carried out in Pakistan.

Type 1 cases in Nigeria

Between July and August 2016, three cases of wild poliovirus (type 1) were reported from Borno State, Nigeria in children between 2 and 5 years of age; two of them developed acute flaccid paralysis. This is the first time a wild poliovirus was detected in the country since 2014. However, no more wild poliovirus has been reported in Nigeria since then. But with most areas in Borno remaining inaccessible, a huge population of children aged less than five have not been immunised.

A year after 156 countries, including India, made a synchronised global switch from trivalent (containing all three strains of the polovirus — type 1, type 2 and type 3) to bivalent (only type 1 and type 3 strains) oral polio vaccine, several vaccine-derived poliovirus (VDPV) type 2 have been detected from the environment in Bauchi, Gombe and Sokoto in Nigeria in 2017.

SAGE has expressed “concern over the ongoing circulation of VDPV2 in Nigeria”. Since there is increased risk of type 2 outbreak as the immunity levels wane, SAGE had recommended that countries that have circulation of both wild poliovirus (type 1 and/or type 3) and vaccine-derived poliovirus type 2 should give “priority to stopping vaccine-derived polovirus type 2 over wild polio virus elimination”. At least two doses of oral polio vaccine containing only type 2 should be given before the next round of immunisation using bivalent oral polio vaccine, SAGE has recommended.

All the 156 countries that switched to bivalent oral polio vaccine have introduced at least one dose of inactivated polio vaccine (IPV) containing all the three strains in a killed form into their routine immunization programmes.

The last time wild poliovirus type 2 was detected anywhere in the world was in 1999. On 20 September 2015, wild poliovirus type 2 was formally declared as eradicated. But with the continued use of OPV, the live, weakened type 2 strain excreted by an immunised child can, under rare instances, turn virulent and cause vaccine-associated paralytic poliomyelitis in unprotected children. Since its eradication in the wild in 1999, all type 2 cases have been caused only by vaccine-derived polioviruses.

Polio cases, whether caused by wild type or vaccine-derived, can be eradicated only when oral polio vaccine is eventually withdrawn once the transmission of wild polio type 1 and type 3 have been eradicated.

Published in The Hindu on May 1, 2017

The big test for malaria vaccine RTS,S

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In 2015, Africa accounted for 92% of global deaths and 90% of all malaria cases.

Beginning next year, the World Health Organisation will begin pilot tests of the injectable malaria vaccine RTS,S (or Mosquirix) on 750,000 children aged 5-17 months in Ghana, Kenya and Malawi. The vaccine has been successfully put through a Phase III trial, in which the drug is tested for safety and efficacy. Any decision on wider use will be taken based on the results of the pilot tests in the three countries. If the vaccine does indeed prove to be ready for large-scale use, it will be a milestone in the fight against malaria. Although the number of cases globally and in the African region came down by 21% between 2010 and 2015, in 2015 itself the number of deaths worldwide on account of the disease was as high as 429,000. According to WHO estimates, Africa accounted for 92% of these deaths, and 90% of the 212 million new cases that year. In such a scenario, even a vaccine with limited benefits could yield a substantial improvement. The vaccine, given in four doses, protects against Plasmodium falciparum, which is the most prevalent malaria parasite in Africa. The three countries have been chosen as they have settings with moderate-to-high transmission of malaria and already have in place malaria control programmes such as the use of bed-nets, rapid diagnostic tests and combination therapy. Each country is to decide where precisely to run the pilots.

The first three doses of the vaccine will be administered with a minimum interval of one month between each dose, followed by the fourth dose 15 to 18 months after the third dose. The first dose will be administered at about five months of age and the third dose has to be completed by nine months of age. While the drop-out rate increases as the number of doses increases, the biggest challenge is the fourth dose, which warrants a new immunisation contact to be made 15 to 18 months after the last dose. In Phase III trials, the efficacy of the vaccine was around 30% when children received all the four doses; the vaccine also reduced the most severe cases by a third. But there was a significant drop in these benefits when children did not receive the fourth dose. Given the low protection efficacy of the vaccine even in tightly controlled clinical settings, the pilot tests will be useful in evaluating the likelihood of replicating the immunisation schedule in the context of routine health-care settings. Also, the extent to which the vaccine reduces the all-cause mortality has to be evaluated as this was not “adequately addressed” during the trial. There is, specifically, a need to ascertain if excess cases of meningitis and cerebral malaria seen during the trials are causally related to the vaccination. Unlike other vaccines, the less-than-optimum protection offered by this vaccine would mean that existing malaria intervention measures will have to be used in conjunction to reduce the incidence of the disease.

Published in The Hindu on April 28, 2017