‘Drug & Vaccine Funding, Surveillance Critical To End Neglected Tropical Diseases’

The disease, which is transmitted by the bite of the culex mosquito, leads to symptoms like fluid retention in the lower extremities (lymphoedema) or in the scrotum (hydrocele). Last year, there were 621,178 cases of lymphoedema and 127,100 cases of hydrocele in the country, as per data from the National Center for Vector Borne Diseases Control.

Lymphatic filariasis is part of a group of 20 infectious diseases that the World Health Organization calls “neglected tropical diseases". At least 11 of them are active in India, including dengue, chikungunya, rabies, visceral leishmaniasis (kala azar), etc.

Kala Azar cases in India dropped from 9,241 in 2014 to 520 in 2023. Trachoma, an eye infection that can cause blindness, was also eliminated in all the 27 high-risk districts across 23 states and Union territories surveyed in 2017, as were Yaws (2015) and guinea worm (2000). However dengue, for which there may be a vaccine by 2026, claimed 485 lives in 2023.

Rains and floodplains provide the ideal environment for vectors such as the mosquito and sandfly to breed. While visceral leishmaniasis and trachoma are on their way to being eliminated because of control measures undertaken by the government, the other diseases--particularly those not amenable to treatment by chemotherapy or surgery--are harder to contain, according to microbiologist and immunologist Nirmal Kumar Ganguly, Padma Bhushan awardee and former director of the Indian Council of Medical Research.

Even when caseloads of these diseases decrease, we cannot afford to let down our guard because they can come back, he told IndiaSpend in an interview.

Edited excerpts:

Chikungunya re-emerged in India in 2005 after three decades. What caused the sudden surge in cases?

Since the first cases of chikungunya were reported in India, the pathogen that causes the disease has undergone a mutation. Chikungunya stays in a place for five to seven years. Its diagnostic test is available in the market. There is no drug to treat it, but we do have a vaccine under trial in India.

The re-emergence of Chikungunya in India can largely be attributed to several factors including increased mosquito vector density, urbanisation which leads to greater breeding sites for mosquitoes, and global travel and trade facilitating virus introduction. Climate change also plays a role in expanding the geographic range of mosquito vectors.

Similar re-emergence could potentially occur with other diseases if vector control and surveillance are weakened. When I was a medical student, I did not see a single case of malaria or kala azar or visceral leishmaniasis (VL), even though I got malaria which was treated using quinine. After the 1970s, malaria and VL came back with a vengeance.

The number of cases of trachoma (a disease of the eye that causes blindness) and VL are declining in India. How soon can we expect trachoma and VL to be eliminated from the country?

We are in the process of eliminating VL in all the endemic areas, but there is no policy for surveillance or containment measures in non-endemic areas, where there is a possibility of migration by carriers of the disease, possibly in search of water or other resources.

In the fight against VL, 2023 marked a significant milestone as all endemic blocks achieved the elimination target of less than one case per 10,000 people in the affected districts. The target was to limit trachoma prevalence to 5% of the population in endemic areas to get the elimination certificate.

Now, to get the elimination certificate from WHO, All India Institute of Medical Science (AIIMS) and WHO conducted a comprehensive study to assess the prevalence of trachoma. The study is nearing completion, with findings soon to be presented to the Union Health Ministry for approval before submission to WHO for final clearance.

There is a WHO process for this. The ministry will report it to WHO, which will take it first, it will go to the regional assembly, then to the general assembly, and then we will declare [the area] trachoma-free. Preliminary results of the survey show that the prevalence is at 3.5%, which means it is no longer a disease of public health importance.

What makes the measures for elimination of trachoma and VL effective?

Trachoma, which is caused by a bacteria transmitted from one infected person to another, causes grains to form in the eyes which leads to blindness. It is amenable to treatment using tetracycline or antibiotics, although some people have to undergo surgery.

In India, ophthalmology is fairly well developed, and there are many field stations. There is a network of ophthalmology clinics such as Shankar Netralaya, Shroff’s, Agarwal Group, Aurobindo, etc., all over India, and the Indian government’s policies for blindness control has helped bring the disease under control.

Funds were made available from the United Nations and Queen Elizabeth Diamond Jubilee Trust. This helped us perform a lot of free operations.

India follows the WHO-recommended “SAFE” strategy, which includes surgery for trichiasis, antibiotics to clear infection, facial cleanliness, and environmental improvement. This comprehensive approach, combined with thorough surveys to verify elimination and extensive community education efforts, has been pivotal in controlling the disease.

As for VL, it affects the internal organs like liver, spleen, etc., as opposed to dermal leishmaniasis (DL) which causes sores on the skin. If VL is left untreated, it can cause anaemia, spleen enlargement, cancer of the liver, etc.

Now trained health workers visit all houses to identify individuals exhibiting symptoms of VL and Post-Kala-Azar Dermal Leishmaniasis (PKDL), referring them to government hospitals for further evaluation.

All symptomatic cases of VL and PKDL are screened using Rapid Diagnostic Tests (RDTs) after clinical assessment by a medical officer. Confirmed cases receive free treatment at government hospitals, are monitored until treatment completion, and followed up for 12 months to detect any Adverse Drug Reactions (ADRs), treatment failures, or relapses.

VL cases are further followed up for three years to detect PKDL cases. For each case, neighbours, relatives, and nearby houses (at least 250 houses) are actively screened for symptoms of VL, and anyone with symptoms is tested.

Villages reporting VL cases are identified and undergo Indoor Residual Spraying (IRS) twice a year to control the sandfly (phlebotomus argentipes) population, the vector for the disease. It is a winged insect smaller than a mosquito that lives in soft soil and in cattle sheds.

Most people now live in houses that are made of bricks and concrete, so these vectors are deprived of dwelling places. However, among the poorest of poor in villages, such as the moosahar community, who dwell in primitive houses and eat grains out of ratholes, the disease is hard to detect and treat.

Sandflies were found to be resistant to dichloro diphenyl trichloroethane, so synthetic pyrethroids are being used since 2016. The inside of every room in every house, including places of worship, toilets, and cattle sheds, are sprayed. We use pressure pumps to spray the walls of the houses so that the flies don’t nest there. Spraying typically occurs once in March-April and again in July-August.

Are there any vaccines that can assist with the elimination of VL?

A large number of VL cases are asymptomatic, which is the case for every infectious disease. A study found that 1.4% of the asymptotic infections later turn into Leishmaniasis.

Vaccination can help limit transmission via asymptomatic infected persons. There are three vaccines which are in advanced stages of research, one of which is being manufactured in India by Gennova Bio in Pune and has reached phase two of the trials. I am one of the evaluators of the vaccine’s trial results. Another vaccine is in the trial phase in Sudan. Given the political situation there, the trial has moved to Kenya. The third one is progressing slowly due to lack of funding.

There were reports that miltefosine, a cancer drug used to treat Post-Kala-Azar Dermal Leishmaniasis, caused blindness among some patients. Are there other drugs or combination therapies under trial for use in India that are safer?

The drugs that were used to contain the spread of kala azar (VL) were discovered in India, in Calcutta Tropical School by Upendranath Brahmachari. It was called urea stibamine, and it was very toxic. So the search for new drugs continued, and doctors C.P. Thakur, T.K. Jha and Shyam Sundar found amphotericin B, which was an antifungal drug. However, it caused kidney damage. So Dr Bimal Kumar Bachhawat's discovery of the liposomal sac through which the drug was delivered to a specific site came in handy. This solved the toxicity problem. Gilead made this drug, but it was very expensive, so it started to give it for free. These drugs were injectables.

Then we started work on a drug that could be given orally. I had a role to play in this. We came across research that suggested that the anti-cancer drug miltefosine worked on parasites too. We did trials with the help of the WHO in Bihar, eastern Uttar Pradesh and West Bengal. We found solutions for all the side effects, except that it could not be given to people with anaemia or to pregnant women. But the drug worked and we managed to contain the spread. It was a ray of hope.

There were logistical issues. We needed to check the haemoglobin. Today, haemoglobin can be checked without pricking, but back then there were challenges. Within three years we completed the trial and the drug was incorporated into public health policy. After that, we got into an agreement with Nepal and Bangladesh to use miltefosine that was manufactured by German Remedies under license. The trials conducted in Nepal and Bangladesh were also successful.

The next problem we discovered was that in some affected people who were treated with miltefosine, there was a relapse because they were resistant to the pentamidine pump that was in the drug. So we had to monitor the patients for at least a year, which was difficult, and we were searching for alternatives. We tried paromomycin, which caused some deafness and also resistance. That’s when we turned to a combination of miltefosine and ambosine, which is how we currently treat malaria and VL.

Do we know what happened to the people who were given miltefosine between 2016, when the first case of post-treatment eye problems was discovered, and 2022, when the guidelines for treatment were revised?

During follow-up, we saw that there was a relapse after three to six months. It turns out that the parasite developed resistance to the drug, and the people who were treated with the drug relapsed.

Amphotericin B, the antifungal drug, cured leishmaniasis but damaged the kidneys of patients. Gilead started making it, and to ensure that it was available, the WHO got into an agreement with Gilead that allowed us to get it for Leishmaniasis elimination for free.

Because every fifth person in India is diabetic, diabetic retinopathy is a side effect we need to consider. Some people who availed of the treatment for three-four weeks experienced loss of vision. Whether they were diabetic or potentially diabetic, we haven’t investigated. Unlike in the trachoma elimination programme, there is no provision for checking for diabetes in the PKDL elimination programme yet.

At present, the programme does not administer drugs for more than 28 days. Also, the main therapy in the programme is not miltefosine but amphotericin B – 10 milligram. In some places, they are making it 20, because some resistance is being found. There are some relapses being found. The long term follow up for miltefosine as a treatment for PKDL is underway.

What makes lymphatic filariasis difficult to eliminate?

Many infected individuals do not show symptoms for years, making it difficult to identify and treat early. Traditional diagnostic methods rely on the detection of microfilariae in blood samples, which must be collected at night when these parasites are most active. The adult filaria worms hide in the lymph nodes. There are few rapid diagnostic tests that can detect the Broucheria bancroftii worms, which is the strain of the disease most common in north India.

Mass drug administration (MDA) for lymphatic filariasis is conducted in the districts in which LF is endemic. How frequently are cases reported from outside of these districts?

While MDA for lymphatic filariasis is primarily focused on endemic districts, there are occasional reports of cases from non-endemic areas. The vector of filariasis is found in eastern India--Odisha, West Bengal, Assam, Andhra Pradesh. If some area is filaria-free, the MDA will stop there for two years. However, someone with filariasis can travel there. So there is a need for constant surveillance.

What are the chances of a healthy individual not living in endemic districts being affected by NTDs?

The risk of a healthy individual contracting NTDs in non-endemic districts is generally low but not negligible. This risk can increase with factors such as travel to endemic areas, environmental changes that expand the habitats of vectors, and insufficient vector control in new areas.

For diseases like PKDL, there is no animal reservoir. It is humans who host the disease. Therefore, surveillance and transmission control is the only way to be sure that the diseases are contained.

How has climate change affected the epidemiology of NTDs?

Both climate change and urbanisation are altering the epidemiology of NTDs. The Konkan Railway went to Goa. The labourers who built the rail network carried malaria to Goa. Wherever buildings are constructed, water is involved. If there is not enough thought put into drainage and sanitation, then you get malaria there. Development can bring vectors along with it.

As the temperature increases, kala azar cases are found at higher altitudes, up to 1,000 feet higher. With the rise in temperatures due to climate change, sandflies--the vectors for kala azar--are finding suitable conditions in previously cooler regions. For example in Nepal, higher temperatures have enabled the breeding of sandflies in areas historically too cold for them, leading to the emergence of VL in new geographic locations including the hilly and mountainous regions--like we have malaria in Almora in the hills of Uttarakhand. There is a strong relationship between climate change and dengue.

Climate change affects the epidemiology of NTDs by expanding the habitats of vectors and intermediate hosts, thus altering transmission patterns. Warmer temperatures and altered rainfall patterns can extend the breeding seasons of vectors and expand their geographic range, potentially introducing diseases to previously unaffected areas.

Additionally, the habitats of these vectors are evolving. For instance, Anopheles dirus, which was previously confined to mountainous regions, can now be found in the plains. Similarly, Anopheles stephensi, originally found in Maharashtra, has expanded its range. [Both these vectors cause malaria.] This is a very good example of the impact of the environment on vector behaviour.

Sandflies would perch on walls when an area was being sprayed, so we started spraying insecticides on walls. They adapted to this, and instead of walls, started lurking outside the doors, returning to bite humans when they step outside or sleep outside to escape the heat indoors. Therefore, monitoring the habitats and behaviours of these vectors is essential.

Which interventions (drugs, vaccines, etc.) should be accorded priority for controlling the spread of NTDs?

We need to reduce vector populations using both chemical and biological control measures.

Chemical control can include the use of insecticides through methods like Indoor Residual Spraying or larvicides in water bodies. Biological control measures might involve introducing natural predators of the vectors or biological agents that interrupt the vector's life cycle.

Integrated vector management that takes care of all vectors is required. If there are malaria mosquitoes, filaria mosquitoes or infected sandflies, it means we cannot spray for individual vectors. An integrated approach ensures sustainable and effective vector control while minimising environmental impacts. A new tool in the fight against filaria is killing the bacteria Wolbachia, which is in a symbiotic state with the worm. An antibiotic will kill the bacteria, killing the filaria worm along with it.

Vector monitoring is also very important. Sandflies have to be trapped to check if they have Leishmaniasis parasites, and if they do, it means transmission is happening. That should set off decisions to control transmission.

Enhancing sanitation facilities and access to safe water are critical in reducing environmental factors that favour vector breeding. Proper waste management, construction of well-designed drainage systems, and ensuring that communities have access to clean water, can significantly reduce the incidence of vector-borne diseases.

Vaccines are a critical tool in preventing disease and reducing transmission. Vaccination campaigns must be robust, reaching high coverage to create community immunity and prevent outbreaks.

Awareness programmes can educate community members on how to reduce exposure to vectors, the importance of using bed nets, the benefits of participating in vaccination and MDA programmes, and the need for improved sanitation. Community involvement increases the success rate of public health interventions by ensuring that preventive measures are widely adopted and maintained.

As always, drugs and drug delivery play a key role in containing the spread of the disease. The continuation and expansion of MDA programmes where diseases such as lymphatic filariasis, onchocerciasis, and schistosomiasis are endemic, is crucial. These programmes involve the periodic distribution of medications to at-risk populations, irrespective of individual disease status, to eliminate the reservoir of infection. Scaling up these programmes to cover all at-risk populations ensures a reduction in disease prevalence and transmission.

We also need better diagnostic tests. A new test--loop mediated isothermal amplification assay (LAMP) developed by Poonam Salotra--detects a positive case [of VL] very early, even in seven days, but the policy says [that the test is to be administered only if the fever lasts] 14 days, so we need to modify policy to keep up with technology. We also need more research on what happens due to climate change. Advocacy will have to be increased. Communication partnerships will have to be forged.

Last but not the least we need manpower. The registered medical practitioners or quacks that people tend to visit when they get sick need to be included in the Leishmaniasis treatment and elimination programme. Accredited social health activists [or ASHAs] were meant to provide birthing support, immunisation support and nutritional support. They get incentive for these tasks. They cannot be expected to perform every task related to public health. We need dedicated link workers.

For all of this, we need funds. It is a disease of the poorest, who do not have the wherewithal or the voice to get treatment on their own. If very few people are dying, or a few hundred cases are detected, the numbers are considered too small. After all, more people die in traffic accidents. Donors say, why should we fund this? And if cases fall, we turn our attention away. The problem isn’t over. Just basing the situation on numbers isn’t enough. We were polio-free in 2014, and now we have a case of poliovirus in the country.

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