The New Nation - Internet Edition

Visceral leishmaniasis, or kala-azar as it is commonly known, is a sandfly transmitted parasitic illness marked by prolonged fever, splenomegaly, anorexia, and wasting. Considered to be a major neglected tropical disease in South Asia, kala-azar has resurged in endemic regions of Bangladesh since the 1990s, with the highest rates in the districts of Mymensingh, Pabna, and Tangail (1). In Mymensingh specifically, the average annual incidence rate between 1994 and 2004 was 5.8/10,000, and currently is as high as 300/10,000 in the most affected communities (1,2).

Post kala-azar dermal leishmaniasis, or PKDL, was first clinically described in Bengal by Brahmachari in 1922 (3). Diverse dermal lesions - from hypopigmented pinpoint marks, to erythematous papules, nodules, and others - appear in individuals who are otherwise asymptomatic, usually months to years after the occurrence and apparent effective treatment of classic kala-azar (4). Affected persons, though clinically well, harbour the Leishmania parasite in their skin lesions; sandflies which take a bloodmeal may thus become infectious, making PKDL patients an important reservoir in anthroponotic leishmaniasis transmission.

Despite being long recognized clinically, research on the risk factors, epidemiology, and management of PKDL is quite limited, especially in South Asia. Anecdotally, the number of PKDL patients in certain kala-azar endemic pockets of Bangladesh is clearly on the rise, but actual statistics remain incomplete and are only just beginning to be officially collected. PKDL is essentially a clinical diagnosis, because dermatopathological sampling of patients is impractical, and there is a lack of definitive laboratory testing. Under current Bangladeshi national guidelines, patients with PKDL are treated with 120 intramuscular sodium antimony gluconate (SAG) injections, in 20/month cycles over 6 months.

An active surveillance study exploring kala-azar, kala-azar treatment failure/relapse, and PKDL cases was commenced in the most affected upazilla of the country, Fulbaria, Mymensingh, in June of this year (2007). A field team selected communities with the highest rates of disease based on recent governmental data and administered surveys to individuals at their homes. Patients - current and from the past 5 years - were identified by symptom and treatment history oriented questionnaires, appropriate examination by physician, and rk39 (rapid, fingerprick blood) testing in the field. The study aims include a complete survey of 3 villages and a target sample population of more than 20,000 respondents. The data obtained will be compared with governmental passive surveillance statistics to assess rates of under-reporting. In addition, risk factor, laboratory, and further clinical characterization of especially current patients is being undertaken.

By November of 2007, interviewers have surveyed approximately 8,400 respondents with the completion of the study's primary field site of Chouder Village. From this population, a total of 32 current and 11 recent (treated and resolved within the last 5 years; one death during treatment) PKDL patients have been identified, and preliminary review of this emerging cohort has revealed several notable findings. While the village point prevalence for PKDL is 3.8/1,000 residents, one para (neighborhood), Nodipar demonstrated a rate nearly twice this, at 7.3/1,000 (Table 1). Also, rates of PKDL amongst treated kala-azar patients have been higher than expected in the entire community at 13.9% and reached 16% in 4 of 9 paras (Table 2).

Closer exploration of individual cases reveal important patterns regarding timing of PKDL related to kala-azar and patients' response to treatment. Based on respondents dating in the detailed surveys, presentation of PKDL lesions occurred within 2 years after kala-azar treatment in the majority (24/40) of patients, with 20% of patients within 6 months, and 40% between 6-24 months (Table 3). Also, of the 10 patients who experienced resolution of PKDL after treatment and from whom complete information was obtainable, 7 actually received less than the standard 120 day SAG regimen, secondary to extreme pain/injection intolerance, early and complete disappearance of lesions, or contemporaneous death or severe illness of co-patients receiving SAG (Table 4). Of note, these patients demonstrated similar timeframes of resolution to the 3 patients who received the full 6 month treatment course, with their lesions generally beginning to regress within 3-5 months of initiating treatment, and completely disappearing within 6-9 months (Table 4).

Additionally, three of the youngest patients presented with symptoms consistent with treatment-relapse kala-azar along with their PKDL lesions. A brief clinical description of one may be most illustrative: A 3.5 year-old female, whose father had kala-azar at the time of her birth, was first diagnosed with kala-azar at age 6 months after ongoing fever and poor growth. She improved after 20 continuous days of SAG injections as an inpatient at the Upazilla Health Complex Hospital, but again at age 1.5 (1 year later) presented with prolonged fever and marked anorexia. At that point, physicians at governmental facilities (based apparently on both clinical judgment and positive aldehyde (AT) testing) again felt that she had active kala-azar disease, and she was treated with 60 injections of SAG, in 20 injection/month cycles over 3 months. Approximately 2 months after the completion of this second regimen (21 months prior to our initial evaluation), she broke out with hypopigmented papules diffusely over both legs, and again experienced abdominal pain and suppressed appetite. At the time of our field examination and diagnosis, she appeared stunted and very ill, had conspicuous hypopigmented papules - confluent in areas - densely spread over her legs, arms, and mainly the cheeks of her face; she continued to have abdominal fullness with mild splenomegaly, regular fevers and debilitating anorexia, and had a recent history consistent with repeat respiratory and skin infections.

Supported by: United States Agency for International Development and Centers for Disease Control, USA

Our growing experience with PKDL patients from Mymensingh challenges the existing understanding of the disease in Bangladesh, and suggests that PKDL is a more common and complex clinical phenomenon than currently assumed. South Asian PKDL is conventionally described as occurring in a limited proportion of treated kala-azar patients, who are otherwise asymptomatic, usually 2-3 years after classic kala-azar disease, and that spontaneous cure is never seen - making treatment mandatory (4). In con trast, initial evaluation of the study population in Fulbaria, Mymensingh reveals that a majority of patients' dermal lesions appeared within 2 years of resolution of KA, and in several individuals as early as within 6 months. Also, we have identified a few respondents whose PKDL lesions demonstrated rapid increase followed by steady improvement towards disappearance without any intervention, which raises the possibility that the disease may resolve on its own (without treatment). Considering the observations of the patients evaluated to date, PKDL appears to naturally evolve in distinct patterns and rates, varying significantly at the individual level.

In addition, a number of our PKDL patients described ongoing fevers, while at least three also had re-appearance of anorexia and abdominal fullness, all classic kala-azar symptoms. These observations indicate that the emergence of PKDL consistent lesions is not always independent of other visceral leishmaniasis features, and may occur in patients who had ineffective management of their original kala-azar and thus a persistence of systemic symptoms, often known as treatment failure or relapse cases.

In sum, the appearance of PKDL consistent skin lesions may be more closely associated with classic kala-azar than initially assumed in South Asia, representing a manifestation within a spectrum of Leishmania-host/ immunity interactions rather than a completely distinct clinical entity - a concept which has best been described in the framework of PKDL seen in Sudan (4).

These early observations also call into question the existing national PKDL treatment and disease control strategies. The current treatment regimen of 120 SAG injections is not only particularly lengthy and painful, but also risky: prolonged use of the drug increases the potential for serious cardiac side-effects as well as exposure to 'toxic' drug batches, which often appear on the market unexpectedly and may be discovered by the occurrence of multiple sudden fatalities within a short time (5). In fact, the unexplained and relatively sudden death of a 7-year old girl from Chouder in 2004, who was overall well and had completed 57 SAG injections in the midst of her PKDL treatment (as explained by several family members during a thorough verbal autopsy), raised strong concern for drug-related toxicity.

Additionally, this rigorous regimen is supported neither by comprehensive clinical trials in the literature, nor by the practices of other kala-azar endemic countries. For example, in neighbouring Bihar state in India where antimony-resistance is a major problem, SAG is rarely used for more than 3 months, and in East Africa, PKDL - when treated, is usually approached with short course, combination therapy, including more effective alternatives such as amphotericin or paromomycin. The experiences of our 7 patients who achieved resolution with shorter than standard treatment similarly suggest that the arduous 6 month SAG course is not always necessary for resolution.

Also, the experience from Chouder indicates that PKDL may occur in a notably higher percentage of treated kala-azar patients, and be more prevalent, then assumed. Though the determined point prevalence (of 3.8/1,000) for the entire village is slightly less than 4.8/1,000 - the figure reported from the only existing community based study, from an endemic area of Varanasi, India, published in 1989 - a third of Chouder's paras had rates higher than this of above 5.0/1,000 (5). Similarly, the proportion of our kala-azar patient cohort which has developed PKDL has been striking, with 14% in the entire community and 18% in two of the most affected para, significantly greater than the conventional 5-10% repeated throughout the literature for South Asian patients. Our current calculations likely underestimate the true rates of PKDL emergence in treated kala-azar patients, because identified kala-azar patients from the past 5 years - particularly those with more recent illness - may present with characteristic dermal lesions any time in the future.

Preliminary assessment of any ongoing study, particularly when sample sizes remain small, is vulnerable to mis- or over-interpretation, and analysis of eventually completed data may not support initial observations. Additionally, disease rates and patient characteristics from the highest-endemicity region of Bangladesh may not ultimately reflect and be generalizable to less affected areas of the country or elsewhere.

Nevertheless, these early community based data from Mymensingh urge not only further research into PKDL but also a timely re-evaluation of current national control measures. Ideally, kala-azar patients should be followed regularly for development of PKDL consistent skin lesions, with enhanced community based identification. Likewise, research on PKDL's epidemiology and clinic features would be best approached with close longitudinal observation (rather than cross-sectional or retrospective analysis). Finally, along with active and early case detection, disease control efforts should include an immediate exploration of alternative kala-azar and PKDL treatment strategies, and associated measures such as targeted vector control, particularly in areas with a high-density of affected individuals. -HSB

Easir Abedin

Bacteria are everywhere - they live on our worktops, on our cutting boards and rolling pins, in our cupboards and, of course, on our food. Not necessarily, dangerous bacteria are very rare and are far outnumbered by harmless or helpful bacteria. This means that your worktop will contain a huge mass of harmless bacteria.

If a harmful bacterium were to arrive on your worktop, the well established harmless bacteria would compete with it for food and space and would probably win - the bacteria in your kitchen (for the most part) actually help to keep your food safe!

Feeding the World

Bacteria themselves can be eaten as food though this seems unpleasant to most people. In many parts of the world there is not so much a shortage of available food, as a shortage of protein - some bacteria comprise up to 50% protein and in many cases it is what nutritionists call 'complete' protein - this means it contains all the essential amino acids. ICI actually marketed a bacterial feed called Pruteen, extremely high in proteins - originally it was destined for the human marked but this idea failed and it is now sold as a commercial feed for farm animals. One of the advantages of bacteria as food is that they can often be fed on waste products (eg methane gas) or widely available, non-protein, foodstuffs such as molasses (treacle).

An example of a bacterial food that is consumed by (at least some) people is cyanobacteria - this is a type of bacteria that sometimes grows into long filaments - these are removed from the salt water in which they grow and are left to dry in the sun into 'mats' of fibres that can be made into a type of biscuit. One such cyanobacterium is Spirulina, originating in the salty lakes of Chad and Mexico. 'Health food' stores sometimes stock this food.

Plant Feeders

All plants and animals need nitrogen - this forms the 'amino' part of amino acids and without it we would have none of the vital proteins needed for life. About 80% of the atmosphere is made of nitrogen but as it is, animals and plants cannot make any use of it - to be of use it needs to be in a form known to scientists as 'fixed'.

There are only three things that can turn atmospheric nitrogen into fixed nitrogen:

1) Lightning

2) Manmade methods

3) Bacteria

Of these, bacteria make at least half the worlds useable nitrogen, and a hundred years ago (before man-made methods) they made about 85-90% of it. Not all bacteria can make useful nitrogen - those that can are called nitrogen fixing bacteria and most can only perform this process if there is no oxygen around.

This is where plants come in. Some plants can form nodules - these are lumps on the roots that surround the nitrogen-fixing bacteria. Inside the nodules are special mechanisms for absorbing oxygen that let the bacteria get on with making useable nitrogen - this goes directly to the plant. When the plant dies or its leaves fall off, the nitrogen gets into the soil and acts as a fertiliser for other plants.

Some plants that can perform this are:

Clover

Soya bean

Lentil

Pea

These are known as leguminous plants or legumes. They can be grown specifically by farmers in poor soil and they will increase the nitrogen content, acting as a natural fertiliser, if ploughed in. This is one of the main bases for crop rotation - alternating leguminous and non-leguminous crops reduces the need for fertilisers.

Other plants that are not legumes can also harbour nitrogen-fixing bacteria and these include important plants such as:

Leucaena (An important tree for firewood and fertilising soil in Australia)

Alder (important in mountainous regions - its nitrogen-fixing bacteria gradually improve the generally poor soil in these regions).

Bog Myrtle, serves a similar purpose to Alder but in heath and bog land.

This explains where plants get their nitrogen, so what about animals?

They get it from simply eating the plants, or eating the plant eaters, or eating animals that have eaten the plant eaters and so on.

Not all nitrogen-fixing bacteria live associated with plants - many live in the soil itself and many more live in the sea. The sea-dwelling ones are thought to be very important but the ones living 'loose' in the soil are not, contributing only about 1/100th of the amount of nitrogen that the plant-associated bacteria do.

Plant Protectors

As well as providing nitrogen for plant food, bacteria can also act as guards for our crops. Each year, insects destroy tens of thousands of tons of food - pesticides can aid in the battle against these creatures but they also poison small animals and are not guaranteed safe for humans.

So what can bacteria do?

A bacterium was discovered in the early 1990's that contains a poison only toxic to insects. If insects consume the bacteria, they die. Other animals are not affected and the damage can even be limited to certain insects only by carefully choosing the type (strain) of this particular bacteria used.

Grass Chompers

Plants store sugars (carbohydrates) in different forms to animals - this is one of the things that makes plants so much less fattening than animal products - the energy is there but cannot be broken down directly by animals.

This is where bacteria come in. Bacteria live all over our body and especially in the gut. Some animals (aall those that only eat grass, leaves and other fibrous plant material) have bacteria that can break down the starch and cellulose into fatty acids that can be used by the animal to make amino acids and other essential products.

Animals that have bacteria that can break down cellulose can use fibrous plants as food

Animals without bacteria that can break down cellulose cannot use fibrous plants as food

The animals that are able to gain nourishment from plants with the aid of bacteria can do so as they have more than one stomach. Cows and similar animals are called ruminants as they have a complex intestinal arrangement with several compartments often referred to as stomachs. One of the compartments, preceding the true stomach (abomasum) is called the rumen and in here the food is mixed with saliva and the bacteria that can degrade cellulose. From here goes to the reticulum where it is turned in to cuds that are regurgitated so the animal can chew the plant material further ('chewing the cud'). This material is re-swallowed and this time travells into the abomasum to be subjected to normal digestion processes.

It is not only mammals that can do this. At least one bird can too - locals in Venezuela call it the stinky cowbird, due to its cow-like smell. This is due to the bacteria making gasses similar to those of a cow. In this case the bird's oesophagus (throat) and crop act as the rumen does in cows and sheep.

The bacteria that aid the cowbird are not just good at digesting grass, they can also detoxify powerful plant poisons called alkaloids - these are a major plant defense mechanism against animals and the ability to eat such plants gives the stinky cowbird a greater range of possible food.

A similar ability to this has been used in Australia to allow goats and sheep to eat the leaves of the Leucaena tree, which are normally poisonous to these animals. This tree is widely grown in Australia as it is fast growing and its leaves are packed with nitrogen. This makes them good for the ground when they fall and decompose. It was discovered in the 1980's that Hawaiian goats could eat the leaves without harm and the bacterium responsible was isolated and put into the rumen of other goats and sheep. Once it had been allowed to grow in numbers, it allowed the animals to safely eat the leaves that were once poisonous to them.

Making Vitamins

Vitamins are only needed in very tiny quantities. The human body does not make its own vitamins and so needs to have them in its diet. The good news is that many of the bacteria in our intestinal tract produce useful vitamins as by-products - we absorb these and so bacteria can help prevent certain deficiency diseases. This is extremely useful if our diet does not contain all the vitamins we need.

This was demonstrated in an experiment in which army volunteers were fed polished rice (no vitamin B1 content) for two weeks and remained perfectly healthy when they should have contracted beriberi. If their intestinal bacteria were killed by antibiotic treatment, then they developed these diseases within a few days.

Vitamin Required for Primary non-bacterial source

B(many types) Many functions including: Red blood cell formation NervesSkin Liver, kidney heart, eggs, milk, cheese, fish, vegetables, wholemeal flour

C Skin Wound Healing Citrus fruits, green vegetables, tomatoes, potatoes

H Muscles Protein synthesis Yeast, liver, kidney, egg white

K Blood clotting Spinach, cabbage, Brussels sprouts

Carotene* Antioxidant - can be converted to vitamin A Milk, cabbage, lettuce, carrots

Lysine* Essential amino acid Potentially, any protein

*These are not, technically, vitamins but are still vital products produced by some intestinal bacteria.

It is interesting to note that many of the products we buy have added vitamins: margarine and bread being good examples. Many of the vitamins added, together with some of the vitamins found in pills, are produced by bacteria under commercial conditions.