DENGUE is the most widely distributed mosquito-borne viral disease. It continues to spread rapidly because of climate change, rapid urbanisation and population growth. These conditions create a high population density in pockets of compact areas that occur more naturally and easily in urban areas. Outbreaks are usually seasonal, peaking during and after rainy seasons, May–October in Bangladesh. Dengue has been classified by the World Health Organisation as one of the top ten threats to public health globally.

Epidemiology

DENGUE is caused by a virus that is transmitted by the bite of female mosquitoes of the species Aedes aegypti. or Aedes albopictus. The former is a domestic insect and the latter habitats in bushes and shrubs around households. The mosquito prefers human blood but also bites mammals like dogs and cattle. These mosquitoes also spread Zika and chikungunya. The virus has four serotypes: dengue virus 1, 2, 3, and 4.

Dengue emerged as a worldwide problem since the 1960s and, once limited to the Southeast Asia and the Caribbean islands, is now almost endemic in 129 of the 195 countries and is found at higher altitudes now, eg Nepal, Bhutan and Myanmar in this region, because of global warming. The disease is also observed now in Central and South America, Southeast Asia and the Pacific Islands. Even in the United States, local cases of dengue occur periodically in some states.

Almost half of the world’s population, four billion, live in areas now with a risk of dengue. Each year, up to 400 million people are infected, 100 million get sick and 40,000 die from it.

The external incubation period, ie the period between the mosquito picking up the virus from an infected person, while feeding on the blood, to the ability to infect another human host, after the virus replicates in sufficient number in the mosquito, is 8–12 days. This means that an Aedes infected for the first time cannot infect a healthy person even if it bites an infected person within a week of getting infected. This is important epidemiologically to understand the transmission potential or the potential of spread of the disease. This however, is also based on the intrinsic/internal incubation period — the period between the entry of the virus into a human host and the appearance of clinical features, which is usually 5–7 days. In these 5–7 days, the following events occur in an infected person.

The mosquito injects the virus into the skin of a healthy person. Some cells in the skin, called antigen presenting cells, or the APCs, eg dendritic cells or Langerhans cells, monocytes/ macrophages (biggest white blood cells that engulf antigens- pathogens) pick up the virus and travel to the lymph nodes and the liver where they replicate and infect more APCs. These then spread throughout the body of the infected person, besides the skin and the liver, ie to the spleen, more lymph node, kidney, bone marrow, lungs, thymus, brain and heart muscle. The clinical features appear after this period. It should take at least 12 days, therefore, between the virus maturation in an infected mosquito to the overt appearance of the disease in an infected human host. However, if the mosquito is already infected or if the mosquito has emerged from the eggs of an infected mosquito then biting of this mosquito will cause development of the disease in about a week, the fastest, after five days.

This should explain if the disease has been transported from somewhere else or developed locally. As the disease is predominantly urban and peri-urban, to say that transmission has occurred in a rural area, it will necessitate to ascertain at least one of the following three conditions: (a) Aedes aegypti has been noticed locally for sometime by now; (b) some of these mosquitoes were already infected before infected people came in from outside; or (c) the disease developed among the locals after five to seven days of coming in of people from outside. If otherwise, it would mean that those who manifest the disease have been infected somewhere else.

The potentiality of transmission also depends on the longevity of the mosquito, which is about a month. The same person can be infected with dengue virus multiple times. While a single infection causes classical symptoms and immunity, multiple infections, if caused by different serotypes, might prove to be fatal. As Bangladesh now shows the presence of all the four serotypes, to varying degrees, the potential to cause severe form of the disease is multiplicative.

As an infected mosquito can pass the virus to its next generation through eggs, called trans-ovarian transmission, so may a pregnant woman already infected with dengue, pass the virus to her fetus during pregnancy or around the time of birth. Breastfeeding mothers have been advised to continue breastfeeding though. Dengue can be spread through blood transfusion, organ transplant, or through a needle stick injury.

Aedes aegypti is most active — in terms of flight range, feeding frequency, mating, egg laying, egg maturation time, life span — in and around 26 to 30 degrees Celsius (mean) and when humidity is above 75 percent (mean) within this range of temperature. The weather variations that are helpful to transmission are either 28–30°C mean temperature and more than 80 per cent mean humidity; 24.5–26.5°C mean temperature and more than 62 per cent mean humidity; or a maximum of 32.5°C and more than 92 per cent humidity. Rainfall is not important unless humans create conditions that facilitate biting and provide opportunity for mosquito to lay eggs. Torrential and running water, in fact, is detrimental to the mosquito to fly and lay eggs and egg sticking to the wall of the water container.

It may be noted that larger epidemics usually begin earlier, develop faster and also fall quicker. The public health department should, therefore, adopt mitigation measures before the above mentioned weather conditions develop.

Entomology

AEDES feed on blood to lay eggs. Eggs are laid close to each other in standing/still, clean water contained in buckets, bowls, animal dishes, flower pots, trays including that under refrigerators, flower vases, cups, saucers, bowls, fountains, tires, tree holes, water collected in depressed mud surfaces created from the thumping of horse or cattle hoof, or in crevices of built areas etc. The laid eggs, looking like small black dirts, stick to the surface of the container, submerged in the accumulated water. Eggs hatch in a few days to a few months, if completely under water, or may sustain up to eight months in case the water dries up prematurely, only to hatch after coming in contact with water. The hatched larva, within five days, become pupa, from which emerges the young adult Aedes in 2–3 days. An adult Aedes does not fly, in its entire life, for more than a few blocks.

Aedes aegypti bites primarily during the day for approximately two hours after sunrise and several hours before sunset. It can bite at night as well. This mosquito can bite people without being noticed as it approaches from behind and bites on the ankles and elbows.

The estimation of what percentage of the breeding sites in a locality contain larva is called Breteau Index. It indicates the density of mosquito in a location. It is an indirect measure of the possibility of transmission of a given mosquito borne disease in that location. A Breteau Index that is higher than 20 per cent is assumed to be a warning sign.

Clinical features and pathogenesis

DENGUE symptoms range from none to serious flu-like symptoms. About 20 to 25 per cent people infected with dengue will get sick and show the clinical features. Typically, the disease course is divided into three phases — febrile, critical and convalescent. Symptoms of dengue typically last 2–7 days. Most people will recover after about a week. Sometimes, even if the fever is gone, the next phase can be dangerous for about one in 20 people who would develop severe dengue. Warning signs generally begin in 24–48 hours after the remission of the fever. Recovery from infection gives immunity from the same dengue serotype, but this immunity, when developed subsequently against another serotype, increases the risk of severe dengue due to antibody-dependent enhancement of immunity, that leads to plasma leakage from the blood vessels in the different organs in the body (a phenomenon that is known as dengue haemorrhagic fever) resulting in reduction of blood volume from the circulatory system causing shock — the dengue shock syndrome which is a mix of clinical features that mimic many different types of diseases. In normal conditions, platelets prevent haemorrhage, but due to the failure of the bone marrow to produce adequate platelet, this facility is turned off.

Severe dengue can be life-threatening within a few hours and should require care at a hospital. Mild symptoms may be confused with other illnesses that cause fever, aches and pains. Dreaded conditions due to internal bleeding, may develop even before the development of fever or any serious clinical features. The most common symptom of dengue is fever and headache with any of the following: nausea, vomiting, rash, aches and pain and tenderness behind the eye, in the muscle, joint, abdomen and b tenderness in the bone — pain felt when pressed. Warning signs that relate to bleeding are bleeding from the gum, nose, ear, conjunctiva (white part of the eye), skin (seen as rash or localised blackening), blood containing vomit, blood containing stool, swelling of the abdomen, feeling tired, restless, or irritable, cold clammy skin, difficult breathing etc. Squeezing of the skin of the arm with even another hand in a patient can cause dark spots in the squeezed areas- signalling the occurrence of internal bleeding in the body.

Laboratory diagnosis

INFECTION with dengue virus may be identified through (a) RT-PCR test, (b) test for dengue NS (non-structural) 1 antigen (which is positive after 3 to 4 days of infection), (c) enzyme-linked immunosorbent assays (ELISA), or (d) rapid diagnostic tests (RDTs) for immunoglobulin type G or IgG, a long-lasting antibody.

A single positive anti-dengue virus immunoglobulin M (dengue IgM) test result, although available before IgG based diagnosis, is not sufficient proof of dengue virus infection. IgM-based positive result may be due to potential cross-reactivity with members of the genus of other circulating flaviviruses, eg, Zika or Japanese Encephalitis virus, etc in dengue-endemic areas. We also need to remember that some tests may have unacceptably high rates of false-positive or false-negative results. The tests should have a sensitivity of =75% (infected people identified as infected) and specificity =98% (non-infected identified as non-infected), especially, when it is used as pre-vaccine tests. Unfortunately, only Euroimmun Anti-Dengue Virus NS1 Type 1-4 ELISA (IgG) and CTK Biotech OnSite Dengue IgG Rapid Test are the two available, as of now, which ensure these levels of sensitivity and specificity (these tests however, are yet to be approved by USA-FDA).

Home treatment

REST as much as possible is a fundamental home-based treatment. Paracetamol may be taken to control fever and relieve pain. Aspirin or ibuprofen should be strictly prohibitive. Drinking of fluids will be necessary to stay hydrated, added with salt. Sponging the patient’s skin with cool water will be useful to reduce fever.

Preventing the disease

PREVENTION may be primary prevention or secondary prevention. Preventing a disease means, preventing spread of a disease entirely or partially, when the disease has already developed. Partial prevention prevents further transmission of the disease. This is effectuated through cutting the potential time of transmission, attained by early diagnosis and treatment and taking active measures to prevent new or further infection from the infected person.

Primary prevention may be helped by wearing loose-fitting, long-sleeved clothes — both shirts and trousers. A 0.5 per cent concentration of permethrin may be used to treat clothing and gear. Permethrin kills or repels mosquitoes. The advantage of permethrin is that clothes treated with it provides protection even after multiple washings. But it is advisable to read product information to find out how long the protection will last and how and where to use it. Permethrin should not be used directly on the skin.

It will be useful to fit screens on windows and doors and repair holes in screens. If affordable, the use of air conditioning will help or use of mosquito net treated with permethrin. Mosquito nets should be compact, white, rectangular, with 156 holes per square inch, and long enough to tuck under the mattress. Holes in the net should be repaired. It will be unsafe to fix the net near any candles, cigarettes, burning repellant or open fires. If the net is not treated with insecticide it will be unsafe to sleep directly against the net, as mosquitoes can bite through holes in the net.

Mosquitoes should be prevented from laying eggs. Once a week, we should empty, turn over, cover, throw out or dry up items that hold water, indoors or outdoors, such as tires, buckets, planters, toys, pools, birdbaths, flowerpots, trash containers and other water containers.

Primary prevention also includes, a vaccine, available for use in children aged 9–16 years with laboratory-confirmed previous dengue virus infection and living in areas where dengue is endemic if vaccine is given to a previously uninfected person, a subsequent infection will have a greater probability to cause more severe outcome. The vaccine is not approved for travellers who are not living in a dengue endemic area. Dengvaxia, a tetravalent, live-attenuated, recombinant DNA vaccine, is the only vaccine approved by the US Food and Drug Administration. It is made by Sanofi Pasteur. The vaccine prevents dengue caused by all four dengue virus serotypes.

Controlling the disease

COMMON organophosphates used as adulticides include malathion. Plant-derived pyrethrins (pyrethrum) are extracted from chrysanthemum flowers. Synthetic pyrethroid is similar to natural pyrethrins. Ultra-low, but measured volume is sprayed. Examples of synthetic pyrethroids include permethrin, sumithrin, and deltamethrin. Both plant-derived pyrethrins and synthetic pyrethroids kill mosquitoes by injuring their nervous systems.

Emerging methods, tested for many years, include: genetically modified mosquitoes and irradiated male mosquitoes which lose capacity to impregnate a female mosquitoes, and controlling mosquitoes with Wolbachia. These techniques are useful in case of insecticide-resistance. But the success is still being evaluated.

Larvicides are more practical, efficient and effective than adulticides. These come in many forms. Liquid larvicides are applied directly to water. Tablets, bits, pellets, granules, briquette larvicides are applied to areas where mosquitoes lay eggs. Mineral oil-based surface films suffocate the larvae and pupa in water. Mineral oil-based films are, in fact, the only effective methods for killing pupae. Bacterial larvicides are Bacillus thuringiensis subspecies israelensis found in the soil and is toxic to mosquito larvae, blackflies, and fungus gnats. This has been used for mosquito control for more than 30 years. Another bacteria- Saccharopolyspora spinosa is also found in soil and is toxic to mosquitoes, ants, fruit flies, and other insects.

Over time and because of repeated use, insecticide resistance can occur in mosquito populations. It is, therefore, necessary that frequent monitoring is done to check it. People bestowed with the responsibility need to keep in mind that Aedes Aegypti is a domesticated insect and outside fogging may work only against Aedes albopictus. Controlling the lethal dose of adulticide in different weather conditions and air velocities may reduce its lethality.

AM Zakir Hussain is a former director, Primary Health Care and Disease Control, former director of IEDCR, DGHS, former regional adviser of SEARO, WHO and former staff consultant, Asian Development Bank, Bangladesh.