Dengue
by Kenneth Lyen
INTRODUCTION
In recent years, many of my medical colleagues, students and patients, have contracted dengue fever. The number of new cases of dengue in the first eight months of 2020 has already exceeded 27,000, which surpasses the highest number of cases in a single year, which was 22,170 in 2013.
Almost all displayed the classical symptoms of high fever, headaches, pain behind the eyes, and skin rash. The platelet count of one of my medical students fell to 7,000 (normal range 150,000 to 400,000 per microlitre), which is dangerously low, and he was very ill. He was given a platelet transfusion and luckily he survived. A few years ago, another student caught dengue while on holiday in Malaysia, and sadly he died there. This brought home to me how dangerous dengue can be.
GLOBAL INCIDENCE
According to the World Health Organisation: “Dengue is regarded as one of the most important arboviral infections in the world which is transmitted by Aedes mosquitoes, mainly Aedes aegypti and Aedes albopictus. The infection might start off like a mild flu-like illness, but occasionally develops into a potentially lethal complication or severe dengue, such as dengue haemorrhagic fever and dengue shock syndrome. As per the World Health Organization, dengue has shown a 30-fold increase globally over the past five decades.”
One estimate indicates 390 million dengue infections per year (95% credible interval 284–528 million), of which 96 million (67–136 million) manifest clinically (with any severity of disease). It is found in “more than 100 endemic countries. Every year, hundreds of thousands of severe cases arise resulting in 20 000 deaths.” Dengue is considered to be the most important acute systemic insect-borne virus infection in humans worldwide (5).
SOUTH-EAST ASIA CASES IN 2019
Last year (2019) Singapore has seen a huge surge in the number of cases of dengue, totalling 16,100 cases, causing 20 deaths (6). In the first seven months of 2020, Singapore already saw more than 22,400 cases and there have been 20 deaths (6a).
Other South-East Asian countries are also not spared. Malaysia reported 85,270 cases with 121 deaths in the first half of this year, compared to 46,544 cases with 76 deaths in the same period last year (7). The Philippines reported 208,918 cases with 882 deaths in the first half of this year, doubling the 102,298 cases with 540 deaths in the first half of 2018 (6). Thailand reported 49,174 cases from January to June 2019 and 64 deaths, compared to 17,302 cases in 2018 claiming 21 deaths (8,9). Data from Indonesia is a little bit hazy, and it is estimated that there were 13,000 cases in the first quarter of 2019, claiming 133 deaths, which contrasts with their annual incidence of approximately 120,000 with about 43 deaths (10,11).
THE MOSQUITO VECTOR
Dengue fever is a viral illness transmitted by the female Aedes mosquito. The recent escalation in the incidence of dengue is correlated with the dramatic increase in the numbers of mosquitoes which transmits the disease.
It is proposed that the rise in mosquitoes is linked to climate change associated with global warming and increasing the sites for mosquitoes to breed (12).
CLINICAL FEATURES
a) Milder Cases: Dengue Fever
Some 4 to 10 days after being bitten by a mosquito, symptoms may appear. However, the majority of cases infected with dengue have no symptoms. or have a low-grade fever. More severe cases may present with sudden onset of high fever, headaches, pain behind the eyes which worsens with eye movements. There may be aches and pains in the joints and muscles that can be quite intense, and accounts for the older term for dengue, “breakbone fever”. Other symptoms include tiredness, nausea, vomiting and abdominal pain.
The initial rash comprises a flat reddish rash together with a slightly raised feel (maculopapular). A few days after the onset of fever, there may be a generalized skin rash resembling a flush, so that if you press your hand onto the rash and suddenly release your hand, your pale handprint is left behind for a couple of seconds.
About a third of patients might manifest some bleeding due to a low platelet count. This includes bleeding from the gums, the stools and urine, and there may be a skin rash consisting of tiny red dots called petechiae. The latter can be induced by placing a tourniquet or blood pressure cuff around the arm and pumping the pressure between systolic and diastolic. In an area of 2.5 x 2.5 cm, the test is positive if there are more than 20 petechiae. The test is known as the Hess tourniquet test or the Rumple-Leede test.
During the recovery phase, the rash may have “islands of white”.
b) Serious Cases: Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS)
Some patients with dengue seem to improve, their fever settles, and then 1-7 days later, they develop a serious complication of dengue. This can present with severe abdominal pain, bleeding into the skin which can appear as little red dots (petechiae) due to tiny capillary bleeds. There may also be bruises, nosebleeds, stools with blood, or bleeding into the urine. The fever may come back, and there can be vomiting, restlessness, difficulty in breathing, dizziness, the skin becomes cold and clammy, and there may be progressive drowsiness leading to coma. The heart rate can be fast or paradoxically slow. The liver may be enlarged. The pulse pressure, which is the gap between the higher systolic blood pressure and the lower diastolic blood pressure can be quite narrow, less than 20 mmHg. The blood pressure drops to dangerously low levels and the patient can go into shock (13).
Severe dengue hemorrhagic fever appears to be more common if one contracts a second dengue infection caused by a different serotype. The antibodies elicited by the first infection does not appear to protect adequately against an infection by another serotype. Indeed the antibodies might even facilitate the second dengue virus entering the cells, and hence promote a more widespread and serious infection.
DIAGNOSIS
Confirmation of the diagnosis requires one of the following blood tests (14):
1 NS1: This is the best test currently available for the early diagnosis of dengue, and is detected by an enzyme-linked immunosorbent assay.
2 PCR: The polymerase chain reaction test detects the presence of dengue RNA early in the course of dengue.
3 Dengue IgM: This test becomes positive after the 4th day of the first dengue infection. There is some degree of cross-reactivity with zika virus.
4 Dengue IgG: The immunoglobulin G test becomes positive after the 7th day of the first encounter with dengue.
5 Dengue IgG: The Immunoglobulin G test becomes positive after the 4th day of the second encounter with dengue. However, this test is not useful for the diagnosis of dengue because it remains positive for many years after a previous dengue infection.
Most publications say that there are four serotypes of dengue: DENV-1, DENV-2, DENV-3, and DENV-4. Recently a fifth serotype has been found (14).
OTHER INVESTIGATIONS
Blood is taken for the platelet count, which can be low in half the cases of dengue fever, and result in bleeding. If low, it is advisable to repeat the platelet count daily in anticipation of it dropping further. The white blood count might also fall, which is a common response to viral infections. The hematocrit is measured by spinning a capillary tube filled with blood, and measuring the percentage of red cells compared to the plasma; if this rises, then it indicates an increased concentration of red blood cells, can herald impending dengue shock (15).
The liver enzymes can be elevated. If there is any signs of bleeding or bruises, tests can be done for clotting factors, namely the prothrombin time, and the partial thromboplastin time.
Before the diagnosis of dengue has been secured, investigations should exclude other infections and this may include culturing the blood for bacteria, and microscopy to look for malaria parasites. Blood can be taken for antibody tests to detect bacteria like streptococcus, mycoplasma, and tests for other viruses, such as the zika virus.
Ultrasound examination can be useful in detecting fluid permeating into the lungs, the abdomen or into the pericardium surrounding the heart. The gall bladder wall may also be thickened.
TREATMENT
Currently there is no antiviral antibiotic available for the dengue virus. Treatment is therefore largely supportive (15).
Fever can be treated with paracetamol. It is important not to administer aspirin or ibuprofen, as these can reduce platelet stickiness and thereby cause bleeding when the platelet count is low.
During the recovery phase of dengue, the skin rash develops classic "islands of white in a sea of red".
Severe dengue should be treated in an intensive care unit. Appropriate fluids are given intravenously and the rate of infusion guided by constant monitoring.
OUTCOME
The outcome of mild cases of dengue fever is excellent, and the mortality is well below 1%. It is estimated that about 5% of dengue fever progresses to the more severe dengue hemorrhagic fever.
Treated, the mortality of severe dengue hemorrhagic fever ranges from 1% to 5%, but if untreated, the mortality can be as high as 20% to 50%.
DENGUE VACCINES
Dengue vaccines have been plagued with problems. The first vaccine to enter major clinical trials is Dengvaxia developed by Sanofi Pasteur. This is a polyvalent vaccine that contains four dengue virus serotypes: DENV-1 to DENV-4. Three doses of the vaccine were given at 0, 6 and 12 months.
In 2014, stage 3 trials were conducted in Latin America and South-East Asia involving 31,000 children aged between 2 to 14 years. Results showed that it was only effective in 64.7% in Latin America, and 54.6% in South-East Asia of vaccinated children. Overall, severe dengue was reduced by 80%, and hospital admission was reduced by 65.6% in children over 9 years old (16).
In 2015, the vaccine was approved in the Philippines, Mexico and Brazil, and full-scale trials began in 2016. Four south-east Asian and seven south American countries took part in the trial. Initially not all recipients were tested for dengue antibodies which would indicate previous infection. In the Philippines, 700,000 children received the vaccine. Some 600 children died after receiving the vaccine (17). Although there has been some dispute as to whether or not some may have died of other causes, it created an angry reactions by the parents of the deceased children. The Philippines government blamed Sanofi Pasteur for endangering the safety of children, and they stopped the trial. Panic spread throughout the Philippines, resulting in widespread fear of all vaccines, and the vaccination rate for all vaccines fell below 70%. This led to a sudden surge in cases of measles, affecting over 23,000 children in 2018-2019.
Further investigation showed that the vaccine only caused deaths in children who did not have prior dengue. Those who had dengue fever previously, as evidenced by presence of antibodies, were protected against later dengue infections. Hence Sanofi Pasteur changed their vaccination policy to give Dengvaxia only to children who have previously been infected by dengue (18, 19).
In 2016, Takeda, the Japanese Pharmaceutical company, conducted a trial of their new tetravalent dengue vaccine on 20,000 children aged 4 to 16 years in Latin America and South-East Asia. The vaccine consisted of two doses given 3 months apart, and was well-tolerated with no serious side effects. The results showed an overall 80.2% efficacy; it was most effective against dengue serotype 2, and less effective against serotypes 1 and 3. Whether it protected against severe dengue could not be evaluated at this time because of the insufficient number of participants in this trial (20). The problems of Sanofi Pasteur’s Dengvaxia may have helped Takeda in the propagation of their vaccine. Only time will tell whether the Takeda vaccine will be universally adopted.
MOSQUITO CONTROL
Prevention of dengue is best tackled by eradicating mosquitoes, and stopping them biting people (21).
Additional Info: Rise of dengue in Honduras 2019
New York Times 2 January 2020 had an article on the dengue epidemic affecting the Honduras, a country in Central America with a population of nearly 10 million (22). In 2018 there were 3 deaths from dengue, but in 2019 there were 107,000 cases of which at least 175 died from dengue. This dramatic rise in dengue can be attributed to several factors, of which climate change is a major contributor. Poverty, lawlessness, political corruption, shortage of trained public health personnel, and apathy among the general population have also been additional factors. Dr Dinorah Nolasco, the regional director in Cortes, said: "If I'm a mother and I have three children, four children, I'm going to be thinking about what I'm going to feed them... they'll be thinking least of all about dengue."
REFERENCES
1. Bhatt S, Gething P.W.,Brady O.J. et al The global distribution and burden of dengue. Nature. 2013; 496: 504-507
2. Shepard DS, Undurraga EA, Halasa YA, Stanaway JD (August 2016). "The global economic burden of dengue: a systematic analysis". The Lancet. Infectious Diseases. 16 (8): 935–41
3. WHO Increase in dengue https://www.who.int/wer/2016/wer9121.pdf
4. Trends of Dengue Disease Epidemiology: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428083/
5. Dengue in other countries: https://www.who.int/docs/default-source/wpro---documents/emergency/surveillance/dengue/dengue-20190829.pdf?sfvrsn=5160e027_14
6. Singapore: https://www.nea.gov.sg/dengue-zika/dengue/dengue-cases
https://www.straitstimes.com/singapore/health/dengue-cases-climb-again-after-several-months-of-decline
6a. Singapore https://www.gov.sg/article/dengue-know-the-symptoms-and-how-to-protect-yourself
7. Malaysia and Philippines: https://www.who.int/docs/default-source/wpro---documents/emergency/surveillance/dengue/dengue-
8. Thailand https://menafn.com/1098782548/Thailand-to-control-dengue-fever
9. Thailand http://www.xinhuanet.com/english/2019-06/15/c_138144354.htm
10. Indonesia http://www.xinhuanet.com/english/2019-06/15/c_138144354.htm
11. Indonesia https://www.straitstimes.com/asia/se-asia/indonesia-sees-spike-in-dengue-cases
12. Rise in dengue due to global warming:
https://www.sciencedaily.com/releases/2019/03/190328150856.htm
13. Pathogenesis of vascular leak: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461104/
14. Serotypes of Dengue virus: is there a fifth serotype?
https://www.sciencedirect.com/science/article/abs/pii/S0377123714001725?via%3Dihub15
15. Investigations and Treatment: https://emedicine.medscape.com/article/215840-overview#showall
16. Dengue Vaccine: https://www.who.int/immunization/research/development/dengue_vaccines/en/
17. Dengvaxia in the Philippines:
18. Dengvaxia Controversy: https://en.wikipedia.org/wiki/Dengvaxia_controversy
19. Epidemic of Fear (Fortune Magazine): https://fortune.com/longform/sanofi-dengue-fever-vaccine-dengvaxia/
20. Takeda Dengue Vaccine: https://www.nejm.org/doi/full/10.1056/NEJMoa1903869
21. The Mosquito: https://kenlyen.wixsite.com/website/mosquito-1
22. Climate change and political chaos fuel a deadly epidemic:
https://www.nytimes.com/2019/12/29/world/americas/honduras-dengue-epidemic.html
Written by Kenneth Lyen
24 September 2019, Updated 1 Sept 2020
%20a.jpg)