Neurologic Complications of Dengue

Dengue Shock Syndrome

What is Dengue Shock Syndrome?

Dengue Shock Syndrome is a collection of symptoms resulting from a dengue infection. Its symptoms – including hemorrhaging – resemble those you’d see after an accident, when someone is ‘in shock’. Typically, older children or adults suffer 2–7 days of high fever and show two or more of the following symptoms:

  • severe headache,
  • retro-orbital eye pain,
  • myalgias,
  • arthralgias,
  • a diffuse erythematous maculo-papular rash, and
  • mild hemorrhagic manifestation.
  • Subtle, minor epithelial hemorrhage, in the form of petechiae, are often found on the lower extremities (but may occur on buccal mucosa, hard and soft palates and or subconjunctivae as well), easy bruising on the skin, or the patient may have a positive tourniquet test.
  • Other forms of hemorrhage such as epistaxis, gingival bleeding, gastrointestinal bleeding, or urogenital bleeding can also occur, but are rare.
  • Leukopenia is frequently found and may be accompanied by varying degrees of thrombocytopenia.
  • Children may also present with nausea and vomiting.
  • Patients with DF do not develop substantial plasma leak (hallmark of DHF and DSS, see below) or extensive clinical hemorrhage.
Dengue virus image
Dengue virus: Dengue Shock Syndrome

Serological testing for anti-dengue IgM antibodies or molecular testing for dengue viral RNA or viral isolation can confirm the diagnosis, but these tests often provide only retrospective confirmation, as lab results are typically not available until well after the patient has recovered.

Clinical presentation of DF and the early phase of DHF are similar, and therefore it can be difficult to differentiate between the two forms early in the course of illness. With close monitoring of key indicators, the development of DHF can be detected at the time of defervescence so that early and appropriate therapy can be initiated.

The key to successfully managing patients with dengue infection and lowering the probability of medical complications or death due to DHF or DSS is early recognition and anticipatory treatment(For more detailed guidance on management for DF please see the recommended treatment courses for DHF in the links listed below.)

Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS): The third clinical presentation results in the development of DHF, which in some patients progresses to DSS. Vigilant is critical for identifying warning signs of progressing illness and early symptoms of DHF which are very similar to those of DF. Case Definitions Page

There are three phases of DHF:

  1. the Febrile Phase;
  2. the Critical (Plasma Leak) Phase; and
  3. the Convalescent (Reabsorption) Phase.

The Febrile Phase: Early in the course of illness, patients with DHF can present much like DF, but they may also have hepatomegaly without jaundice (later in the Febrile Phase). The hemorrhagic manifestations that occur in the early course of DHF most frequently consist of mild hemorrhagic manifestations as in DF. Less commonly, epistaxis, bleeding of the gums, or frank gastrointestinal bleeding occur while the patient is still febrile (gastrointestinal bleeding may commence at this point, but commonly does not become apparent until a melenic stool is passed much later in the course). Dengue viremia is typically highest in the first three to four days after onset of fever but then falls quickly to undetectable levels over the next few days. The level of viremia and fever usually follow each other closely, and anti-dengue IgM anti-bodies increase as fever abates.

The Critical (Plasma Leak) Phase: About the time when the fever abates, the patient enters a period of highest risk for developing the severe manifestations of plasma leak and hemorrhage. At this time, it is vital to watch for evidence of hemorrhage and plasma leak into the pleural and abdominal cavities and to implement appropriate therapies replacing intravascular losses and stabilizing effective volume. If left untreated, this can lead to intravascular volume depletion and cardiovascular compromise. Evidence of plasma leak includes sudden increase in hematocrit (≥20% increase from baseline), presence of ascites, a new pleural effusion on lateral decubitus chest x-ray, or low serum albumin or protein for age and sex. Patients with plasma leak should be monitored for early changes in hemodynamic parameters consistent with compensated shock such as increased heart rate (tachycardia) for age especially in the absence of fever, weak and thready pulse, cool extremities, narrowing pulse pressure (systolic blood pressure minus diastolic blood pressure <20 mmHg), delayed capillary refill (>2 seconds), and decrease in urination (i.e., oliguria). Patients exhibiting signs of increasing intravascular depletion, impending or frank shock, or severe hemorrhage should be admitted to an appropriate level intensive care unit for monitoring and intravascular volume replacement. Once a patient experiences frank shock he or she will be categorized as having DSS. Prolonged shock is the main factor associated with complications that can lead to death including massive gastrointestinal hemorrhage. Interestingly, many patients with DHF/DSS remain alert and lucid throughout the course of the illness, even at the tipping point of profound shock. CDC:

Doctors: See case definition for DHF and DSS. Adobe PDF fileExternal Web Site IconThere are no good videos about dengue shock syndrome, but this text video might help:

Dengue Bribery in Philippines?

Was there Dengue bribery in Philippines? Questions hover over Asia’s first dengue vaccination program in Philippines.

Dengue Mosquito
Dengue Mosquito: Asian Tiger

The Aedes aegypti mosquito carries the dengue virus, Zika virus, and other mosquito-borne illnesses as it travels from person to person.

Asia’s first dengue vaccine has been distributed in a mass school-based immunization program in the Philippines. So far, the program appears to be running without difficulties, but some health professionals are concerned that the vaccine was released before researchers could ensure its long-term safety.

From the beginning, the vaccine’s French manufacturer Sanofi Pasteur has been concerned about a potential problem with the vaccine — that while it could help prevent dengue initially, it could later increase the severity of the disease, according to Dr. Antonio Dans, a professor at the University of the Philippines College of Medicine.

“The real dengue we are afraid of is severe dengue, not the mild ones,” Dans said in a statement. “If a vaccine prevents mild disease but causes severe dengue, we shouldn’t be using it at all.”

This possibility is being monitored by the vaccine’s developer, Dans said in a news release; and since the phenomenon may happen a full three years after immunization occurs, it will take some time to study the vaccine’s long term effects.

However, as the virus infects as many as 400 million people annually, the vaccine for dengue has been awaited with increasing impatience. In an effort to stem the spread of the virus in regions heavily burdened by the disease, the WHO recommended that the drug be introduced in dengue-endemic sites while awaiting prequalification.

According to the organization, the WHO is now waiting on an application from the vaccine’s manufacturer.

The vaccine, Dengvaxia, has also been registered in Mexico, Brazil and El Salvador. Now, the Philippines — which in 2015 saw an almost 60 percent increase in dengue cases from the year prior — has become the first to make the vaccine commercially available.

“This initiative sends a strong message to the rest of the … world that dengue vaccination is a critical addition to integrated disease prevention efforts,” according to a statement from the vaccine’s developer Sanofi Pasteur.

The official launch of the school-based immunization program on April 4 sidestepped a prequalification procedure by the WHO, as is standard for new vaccines to ensure safety and effectiveness. This raised additional concern from some medical professionals, according to Philippine media network GMA, who say the immunization program should not have skipped the prequalification process, especially considering such limited knowledge of the vaccine’s long-term side effects.

Still, the company said the Dengvaxia vaccine, which took 20 years and $1.8 billion to develop, should prevent 80 percent of dengue-related hospitalizations and up to 93 percent of cases of severe hemorrhagic dengue fever. The vaccine is designed for people ages 9 to 45, and is administered in three separate doses over a six-month period.

Since the start of the immunization program last month, Dengvaxia has been administered to more than 200,000 grade-school students in the capital city of Manila. Of 17,000 people who were injected with the vaccine in the Philippines in February as part of the clinical study, just 27 developed side effects, Health Undersecretary Vicente Belizario told reporters.

According to Health Minister Janette Garin, the $103 million program aims to administer the first dose of the vaccine to 1 million children by June.

The history of developing a vaccine for dengue has been wrought with challenges. An effective vaccine must protect against four closely related viruses that can cause the disease, and researchers have had limited understanding of how the virus affects the immune system. Among other barriers making vaccine development more difficult, there are no easily measurable sign (such as antibodies) that a person is immune to the disease.

The WHO estimates that dengue fever, the world’s most common mosquito-borne virus, infects an estimated 390 million people around the world each year. So far this year, more than 33,000 dengue cases have been recorded in the Philippines alone. Read more…

 

Dengue Pandemic

Are we looking at a Dengue Pandemic soon?

Will Climate Change Bring a Dengue Pandemic?

Dengue Pandemic Vector
Dengue Pandemic Vector

Dr Shahera Banu, and colleagues from QUT’s Faculty of Health, investigated the impact of climate change on transmission of the mosquito-borne disease and found there would be “devastating” consequences. Dr Banu analysed high-risk areas for dengue fever transmission in the Asia-Pacific region, with particular focus on Dhaka, the capital of Bangladesh and a megacity of 11.8 million people.

Using modelling from the Intergovernmental Panel on Climate Change (IPCC) which predicts an annual average temperature rise for the South Asia region of 3.3 degrees by 2100, the research found there would be a swell of dengue cases. The research has been published in the journals PLOS One and Environment International.

“Without any changes in the socio-economic situation, by the end of this century there will be a projected annual increase of 16,030 cases in Dhaka,” Dr Banu said.”The consequence of this will be devastating.”

The warmer temperatures and humidity would provide optimal conditions for mosquitos to thrive, Dr Banu said. The research collected the monthly number of dengue cases in Dhaka from January 2000 to December 2010 and estimated 377 cases attributable to temperature variation in 2010.

“Assuming a 1 degree temperature increase in 2100, we project an increase of 583 cases, for 2 degrees it would be 2,782 but it is at 3.3 degrees, a rise the IPCC has projected, that will have an overwhelming impact,” Dr Banu said.”Our results show that the monthly temperature and humidity were significantly associated with the monthly dengue incidence in Dhaka.

“These results are consistent with findings of other studies and may assist to forecast dengue outbreaks in different regions.”

Dengue Epidemic Viral Diagnosis
Dengue Epidemic Viral Diagnosis

Dr Banu said places with similar weather conditions to Dhaka would also likely be at risk from a climate change-driven increase in dengue cases.”We’re hopeful this research will be helpful for improving surveillance of dengue fever and control through effective management and community education programs in Bangladesh and other countries in a similar situation,” she said.

Here’s a report about Singapore’s recent, unexpected dengue outbreak: Epidemic resurgence of dengue fever in Singapore in 2013-2014: A virological and entomological perspective. Long story short: The culmination of the latest epidemic is likely to be due to a number of demographic, social, virological, entomological, immunological, climatic and ecological factors that contribute to DENV transmission. A multi-pronged approach backed by the epidemiological, virological and entomological understanding paved way to moderate the case burden through an integrated vector management approach.

Chinese Dengue Experiment

The government in Guangzhou province is carrying out a Chinese dengue experiment.

How do you fight a swarm of disease carrying mosquitoes? By breeding an uninfected swarm of your own. While the idea may sound counterintuitive, that’s exactly what scientists are doing to help fight Dengue fever, the deadly mosquito-spread epidemic that has plagued much of the Pearl River Delta.

mosquito factoryGuangdong has taken a number of different approaches in the fight against Dengue fever over the years: patriotic campaignsremoving abandoned cars, and mass fumigation. However, the fever has continued to spread and infected over 47,000 residents in the PRD last year.With the high season of Dengue now upon us, authorities are going on the offensive to ensure there won’t be a repeat of last year’s “full-blown crisis“.

Scientists from Sun Yat-sen University are fighting against mosquito-spread Dengue fever by releasing sterilized male mosquitoes of their own, in hopes of eventually eliminating the female mosquitoes carrying Dengue.
To do so however, they need to be breed a lot of mosquitos. The Science City is breeding a million male sterilized mosquitoes every week and releasing them on the city’s Shazai Island in Nansha District, making the mosquito factory the largest in the world. According to team leader Xi Zhiyong, they’re confident that their hard work will pay off: We need to be very thorough and precise with our scientific data. Our objective is to have our findings published in the world’s top scientific periodicals and exert international influence in the fight against Dengue fever. More

Dengue Vaccine Not For Children

A Newly Developed Dengue Vaccine, but Not For Children

There’s good news and bad news about Sanofi’s new dengue vaccine. The worst news is there is a dengue vaccine but it is not for  children – especially the young ones, those most at risk.

A new vaccine to treat dengue – leading cause of illness and death among children in some Latin American and Asian countries – makes young children more likely to contract the disease. So says a study in the New England Journal of Medicine. The good news is that it protects children nine years old and older from the infection. That’s a bummer because it is young children who are most at risk.

Every year 500,000 people — many of whom are children — are hospitalized  severe dengue; and about 12,500 die. Another disappointment is that the vaccine only protects two thirds of people treated. The remaining 33% got infected with dengue.

And another bummer: children who were vaccinated when they were younger than 9 were more likely to be hospitalized, especially if they were between two and five years old at the beginning of the trial. Kids nine or older at the trial’s start were 80% less likely to be hospitalized from dengue two years later, compared to their peers receiving a placebo. In that 80% group, two-thirds of the kids didn’t contract dengue of any kind.

Cameron Simmons, a dengue virus researcher at the University of Oxford, says it’s not clear why the results were different among the age groups. “It’s possible the results are chance findings,” Simmons writes. “It’s also possible that some children may not have been hospitalized despite being ill. Because the study examined hospitalizations, there may have been illnesses that were missed”.

Melanie Saville, chief medical and clinical officer of dengue research at Sanofi said that the study enrolled more than 35,000 youths aged 2-16 in three clinical trials in six Asian and five Latin American countries, including Thailand, Mexico, and Colombia. Most received the Sanofi dengue vaccine; the rest got a placebo. Three to four years later, the researchers checked on the participants.

“Based on the data available today… we conclude that our candidate vaccine will have the greatest public health impact if used in people nine years of age and older,” Dr Saville says. The vaccine “promises to be a real tool for endemic countries.” That’s a nice way of saying that this Dengue Vaccine is not for children.

It’s still too early to determine the cost of the vaccine, Dr. Saville says. Sanofi’s focus is getting the drug approved in countries where dengue is endemic. “The regulatory approval process has started in several countries of Asia and Latin America,” Saville says.

So…the first Dengue Vaccine is Not For Children. Will we find that dengue vaccines in general aren’t safe for children?

Dengue and Tourists

There’s a problem with Dengue and Tourists

Here’s what I’m talking about: A staggering 69 per cent of foreigners living in Phuket or visiting the island receive little to no warning about the dangers of dengue and how the disease is transmitted, according to the results of the latest online poll by The Phuket News.

The recent bout of wet weather over Phuket has left puddles of fresh water strewn all over the island, the perfect breeding grounds for mosquitoes that carry the potentially lethal dengue virus.

But the Phuket Provincial Health Office (PPHO) recently reported that the number of dengue cases at Phuket hospitals so far this year is “no more than normal”, as the return of the annual southwest monsoon also brings an annual spike in the incidence of dengue.

The PPHO and local authorities weeks ago launched campaigns to raise awareness of the disease as they do every year, but the campaigns are in Thai and aimed at educating Thai-speaking residents.

To this, The Phuket News asked our readers: “Do you think the government does enough to warn foreigners about dengue?”

Testament to how little warning foreigners in Phuket receive about dengue, only 2pc of respondents to the poll said “Yes, foreigners are given ample warning about dengue” – and all those respondents were Thai.

Compare that with the 10pc of respondents who said: “Dengue? What’s dengue?”

And of that 10pc of respondents to the poll, 12pc were “Foreign visitors to Phuket”, better known simply as tourists.

Only 4pc of people who voted in the poll said “Yes, but there is room for improvement” in the efforts to warn foreigners about dengue, while 17pc said: “Not really, I see some effort to warn foreigners, but not enough.” Phuket News.

Watch this warning about dengue and tourists:

 

New Drug Trial for Dengue

There’s a New Drug Trial for Dengue

Asthma drug against dengue to be tested in clinical trial

Asthma drug against dengue to be tested in clinical trial

Blood meals taken from humans by the female mosquito Aedes aegypti are the vector of Dengue feverA drug that has been used for over 30 years as an asthma and allergy medicine is now being tested to treat symptoms of dengue fever. The National University of Singapore (NUS) and Duke-NUS Graduate Medical School Singapore (Duke-NUS) are running a clinical trial, in collaboration with National University Hospital (NUH) and Singapore General Hospital (SGH), called KETODEN, to test the drug Ketotifen on patients who are infected with dengue.

Research that preceded the trial was done at Duke-NUS while the trial is being conducted in the Investigational Medical Unit (IMU) at NUS with patients from SGH and NUH.

Ketotifen is traditionally used to reduce the incidence of asthma and allergy attacks in patients. It works as an antihistamine and mast cell stabiliser. One of the symptoms of asthma is vascular leakage, or movement of fluid in the body that occurs when blood vessels are damaged. This is caused by the activation of a certain type of immune cell, the mast cell. Ketotifen works by blocking mast cells, which helps stop vascular leakage.

Assistant Professor Ashley St. John and her team, from the Duke-NUS Emerging Infectious Diseases Programme, were able to show that mast calls react strongly to  virus infection and release pro-inflammatory proteins, which may cause vascular leakage. It is hypothesised, that like in asthma, if Ketotifen can block mast cell activation in dengue, it may be able to block some of the more severe symptoms of dengue.

In dengue, mast cell activation leads to vascular leakage in animal models. Vascular leakage is the main complication of dengue where fluids from the blood are lost from blood vessels into other parts of the body such as the lining of the lungs. This reduces the overall blood volume and creates problems from excessive fluid build-up in areas such as the lungs or abdomen. Excessive or uncontrolled vascular leakage leads to dengue haemorrhagic fever or dengue with complications, in human patients.

The trial, led by Professor Paul Tambyah from the Department of Medicine at the NUS Yong Loo Lin School of Medicine, is aimed at determining if Ketotifen can safely alleviate these complications. Currently, dengue patients are often managed in outpatient clinics by providing fever and pain relief and advice on fluid intake. If vascular leakage is detected, or if patients have other complications, then they may be admitted for observation or intravenous fluids to prevent shock. However, there is no approved treatment to prevent vascular leakage during .

Dengue fever is a mosquito-borne viral disease that is endemic in many parts of the world, including Singapore. Last year Singapore saw a rise in the number of dengue cases to almost 900 a week in peak months. This year, there have already been almost 3000 cases of dengue fever. Infection can lead to high fever, muscle aches, rash and vascular leakage. Vascular leakage is a key factor in the development of these more severe forms of the virus. There is currently no medicine approved for the treatment of .

The collaborators of this trial at Duke-NUS, NUS, NUH and SGH are hopeful that Ketotifen will prove efficacious and prove to be an effective treatment for dengue, in a region that sorely needs one. Credit.

https://www.youtube.com/watch?v=p6rwW0PY4nA

 Explore further: Team finds powerful dengue neutralizing antibody

Malaysia’s Dengue Research Fail

Malaysia’s Years of Dengue Research Failure

GEORGE TOWN – Malaysia appears to be heading nowhere with dengue research.
The plan to release genetically altered male Aedes mosquitoes so that they cannot breed with wild females has proven too costly and impractical.
Another plan for a dengue vaccine by a pharmaceutical company which was slated to be marketed next month was shot down by the Health Ministry since it was not satisfied with the research data.
Health Minister Datuk Seri Dr S. Subramaniam said the genetically changed mosquitoes were only useful in small areas but “dengue is all over the place” in Malaysia.
Dengue cases reached an all-time high of nearly 100,000 last year.
“We would have to flood the country with huge numbers of mosquitoes.
“We are concerned because nobody has studied the ecological effects of releasing such a huge number of genetically changed mosquitoes”
The genetic modification of Aedes came from Oxford University and Malaysia’s Institute of Medical Research tested it in the laboratory in 2006.
Speaking to reporters after launching the 9th National Conference for Clinical Research here yesterday, Dr Subramaniam also said the dengue vaccine’s clinical trials were completed and the pharmaceutical company wanted to market it.
“But the research data they gave us is not enough for us to use the vaccine on a large scale.
“We are back to square one with dengue research,” he said.
He said Malaysia had to take the lead in dengue research.
“We cannot rely on developed nations for medical discoveries which tend to be skewed towards issues they face.
“Malaysia has our own set of medical problems so we need to scale up our research,” he said.

Why did Malaysia’s dengue research fail? No-one seems to know. It’s good to see a government like Malaysia’s being so open about the failure of its dengue research. In science, most things fail. Malaysia back to square one in dengue research
Thursday, May 28, 2015. The Star/Asia News Network. By Arnold Loh

Dengue in Singapore

How They’re fighting Dengue in Singapore.

SINGAPORE: Dengue has been a pest in Singapore for as long as anyone can remember. So what are they doing to combat dengue in Singapore? Well, as is typical of Singapore, they’re taking a high-tech approach.

The Agency for Science, Technology and Research (A*STAR) will be collaborating with biotechnology company Visterra to further development of an antibody to treat dengue fever, the agency announced on Friday (May 22).

The antibody, VIS513, is designed to neutralise all four serotypes of the dengue virus. Developed by Visterra, it demonstrated in pre-clinical studies on animal models a rapid reduction in the concentration of virus after it was administered. This result supports its potential use for treatment of dengue virus infection, said A*STAR.

Under the terms of the collaboration, Visterra retains all rights to develop and commercialise the antibody globally, added A*STAR.

A*STAR’s Drug Discovery and Development unit (D3) and Visterra will also work with infectious disease experts at Duke-National University of Singapore to generate additional data necessary to initiate clinical trials, said A*STAR. Upon completion of these activities, D3 and Visterra will conduct clinical trials in humans in Singapore.

“We are encouraged by VIS513’s preclinical data, which demonstrate its potential to broadly neutralise all four dengue virus serotypes, as there is currently no specific treatment for dengue, and prevention depends solely on limiting or eradicating mosquitoes that transmit the virus,” said Prof Alex Matter, Chief Executive Officer of D3 and A*STAR’s Experimental Therapeutics Centre (ETC). “We are looking forward to working closely with Visterra and advancing VIS513 into the clinic.” Read more…