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Communicable takes on hot topics in infectious diseases and clinical microbiology. Hosted by the editors of CMI Communications, the open-access journal of ESCMID, the European Society of Clinical Microbiology & Infectious Diseases.
[00:00:00]
[00:00:07] Annie: Hello and welcome back to Communicable, the podcast brought to you by CMI Communications, ESCMID's Open Access Journal for covering infectious diseases and clinical microbiology. My name is Annie Joseph. I'm a clinical microbiologist at Nottingham University Hospitals in the United Kingdom and associate editor at CMI Comms.
today I'm joined by my co-host, Nav Narayanan, fellow editor at CMI, comms and Clinical Associate Professor and ID pharmacist at Rutgers University in New Jersey in the US Hi Nav.
Hello, Annie. It's great to be here again.
[00:00:40] Annie: so today Nav and I are quite excited for the topic. we're gonna be covering dengue, which is becoming increasingly relevant in more geographical settings in the context of our rapidly warming world.
we're excited to welcome our two guests who are real experts in the field. We're so lucky to have them with us today. Our first is Dr. Steven Lim. Steven is a consultant in internal medicine and infectious diseases at the Raja Permaisuri Bainun Hospital in Perak, Malaysia. Steven's work spans across a broad spectrum of infectious diseases with particular interests in HIV, multi-drug resistant infections and neglected tropical diseases.
[00:01:20] Annie: He's a strong advocate for evidence-based medicine and is actively engaged in research, education, and national guideline development. And he's also an experienced clinical trialist, and has led both investigator initiated and industry sponsored studies. He serves as the president of the Malaysian Society of Infection Control and Infectious Diseases and Leads Malaysia's Clinical Working Group in the Global Dengue Alliance, an international collaboration between dengue endemic countries and the Drugs for Neglected Diseases Initiative, which aims to accelerate the development of effective dengue therapeutics.
Welcome, Steven to Communicable.
Hi Annie. Thanks for having me. Hi, Nav.
[00:01:58] Nav: Welcome Steven. our second guest, another expert in the field is André Siqueira from the nonprofit organization, drugs for Neglected Diseases Initiative, headquartered in Geneva, Switzerland, where he leads the Dengue Global program.
[00:02:12] Nav: Andre has worked in clinical research for the past 15 years focusing on acute febrile illnesses such as malaria, dengue, and chikungunya. He's designed and conducted several observational and intervention studies for the prevention and treatment. Of the diseases and was part of the team that described the risk of microcephaly in fetuses of pregnant women infected with Zika.
[00:02:31] Nav: He is also one of the principal investigators for the butantan-dengue Vaccine Clinical Trial and founded and coordinated the chikungunya Clinical and Applied Research Network. REPLICK. He's a member of several national and international advisory committees, including cepi Scientific Advisory Committee and Brazil's National Malaria and Arbovirus programs involved in drafting the most recent, versions of the clinical management guidelines for malaria, chikungunya, and dengue for the Ministry of Health.
welcome Andre. It's really a pleasure to have you on communicable.
[00:03:04] Andre: Thank you. It's a pleasure to be with you as well. Nav, Annie and Steven.
as our listeners know, we usually start with a get to know you question so here's the question for this week. Outside the world of science, what is a skill or hobby that you enjoy or are secretly very good at? Steve, what's your secret skill or hobby?
I really enjoy comedy. especially those comedy that involves, political satire. I'm a big fan of the shows like Saturday Night Live. I'm sure it's, a hit in us the Daily Show, especially those, hosted by John Stewart, one of my favorite comedian, the Late Show with, Stephen Colbert.
[00:03:38] Steven: I guess life is stressful sometimes. I just need some regular doses of humor and occasionally sarcasm to keep me going, a way to follow the world events from a more, uh, critical perspective.
So, are we gonna see Steven Lim, Netflix special soon enough? Are you, uh, you know, I'm working on that,
[00:03:55] Speaker 5: yeah.
Andre,
[00:03:56] Andre: I started taking some surfing lessons, and you have to really focus on being in the sea, not being taken by the waves, but trying to ride them. it's really something I've been enjoying and, you can really concentrate on that and forget everything else while there at the sea.
[00:04:12] Annie: Wow, I'm really impressed.
So, now we know our guests a little bit better we'll get into the topic of the day and they can share their, professional knowledge with us. We have quite a global listenership at communicable And so some of our listeners will be quite familiar, with Dengue. but people in non-endemic countries, like myself will be less familiar. So Steve, could you kick things off by giving our listeners, a brief refresher on dengue, the virus, the vector, the disease gets us all up to speed.
so Dengue has been around for centuries. the first major documented epidemics, happens in the 1700. Dengue is caused by this dengue virus is actually a, member of the cis flavivirus, which is closely related to the yellow fever virus. So it exists, in four distinct serotypes.
[00:04:59] Steven: And I would like to thank the virologists for not giving complicated names for these serotypes. these serotypes are known as, DEN-1, DEN-2, DEN-3, and DEN-4. So, dengue virus are mainly, spread by Aedes aegypti and also Aedes albopic tus mosquitoes. one thing special about these mosquitoes is that they thrive in a very densely populated area, and especially in the tropics and also subtropical regions.
[00:05:24] Steven: if you open the medical textbooks. Dengue is typically recognized as tropical disease, but, emerge as a major global health threats, in the 20th centuries spreading beyond its traditional endemic regions in Asia, as well as in Americas to other parts of the world that you never think of, for example in Europe.
in 2019, the WHO actually identified dengue as one of the top 10, global health threats listed alongside climate change and also, antimicrobial resistance. back to the, clinical aspects of the disease. dengue is a very dynamic disease, and I still find it fascinating even after.
[00:05:58] Steven: Treating for almost 20 years. the illness can range from a mild febrile illness to life-threatening severe disease or severe dengue. the good news is that over 95% of the patients, experience only mild to moderate illness, typically with symptoms like fever, joint pains and, muscle pains and sometimes diarrhea and also nausea, vomiting, they typically recover within a week without any complications with some symptomatic, treatments.
However, the other three to 5% unfortunate patients actually may progress to severe dengue, most often due to a significant plasma leakage leading to a hypovolemic shock. Sometimes, they might develop severe bleedings and organ impairment as well. something's unique for dengue.
the better physiologist reflects the complex interplay between the virus and also the, host immune response. the virus actually triggers the immune-mediated changes in the vascular permeability leading to, plasma leakage. Essentially the plasma actually leaks out from the intravascular compartment into the interstitial space, as well as the serosal space.
If this allows to go on, it will result in heme concentrations, uh, hypervolemia and potentially, hypovolemic shock. In some cases, the capillary leakage is, so severe not only , plasma leaks out, but also the, blood cells, the red blood cells will also escape and giving rise to what we call occult bleeding.
[00:07:20] Steven: meaning that you won't see the bleeding through the naked eyes, but , they bleed from the capillaries because of the severe plasma leakage and also the bleedings. There are four types of, stereotypes in dengue. some of you might ask, if you are infected with dengue, whether we will develop, immunity against a subsequent infection. So the answer is actually yes and no. a first infection with one serotype actually provides a lifelong, protection against the same serotypes.
[00:07:45] Steven: For example, if you're being infected with DEN-1, your body will actually produce, antibodies and memory cells to protect you against the subsequent DEN-1 infections. but we know that in the endemic countries, like in Malaysia, in Americas, you, tend to expose to more than one, times of, dengue infections.
[00:08:00] Steven: And sometimes it can be infected with different serotypes of dengue. So if the person is reinfected with, different serotypes, the antibody that you produce will not actually protect you against that different stereotypes, right? This is what we call antibody dependent enhancement
[00:08:15] Steven: When the antibody binds to the. Virus, which are from different stereotypes, but it doesn't neutralize it completely. In fact, it actually enables the, virus to, enter the immune cells, in a easier way with the, antibody and, viral complex. it helps them to, replicates, in a faster rate and subsequently cause a more severe, immune response and subsequently, severe dengue.
[00:08:36] Steven: this antibody dependent enhancements, is important whenever we look at dengue. even at the population level because, in endemic countries like Malaysia, as I mentioned, people are often exposed to dengue multiple times. so this stereotype shift may play a role, especially with outbreaks.
[00:08:53] Steven: when the, predominant circulating serotype changes, many individuals are suddenly vulnerable or exposed to serotype, which are different from their previous infections. And this will set a stage where most of the patients will actually develop a severe disease because of these, antibody dependent enhancement phenomenon.
, There's some complexities with dengue, especially with some of the pathophysiology. So I think that primer is, quite helpful .
Andre, would you be able to just take us a little bit through the epidemiology in, particular, the classical way that we think about distribution and then what's happening now and how things are emerging and expanding?
[00:09:27] Andre: Steven mentioned that it was usually seen as a tropical disease, so distributed in tropical areas.
[00:09:33] Andre: have very clear, description of dengue transmission, especially in Southeast Asia. South Asia and Latin America the main places describing dengue outbreaks. in Southeast Asia. You usually see a more endemic transmission. with high seasons and low seasons, but a constant transmission that Stephen can correct me if I'm wrong, but not varying too much between [00:10:00] years while in Latin America, what we've seen for the last 40 years is , outbreak years followed by calmer years, two or three years interval between major outbreaks.
[00:10:11] Andre: this is really related to population dynamics, but also the virus dynamics. as Steven mentioned, we have four viruses, and the, Protection. the immuno protection is specific, for each of the serotypes. in Latin America, usually when there is a shift of the predominant serotype and enough, vulnerables in the population, so susceptibles then you see the outbreaks occurring and, then they, vary a lot.
It has been well described that in Southeast Asia. it was seen as a pediatric disease in most intense transmission places in Latin America. We saw a lot occurring in the adult population.
a very relevant tropical area is Africa. but there is a lack of description of transmission in Africa, and, it's mainly due to lack of investigation. we run re epidemiology studies.
[00:11:04] Andre: There is in some places a high level of transmission as you seen from prior exposure to the virus. And now there is an increase in interest to understand How the disease affects the African continent of course, , there's a major focus in malaria and not many other febrile illnesses, but dengue also contributes, to that.
and what we've seen in probably the last 10 years, is that the dengue transmission areas are expanding. So areas that were not suffering from dengue transmission are now suffering, transmission and, epidemics. And this seems to be an increasing trend as, Annie mentioned in the introduction with, warming temperatures, and more unstable weather, it is likely to occur even more for example, based in Brazil and.
[00:11:54] Andre: Five years ago, we didn't hear about dengue in the south end part of Brazil. But in the last four years there have been major outbreaks and when they occur in these areas where there is a high proportion of elderly individuals, we saw a lot of elderly individuals that had no prior exposure to dengue infected and having complications.
[00:12:14] Andre: So the lethality amongst, especially individuals above the age of 70 was really high. About 30% of the ones with warning signs. So it's really worrying.
[00:12:26] Annie: Wow, 30%. that's way higher than I, I had even imagined. And I guess it just shows the, danger of, an emerging virus in a completely naive population, the impact of that is gonna be very different to the endemic setting. we need to wake up and start thinking about this.
you touched on diagnostics, a little bit there and, the kind of lack of access in some geographical regions, Andre. if we just talk about diagnosis for a minute from, a purely clinical, setting, how can you distinguish dengue from other febrile arboviral infections like chikungunya or Zika, especially in places where these are likely to co circulate?
[00:13:06] Annie: And Steve, do you want to comment first?
Well, it's not always straightforward and sometimes can be challenging to differentiate, these infections, because many of these tropical infections presents as a acute febrile illness with a lot of overlapping features. so dengue often comes with high fever, severe headache, retro orbital pain, Musclealgia and arthralgia and, sometimes diarrhea and, nausea, vomiting.
typically they have thrombocytopenia as the disease progresses. while chikungunya, sometimes they come with fever, but usually present with more of, severe and often prolonged joint pain. So that will be the classical features of, chikungunya, while Zika, we don't usually see Zika in Malaysia, but I, believe that's underdiagnosed.
[00:13:47] Steven: Zika is usually mounted disease and sometimes we come with some conjunctivitis and rash. If I can remember correctly, I have only diagnosed and treated one Zika patients before throughout my whole career. I still believe that it's, circulating around in Malaysia and in this regions, it's just that we don't actively diagnose it.
so to, complicate things further, in Malaysia we also endemic for malaria, leptospirosis, Scrub typhus. And I can go on and on so in practice we can't really rely on clinical features alone. good diagnostics would definitely help a lot especially for clinicians.
[00:14:21] Steven: still at least in my setting, the general teaching is to, always suspect dengue first, always try to rule out dengue. then we think about other possible differential diagnosis for patients who present with, acute febrile illness. just purely because of the high prevalence of dengue in our regions and also the serious consequences of missing an early dengue diagnosis.
[00:14:41] Nav: Yeah. Steven, I guess along those lines, when it comes to diagnostic testing. you mentioned the beginning, very nicely that we've had dengue with us for a very long period of time. Right. How has the diagnostic testing sort of evolved over the years?
[00:14:54] Nav: is it. Completely advanced in recent years, or is it what we've been doing, 50 years ago?
[00:14:59] Steven: over the past decades, I think the dengue diagnostics have really improved. NS1 antigen tests are now widely used, for early detections. usually within the first five days of illness.
we should be able to detect NS1, antigen tests positive for actual dengue disease. but it also depends on how long the Viremia lasts. as the disease progresses, the dengue IgM and IgG serology. Can help, although there's some cross reactivity with other flavivirus or past infections, or any recent infections may lead to false positives.
[00:15:31] Steven: So the result should always be interpreted, in the context of history and also clinical features. in Malaysia, almost all our hospitals and clinics use, rapid combo tests. That includes NS1 antigen, Dengue IgM and Dengue IgG. molecular tests like RT PCR are mainly done in research labs, usually for, outbreak settings and for surveillance purpose.
but in routine practice, the rapid combo tests remain the backbone of our clinical diagnosis.
[00:15:57] Annie: Andre, is there anything you want to add around the diagnostics and, perhaps some of the newer, antigen and, and biomarker tests that perhaps our listeners may not be familiar with?
[00:16:07] Andre: yeah, I think Steven summarized perfectly there's been a lot of effort now trying to develop more accurate, RDT, so rapid diagnostic tests and even some work being done on, near care molecular testing.
[00:16:21] Andre: as Steven mentioned, it's very difficult to differentiate clinically between these conditions, although we will find some tables trying to differentiate the intensity of different symptoms between these zabar infections and other conditions that are very well, listed. in reality, we do need good diagnostic tests to really be sure if that person is infected or not, with dengue We, have new RDTs being developed still to demonstrate that they do perform much better compared to others. But we would like to see that coming the next years and the possibility of having this multiplex panels that could differentiate and give the diagnosis of, these diseases.
There are some in the market, but they are still very expensive and inaccessible to the general public. it would be for one test around, a hundred and $500. So it's quite something difficult for one individual to cover and especially not for public health situations. and you mentioned also biomarkers, there's also an interesting element to work on. we currently don't have good biomarkers, but we are looking at biomarkers that could predict progression to severe disease and complication, because this is also a hallmark of dengue epidemics. The numbers are so high and, health system get overwhelmed.
the physicians , and the health system have to be very well prepared to stratify and classify the patients, and decide on treatment. and it takes time, it takes experience, it takes, a lot of, planning. And if we have a test that could identify that individual with dengue or, or any other febrile illnesses then it, would definitely help a lot to reduce lethality, overwhelming, health systems as well.
Thank you both. it just shows some of the complications in managing these cases, even at the diagnostic stage and, understanding the risk of progression. From a management perspective, especially for listeners that have not seen a case of dengue, particularly severe dengue, What would you say are the best practices when, it comes to management of a patient and, what are the things that really should be at the forefront of their mind if they do have a case that they encounter?
[00:18:42] Steven: I said previously, that dengue is a very dynamic disease. and, 95% of the patient actually will progress and recover without any complications. they may not need any interventions. Most of them can be managed at home without admissions to hospitals. this 5% of patients still, at risk of developing severe disease, severe dengue plus severe plasma leakage.
we don't know who are these 5%. it's very different compared to for example, pneumococcal disease, where we kind of predict that, those who are gonna have severe pneumococcal disease will be elderly patients with multiple comorbidities, but in dengue's a bit different.
based on our experience and based on our data, we have seen a lot of young patients, even though they are fit and well, some of them actually progress to severe dengue they deteriorate and some of them actually died. I an adult medicine physician, the youngest patient I've seen who died from Dengue was, 16 years old.
[00:19:38] Steven: And I've seen, pregnant ladies die of dengue. so it's very difficult. it's very challenging for us as clinicians to, decide who are the ones that we. look after when the patients have dengue, Who are the ones that we need to pay more attention? Who are the ones we need to emit the patients earlier for close monitoring?
[00:19:55] Steven: So I think picking up this, 5% of patients and keep them under close monitoring [00:20:00] is quite a challenge because as of now, there's no, specific antiviral for dengue. of course, the Global and Dengue Alliance, we are working on this, we are hoping that we can actually develop the, effective antiviral for dengue in the near future.
the cornerstone of management for dengue at the moment is still good supportive care, despite dengue being a disease for around more than 200 years. and when I say supportive care I specifically means, judicious fluid management. But to do this well, I think every clinicians, must recognize there are three phases of dengue Recognizing this phase actually helps us to, guide our management in each phase of the disease. the first phase is the, febrile phase. Usually they last for two to three days, sometime up to five days.
[00:20:42] Steven: So during this, phase, patients usually present to the healthcare facilities with, symptoms like fever, muscle pain, and joint pains. nausea and vomiting and some GI symptoms, diarrhea. So at this stage, usually the management is purely symptomatic and a lot of times they can get away with just some adequate oral intake oral fluid to make sure that they're well hydrated .
[00:21:03] Steven: But, as the disease progresses, they'll go into what we call a defervescence phase. That will be around day four to day five or day six. And sometimes we, clinicians prefer to call it a critical we call it critical phase is just a reminder that these are the phase where even though patient may feel better because of fever subside, the 24 to 48 hours of critical phase period is a time that the, plasma leakage may occur.
[00:21:27] Steven: So usually plasma leakage won't occur during the first few days of the disease. During the febrile phase. when the fever settles,
[00:21:33] Steven: We need to monitor closely for warning signs. Because we don't know who are the ones gonna develop. Warning signs, as I mentioned before, 5% of them. warning signs. what it means is that those with, abdominal pain, those with, giddiness persistent nausea and vomiting, diarrhea, along with, rising hematocrit, or sometimes we use our ultrasound by bedside to detect any fluid flow in abdomen.
[00:21:54] Steven: So these are the patients that we need to detect Early warning sign essentially tells us that this patient may be progressing or already having ongoing plasma leakage. leading to shock, and less commonly from bleeding or organ failures.
[00:22:06] Steven: And roughly about 1% of those who develop, severe cases can be fatal. so managing fluids, again. In the presence of plasma leakage it's an art, I would say. just imagine that you are filling a, leaking bucket, All of us have filled out bucket before, but imagine that you're trying to fill out bucket, when it's leaking, the, the rule of the game is that you must, add the water just enough to maintain the circulations, maintain the perfusions in the patients, but not too much to the extent that the fluid start to overflow to the third space remember that when the patient having plasma leakage, the more fluid you add onto the patients, especially when you're giving intravenous, , drips with crystalloids more fluid will actually, be leaked out into the third space.
[00:22:46] Steven: Too little fluid actually raise hypervolemic shock if you don't replace enough. But too much fluid also sometimes may cause of fluid overload and pulmonary edemas. Now, after critical phase, after this 24 to 48 hours patient may Finally go into recovery phase, usually by day six on day seven, these are the time that patient will remain well.
[00:23:05] Steven: if they had plasma leakage. The plasma, the capillary, leakage was stopped. The permeability will close up and the fluid from the third space will start to get reabsorbed back into intravascular compartments. sometimes we call it reabsorption phase. basically during this time is even more important not to continuously giving IV drips so that we will make sure that all the fluid from the third space will get reabsorbed back into intravascular compartment, without any, interference.
[00:23:30] Steven: so I think it's important to recognize these three phases, febrile phase, critical phase, and also recovery phase because each of these phases requires a different, clinical approach, especially with regards to fluid management.
[00:23:43] Annie: Thanks, Steven. That, was really interesting. So you mentioned, fatal outcome, in, a pregnant woman that you cared for, in pregnancy.
[00:23:51] Annie: Is the course of disease generally more severe and, even if it's mild, does it have an association with adverse pregnancy outcomes?
So, I guess any infections in the pregnancy, they tend to have a higher risk of complications and, more severe symptoms and complications. if you think a non-pregnant, individuals, having to monitor the hematocrits, having to monitor their food status and to decide how much to give, how much not to give is challenging. I think the pregnant ladies even, more challenging because we all know that pregnancy is a different ball game.
everything changes, the usual, monitoring, especially based on the blood parameters, like for example, hematocrits, practically not reliable because the baseline hematocrit will change also depending on which trimester the, pregnant ladies is in.
[00:24:36] Steven: So we can't rely on that to tell us, you know, whether the patient is hemo concentrating, having a plasma leakage, having a higher, hematocrit when the, pregnant ladies actually generate, will have a normal hematocrit, especially during the, third trimesters. they tend to, have high risk of developing severe disease because of physiological changes in their body as well as the difficulty for clinicians to monitor them and to make good clinical judgment, especially with regards to, fluid managements, during the dengue illness
[00:25:04] Nav: and Steven, when it comes to other comorbidities, We have patients, of, chronic diseases globally, ,
[00:25:11] Nav: What do you keep in mind when you have a patient that you know has diabetes, cardiovascular disease, other chronic comorbidities, and how that affects the risk stratification? Are you more worried about them having, severe dengue? Do you watch them more closely? Are you more likely to admit them to the hospital because of their baseline comorbidities?
Patients with all these comorbidities definitely will give them a high risk of developing, severe outcomes, during their dengue illness. for me, I usually have a very low threshold to emit them, even though they come in early during the febrile phase, especially when they have uncontrolled diabetes, if they're known to have, chronic kidney disease.
heart disease, so these are patients that we tend to emit earlier, even though they're, well, the reasons because we know that dengue is a short disease, but when they develop, acute complications like plasma leakage, it can happen immediately. And sometimes we need to catch them early, especially in the healthcare setting rather than patient developed plasma leakage complication at home.
[00:26:13] Steven: especially among these populations where they themselves are at risk of severe outcomes, and sometimes these patients with, comorbidities, they may not deteriorate just because of the, dengue infection itself, they deteriorate because of the decompensation of their underlying, comorbidities.
[00:26:30] Steven: For example, uh, patients with heart failures sometimes they may go into decompensate heart failures because of the stress of the infections of the dengue, So. If possible, we want to emitt them early and then, monitor them closely. And again, these populations of patients with, comorbidities, especially those with heart failure.
[00:26:47] Steven: With, renal disease, fluid management is even more challenging. the chance of fluid overload is actually much higher. So sometimes we do rely on, blood parameters, clinical assessments, we also rely on some ultrasound imaging to look for any free fluid in the abdomen to help us to make a clinical judgment on how much fluid to give if really necessary, and when to stop the fluid,
[00:27:07] Annie: So you've mentioned about the, defervescence or critical phase where, you could potentially be falsely reassured. The temperature settles, they look well temporarily, as one of the, the pitfalls potentially in dengue management. Have you got any other, potential pitfalls that you want to highlight that you might see even amongst experienced clinicians managing dengue cases?
[00:27:30] Steven: so I, think the main pitfalls in dengue management is still always the, overzealous fluid replacements. Sometimes when we manage dengue, they may appear a bit dehydrated, we tend to have a lower threshold to start IV drips. and I think we need to understand that, managing fluid in dengue is different for how we manage fluid in the patient with sepsis because like I said, in in dengue, they sometimes they have this plasma leakage, which complicates our fluid managements. I've seen patients with over five liters of positive balance, fluid balance after days of vigorous IV fluid resuscitations. and these are the patients, that all these fluids, end up in the lungs, in the abdomen, and resulting in, acute pulmonary edemas and respiratory distress.
[00:28:13] Steven: I think, we just have to be very careful not to be too overzealous about giving fluids because it's something easy to do, but also can be harmful if you don't do it correctly. another pitfall is the, failure to recognize dengue shock.
Early or timely. unlike septic shock, again, I'm comparing with sepsis. dengue patient may look very well and alert until they suddenly slip into hypervolemic shock, I have instances where I've spoken to the patients early in the mornings and then after one hour patients collapse in the ward, so detect this early, the dengue patient must be reviewed frequently. at least in my hospital.
[00:28:49] Steven: We make it a point to review the patient at least three to four times a day. And then also we monitor their bloods, their flu blood counts, their platelet counts, the Hemato Creek. Trends. And also we monitor their, their, vital signs, especially the pulse rate when we are looking for any tachycardias, any weak pulse, any breathing.
[00:29:06] Steven: in hope that we can intervene before they reach the point of no return. sometimes we may overlook other causes of deteriorations, and I know they have emphasized a lot about plasma leakage, sometimes you may have steady patients that remain in shock despite.
[00:29:20] Steven: Multiple rounds of, fluid resuscitations. in that kind of situations, I think it's important to consider other possibilities, and I can list down three possibilities why a patient remain in shock and not improving despite us giving, few rounds of, fluid resuscitation. So number one is we are not giving enough fluid. sometimes we underestimate the severity of the plasma leakage. patient may be in decompensated shock. they may require much. Higher volumes of, resuscitation, at least 10 to 20 ccs per kg per hour of fluid rather than just five or, three ccs of fluids.
The second possibility is that maybe we are giving the wrong fluid.
[00:29:58] Steven: usually our first line of [00:30:00] IV drip that we are using, is, crystalloids. Usually we use normal salines, so I'm not sure what fluid you use, Andre in, in Brazil. Do you use normal line as well for fluid resuscitations?
[00:30:11] Andre: Yes. We usually begin with normal saline. Yeah.
there's a lot of debate about whether to give crystalloids or colloids, especially when you're having an ongoing plasma leakage, because colloids in principle, they have a higher oncotic pressure.
[00:30:25] Steven: You might be able to keep the fluid in the intravascular compartment in the presence of plasma leakage. but that haven't, been, proven, at least in the clinical trials to show that, colloid has a better outcome. But having said that, sometimes after multiple rounds of crystalloids, a patient not improving and you still think that it's, due to plasma leakage.
[00:30:42] Steven: Maybe you have to change your strategy, change your fluid to a colloids, maybe at albumins in hope that we can keep the fluid inside the, intravascular compartments. if the plasma leakage getting more and more severe, sometimes they may start to leak out. Bloods patient may have occult bleeding.
[00:30:57] Steven: So if the patient develop occult bleeding. a normal saline of crystalloids will not help at all. In fact, it will cause more harm. So we have to be alert and detect any possibility of occult bleeding. And also to, administered, blood products immediately so the patient won't continue to progress into hypovolemic shock amount organ failures.
third possibility is that, it's not fluid problem at all because, in dengue, a lot of times the main pathophysiology is, plasma leakage. But we know that there's probably about one to 2% of patients when they develop severe dengue is not because of plasma leakage, but because of, dengue related organs functions.
[00:31:31] Steven: For example, myocarditis, dengue myocarditis. we have seen quite a number of dengue myocarditis causing, cardiac dysfunctions. Going into cardiac failures. We have seen dengue causing acute kidney injuries, liver failures, or, cytokine storms like, HRH, that can rapidly lead to multiorgan failure.
in that sense, if you encounter a patients, we are not responding to fluid. maybe it's because of the organ failures rather than fluid issues. then you have to move your strategy into, organ support rather than focusing, on fluids.
[00:32:02] Nav: Thank you, Steven. That was a really wonderful overview of management. at least for me. two big takeaways. One is that. It's such a small percentage that ends up needing such critical intervention. and it really tells you that the scale of incidents, of dengue is so much larger than is, seen by the, standard observer just because the percentage is so small that actually needs such, intervention.
[00:32:30] Nav: And so, clearly a major, major, major global threat that we're sort of dealing with and it's expanding. And the second thing is, we've only been talking about fluid management the entire time, I wanted to, ask you, Andre, about, some of the work that you have ongoing, and looking to if there's anything more than fluids, If there's actually antivirals or other drugs that we can use, for treating Dengue.
in your work with DNDi, could you talk to us about some of the promising drug candidates, either new drug candidates or even repurposed drugs that are under investigations and right now where they're at in terms of clinical trials
[00:33:05] Andre: Yeah, I think, Steven lays out perfectly. how should treat dengue patients and it's a lot based on fluid.
[00:33:12] Andre: Administration and it can work really well. But what we also see is that if, the health systems are not prepared, the health professionals don't know dengue, if it's not administered correctly, it can lead to a much higher rate of complications. So even in a country, you can see sometimes a, 10 to a hundred fold difference in mortality from dengue due to that preparation.
as Steven also mentioned, many special situations such as pregnant women, elderly individuals with comorbidities, it's much more difficult to manage that than, healthy adults that you can give high amount of fluid and they will tolerate well. So, that's why we believe that.
[00:33:58] Andre: we need to develop treatments effective and safe treatments for dengue. the focus of us at DNDI has been to, prevent progression through severe disease. for that we are part of, dengue Alliance, which has six organizations from endemic countries, from Brazil, India, Thailand, and Malaysia.
[00:34:18] Andre: So Steven is a, participant of the Dengue Alliance, we have a broad approach of working with repurpose drugs and also new compounds that are in the pipeline, and also exploring both antivirus and host directed therapies As the viremia can be very short. As for other acute viral infections, we have a very short window for intervention.
[00:34:41] Andre: So that is a challenge, as we mentioned, regarding identifying the patients and, deciding on treatment. the host directed therapies due to the cytokine storm that leads to complication can be very helpful even in later stages. DNDI operates, in collaboration with academic partners, governments, and also industry to select good candidates that can progress to clinical trials.
[00:35:10] Andre: And eventually deliver effective and safe treatments to the ones that need it the most.
[00:35:16] Andre: We know that dengue has been causing epidemics for, many decades, but so far we don't have a treatment and that's. due a lot to, lack of investment, as dengue was not seen as a priority for developers.
we saw how quickly treatments and vaccines were developed for COVID, for example. So we believe that this can also be achieved for dengue.
[00:35:40] Andre: We also have some operational hurdles for, running the trials as we don't have, effective treatments for dengue and the rates of complications can be very high.
[00:35:50] Andre: So we want to demonstrate that the drug, it has a, public health and clinical effect. if we go with. deaths as outcomes or severe disease, it would lead to very large and, unfeasible trials. and we don't have any clear surrogate marker, so we have to interact also with regulatory bodies such as EMA, FDA to try to agree on how we could reach that conclusion of a treatment being effective.
[00:36:20] Andre: Also operational hurdles such as, we don't know where epidemics and cases will be. So you can set up very well, very good sites for the clinical trials, but the patients don't arrive. And what we saw is a very high number of trials that have stopped earlier because they were running for a much longer period than anticipated.
[00:36:42] Andre: So it incurs very high costs. And, the industry partners, they don't want to make that investment if they don't know what the results will be in a short or medium term. So this is a also a challenge that in the Dangue Alliance we are trying to overcome working with, innovative ways to deliver the trials such as mobile teams, modeling and forecasting to direct that resources so we can reach that, Conclusion on if the treatment works or not, and then move to the following phase. .
We are now in a very exciting time and think steven will agree with me,
[00:37:21] Andre: so, amongst the pipeline of candidates, many of are now entering phase two and phase three. So there is a, monoclonal antibody that has shown very good antiviral effect in phase two trials conducted in India. So the plan is to have a global phase three trial beginning next year. and to evaluate how they can reduce, duration and, intensity of symptoms as well as progression to severe disease.
this, would also benefit a lot, mainly people in the higher risk groups. And we have antivirals that are now being evaluated in phase two trials with very promising, preclinical data as well as broad spectrum antivirals that could have an effect not only against dengue, but also against chikungunya, influenza, COVID at the same time.
[00:38:12] Andre: So that could eventually overcome the hurdle of having a very precise diagnostic test when the patient presents.
[00:38:21] Nav: Thank you, Andre.
[00:38:21] Nav: I think it's quite interesting how some of the therapeutic trials, are really dependent on some of the diagnostics or lack thereof, It's very, promising to hear that there are at least things in the pipeline and at least things being, studied in large clinical trials.
[00:38:36] Annie: Yeah, it is really exciting to hear that things are, coming through the pipeline, but I just wonder how does DNDI even sort of approach prioritizing the different candidate drugs for diseases like dengue when the burden is so enormous, but the commercial incentive is so small. Are you able to, give us your insight on, the prioritization process, Andre,
[00:38:57] Andre: that's a very good and, challenging point.
we are, we are taken a portfolio approach. so we have a, clear emergency and, we, believe that we need to move fast to deliver this treatment. So we want to increase, the probability of success on that. So for that, we are also exploring possibility of having the trials run as platforms so we can incorporate the new candidates that are arising, working a lot in policy and advocacy to, to reinforce the need for these dengue treatments and funding for that, as we know we need funding to run that, not only goodwill.
we work a lot with, the Dengue alliance as well, in having the preclinical working group that is evaluating in vivo and in vitro models, the performance of both antivirals and host directed therapies trying to select the best candidates to go to, clinical trials. So there's been trials in, steroids, And other host directed therapies, and [00:40:00] many may have failed because the evidence for, the activity against the disease was not there. And we want to take this stage approach and having that evidence in place so we can, move more assertively and deliver that.
along the lines of efficiency and, drug candidate selection, , are trials incorporating the wide population as a whole? Is it focused on any specific vulnerable patient population? or how do you sort of manage, that type of heterogeneity across, at risk population and then who you actually enroll and, manage in a clinical trial?
This is a really good point. we mentioned that disease express is very different in different geographical locations. So we want to cover that by having this global trial. And also we have planned, analysis to try to find out how different compounds could have, a better performance in, different settings.
[00:40:57] Andre: So the place with more pediatric population, we want to cover that as well. If, it's a place where elderly individuals are the ones most at risk. So if you can identify really well the risk of that individual to progress to severe disease, they would be very good candidates for, monoclonal antibodies.
[00:41:16] Andre: We are working also on reducing the price, but currently they are still expensive. we are working closely also with groups from WHO, On having ways to include these risk groups earlier in the clinical development, process such as pregnant women, children, which many times they are excluded from trials, but are the ones that we want to, target for, reducing the burden of disease.
so we are actively working on that. also in the preclinical testing to reduce that gap, that lead time to have evidence showing that we can use these products in these specific groups. So they are being incorporated in our clinical trial plans and, discuss actively to be safe and also showing effectiveness in that group.
Yeah, that's such an important point, isn't it? And I think across all areas of infectious diseases, inclusion of, pregnant people and children in, new therapeutic trials is, traditionally been not as great as we would want. And I think it's just a really important approach when they're at the higher risk of, complications in diseases such as dengue.
Is there anything else, either of you'd like to add on the kind of drug development side of things? if I may add. what we are trying to, Developed, for the therapeutics is to have a, drug which is easily accessible and can be administered in a population scale, order to do that, we need, a drug which is preferably oral, that patient, can take the medication at home, and does not necessarily need to be admitted through intravenous lines.
[00:42:53] Steven: it has to be, inexpensive in order for us especially during the outbreaks, give to the, populations that's affected in order to prevent, severe dengue. it's a challenge, but I think eventually we will prevail, hopefully in a few years times.
Yeah. Such great points. Steven. You know, even if, A candidate drug is developed and is effective if you can't get it to people who need it in a timely way and administer it to outpatients who are at risk and all of those pragmatic things, it almost starts to not matter in, most, healthcare settings where dengue is endemic.
It just needs to have all those practical aspects of, drug delivery as well as efficacy. So in the infection world, we know that prevention is better than cure, we know that. So, we're gonna move on to talking about dengue prevention. what have we learned about the, dengue deployment vaccines?
[00:43:43] Annie: So there's two now there's Dengvaxia and Qdenga. Have we got lessons yet about, how these vaccines work in real life? Steven, you've also already, explained really nicely the importance of antibody dependent enhancement and how that, also plays into vaccine deployment. do you want to give us your pearl of wisdom about that?
so I think the story of Dengvaxia is a sad one. but at the same time, it actually offers, important lesson, especially for vaccine researchers, health authorities, and also the public health communications. So for those who don't know, the vaccine was the first dengue vaccine that was rolled out, in the market.
[00:44:22] Steven: And of course the scientific, Community as well as the healthcare, providers are very excited. if you are managing dengue for years, you know, struggling with fluid management and all. finally we have something to prevent, dengue in the community. so what happened is, in Philippines, there was a mass vaccination program that was launched, specifically for children.
[00:44:43] Steven: but it was later they discovered that, the vaccine actually increases the risk of dengue in individuals who Have never been infected before. these are the individuals who are what we call sero negative. So basically they have never been exposed to dengue infections.
[00:44:58] Steven: Then they receive the Dengvaxia vaccines as a preventions. in sero negative people. this Dengvaxia actually acted like, I would say like artificial primary infections. and it does help them to produce antibodies as what, vaccine should do. But, the antibodies that they produced by this, Dengvaxia was insufficiently protective in this populations was sero negative because their immune systems are not prime against the, the true infections before.
when these individuals later encounter, a natural dengue infections, these antibodies actually, unable to, neutralize the actual virus completely. And they actually facilitate the viral entry, through this, antibody dependent enhancement into the immune cells. And then they facilitate the viral replications and subsequently to a more, exaggerated, immune response and subsequently severe disease with severe plasma leakage.
[00:45:49] Steven: So for this reason Dengvaxia is now recommended only for individuals, who we will confirm or prior disease infections, meaning that, uh, they need to be sero positive before they, are allowed to receive this, vaccine Dengvaxia. So there are, there are many contributing factors about this, phenomenon.
[00:46:05] Steven: I think one of the contributing factors will be the, the vaccine design. Dengvaxia actually uses a yellow fever virus as a backbone. So while it expresses the structural proteins of all four, dengue serotypes because it's a yellow virus backbone, it, lacks this, non-structural proteins, important ones like those in the dengue virus, like NS1 which are important for the T-cell activations and, durable immunity.
So as a result, it generates weaker and less balanced protection compares to, a natural dengue infections. by contrast, now we have a new vaccines called Qdenga or also known as a TAK 0 0 3. it uses a live attenuated a DEN-2 virus as a backbone. So they use actual dengue virus as a backbone for the vaccines.
[00:46:49] Steven: And this will enable, the vaccine to stimulate a broader and more robust, immune response. So this design actually provides a good protection even among the, uh, serial negative individuals. And so far, based on the clinical trials, no safety concerns similar to, dengvaxia has been observed, meaning that those sero negative, Individuals who received this Qdenga vaccine, did not show that they have a high risk of developing, severe dengue, during the follow ups. up to now, they have followed the patient up to, I think, almost five years the cumulative vaccine efficacy against symptomatic dengue was about 61%, over the four and a half years for all participants.
[00:47:26] Steven: with the high efficacy among the sero. Positive individuals as expected. However, the efficacy against DEN-4 remains uncertain purely because it has a low number, of cases recorded in the clinical trials. But for Malaysia for us, it's not much of issue.
[00:47:40] Steven: Even though they're not much of conclusive, results for DEN-4 virus because in countries like Malaysia, our predominantly circulating serotype it's a race between so these two serotypes are the main serotypes in Malaysia and is well covered by these, Qdenga vaccines.
[00:47:57] Nav: When we think of prevention, vaccine is always at the top of the list. and so I think getting vaccines right and, deploying them is, as important as can be.
[00:48:05] Nav: dengue it's a vector-borne infection. In terms of actual disease control in the population. I'm curious, especially if this differs, in different parts of the world.
[00:48:14] Nav: but where do you see vector control strategies evolving, especially in the context of, climate change and, in insecticide resistance, what do you see happening now over the world and, how are things moving forward, in light of these challenges?
the expansion of dengue is closely related to urbanization, the whole world globally. urbanization is something that we cannot stop. as, new cities are built, more and more, people both are living at the same place in a highly dense area, I think dengue will sooner later become prevalence in that particular area.
[00:48:47] Steven: So I think, vector control with fogging, trying to eliminating the breeding sites for the mosquitoes, remains important. I feel that, We have done a lot with regards to vector control, and we have come to a point where there are not much more we can do to improve the outcome or the situations.
[00:49:04] Steven: Looking at the global, situations with dengue, epidemiology. we need to be innovative. in some countries like Malaysia, we also deployed, wolbachia, infected mosquitoes as a way to reduce these mosquito populations that can transmit, dengue, and it's promising tool.
and currently we are trying to scale up the, the wolbachia-infected mosquitoes, campaigns, in several, parts of our country. genetic control methods are also being tested as well. But ultimately I think this needs a strong, community participations, I think, People have to realize that, dengue comes from mosquito bites. If you don't have mosquitoes, you won't have dengue. they have to take some responsibility to try to, prevent mosquito breeding in their own house, in their own areas. You know, there's so much we can do as a, governments authority, but I think the people themselves also have to realize that they have, much more important responsibility within themselves to prevent the, spread I think we as [00:50:00] clinicians, we need to educate patients and communicate to our communities about preventions and tell them that, there's no treatment available currently. All we rely on again, is fluids close monitoring.
despite, so many years of managing dengue, we are still fall back into the sub so-called supportive managements. We don't have effective treatments, so they have to realize that to start taking some responsibility and, reduce the burden of dengue in their own community.
[00:50:25] Nav: Thank you Steven. Yeah, it's such a multi-pronged approach, right? From epidemiologic surveillance and understanding the incidents in your communities and clinicians being aware of this, and even just, focusing the community, understanding and their baseline risk. it's fascinating.
[00:50:40] Nav: innovative scientific methods to, infect mosquitoes with wolbachia to reduce viral transmission. it just speaks to, funding and supporting, scientific endeavors to advance innovative methods, and how important that is for us.
we've covered a lot of aspects really in interesting clinical insights, Steven, from your clinical practice or extensive clinical practice of managing dengue and, hearing from Andre as well, the potential drug candidates that are soon coming into clinical trials in, real world settings.
then coming back to prevention and some of the challenges that are specific to dengue around antibody dependent enhancement and some of the lessons learned from vaccine deployments so far. it really is one of those multifaceted diseases, of global burden of importance. So to wrap up, If you guys had to set one urgent priority for global research to address dengue in the warming world, maybe you have millions of pounds to do so what would it be? Andre? Do you want to go first?
that's a really good question. I think for dengue, what we need is this integrated approach in terms of how will this combination of vaccines, innovative vector control measures and treatments work?
[00:51:57] Andre: be suited for different scenarios. now we have. Good vaccines in the pipeline and we have the wolbachia as mentioned, but we still need treatment. So I would invest a lot to, develop these treatments and, work on ways and understand how they could, reduce the burden and especially the complications that Dengue is likely to cause in the following years.
Unfortunately, although we have these new tools, they won't be covering all the transmission areas that we have now, and we are likely to see an expansion of the transmission areas as we've seen recently, even in Europe, in, the US and, others. So, we will need to have good countermeasures, and treatments will be a part of that.
[00:52:42] Andre: So how we can combine that, how we can reach, and deliver those solutions quickly. if we have good investment, I'm certain that we can do that in a reduced timeframe
and Steven,
[00:52:55] Steven: the World Health organizations they have a target by 2030. to have zero dengue deaths. So we are talking about a global, infectious disease at a global scale like Dengue, and we want to achieve zero dengue deaths. personally, as a clinician, I think it's impossible to achieve that without, effective therapeutics.
[00:53:16] Steven: if you have all the resources in the world, the top priority is to develop safe and effective therapeutics. I've talked a lot about supportive care. And supportive care does save lives. despite the challenges we have managed our dengue patients with, supportive care in our hospitals with, hospital resources and close monitoring. but all these are not sustainable, especially when the cases are going up. We can see that dengue cases is not coming down anytime soon. I think it's the worst, dengue season we have last year. I think this year, probably not by next year or so, the numbers will be doubled. So I think an oral antivirals, that can be given early, at the first diagnosis of Dengue, much like how we do, for COVID-19 previously, would be a game changer.
[00:53:57] Steven: So, I would put my money on the, therapeutics for Dengue.
Thank you both. I think it's always helpful to hear, Experts relay where the priorities should be. Andre, Steven, I think we've really had just a fascinating discussion. I've certainly learned so much from you. and, we really value your expertise.
as we close, do you have any final thoughts that you'd like to share with us, with the listeners? thank you for, hosting us. It was really a pleasure to be here discussing Dengue as a highlight we need to work collaboratively. collaborating with these different expertise, exploring these different scenarios, and also exploring outside the field usually opens the mind to new solutions.
[00:54:41] Andre: So we keep doing the same thing we've been doing for, decades. We want to, innovate, so we need to open and reach people who are proposing, new approaches and testing new things. I think that with innovation, we can definitely improve people's life.
for me, my message is. Pretty simple. I just wanna say that, dengue has gone global. it's no longer a tropical disease anymore. with climate change and global travels, and we know that dengue does not respect borders. it has gone as far as places like France, parts of Europe's and mediterranean countries.
[00:55:15] Steven: it's timely that all clinicians around the world should at least know, how to recognize dengue, how to diagnose, and how to have some basics, knowledge and how to maneuver in terms of the fluid management and monitoring like what Andrea said, time that the whole world should come together collaborate, , implement vaccine rollouts and, other strategies to move forward.
[00:55:36] Annie: That's great. Nice messages to end on innovation and collaboration, which I guess is true for lots of infectious diseases, isn't it?
[00:55:43] Annie: Thank you so much again to our guests. Steven Lim in Malaysia and Andre Siqueira in Brazil. and thank you for listening to Communicable the CMI Comms podcast.
[00:55:53] Annie: This episode was hosted by me, Annie Joseph in Nottingham UK and Nav Narayanan in New Jersey, US both editors at CMI, comms ESCMID's Open Access Journal. It was edited and produced by Dr. Katie Hostetler and peer reviewed by Dr. Loora Grünvald of the University of Tartu, Estonia. Theme music was composed and conducted by Joseph McDade.
[00:56:16] Annie: This episode will be citable with a written summary referenced by a DOI in the next eight weeks. And any literature we've discussed today will be found in the show notes. you can subscribe to Communicable wherever you get your podcasts, or you can find it on ESCMID's website for the CMI Comms Journal.
[00:56:32] Annie: Thank you for listening and helping CMI, comms and Smid move the conversation in infectious diseases and clinical microbiology further along.