Dengue: The Disease That Exacerbates With Subsequent Infections
Introduction
Dengue is a zoonotic viral infection that spreads from Aedes mosquitoes to humans. Understandably, vector presence becomes a limiting factor modulating disease transmission. While temperate countries are rather protected from dengue, others in the tropical areas have been battling against this recalcitrant infection for decades. To paint a picture, Malaysia has been grappling with hundreds of thousands of dengue cases. Thanks to climatic conditions, the warmth and moisture in tropical regions are all the ingredients of a thriving mosquitoes population. Noteworthy is that secondary dengue infection carries a two fold higher risk to progress into severe complications relative to first-time dengue patients. As counter-intuitive as it may seem, the acquired active immunity attained through our first dengue infection is exactly what leads to the poor prognosis in secondary infections. More worryingly, this baked-in hyper-endemic disease seems to be going nowhere, which underpins exactly why it requires much attention.
Dengue viruses (DENVs): A Molecular Overview
Dengue viruses (DENVs) are a group of mosquito-borne Flavivirus belonging to the Flaviviridae family. In essence, they are enveloped, single-strand positive-sense RNA viruses. Its genome comprises approximately 10,700 nucleotides, including those which code for both structural and non-structural proteins. Dengue viruses are further divided into four closely-related serotypes: DENV-1, DENV-2, DENV-3 and DENV-4. All of them share a facsimile in nearly 65%-70% of their nucleotides while exhibiting a discrepancy in the region of 25%-40% when it comes to the amino acid level.
Symptoms
The incubation period (time between exposure and symptoms onset) of dengue more or less ranges from 3 to 14 days. Symptoms can differ widely from self-limiting acute febrile illness to life-threatening dengue shock syndrome, if we are to mention the whole continuum with outliers inclusive. Nonetheless, it is reassuring that most symptoms include an acute onset of fever, headache, muscle as well as joint pains, and a characteristic skin rash akin to those of measles. Thanks to advancement in healthcare systems, this common illness now harbours promising recovery - with a satisfactorily low mortality rate of 0.5 per 100,000 population in Malaysia - when patients receive adequate treatment. Yet, it remains important that keep in mind the aforementioned red flags as timely treatment is key. Since DENV invades platelets, bleeding secondary to thrombocytopenia is a significant risk that demands attention.
Thankfully, there are several constitutional symptoms highly suggestive of dengue, which can prompt most infected individuals to seek out treatment immediately before complications set in. On one hand, fever and headaches can be indecisive determinants shared across plenty of viral infections. On the other hand, what sets dengue apart lies in its ability to cause muscle and joint pains aside from a characteristic rash described as “islands of whites in a sea of red”, quite literally in reality. Noteworthy is that certain dengue patients can experience incapacitating myalgia and arthralgia, which is exactly why dengue is also dubbed as “bone-breaking fever”. Such tenderness is stemmed from the virus wreaking havoc by triggering a storm of widespread systemic inflammatory immune response. Additionally, a characteristic erythematous rash on the limbs featuring classic “islands of white sparing” is also what we can look out for before blood assays confirm the diagnosis of dengue. Fantastically, a blanch test is how doctors can somehow foretell the diagnosis of dengue before laboratory tests are made available. In terms of pathophysiology, the rashes happen out of a compromise in capillaries integrity and platelet counts owing to DENV.
Figure 1: Skin rash from dengue fever
Complications
The clinical course of dengue can be divided into three distinct phases - the febrile phase, the critical phase and the recovery phase - at a glance. The febrile phase is where sudden-onset fever, headache (usually retro-orbital), pains and rashes first occur during days 1 to 3. For certain individuals, the fever resolves in a few days. And, the disease has gone nowhere, yet it has moved on to the next stage. Here comes the critical phase, which is characterised by thrombocytopenia following defervescence. This typically comes into play during days 3 to 7 of the illness. In this phase lies the risk of plasma leakage and bleeding, which makes risk mitigation as well as management much more critical than before. Fortunately, more than 95% of cases progress to an uncomplicated recovery thereafter. Yet, the scarce outliers, among all dengue patients, can proceed to life-threatening dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS). Such complications are considered to be extremely rare, yet those with secondary infection bear an increased propensity.
Dengue haemorrhagic fever (DHF): This is characterised by haemorrhagic manifestations and plasma leakage, whereof evidenced by a rise in haematocrit ≥ 20%, pleural effusions or ascites.
Dengue shock syndrome (DSS): This occurs when plasma leakage is so remarkable that the patient’s circulating blood volume drops dangerously low, leading to hypovolemic shock. This is a medical emergency that can rapidly spiral into multi-organ failure, internal haemorrhage and death if not treated immediately with proper fluid resuscitation.
Antibody-Dependent Enhancement (ADE)
Natural recovery from infection with one of the dengue strains yields lifelong immunity against that particular serotype, but not others. Such adaptive immunity sounds like another promising second nature, yet the infected individuals in question have just jumped from the frying pan into the fire. They become more susceptible to dengue than any other populations. Should this cohort be infected with dengue once more by another DENV serotype, sequential dengue infections can - in reality - facilitate disease aggravation. This paradoxical phenomenon is believed to have antibody-dependent enhancement (ADE) as the dominant causative factor.
Well, the complex relationship between DENV serotypes - with each having both close relativity and subtle differences to one another - means that antibodies created against one serotype can cross-react with those of other serotypes via their common structural elements while not being able to neutralise them adequately. The whole process is mediated mainly by IgG antibodies. Interestingly, the coating of IgG antibodies on virions enhances viral uptake by FcγR-bearing immune cells which switches on cascades that end up in infectious virus maturation and immune suppression that favours viral replication. These catastrophic physiological processes render in higher viremia and, understandably, a higher risk of dengue-pertinent complications. Conversely, other viruses taken up by FcγR-bearing immune cells typically do not contribute to pathological ADE since the infection is able to be aborted upon FcγR engagement.
Figure 2: Antigen-dependent enhancement
Dengue Prevention and Control
Despite tropical climate making a recipe for mosquitoes infestation, we are not totally in vain. There are a few precautions we can take to make our environments less hostile towards these vectors, or to stave off their invasions, to say the least.
Eliminate stagnant water: Frequently clean up water-holding containers such as buckets, pots, old tires and, even, ditches.
Fogging: The Ministry of Health (MoH), say, in Malaysia, has been deploying the fogging method in an attempt to get rid of Aedes mosquitoes within dengue hotspots.
Figure 3: Fogging
(Source: Google)
Wearing long-sleeved clothes: This is pretty straightforward. Wearing long clothes reduces the surface area of our skin exposed to mosquitoes.
Mosquitoes repellents: There are commercially-available lotions and patches in circulation, whereof we can apply on our skins to keep mosquitoes at bay.
Vaccination: In recent years, major approvals of a dengue tetravalent vaccine - QDenga - has ushered in new hopes for our regional battle against dengue. QDenga is efficacious in bestowing protection against all four dengue serotypes, and it is granted a conditional registration for public deployment in Malaysia starting from February 8, 2024.
Development of Dengue Vaccines
The perpetual quest for a decent dengue vaccine has been around for more than 80 years, yet the process has been pretty much futile and held up for decades owing to a single immunological hurdle: antibody-dependent enhancement (ADE). In this regard, a dengue vaccine must be able to confer equal protection against all four DENV serotypes in order for it to be functionally viable. Should it induce a weak or unbalanced immune response to any one strain, subsequent natural infection can blow up into severe complications.
QDenga overcame these aforementioned hurdles by exploiting live-attenuated DENV-2 for good reason. Essentially, DENV-2 forms the genetic backbone in question, and it is then genetically modified to express surface antigens of the other three serotypes. Delving deeper, the DENV-2 NS1 component of such a backbone induces antibodies that not only bind to DENV-2 NS1, but also cross react with NS1 from other serotypes. This is done with a view to protect against severe dengue by halting viral NS1-mediated vasculopathy.
*Note: To demystify jargons, NS1 here refers to Non-structural Protein 1, a glycoprotein produced by DENV.
Conclusion and Future Implications
To recapitulate, dengue is a mosquito-borne viral disease that affects hundreds of millions of the global population each year. It is caused by a group of flavivirus called DENVs, and the disease is hyperendemic within tropical as well as sub-tropical regions. Symptoms can range widely from uneventful self-resolving febrile illness to life-threatening haemorrhagic shock. Nonetheless, arthralgia and a characteristic rash are among the most common red flags of dengue, alongside fever - the unspecified viral sign that points to nothing. Most patients undergo an uncomplicated recovery unless heavily untreated. Nevertheless, those with subsequent dengue infections are at risk of more severe disease manifestation owing to antibody-dependent enhancement (ADE), which arises out of antibody cross-reactivity with different DENV serotypes.
It is not until recent years have our global long-lasting quest for effective dengue vaccines come to fruition. Even so, we still have a long way to go in understanding and circumventing the notoriously complex immunological bottlenecks that have pushed back on this endeavour for decades. Neutralising antibodies remain the indispensable mainstay, yet we should make it a point to look into epitope specificity, avidity and the durability of memory B-cell pools moving forward.
References
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