Dengue hemorrhagic fever: a growing global menace

Dengue virus (DENV) is one of the most important arboviruses (arthropod-borne viruses) from a public health perspective and is known to cause dengue infection, which is mainly transmitted by Aedes aegypti (Mutheneni et al. 2017). DENV is an enveloped globular virus with icosahedral symmetry containing 11 kilobases of single-stranded RNA (Paul et al. 2021) that encodes an open reading frame containing three structural and seven nonstructural proteins (Uno & Ross 2018). Based on antigenic differences, four DENV serotypes with 65% genomic similarity, namely DENV-1, DENV-2, DENV-3, and DENV4, were identified in addition to DENV-5, recently discovered in Malaysia (Bashyam et al. 2006; Mustafa et al. 2015). Within each serotype, there are several genotypes (Simmons et al. 2012) that are phylogenetically based on sequence variation in the envelope (E) gene: DENV-1 (I–VI); DENV-2 (Asia I, Asia II, Asia/America, America, Cosmopolitan, Forest); DENV-3 (IV); DENV-4 (Asian I, Asian II, Asian/American, American, Cosmopolitan, Forest). These serotypes can elicit differential immunogenic effects by infecting different target cells, thereby eliciting a powerful cytokine response that in turn influences the severity of the disease. In addition, secondary infection with a heterologous serotype may elicit a faster immune response than primary infection due to antibody-dependent enhancement (ADE) (Bosch et al. 2020).

The World Health Organization (WHO) considers dengue fever (DF) as a serious hazard to public health. Climate change, accelerated population growth, and lack of medical facilities are some of the factors that have led to the rise of the DENV. There are 400 million cases of dengue each year, affecting 5 billion people, and some places have mortality rates of up to 520. More than 100 countries are affected by dengue infections, including the United States, and Europe (Lee et al. 2020). Symptoms of the disease may vary from mild to severe (Wang et al. 2020). More than half of the world's population is at risk of contracting this disease, which has increased sharply in recent years. More than 120 countries are affected by the dengue hemorrhagic virus DHF, which poses a global public health burden. In 2019, an alarming 5.2 million cases of dengue were reported (Paul et al. 2021). In 2022, Asia is responsible for 70 dengue cases worldwide, while 50 people are at risk worldwide (Wang et al. 2020). It is believed that dengue infections affect 390 million people worldwide every year and kill up to 36,000 people. 2,597,067 cases and 2,065 deaths were documented on August 24, 2022 (Armenda et al. 2021).

The countries with the most reported deaths are Brazil, Vietnam, and the Philippines. There have been over 2,000 new cases and over 2,000 new deaths since the last update. According to recent studies, nearly a billion people worldwide are at high risk of contracting the disease because they live in tropical and subtropical areas (Adimy et al. 2020). Dengue hemorrhagic fever (DHF) affects 450,000 people each year, despite the fact that 100 million cases of classic DF are reported each year. Southeast Asia has a higher prevalence of life-threatening bleeding disorders than either Africa or America (Kayesh et al. 2023).

There is still a lack of a specific antiviral drug and an approved vaccine to treat and prevent DENV infection. DF and dengue hemorrhagic virus DHF remain a major public health concern worldwide. DHF has recently been reported in several dengue outbreaks and has resulted in high mortality. Clinically, DHF poses a major risk; due to the complexity of its aetiology disease causes are still unknown. In this review, we summarize and discuss the mechanisms underlying the development of DHF. We also presented the most recent views on DHF prevention and control. The pathophysiology of DHF, as well as treatments and prevention strategies, are discussed in detail in this paper. This study offers important information and perspectives on the pathogenesis of DHF as well as preventive and curative measures.

We looked through a number of databases, including Science Citation Index, Journal Citation Reports, Sci Search, Google Scholar, PubMed, Medline, SCOPUS, as well as Biological Abstracts. Access was gained to the publicly available databases. Relevant data were searched using the phrases ‘dengue fever’, ‘dengue fever and climate change’, ‘dengue hemorrhagic fever (DHF), and other infectious diseases’, ‘risk factors and dengue fever’, ‘dengue fever and modeling’, ‘infectious diseases transmitted by vectors’, ‘models of vector-borne diseases’, ‘monitoring for the early detection of infectious diseases’.

The following criteria were utilized in the selection process: (1) studies validated through a peer-reviewed process, (2) full-text research articles, (3) studies published in English, and (4) studies solely considered the map depicting the progression of dengue risk with population growth in addition to socioeconomic, demographic and epidemiological factors, serotype transmission of DF by vectors, cases of DF, and its distribution. The justification behind the inclusion standards was to concentrate on the rise in population, especially in mosquito density, in addition to financial, ecological, and epidemiological as well as demographic characteristics connected with dengue transmission. Articles that did not fit the aforementioned criteria were excluded.

The key steps by which DENV infection induces DHF have been a subject of controversy. DENV antibodies can influence the course of the disease in various ways. In one study, passive transmission of DENV antibodies increased viral loads in non-human primates, while a recent study showed a positive relationship between peak viral load and disease severity in humans. The idea about ADE functions in vivo is supported by the observation that DHF persists after primary DENV infection in infants, born to DENV-immune women who subsequently acquire DENV antibodies through the placenta. Primary DENV and clinically mild secondary DENV infection suggest that other variables are also involved. In patients with severe disease, in vivo immune complex formation has been associated with complement activation. Cross-reactivity of anti-E antibodies with plasminogen has been associated with bleeding in acute DENV infection, but not with DHF (Harapan et al. 2020). In addition, potential pathologic factors include cytokine production and cytolysis by activated T cells. Elevated levels of activation markers such as soluble TNF receptors, soluble IL-2 receptors and soluble CD8⁺ have been associated with disease severity.

Similar associations with disease severity were found for the expression of activation markers on circulating CD8⁺ T cells and for an increased population of DENV epitope-specific T cells. Acute DEN infection leads to increased production of several cytokines, including IFN, TNF, IL-10, and chemokines (Khanam et al. 2022). Although both type 1 and 2 cytokine levels are elevated in DHF, the timing of their synthesis appears to be critical as induction of type 1 cytokines occurs earlier and is associated with more severe disease. Analysis of T cell responses to DENV revealed an association between in vitro TNF responses to DENV antigens (Waickman et al. 2022).

Individuals are affected four times by DENV types (DENV1, DENV2, and DENV3) (WHO 2022). These four serotypes are genetically related and have a 65% genomic similarity. In October 2013, the sixth DENV-5 variant was discovered (Mustafa et al. 2015). A study indicated that DENV-2 and DENV-3 may induce severe illness while DENV-4 causes a mild infection; DENV-1 patients appeared to have a higher chance of developing DHF and Severe Dengue (SD) than patients with DENV-2 or DENV-3. According to a phylogenetic study, these variations may be caused by DENV-1 and DENV-2 viruses of genotypes 1 and are cosmopolitan, respectively (Yung et al. 2015).

Dengue viruses have significant gene mutation rates and mutation frequencies over a hundred times higher than DNA genomes. The phylogenetic analysis showed that DENV-5 and the other four serotypes shared a common ancestor. DENV1-4 follows the human cycle, while DENV-5 follows the sylvatic cycle (Mustafa et al. 2015).

The interaction between virus surface proteins and cellular plasma membrane elements determines whether or not target cells will recognize a virus (Islam et al. 2021). Currently, DENV does not have a defined receptor. The adhesion molecule of dendritic cells (DC-SIGN), the mannose receptor (MR) of macrophages, the lipopolysaccharide (LPS) receptor CD14, and stress-induced proteins, such as the heat-shock proteins 70 and 90 and the ER chaperonin GRP78, have all emerged as candidates with distinct natures in mammalian and mosquito cells. A study indicated that E protein DIII has the receptor(s) binding site (s). Based on the viral strain or serotype and the host cell, the DENV particle involves several mechanisms, such as clathrin-mediated endocytosis or clathrin-independent endocytic pathways (non-classical). The maturation of the virus particle and the identification of viral immunocomplexes by Fcγ-receptors are two additional factors that hinder viral entry (Cruz-Oliveira et al. 2015).

Neurological disorders are those that affect not only the brain but also the spinal cord and other body nerves (Trivedi & Chakravarty 2022). New DHF guidelines and classification were announced by the WHO, and this disease now includes brain involvement (Trivedi & Chakravarty 2022). There are three different pathogenic mechanisms that explain the neurological complications of DF: (1) directly invades the central nervous system, which leads to myelitis, meningitis, and encephalitis; (2) a systemic condition that brings stroke and encephalopathy; and (3) para infection or post-infection immunomediated conditions such as optic neuritis, acute disseminated encephalomyelitis and Guillain-Barré syndrome (GBS) (Herath et al. 2018). Some symptoms of neurological complications include headache, confusion, seizures, hemiparesis, and even coma. In addition, MRI and CT scans both are used to determine more information about neurological complications (Weerasinghe & Medagama 2019).

The range of the neurological and neurological complications of dengue (hemorrhagic) disease is diverse. The neurotropic nature of DF has been confirmed by epidemiological and case series studies as well as in histopathological studies. The spectrum of the neurologic complications is 5.6–14.6% and they are more common within DHF, with a higher prevalence in adolescents and children (Carod-Artal et al. 2013). Neurological manifestations of DHF were being reported in many countries. The affected people range from the very young (3 months baby) to the very old (60 years). Some of the different neurological manifestations include myelitis, encephalitis, myositis, and GBS (Trivedi & Chakravarty 2022).

Approximately 2.5 billion people in over 100 countries have been at high risk of complications due to dengue infection. In Sri Lanka, dengue outbreaks have increased in recent decades. In 2015, a neurological complication (Encephalitis) with cerebral infection and seizure with severe headache was reported in India.

In 2017, the second case was reported in Sri Lanka, having neurological complications (cerebellar syndrome) with Gait ataxia, dysarthria, and horizontal and vertical nystagmus in DHF. In Brazil, neurological complications cases were reported, they have meningitis along with headache, fever, and vomiting and neck stiffness/rigidity (Herath et al. 2018). In Taiwan, the hemorrhagic stroke was reported with dysarthria, headache, vomiting, hemiparesis, and somnolence (Lardo et al. 2018). In Guadeloupe, neurological complication was reported, including sphincter disturbances, abrupt motor, and sensory neurons and spinal lesions at three vertebral segments (Herath et al. 2018). The neurological complications of DHF from 2013 to 2019 are broadly classified (Jugpal et al. 2017) (Table 2).

Ophthalmic complications are those complications that are related to the eyes. In the last 25 years, the geographical distribution of DHF resulted in a global revival of the disease, causing ocular infections in many tropical urban areas. Globally, 2.5 billion people were affected by these complications (Dhoot 2023). Ophthalmologists should carefully evaluate patients with dengue-related eye disease, as some patients have poor visual acuity and are treatment-resistant. Dengue ocular manifestations can occur during many stages of dengue, but are more pronounced in hemorrhagic dengue. Many cases of ocular dengue showed spontaneous improvement in vision (Somkijrungroj & Kongwattananon 2019).

There are various ophthalmic complications that affect DHF patients including myopic shift, corneal pathology, maculopathy, retinal vein occlusions, posterior uveitis, macular edema, and neuro-ophthalmic manifestations. The main symptoms are metamorphopsia, scotomata, floaters, and blurring of vision (Ng & Teoh 2015; Oliver et al. 2019). In 2015, many cases of ocular complication (corneal pathology) with DHF were diagnosed in many areas such as America, Western Pacific, and Southeast Asia having symptoms of lower corneal erosions and peripheral hypopyon corneal ulcer (Ng & Teoh 2015). In 2016, retinal vein constrictions were reported in Malaysia (Velaitham & Vijayasingham 2016). In 2018, the neuro-ophthalmic manifestations were reported in India as having diplopia and acute vomiting (Krishnacharya et al. 2018). From 2019 to 2022, posterior uveitis, macular edema and myopic shift were reported in different areas of the world (Joshi & Wadekar 2021). Tomography, optical coherence tomography, angiography, microperimetry, and near-infrared imaging have an important part in the recognition of all these problems (Somkijrungroj & Kongwattananon 2019). Ophthalmic complications reported from 2015 to 2022 are discussed in Table 3.

The most frequent lymphatic system complication among severe dengue infections is lymphadenopathy. Although they are uncommon, lymph node infarctions and splenic ruptures can be fatal. Another frequent sign of all dengue infection types is splenomegaly. However, it brings a deficiency in platelets and coagulation factors, causing intrasplenic hemorrhage and, ultimately, splenic rupture (Khan et al. 2022a, 2022b). A case reported fever, stiffness, chills, and sore throat. The diffuse maculopapular rash covered the entire body but secured the mucosal membranes and periorbital tissues, and was accompanied by myalgia and frequent vomiting. Upon inspection, toxic facial features, and conjunctival congestion were revealed (Chang 2021).

Along with bilaterally enlarged parotid and submandibular glands, there was also bilateral inguinal lymphadenopathy. Another study indicated vomiting, myalgia, headache, and fever. On assessment, the patient's heart rate was 112 beats per minute (bpm), normal blood pressure (BP) was 92/60 mmHg, respiratory rate was 24 breaths per minute (bpm), and oxygen saturation when breathing room air was 98% (Singh et al. 2018). In addition a case indicated a 5-day history of high fever accompanied by chills, vomiting, and yellowing of skin, the patient neither had a substantial medical history nor an addiction (Joob & Wiwanitkit 2020). The patient exhibited a highly icteric condition, a fever of 100°F, and bilateral subconjunctival hemorrhages. A white blood cell count automatically revealed a concentration of 20.78 with the prevalence of neutrophils and normal platelets. Blood test results revealed a hemoglobin level of 7.78 g/dL, MCV of 98.12 fl, MCH of 37.72 pg, and MCHC of 38.45 g/dL (Khan et al. 2019).

The occurrence of dengue is contingent upon abiotic conditions that directly influence the population dynamics of mosquitoes, hence carrying significant consequences for the transmission of dengue (Yang et al. 2014). The epidemiology of dengue is a multifaceted phenomenon that encompasses the interactions between the host (human and mosquito), the agent (virus), and the environment (including abiotic and biotic variables). The interaction among these factors influenced the level of endemicity (Dutta et al. 2011; Dash et al. 2012).

More than 120 countries are affected by DF. In 2019, a DF case was reported. Despite the fact that 50% of the world's population is at risk for the disease, Asia is responsible for 70% of the dengue burden. According to the Global Strategy for Dengue Prevention and Control (GSPC) of the WHO, the major goal was to reduce dengue mortality to zero by 2030. For this, DF is considered a general threat and needs to be strengthened through international collaboration, preparation, prevention, and management of dengue. In June 2021, the Asian Dengue Voice and Action (ADVA) groups will celebrate World Dengue Day, International Neglected Tropics Association Day (ISNTD), and ASEAN Dengue. The International Forum underscored the critical need for successful cross-sectoral collaborations between the Ministries of Health, Environment, and Education and local private businesses. The forum collected 29,000 signatures from dengue patients in 110 countries for the United Nations WHO's World Dengue Day petitions (Srisawat et al. 2022).

At least seven DENV vaccines have been produced and are based on various platforms, including DNA, recombinant proteins, chimeric live attenuated viruses, inactivated viruses, and live attenuated viruses (Torres-Flores et al. 2022). They primarily work by enhancing immune responses against the E protein and non-structural protein 1 (NS1) of the DENV (Liu et al. 2016). The variety of DENV vaccine in phase I and II clinical trials are important. Clinical trials in phase I/II also assess how well a particular form of disease reacts to a novel therapy. Patients typically get the greatest dose of medication that did not result in adverse side effects in the phase I stage of the clinical study during phase II (Table 5). Phase III clinical studies compare a novel treatment to existing ones to see how safe and effective it is. Phase III clinical trials, for instance, could assess which patient population had higher survival rates or fewer adverse effects. The only DENV vaccine that is presently approved is Dengvaxia, however, phase III clinical studies using the TV-003/TV-005 and TAK-003 have shown encouraging outcomes (Torres-Flores et al. 2022) (Table 6).

Recombinant attenuated DENV vaccine candidates TV003/TV005 from the United States National Institutes of Health and TAK-003 from Takeda Inc. are now conducting clinical phase III trials, and these candidates seem to be the most close to commercialization since Dengvaxia (Park et al. 2022). A large-scale phase III clinical trial is now being carried out to assess the effectiveness of DENVax in dengue-endemic regions of Latin America and Asia (Torres-Flores et al. 2022). TDENV-PIV with AS03B is now being tested in a phase II clinical trial to find the most efficient injection (Redoni et al. 2020). TDENV-LAV, a tetravalent formulation of all DENV serotypes that have been attenuated in PDK and Rhesus lung cells, was investigated in a clinical phase II investigation. The results confirmed the safety of TDENV and the immunogenicity of LAVs (Wasiullah et al. 2022). Phase 1 clinical trials of the US NMRC's monovalent DENV-1 DNA vaccine (D1ME100) were conducted. This tetravalent DNA vaccine produced with Vaxfectin completed effectively its phase 1 trial. Tetravalent live attenuated-prime followed by tetravalent PIV boost and vice versa are heterologous regimens that are being studied in phase I trials. Phase 1 clinical trial with dose escalation and adjuvant formulation of this vaccine, designated V180, was conducted (Prompetchara et al. 2019).

Although various studies on vaccine production are reported there is currently no specific, effective, and safe dengue vaccine (Abidemi & Aziz 2020). Hence, reducing the mosquito population is the primary method of controlling the spread of DF. Use of personal and household protection (such as window screens, long-sleeved clothing, mosquito repellents, insecticide-treated bed nets, vaporizers and coils), administration of appropriate insecticides or predators to the outdoor water-holding containers, and open space insecticide spraying are all components of the vector control strategy. Mosquitoes adore stagnant water. They are unable to procreate and spread illness without it. The term ‘water lying around’ conjures up images of immobility, stillness, and stagnation. It also implied that the volume of water resting in the environment results in breeding grounds for Ae. aegypti mosquitoes, dengue mosquitoes, and possibly other diseases for people (McNaughton et al. 2018). The Ae. aegypti mosquitoes are drawn to the well's clear, pure water to deposit their eggs. Mosquitoes eat the microorganisms in well water. In addition, tap water contains chlorine (Ca(OCl)₂), a sanitizer. The capacity of mosquito eggs to hatch can be impacted by a number of active compounds found in water. When chlorine is added to water media, which has the potential to oxidize Ae. aegypti eggs, the hatching process may interfere (Prameswarie et al. 2023). We contend that this widely held belief is related to a larger logic that gave rise to the lay understanding, specifically that dengue mosquitoes are widespread and breed in a range of environments and types of water. Numerous research has examined the effects of various control techniques, including vaccination, therapy, human self-defense, and vector controls utilizing larvicide and adulticide, on the dynamics of DHF transmission (Abidemi & Aziz 2020).

A suspected case and its 300 fatalities overwhelm the medical system in the Pakistani city of Lahore, which has a population of 496,490, where the greatest dengue epidemic happened in 2011. Incorporating interdisciplinary efforts from the Ministries of Health, Agriculture, Environment, and Horticulture, a Central Emergency Response Committee was created (Khan & Abbas 2014). Data were entered into a central patient tracking system for each confirmed case (Abdur Rehman et al. 2016). Technical endeavors, such as the development of online surveillance systems, global positioning systems, telephone-based surveillance systems, and a toll-free citizen hotline construction of isolation wards and highly dependent units (HDUs), provision of more beds, and hiring of medical personnel are all part of the transformation of the healthcare system (Khan & Abbas 2014; Abdur Rehman et al. 2016).

Furthermore, we should create our own standards for the diagnosis, management, prevention, and treatment of dengue that the WHO or other prosperous nations may embrace. It is best to get consensus from multidisciplinary experts (Srisawat et al. 2022). Lessons from these effective dengue control initiatives should be used as a springboard for creating preventing dengue plans in other epidemic contexts. It is necessary to coordinate efforts across multiple sectors (health, education, environment, government, and community). An effective dengue prevention strategy leads to a fight against dengue worldwide through the use of a video conferencing system, international talks and experience sharing. Moreover, get professional advice on how to handle difficult and serious issues. The ADVA group is therefore aware of this issue. Additionally, they often host webinar series for dengue management that deliver well-informed, targeted, and customized results. Asian-wide initiatives could also have a big influence on dengue in Asia (Srisawat et al. 2022).

DHF presents a formidable global health challenge due to the complexity of the DENV, its multi-system impact, and the absence of a specific treatment. Efforts to control DHF must encompass early diagnosis, vaccination development, and a multidisciplinary approach involving healthcare, education, and government sectors. Thus, DHF remains a pressing concern, demanding continued research and collaborative action to mitigate its impact on public health worldwide.

None.

All the relevant data is included in the paper.

The authors declare there is no conflict.