Arbovirus Infection

0

population

Global

percentage

40

evidence

reference	supports	snippet	explanation
PMID:34957305	REFUTE	About 50 to 100 million people are newly infected annually, with almost 2.5 billion people living at risk and resulting in 20,000 deaths.	This implies a much lower global prevalence percentage than 40%.
PMID:32813703	REFUTE	Dengue fever occurs worldwide and about 1% of cases progress to severe haemorrhage and shock.	The data focus more on severe cases, but the general context implies that the prevalence is significantly less than 40% globally.
PMID:28556417	REFUTE	The estimated seroprevalence of past dengue infection in Tanzania ranged from 50.6% in a health facility-based study to 11% in a population-based study.	Even though specific case studies within countries can indicate high prevalence rates, this does not support a global prevalence of 40%.

0

phase

Incubation

evidence

reference	supports	snippet	explanation
PMID:23226436	PARTIAL	The best-fitting temperature-dependent EIP model estimated that 95% of EIPs are between 5 and 33 days at 25 degrees C, and 2 and 15 days at 30 degrees C, with means of 15 and 6.5 days, respectively. The mean IIP estimate was 5.9 days, with 95% expected between days 3 and 10.	The statement about the incubation period being 3-14 days is partially supported, as the literature provides a more specific range (3-10 days for IIP in humans).

incubation_days

3-14

notes

Typically 4-7 days

1

phase

Febrile

evidence

reference	supports	snippet	explanation
PMID:2665014	SUPPORT	Dengue hemorrhagic fever is characterized by a sudden onset of fever that lasts for 2-7 days and then subsides, at which time hemorrhagic manifestations become evident.	This reference describes that the fever phase in dengue typically lasts for 2-7 days, supporting the statement about the duration of the febrile phase.

notes

Sudden onset of high fever

duration_days

2-7

2

phase

Critical

evidence

reference	supports	snippet	explanation
PMID:32125417	SUPPORT	Dengue is commonly considered an acute illness and follows three phases: febrile, critical in some cases and recovery.	The study identifies that dengue follows a progression that includes a critical phase consistent with the timeframe of 3-7 days.
PMID:34986174	SUPPORT	Dengue usually progress abnormally, especially in the critical phase. The main causes of death were shock, severe bleeding and organ failure.	The critical phase and its associated risks of severe complications including hemorrhage and vascular leakage are clearly outlined.

notes

Risk of severe complications, including hemorrhage and vascular leakage

duration_days

3-7

3

phase

Recovery

evidence

reference	supports	snippet	explanation
PMID:32125417	REFUTE	Here we evaluate this persistence of dengue symptoms during convalescence.	The study indicates that dengue symptoms can persist for more than 30 days and suggests that the burden of dengue may be higher than previously estimated, which contradicts the statement that implies a recovery phase lasting only 2-5 days.
PMID:34302960	REFUTE	Patients were followed-up daily until discharge.	The study implies a longer monitoring period and a more extended duration of platelet recovery post-dengue which contradicts the statement about a 2-5 days recovery period.

notes

Gradual return to normal fluid balance

duration_days

2-5

0

name

Dengue Virus (DENV) Infection

description

A Flavivirus transmitted by Aedes mosquitoes, causing a wide range of symptoms from mild fever to severe hemorrhagic fever and shock.

cell_types

• Dendritic Cell
• Monocyte
• Macrophage
• Endothelial Cell

evidence

reference	supports	snippet	explanation
PMID:23476150	SUPPORT	Among a variety of human cell types targeted by DENV, monocytes, macrophages, and dendritic cells are members of innate immunity, capable of mounting rapid inflammatory responses.	This reference details the involvement of monocytes, macrophages, and dendritic cells in the response to Dengue virus infection.
PMID:24767772	SUPPORT	In the liver, DENV infection occurred in hepatocytes and Kupffer cells but not in endothelial cells. Evidence of dengue viral replication was observed in macrophage-like cells in spleens and lymph nodes.	This reference confirms that macrophages and other cell types are involved in the pathology of dengue virus infection.
PMID:23202502	SUPPORT	Following infection through the bite, cells of the hematopoietic lineage, like dendritic cells, are the first targets of dengue virus infection.	This reference explains that dendritic cells are among the first targets of Dengue virus infection.
PMID:25549406	SUPPORT	In a low percentage of patients, bleeding and loss of plasma (hemorrhage and plasma leakage) may occur. The hyper-permeability syndrome results in plasma leakage and, if the compensatory mechanisms of the body fail to control the plasma leakage or if medical intervention is late, shock may set in.	The reference supports the range of symptoms caused by dengue virus, from mild fever to severe hemorrhagic fever and shock.
PMID:28560571	SUPPORT	There are five dengue viruses, called serotypes (DEN-1, DEN-2, DEN-3, DEN-4, and DEN-5), which belong to the Flaviviridae family and are transmitted to humans through infected mosquito bites.	The reference confirms the classification of dengue virus serotypes.
PMID:23817881	SUPPORT	Dengue fever is one of the most common mosquito-borne viral illnesses in the world. It is usually transmitted to humans through the bite of an infected Aedes aegypti or Aedes albopictus mosquito. Dengue infections are caused by four antigenically distinct but closely related viruses (DEN 1–4).	The reference confirms the causative agents and transmission method of dengue fever.
PMID:30409217	SUPPORT	Among the numerous target cells for dengue virus in humans are monocytes, macrophages and mast cells which are important regulators of vascular integrity.	This reference supports the involvement of monocytes and macrophages in dengue infection.
PMID:25430853	PARTIAL	Primary target cells for DENV are dendritic cells and monocytes/macrophages that release various chemokines and cytokines upon infection. However, recent studies indicate that DENV also replicates in endothelial cells.	This reference partially supports the inclusion of endothelial cells in the list of cell types but acknowledges a debate on their role.

biological_processes

• Viral Infection

downstream

Viral Replication Immune System Activation

subtypes

DENV-1 DENV-2 DENV-3 DENV-4

1

name

Viral Replication

description

DENV replicates primarily in dendritic cells, monocytes, and macrophages, leading to the release of new virions and the spread of infection.

cell_types

• Dendritic Cell
• Monocyte
• Macrophage

evidence

reference	supports	snippet	explanation
PMID:17492597	SUPPORT	F4/80+CD11b+ macrophages and CD11c+ dendritic cells were demonstrated to be targets for DENV-2 infection in the spleen by flow cytometry directed to structural and nonstructural DENV proteins.	The literature confirms that macrophages and dendritic cells are targets for DENV infection, which contributes to the spread of the virus.
PMID:30409217	SUPPORT	Among the numerous target cells for dengue virus in humans are monocytes, macrophages and mast cells which are important regulators of vascular integrity and which undergo dramatic cellular responses after infection by dengue virus.	This reference explicitly mentions monocytes and macrophages as target cells for DENV infection, supporting the statement’s claim regarding cell types involved in DENV replication and spread.
PMID:25430853	SUPPORT	The primary target cells for DENV are dendritic cells and monocytes/macrophages that release various chemokines and cytokines upon infection.	This reference confirms that dendritic cells and monocytes/macrophages are primary targets of DENV infection, leading to cytokine release and immune system activation.
PMID:27348054	SUPPORT	Dengue virus ... targets dendritic cells during infection and leads to production of pro-inflammatory cytokines and chemokines.	This literature asserts that dendritic cells are targeted by DENV, resulting in the release of cytokines and chemokines, which aligns with the statement provided.
PMID:23830563	SUPPORT	Macrophages and dendritic cells (DCs) are at the front line of defence... viruses shunt intrinsic and innate recognition, enter immune cells, and spread from these cells throughout an organism.	The literature indicates the susceptibility of macrophages and DCs to viral infections including DENV, supporting the statement that these cells facilitate the spread of the virus.

downstream

Immune System Activation Cytokine Release Endothelial Dysfunction

2

name

Immune System Activation

description

DENV infection triggers a robust immune response, involving both innate and adaptive immunity.

cell_types

• Natural Killer Cell
• T Cell
• B Cell

evidence

reference	supports	snippet	explanation
PMID:29038620	PARTIAL	NK cells are one of the main effectors in early infection and may play an important role in dengue pathogenesis.	Discusses the role of NK cells in the immune response to DENV infection but does not mention T cells or B cells directly.
PMID:22216280	PARTIAL	Dengue induced massive early plasmablast formation, which correlated with the appearance of polyclonal, cross-reactive IgG for both primary and secondary infection.	Supports the involvement of B cells in the immune response but does not discuss NK cells or T cells directly.
PMID:37939119	PARTIAL	Dengue virus infection induces selective expansion of Vgamma4 and Vgamma6TCR gammadelta T cells in the small intestine and a cytokine storm driving vascular leakage in mice.	Supports the involvement of T cells and mentions cytokine storm but does not include NK cells or B cells.
PMID:29443656	PARTIAL	Understanding how the immune response to DENV is established and how it can resolve the infection or turn into an immunopathology is of great importance in DENV research.	Indicates the importance of the immune response and discusses cytokine storm and antibody-dependent enhancement.
PMID:35869167	NO_EVIDENCE	We observed that circulating ILC2 are permissive for dengue virus infection in vivo and in vitro, particularly when activated through prostaglandin D(2) (PGD(2)).	Focuses on ILC2 cells and does not provide evidence for NK cells, T cells, or B cells in the pathophysiology of dengue.
PMID:34202570	NO_EVIDENCE	DENV utilizes the secreted form of nonstructural protein 1 (sNS1) to counteract the MBL effects, thereby increasing viral survival and dissemination.	Discusses the complement system rather than NK cells, T cells, or B cells.
PMID:23202502	NO_EVIDENCE	Infection of DCs by dengue virus may induce apoptosis, impairing their ability to present antigens to T cells, and thereby contributing to dengue pathogenesis.	Focuses on dendritic cells and does not provide evidence for NK cells, T cells, or B cells in the pathophysiology of dengue.

downstream

Cytokine Release Antibody-Dependent Enhancement (ADE)

3

name

Cytokine Release

description

Infected cells and activated immune cells release a variety of cytokines and chemokines, contributing to the inflammatory response and disease pathogenesis.

evidence

reference	supports	snippet	explanation
PMID:34840991	SUPPORT	Interleukin- (IL-) 18, similar to IL-1beta, is a proinflammatory cytokine produced during inflammation following inflammasome activation. Inflammatory stimuli, including microbial infections, damage signals, and cytokines, all induce the production of IL-18.	This reference supports the involvement of IL-1beta in dengue pathophysiology by highlighting its role in the inflammatory response.
PMID:8813336	SUPPORT	Cytokines released by CD4+ T cells at the onset of an immune response are thought to be decisive for pathological or physiological consequences.	This reference supports the general role of cytokines, including TNF-alpha and IFN-gamma, in pathological immune responses.
PMID:31181280	SUPPORT	Chemokines, amongst inflammatory mediators, play a key role in dengue immunopathogenesis.	This reference supports the involvement of a variety of cytokines and chemokines in the inflammatory response during dengue infection.
PMID:29038620	SUPPORT	IL-12 related to NK cell activation were upregulated in mild DF cases. In vitro PBMC culture models show that DENV-stimulated and IFNalpha-stimulated NK cells were able to express TRAIL.	This reference supports the involvement of IL-12 and IFN-gamma in the immune response during dengue infection.
PMID:27008374	PARTIAL	Significantly higher IFN-gamma levels were found in patients with DHF than those with DF. However, significantly higher IL-12p70, TNF-alpha, and IL-6 levels were associated with DHF only in patients who were infected with DENV2 but not with DENV1.	This reference partially supports the statement, indicating differential cytokine production dependent on dengue virus serotype.
PMID:33634515	PARTIAL	Activation of innate cells and adaptive immune cells which include, B and T cells, macrophages or monocytes and dendritic cells also contribute to the dengue pathology.	This reference indicates that various immune cells, which produce different cytokines, are involved in dengue pathology but does not directly address all the cytokines listed.
PMID:25549406	NO_EVIDENCE	The aberrant immune response to infection is believed to result in a cytokine storm, defined as an imbalance between cytokines driving an inflammation (pro-inflammatory) and those silencing an inflammation (anti-inflammatory).	While this reference discusses a cytokine storm, it does not provide specific details on the individual cytokine contributions listed in the statement (e.g., TNF-alpha, IL-1beta, IL-6, IL-8, IFN-gamma).

biological_processes

• TNF-alpha Production
• IL-1beta Production
• IL-6 Production
• IL-8 Production
• IFN-gamma Production

downstream

Endothelial Dysfunction Vascular Leakage Coagulopathy

4

name

Antibody-Dependent Enhancement (ADE)

description

In secondary infections with a different DENV serotype, pre-existing antibodies can enhance viral entry into cells, leading to increased viral replication and more severe disease.

evidence

reference	supports	snippet	explanation
PMID:23471635	SUPPORT	Since the 1960s, numerous reports have identified a second heterologous dengue virus (DENV) infection as a principal risk factor for severe dengue disease (dengue hemorrhagic fever/dengue shock syndrome, DHF/DSS). Antibody-dependent enhancement (ADE) of dengue virus infection has been proposed as the early mechanism underlying DHF/DSS.	The literature states that secondary infections with a different DENV serotype increase the severity of dengue disease due to ADE.
PMID:34202570	SUPPORT	Usually, the primary infection is asymptomatic or causes mild dengue fever (DF), while secondary infections with a different serotype increase the risk of severe dengue disease (dengue hemorrhagic fever, DHF).	The literature confirms that secondary infections with a different serotype lead to severe disease.
PMID:26497532	SUPPORT	Known as antibody-dependent enhancement (ADE) of infection, the phenomenon occurs when virus-antibody immunocomplexes interact with cells bearing complement or Fc receptors, promoting internalization of the virus and increasing infection.	ADE is described as a process where pre-existing antibodies enhance viral infection through Fc receptor-mediated uptake.
PMID:27796143	SUPPORT	With growing evidence supporting the role of fragment crystalizable gamma receptors (FcgammaRs) in antibody-mediated neutralization or antibody-dependent enhancement (ADE) of dengue virus (DENV) infection, FcgammaR-expressing cells have been increasingly used for measuring neutralizing antibody responses.	Literature links ADE to Fc receptor-mediated mechanisms enhancing dengue severity.
PMID:30844538	SUPPORT	Sequential serotype infections can cause increased disease severity, likely due to antibody-dependent enhancement (ADE) of infection.	Secondary infections with different serotypes and their link to ADE and severe disease are confirmed.
PMID:3277268	SUPPORT	It occurs in infants... born to dengue-immune mothers and in children... experiencing infection with a second serotype. Subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings.	The text directly references ADE due to secondary infections leading to severe disease.
PMID:26104444	SUPPORT	When individuals are infected in the virtual absence of cross-protective dengue antibodies, the dengue vascular permeability syndrome (DVPS) may ensue. This occurs in around 2 to 4% of second heterotypic dengue infections.	The literature supports ADE involvement in severe dengue cases like DVPS due to secondary infections.
PMID:31736948	SUPPORT	In our cohort of Cambodian children, we observed...increased percentages of CD27(+)CD38(hi)CD138(+) plasma cells as early as 4 days post appearance of fever in patients with severe dengue compared to patients with mild disease.	The study indicates an immune response including ADE linked to severe dengue.
PMID:28339786	SUPPORT	Cross-reactive T cell responses induced by a primary dengue virus infection may contribute to increased disease severity following heterologous infections with a different virus serotype in a phenomenon known as the original antigenic sin.	The provided models support increased severity of secondary dengue due to immunological mechanisms, possibly involving ADE.

downstream

Severe Dengue Dengue Hemorrhagic Fever (DHF) Dengue Shock Syndrome (DSS)

mechanisms

Fc Receptor-Mediated Uptake Increased Viral Load

5

name

Endothelial Dysfunction

description

DENV infection and the resulting inflammatory response cause damage to the endothelial cells lining blood vessels, leading to increased permeability and fluid leakage.

evidence

reference	supports	snippet	explanation
PMID:25430853	SUPPORT	The primary target cells for DENV are dendritic cells and monocytes/macrophages that release various chemokines and cytokines upon infection, which can activate the endothelium and are thought to play a major role in DENV-induced vascular permeability.	The article indicates that DENV infection and the resulting inflammatory response cause endothelial dysfunction, leading to increased permeability and fluid leakage.
PMID:25549406	SUPPORT	High amounts of virus in the blood are believed to cause vascular fragility which, together with infection of endothelial cells and high levels of cytokines and other soluble mediators, may result in bleeding.	This supports the statement that DENV infection and the resulting inflammatory response cause endothelial damage, leading to increased permeability and fluid leakage.
PMID:19802578	SUPPORT	Despite considerable progress in understanding the immunological derangements associated with dengue, the pathogenic mechanisms underlying the change in vascular permeability remain unclear.	The focus on vascular leakage during dengue infections supports the statement that DENV infection causes endothelial dysfunction and increased permeability even though the exact mechanisms are not fully understood.
PMID:31181280	SUPPORT	Chemokines, amongst inflammatory mediators, play a key role in dengue immunopathogenesis... As chemokines exert an influence on various homeostatic and inflammatory processes, acting vigorously on vascular endothelial activation and cell migration...	The article confirms that chemokines and inflammatory mediators during DENV infection influence endothelial permeability, supporting the statement.
PMID:37939119	SUPPORT	Severe dengue is associated with a transient increase in vascular permeability. A cytokine storm is thought to be the cause of the vascular leakage.	This supports the statement by describing the role of cytokines in endothelial dysfunction and increased vascular permeability, leading to fluid leakage as part of the pathophysiology of DENV infection.

downstream

Vascular Leakage Plasma Leakage Hemoconcentration

mechanisms

Cytokine-Induced Damage Endothelial Cell Apoptosis

6

name

Coagulopathy

description

DENV infection can disrupt the balance of the coagulation system, leading to abnormalities in platelet function and an increased risk of bleeding.

evidence

reference	supports	snippet	explanation
PMID:25999666	SUPPORT	Thrombocytopenia and platelet dysfunction are common in both cases and are related to the clinical outcome. Different mechanisms have been hypothesized to explain DENV-associated thrombocytopenia, including the suppression of bone marrow and the peripheral destruction of platelets.	This reference provides support by explaining how DENV infection relates to thrombocytopenia and platelet dysfunction, which are associated with the clinical outcomes that include bleeding disorders.
PMID:31854052	SUPPORT	Dengue fever is endemic in Pakistan with seasonal rise in cases. Morbidities and mortalities are proportionately reported to be increasing and associated with disseminated intravascular coagulation resulting in haemorrhagic or thrombotic manifestations in patients having deranged coagulation profiles. [...] Our study showed a significant association of platelet counts, haemoglobin and haematocrit with bleeding.	This reference supports the statement by highlighting that DENV infection is associated with disseminated intravascular coagulation (DIC) and coagulopathy, leading to hemorrhagic manifestations such as petechiae, epistaxis, and gum bleeding.
PMID:2665014	SUPPORT	Dengue hemorrhagic fever is characterized by a sudden onset of fever that lasts for 2-7 days and then subsides, at which time hemorrhagic manifestations become evident. [...] hemorrhagic manifestations become evident. Sometimes there is an associated form of hypovolemic shock known as dengue shock syndrome.	This reference provides supporting evidence for the association between DENV infection and hemorrhagic manifestations, aligning with the described coagulopathy involving petechiae, epistaxis, and gum bleeding.
PMID:11549879	SUPPORT	Dengue virus infection induces transient immune aberrant activation of CD4/CD8 ratio inversion and cytokine overproduction, and infection of endothelial cells and hepatocytes causes apoptosis and dysfunction of these cells. [...] Dengue-virus-induced vasculopathy and coagulopathy must be involved in the pathogenesis of hemorrhage, and the imbalance between coagulation and fibrinolysis activation increases the likelihood of severe hemorrhage in DHF/DSS.	This reference underscores the involvement of coagulopathy and the imbalance between coagulation and fibrinolysis in the pathogenesis of bleeding in DENV infections.

downstream

Hemorrhagic Manifestations Petechiae Epistaxis Gum Bleeding

mechanisms

Thrombocytopenia Platelet Dysfunction Disseminated Intravascular Coagulation (DIC)

7

name

Organ Involvement

description

In severe cases, DENV infection can affect various organs, leading to complications and potential organ failure.

evidence

reference	supports	snippet	explanation
PMID:31815826	SUPPORT	Many children with dengue have liver involvement. Severe hepatitis in dengue is associated with significant organ dysfunction and poor outcome.	The study supports that severe cases of DENV infection can affect the liver, leading to hepatitis and potential organ failure.
PMID:26577971	SUPPORT	Dengue induced renal involvements vary from glomerulonephritis, nephrotic range proteinuria and AKI.	The literature indicates that severe DENV infection can lead to acute kidney injury (AKI) among other renal complications.
PMID:1509881	SUPPORT	Dengue encephalopathy with CNS involvement... laboratory examination showed an unusually high increase of serum transaminases, hyponatremia, and hypoxia.	This reference notes the occurrence of encephalitis and neurological complications in severe DENV cases.
PMID:35139081	SUPPORT	The most common neurological manifestations of DENV are encephalitis and encephalopathy, and movement disorders such as parkinsonism have been observed.	This study supports that DENV infection can cause neurological complications, including encephalitis and other CNS syndromes.
PMID:28034555	SUPPORT	In the BALB/c mouse model, typical liver tissues showed regular hepatocyte architecture, with normal endothelial cells surrounding sinusoid capillary. Based on histopathological observations, the liver sections of BALB/c mice infected by DENV-2 exhibited a loss of cell integrity, with a widening of the sinusoidal spaces.	This research indicates liver tissue damage and loss of cell integrity, suggesting that severe DENV infection can significantly affect liver function.

locations

• Liver
• Kidneys
• Brain

downstream

Hepatitis Acute Kidney Injury Encephalitis Neurological Complications

0

category

Systemic

name

Fever

frequency

VERY_FREQUENT

diagnostic

True

evidence

reference	supports	snippet	explanation
PMID:29147722	SUPPORT	Dengue infections are among the most frequent causes of febrile disease in tropical climates.	The abstract indicates that fever is a very frequent symptom of dengue infections.
PMID:19925879	SUPPORT	Severe dengue has been recognised for more than 200 years, but attempts to define, categorize and explain the condition have hotly contested for more than four decades.	The mention of severe dengue over a historical period implies systemic symptoms, including frequent fever.
PMID:29419375	SUPPORT	Dengue fever is an acute febrile illness with a duration of 2-12 days.	The abstract clearly states that dengue fever is characterized as an acute febrile illness.
PMID:33190156	SUPPORT	Thrombocytopenia was present in 69% of cases and fever was present in 99.1% of cases.	The very high percentage of fever in dengue cases supports the statement that fever is a very frequent systemic diagnostic phenotype of dengue.

notes

Sudden onset, often high-grade

1

category

Musculoskeletal

name

Severe Muscle and Joint Pain

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:25426178	SUPPORT	Dengue fever, also known as breakbone fever, is a mosquito-borne infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles.	The reference states that muscle and joint pains are symptoms of dengue fever, which supports the statement that severe muscle and joint pain is a frequent phenotype of dengue.
PMID:36647994	PARTIAL	We report a patient of dengue, with severe body ache and myalgia... This suggests rhabdomyolysis occurred which led to acute kidney injury.	While this reference describes severe body ache and myalgia in a dengue patient, it does not explicitly state that severe muscle and joint pain is a frequent phenotype but does indicate its occurrence.
PMID:35578548	PARTIAL	Dengue fever is a self-limiting, acute febrile illness caused by an arbovirus. This infection may be asymptomatic or symptomatic with its potential life-threatening form as DHF/DSS.	The reference notes that dengue can lead to severe conditions but because it focuses on pediatric patients, it doesn't specifically confirm the frequent occurrence of severe muscle and joint pain.

notes

Referred to as "breakbone fever"

2

category

Gastrointestinal

name

Vomiting

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:19451025	SUPPORT	Frequent vomiting (> or =3 times a day), marked lymphopenia, thrombocytopenia, and elevated liver enzymes on day 3 after onset of fever were significantly associated with plasma leakage and gallbladder thickening.	The literature supports that vomiting is a frequent manifestation in severe dengue.
PMID:36905276	SUPPORT	Dengue hemorrhagic fever is a syndrome caused by the dengue virus and primarily affects children below ten years of age and is spread by the Aedes aegypti mosquito. Gastrointestinal tract infection is a bacterial and parasitic infection that leads to gastrointestinal tract inflammation.	Dengue hemorrhagic fever includes gastrointestinal manifestations, which include vomiting as a common symptom.
PMID:27812667	SUPPORT	Abdominal pain or tenderness and persistent vomiting (warning signs) are present in the majority of cases with severe dengue prior to clinical deterioration.	Persistent vomiting is mentioned as a common warning sign in severe dengue cases.
PMID:33190156	SUPPORT	Gastrointestinal (GI) features, including anorexia and/or vomiting (69.4%), abdominal pain (39.8%) and diarrhoea (25.6%), were more prevalent than typical rash and pain symptoms.	Vomiting is listed among the frequent gastrointestinal symptoms in dengue cases during the 2019 outbreak in Bangladesh.

3

category

Gastrointestinal

name

Diarrhea

frequency

OCCASIONAL

evidence

reference	supports	snippet	explanation
PMID:33768451	SUPPORT	Patients with dengue fever usually present with fever and rash, but non-specific symptoms such as headache, myalgia, arthralgia, and digestive symptoms are sometimes seen.	The case report mentions diarrhea as one of the digestive symptoms in a patient with dengue fever.
PMID:34715835	SUPPORT	Gastrointestinal symptoms were the most common associated feature, including mostly vomiting (80.4%), decreased appetite (79.5%), constipation (72.7%), and abdominal pain (64.9%).	This study mentions multiple gastrointestinal symptoms, which indicates a notable frequency. While diarrhea itself is not mentioned explicitly in the abstract, the predominance of gastrointestinal symptoms supports the notion that diarrhea may occasionally occur.
PMID:38309298	SUPPORT	Dengue is a vector-borne disease that has a significant impact on global public health. The disease is widespread across the world, posing a risk to nearly half of the world's population.	While this reference provides a general overview of dengue, it corroborates the widespread occurrence of the disease and the variability of its symptoms, hence supporting the occasional appearance of gastrointestinal symptoms like diarrhea.

4

category

Hemorrhagic

name

Petechiae

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:25097856	SUPPORT	The meta-analysis suggests that bleeding (hematemesis/melena), vomiting/nausea, abdominal pain, skin rashes, and hepatomegaly may predict the development of SDD in patients with DF.	While the meta-analysis does not directly mention petechiae, skin rashes, which can include petechiae, are implicated as a predictive symptom for severe dengue disease, suggesting a frequent occurrence.
PMID:16831202	PARTIAL	DF and DHF can be caused by both primary and secondary infection by any of the four serotypes of the dengue virus.	This reference discusses hemorrhagic features in dengue fever and dengue hemorrhagic fever without specifically mentioning petechiae or their frequency.
PMID:26506731	PARTIAL	Laboratory evidences of disseminated intravascular coagulation (DIC) are also demonstrated in all degrees of severity in dengue patients.	While petechiae are not explicitly mentioned, the context of DIC and bleeding disorders could involve petechiae, but it is not clearly stated.
PMID:19893893	PARTIAL	Most of the dengue fever cases are benign, but some cases develop into a severe and possibly lethal vasculopathy, known as dengue hemorrhagic fever.	Early symptoms of severe dengue include vasculopathy, which may encompass manifestations like petechiae, but it is not specifically detailed.

notes

Small red or purple spots on the skin

5

category

Hemorrhagic

name

Epistaxis

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:24595236	PARTIAL	Abdominal pain was seen in 35% DHF patients followed by nausea in 28.3%, epistaxis in 25% and rash in 20% patients (p<0.05).	While epistaxis is reported as a symptom in dengue hemorrhagic fever, it is indicated as occurring in 25% of DHF patients, which may not be considered 'frequent' when compared to other symptoms.

notes

Nosebleeds

6

category

Hemorrhagic

name

Gum Bleeding

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:22363829	NO_EVIDENCE	Clinical history was recorded and patients were placed on fluid and haematological support. Diagnosis was established by Polymerase Chain Reaction (PCR) for dengue virus or detection of dengue virus specific IgM and IgG.	The reference provides clinical history and examination details, but does not mention gum bleeding specifically.
PMID:18381480	NO_EVIDENCE	Of 309 adults with DHF, 10 fatal patients and 299 survivors (controls) were retrospectively analyzed... regarding causes of fatality, massive gastrointestinal (GI) bleeding was found in 4 patients, dengue shock syndrome (DSS) alone in 2; DSS/subarachnoid hemorrhage.	The reference discusses various severe outcomes and bleeding disorders in dengue hemorrhagic fever, but gum bleeding is not specifically mentioned.
PMID:18541082	PARTIAL	All the patients presented with fever followed by generalized morbiliform rash (81.73%), vomiting (79.8%), abdominal pain (65.38%), backache (62.5%), depression (60.6%) and mucosal bleeding manifestations (34.6%).	Mucosal bleeding manifestations are mentioned, which can include gum bleeding, but the reference does not specify the frequency or focus solely on gum bleeding.

7

category

Neurologic

name

Severe Headache

frequency

FREQUENT

diagnostic

True

evidence

reference	supports	snippet	explanation
PMID:36428031	PARTIAL	Clinical signs and symptoms of dengue include a high fever (40 degrees C/104 degrees F) accompanied by two of the following symptoms during the febrile phase: severe headache, pain behind the eyes...	The statement that severe headache, often retro-orbital, is a phenotype of dengue is supported, but the literature does not indicate that this occurs with a frequency of 'FREQUENT.'
PMID:19836681	PARTIAL	Clinically, the onset is abrupt with frontal headache, retro-orbital pain, myalgia, joint pain, prostration and, in many cases, a macular rash usually sparing the face and extremities.	This source supports that severe headache (including retro-orbital pain) is a symptom of dengue, but does not confirm the frequency as 'FREQUENT.'

notes

Often retro-orbital (behind the eyes)

8

category

Systemic

name

Fatigue

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:33099653	SUPPORT	This study aimed to evaluate the prevalence and associations of post-infection fatigue in dengue patients compared with non-dengue fever patients... Of 260 patients, 158 had dengue and, of these, 51 (32%) had fatigue at 2 months.	The study reports that a significant proportion (32%) of dengue patients experience fatigue post-infection, which supports the claim that fatigue is a frequently observed systemic phenotype in dengue.
PMID:26976885	SUPPORT	Some patients present persistent symptoms, including fatigue and depression, as acknowledged by the World Health Organization.	The reference highlights that persistent symptoms such as fatigue are recognized in dengue patients, reinforcing the statement that fatigue is a frequent systemic phenotype associated with the disease.

name	presence	evidence	notes
Dengue NS1 Antigen	Positive	TRUNCATED	Early marker of infection
Dengue IgM Antibodies	Positive	TRUNCATED	Appears ~4-5 days after onset of symptoms
Dengue IgG Antibodies	Positive	TRUNCATED	Appears later and persists, indicative of secondary infection
Platelet Count	Decreased	TRUNCATED	Thrombocytopenia is common in dengue
Hematocrit	Elevated	TRUNCATED	Indicator of plasma leakage

0

name

Supportive Care

description

Includes fluid management, fever control, and monitoring for complications

evidence

reference	supports	snippet	explanation
PMID:20586568	SUPPORT	Focusing on treatment, symptomatic and supportive treatment is the main therapeutic approach.	The literature specifies that supportive treatment is a main approach for dengue treatment.
PMID:28403440	SUPPORT	In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding blood component transfusion to standard intravenous fluids; adding corticosteroids or intravenous immunoglobulin to standard intravenous fluids; and crystalloids versus colloids.	This reference discusses various supportive care interventions including fluid management for dengue fever.
PMID:26506738	SUPPORT	Close monitoring, early detection and prompt management are the keys in successful treatment. In a hemodynamically unstable patient, crystalloid is the fluid of choice in initial management.	The literature mentions fluid management and the importance of monitoring, which aligns with the statement.
PMID:30626246	SUPPORT	Comprehensive treatment including fluids resuscitation and uterine inhibition in pregnant women with severe dengue in preterm or term labor could be useful.	This reference discusses fluid resuscitation as a part of supportive care for severe dengue.
PMID:31701854	SUPPORT	Dengue guidelines for diagnosis, treatment, prevention, and control (WHO, 2011) recommend acetaminophen and isotonic fluid for patients with dengue infection.	The literature mentions acetaminophen for fever control and isotonic fluids for dengue treatment.
PMID:26915248	SUPPORT	Effective antiviral drug to dengue virus is not known, and a basic supportive therapy, including fluid therapy, would be a standard of care and prevent serious type of dengue virus infections.	The literature highlights supportive therapy, including fluid therapy, as a standard of care.

1

name

Platelet Transfusions

description

May be required in cases of severe thrombocytopenia

evidence

reference	supports	snippet	explanation
PMID:22294065	REFUTE	Prophylactic platelet transfusion in DF is neither standardized nor supported by clinical evidence. We conclude that risks, costs and poor resource utilization associated with prophylactic platelet transfusion in DF far outweigh any potential hematological benefit, and as such, should not constitute routine clinical practice.	The literature states that prophylactic platelet transfusion in dengue fever is not supported by clinical evidence and should not be routine practice, thus refuting the necessity of platelet transfusions in cases of severe thrombocytopenia.
PMID:29950498	PARTIAL	A 30-year-old woman with severe dengue...refractory to multiple platelet transfusions...a working diagnosis of idiopathic thrombocytopenic purpura was made, for which intravenous immunoglobulin (IVIg) was administered that led to a rapid rise in the platelet count.	This case report suggests that platelet transfusions might be used; however, it also indicates that the transfusions were ineffective, and IVIg was required to improve the patient's condition.
PMID:30626246	PARTIAL	Platelets transfusions were performed if the count was less than 10,000 cells/ml and active bleeding was present.	This study reported platelet transfusions in cases of very low platelet counts and active bleeding, suggesting that such treatment may be considered in certain severe cases but not as a common practice.

2

name

Pain Relief

description

Acetaminophen is preferred; NSAIDs should be avoided due to bleeding risk

evidence

reference	supports	snippet	explanation
PMID:30575425	SUPPORT	Consensus guidelines for treatment of dengue fever from the World Health Organization and US Centers for Disease Control recommend acetaminophen to manage pain and fever but contraindicate nonsteroidal anti-inflammatory agents (NSAIDs) because of potentially increased bleeding risk, with thrombocytopenia as a complication.	The reference clearly states that consensus guidelines recommend acetaminophen for managing pain and fever in dengue patients and contraindicate the use of NSAIDs due to increased bleeding risk.
PMID:24494608	PARTIAL	In general, acetaminophen is the least potent, while NSAIDs and opioids offer stronger analgesic effects. At the same time, acetaminophen use can cause acute liver failure, and NSAIDs are associated with serious complications impacting the gastrointestinal, cardiovascular, and renal systems.	The reference discusses the efficacy and risks of acetaminophen and NSAIDs, mentioning that NSAIDs have serious complications, which aligns with the bleeding risk. However, it does not specifically address dengue, making it partially supportive.
PMID:25426178	SUPPORT	Treatment of acute dengue fever is supportive, with either oral or intravenous rehydration for mild or moderate disease and use of intravenous fluids and blood transfusion for more severe cases.	The reference implies supportive care as the treatment for acute dengue fever without specifically mentioning acetaminophen or NSAIDs, yet it aligns with the general avoidant approach toward invasive treatments, indirectly supporting the recommendation.

3

name

Vector Control

description

Measures to reduce mosquito populations and prevent bites

evidence

reference	supports	snippet	explanation
PMID:18291003	SUPPORT	Insecticide-treated bednets had an immediate effect on dengue vector populations after their introduction, and over the next 5-12 months, the presence of ITNs may have continued to affect vector populations and dengue transmission.	The study supports the idea that measures to reduce mosquito populations, such as insecticide-treated bednets, are effective in controlling dengue transmission.
PMID:35598649	SUPPORT	Experimental studies of environmental management interventions aimed at vector control were included... there was a statistically significant reduction of the pupae indices related to the elimination of small containers, manipulation of large tanks and cleaning outdoor spaces.	Environmental interventions aimed at vector control significantly reduce mosquito populations, supporting vector control as a measure to treat dengue.
PMID:32853197	SUPPORT	The Singapore dengue control programme succeeded in reducing the dengue force of infection... Key to this success is consideration of dengue as an environmental disease, with a strong focus on source reduction and other environmental management methods as the dominant vector control strategy.	The Singapore dengue control programme's success in reducing dengue through vector control methods aligns with the statement that such measures are effective treatments.

name	evidence
Dengue Virus	TRUNCATED

name	evidence	notes	effect
Aedes Mosquito Exposure	TRUNCATED	None	Vector for transmission
Tropical and Subtropical Regions	TRUNCATED	Endemic areas where transmission is most common	None

0

name

PCR for Dengue Virus RNA

presence

Positive

evidence

reference	supports	snippet	explanation
PMID:12174774	SUPPORT	Viral detection by RT-PCR was evaluated using the sera of 253 patients with clinical diagnosis of dengue... We show with this study that RT-PCR is more sensitive than virus isolation on clinical samples and allows for a rapid detection of dengue infections	RT-PCR is highlighted as effective for the detection of dengue virus, confirming active infection.
PMID:18541082	SUPPORT	Diagnosis was established by Polymerase Chain Reaction (PCR) for dengue virus or detection of dengue virus specific IgM and IgG.	Confirms the use of PCR to establish a dengue diagnosis.
PMID:27955749	SUPPORT	The present study was conducted to evaluate the overall positivity of NS1 antigen detection ELISA and its comparison with viral RNA detection via real time PCR.	The study acknowledges the detection of dengue virus RNA via real-time PCR as one of the diagnostic methods.
PMID:37545366	SUPPORT	The existing strategies for detecting dengue infection mainly employ serological immunoassays and a real time PCR technique.	Indicates that PCR is one of the main strategies for detecting dengue infection.
PMID:15737419	SUPPORT	Our results demonstrated that dengue-RNA was stable in filter paper for 9 weeks at all tested temperatures... PCR results showed a 100% specificity and 93% sensitivity for dried blood samples.	Highlights the use of PCR for detecting dengue virus RNA, confirming active infection.
PMID:33475609	SUPPORT	Both the detection and serotyping of dengue samples were performed using real-time PCR on Rotor Gene Q.	Discusses the detection of dengue virus RNA via real-time PCR.
PMID:33090520	SUPPORT	We evaluated DENV viremia in 8475 blood donations assembled in minipools for the presence of DENV RNA.	The study supports RNA detection as a method for identifying dengue infections.

notes

Confirms active infection

1

name

NS1 Antigen Test

presence

Positive

evidence

reference	supports	snippet	explanation
PMID:21706934	SUPPORT	The combination of the NS1 antigen and antibody tests could increase the diagnostic efficiency for early diagnosis of dengue infection.	The study reveals that the NS1 antigen test can complement current antibody tests to improve early diagnosis of dengue.
PMID:35435434	SUPPORT	Implementing a laboratory-based real-time antigen (NS1) surveillance system for notification coupled with a rapid preventive response...	The system based on NS1 antigen detection improves the timeliness of dengue diagnosis and response.
PMID:30466902	SUPPORT	It was concluded that the dengue infection can be early diagnosed... with the detection of dengue-specific NS1 antigen along with antibodies such as IgG and IgM.	The study supports the use of NS1 antigen in combination with antibodies for early diagnosis of dengue.
PMID:25689887	SUPPORT	the recombinant NS1 protein presents an antigen potential for development of dengue immunodiagnostic kits.	The heterologous expression of NS1 protein is indicated for its diagnostic potential in early dengue diagnosis.
PMID:36512513	SUPPORT	With sandwich SELFIA, we could efficiently detect all four dengue non-structural protein (NS1) serotypes... which will assist in the development of a highly sensitive and specific detection platform for dengue screening.	Superior sensitivity of SELFIA for NS1 antigen detection underlines its importance in early dengue detection.

notes

Useful in early diagnosis

2

name

Serological Testing for IgM/IgG Antibodies

presence

Positive

evidence

reference	supports	snippet	explanation
PMID:25008820	SUPPORT	Dengue-specific NS1 antigen and IgM and IgG antibodies when conducted simultaneously would be able to diagnose confirmed dengue cases categorising primary and secondary dengue along with the duration of the disease, whether early or prolonged.	The article discusses the use of serological tests including IgM and IgG antibodies for the diagnosis of dengue, categorizing it into primary and secondary infections.
PMID:36311743	SUPPORT	We observed a significant difference in anti-aGal IgG and IgG1 levels among dengue severity classifications. Furthermore, a significant positive correlation was observed between the anti-aGal IgG and the number of days with dengue symptoms in patients.	The article evaluates different anti-aGal antibodies including IgM and IgG in people exposed to DENV, indicating their diagnostic relevance.
PMID:32896661	SUPPORT	Primary infections were anti-dengue IgG enzyme-linked immunosorbent assay (ELISA) negative on both day of hospital entry (day 0) and day two or three of hospitalization (day 2 or 3) with a positive anti-dengue IgM on either day 0 or day 2 or 3 hospitalization. The secondary infections were anti-dengue IgG ELISA positive on both day 0 and day 2 or 3 with positive anti-dengue IgM ELISA on either day 0 or day 2 or 3.	The study distinguishes between primary and secondary dengue infections using IgM and IgG antibodies assays.
PMID:29471783	SUPPORT	Dengue IgG antibodies were detectable in samples from most individuals three years after infection. Dengue symptomatic persons had a higher dengue IgG prevalence compared to asymptomatic individuals.	This study supports the presence of dengue-specific IgG antibodies for diagnosing past infections.
PMID:32832567	SUPPORT	Dengue-specific IgM and IgG (secondary response) antibodies in the patient's antisera were tested with the peptides using ELISA protocol.	The research emphasizes the use of IgM and IgG antibodies for dengue diagnosis.
PMID:19026621	SUPPORT	Single and paired positive and negative specimens obtained from various dengue-high prevalent regions and from dengue-free areas were used. All samples were tested by the ImmunoComb Dengue BiSpot kit along with the gold standard assays of Hemagglutination-inhibition (HAI) and MAC ELISA.	The article demonstrates the use of a serological assay that tests for both IgM and IgG antibodies for the diagnosis of dengue.
PMID:35604130	SUPPORT	The OnSite dengue IgG RDT showed minimal to no cross-reactivity to related flaviviruses.	The article confirms the use of IgG rapid diagnostic tests for previous dengue infection, supporting the statement about serological testing.

notes

IgM for recent infection, IgG for past or secondary infection