Dengue hemorrhagic fever

Summary

Dengue hemorrhagic fever (MONDO:0005358) is a disease with 2 cohort genes (4 GWAS associations across 1 studies) and 38 clinical trials. Top therapeutic interventions include ivermectin, ribavirin, and tetanus toxoid.

At a glance

• Cohort genes: 2
• GWAS associations: 4
• Clinical trials: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Dengue hemorrhagic fever
Mondo ID	MONDO:0005358
EFO	EFO:0004227
DOID	DOID:12206
ICD-10-CM	A91
NCIT	C34683
SNOMED CT	20927009
UMLS	C0019100
MedGen	5506
GARD	0024174
Is cancer (heuristic)	no

Data availability: 4 GWAS associations (1 study).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of primarily extrinsic mechanism › infectious disease › viral infectious disease › primary viral infectious disease › Flaviviridae infectious disease › dengue disease › Dengue hemorrhagic fever

Related subtypes (1): asymptomatic dengue

Subtypes (1): dengue shock syndrome

Genetics & variants

GWAS landscape

4 GWAS associations across 1 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs3132468	4e-11	MICB	?	1.34
rs3765524	3e-10	PLCE1	?	1.25
rs6500818	2e-07	RBFOX1	?	1.31
rs10104997	9e-07	RP1	?	1.2

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST001278	Khor CC	2011	2,008	2,018	Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	4
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	2
missense_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs3132468	6	31507709	C>A,G,T	0.13	intron_variant	MICB	4e-11	Tier 4: intronic/intergenic
rs3765524	10	94298541	C>A,T	0.3	missense_variant	PLCE1	3e-10	Tier 1: coding
rs6500818	16	6767374	C>T	0.05	intron_variant	RBFOX1	2e-07	Tier 4: intronic/intergenic
rs10104997	8	54527508	C>T	0.05	intergenic_variant	RP1	9e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLCE1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLCE1	HGNC:17175	ENSG00000138193	Q9P212	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	gwas
MICB	HGNC:7091	ENSG00000204516	Q29980	MHC class I polypeptide-related sequence B	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLCE1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
MICB	MHC class I polypeptide-related sequence B	Widely expressed membrane-bound protein which acts as a ligand to stimulate an activating receptor KLRK1/NKG2D, expressed on the surface of essentially all human natural killer (NK), gammadelta T and CD8+ alphabeta T-cells.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLCE1	Enzyme (other)	yes	3.1.4.11	C2_dom, RA_dom, PLipase_C_PInositol-sp_X_dom
MICB	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig-like_dom, MHC_I-like_Ag-recog

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephric glomerulus	1
renal glomerulus	1
ventricular zone	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLCE1	271	broad	marker	renal glomerulus, metanephric glomerulus, ventricular zone
MICB	133	ubiquitous	yes	granulocyte, leukocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLCE1	1,560
MICB	126

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLCE1	Q9P212	3
MICB	Q29980	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.019	PLCE1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.046	MICB
Adaptive Immune System	1	14.9×	0.088	MICB
Immune System	1	6.5×	0.148	MICB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
immune response-activating cell surface receptor signaling pathway	1	2808.7×	0.005	MICB
negative regulation of defense response to virus by host	1	2106.5×	0.005	MICB
gamma-delta T cell activation	1	1053.2×	0.006	MICB
diacylglycerol biosynthetic process	1	936.2×	0.006	PLCE1
glomerulus development	1	648.1×	0.007	PLCE1
phosphatidylinositol metabolic process	1	443.5×	0.008	PLCE1
phosphatidylinositol-mediated signaling	1	351.1×	0.009	PLCE1
positive regulation of lamellipodium assembly	1	300.9×	0.009	PLCE1
response to heat	1	210.7×	0.011	MICB
response to retinoic acid	1	191.5×	0.011	MICB
release of sequestered calcium ion into cytosol	1	172.0×	0.012	PLCE1
killing of cells of another organism	1	135.9×	0.013	MICB
epidermal growth factor receptor signaling pathway	1	123.9×	0.013	PLCE1
lipid catabolic process	1	122.1×	0.013	PLCE1
Ras protein signal transduction	1	102.8×	0.014	PLCE1
calcium-mediated signaling	1	91.6×	0.015	PLCE1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.019	PLCE1
response to oxidative stress	1	65.3×	0.019	MICB
adaptive immune response	1	42.1×	0.027	MICB
immune response	1	23.5×	0.046	MICB
intracellular signal transduction	1	19.1×	0.054	PLCE1
G protein-coupled receptor signaling pathway	1	18.1×	0.054	PLCE1

Therapeutics

Drugs indicated for this disease

0 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Diphtheria Toxoid	Phase 3 (in late-stage trials)
Pertussis Vaccine Adsorbed	Phase 3 (in late-stage trials)
Tetanus Toxoid	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Anakinra, Ivermectin, Montelukast, Sodium Chloride.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLCE1	0	0
MICB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCE1	3.1.4.11	phosphoinositide phospholipase C

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	PLCE1, MICB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PLCE1	0	—
MICB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 38.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	19
PHASE3	10
Not specified	7
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01134263	PHASE3	COMPLETED	Study of a Tetravalent Dengue Vaccine in Healthy Adults in Australia
NCT01254422	PHASE3	COMPLETED	Study of a Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 11 Years in Malaysia
NCT01373281	PHASE3	COMPLETED	Study of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia
NCT01374516	PHASE3	COMPLETED	Study of a Novel Tetravalent Dengue Vaccine in Healthy Children and Adolescents Aged 9 to 16 Years in Latin America
NCT01411241	PHASE3	COMPLETED	Study of a Booster Injection of Pentaxim™ Vaccine Administered With Dengue Vaccine in Healthy Toddlers
NCT01436396	PHASE3	COMPLETED	Study of Yellow Fever Vaccine Administered With Tetravalent Dengue Vaccine in Healthy Toddlers
NCT02979535	PHASE3	COMPLETED	Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Cervarix®
NCT02992418	PHASE3	TERMINATED	Study of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Adacel® in Healthy Subjects
NCT02993757	PHASE3	COMPLETED	Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Gardasil®
NCT06744777	PHASE3	COMPLETED	The Comparative Efficacy of Standard Treatment Plus Ribavirin vs Standard Treatment Alone in Preventing Clinically Significant Hemorrhage in Patients With Dengue Fever
NCT00468858	PHASE2	COMPLETED	A Study of Two Doses of WRAIR Dengue Vaccine Administered Six Months Apart to Healthy Adults and Children
NCT00617344	PHASE2	COMPLETED	Immunogenicity and Safety of Three Formulations of Dengue Vaccines in Healthy Adults Aged 18 to 45 Years in the US
NCT00730288	PHASE2	COMPLETED	Study of ChimeriVax™ Dengue Tetravalent Vaccine in Adult Subjects
NCT00740155	PHASE2	COMPLETED	Safety and Immunogenicity of Formulations of Dengue Vaccines in Healthy Flavivirus-Naïve Adults
NCT00788151	PHASE2	COMPLETED	Study of ChimeriVax™ Tetravalent Dengue Vaccine in Healthy Peruvian Children Aged 2 to 11 Years
NCT00842530	PHASE2	COMPLETED	Efficacy and Safety of Dengue Vaccine in Healthy Children
NCT00875524	PHASE2	COMPLETED	Study of ChimeriVax™ Tetravalent Dengue Vaccine in Healthy Subjects
NCT00880893	PHASE2	COMPLETED	Study of Sanofi Pasteur’s CYD Dengue Vaccine in Healthy Subjects in Singapore
NCT00993447	PHASE2	COMPLETED	Immunogenicity and Safety of Sanofi Pasteur’s CYD Dengue Vaccine in Healthy Children and Adolescents in Latin America
NCT01064141	PHASE2	COMPLETED	A Study of Dengue Vaccine in Healthy Toddlers Aged 12 to 15 Months in the Philippines
NCT01187433	PHASE2	COMPLETED	Study of CYD Dengue Vaccine in Healthy Children and Adolescents in South America
NCT01488890	PHASE2	COMPLETED	Immune Response to Different Schedules of a Tetravalent Dengue Vaccine Given With or Without Yellow Fever Vaccine
NCT01550289	PHASE2	COMPLETED	Study of a Tetravalent Dengue Vaccine in Healthy Adult Subjects Aged 18 to 45 Years in India
NCT01943825	PHASE2	COMPLETED	Immunologic Mechanisms of Immune Interference and/or Cross-Neutralizing Immunity After CYD Tetravalent Dengue Vaccine
NCT02623725	PHASE2	COMPLETED	Study of a Booster Dose of a Tetravalent Dengue Vaccine in Subjects Who Previously Completed the 3-dose Schedule
NCT02628444	PHASE2	COMPLETED	Immunogenicity and Safety of Different Vaccination Schedules of Tetravalent Dengue Vaccine in Healthy Subjects 9 to 50 Years of Age
NCT02741128	PHASE2	COMPLETED	Safety and Immunogenicity of a Tetravalent Dengue Vaccine in HIV-Positive Adults
NCT02824198	PHASE2	COMPLETED	Immunogenicity and Safety of a Tetravalent Dengue Vaccine Booster Injection in Subjects Who Previously Completed a 3-dose Schedule
NCT03432442	PHASE2	COMPLETED	Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients
NCT00458120	PHASE1	COMPLETED	Safety of and Immune Response to Two Different Dengue Virus Vaccines in Individuals Previously Immunized Against Dengue Virus
NCT00919178	PHASE1	COMPLETED	Safety of and Immune Response to DEN4 Vaccine Component Candidate for Dengue Virus
NCT06642493	Not specified	ACTIVE_NOT_RECRUITING	Efficacy of Fresh Frozen Plasma (FFP) in Treating Thrombocytopenia in Dengue Patients
NCT07602920	Not specified	NOT_YET_RECRUITING	Gut Leakage’ in Dengue
NCT01477671	Not specified	COMPLETED	Prospective Dengue Seroprevalence Study in 5 to 10 Year-old Children
NCT01983553	Not specified	COMPLETED	Long-Term Study of Hospitalized Dengue & Safety in Thai Children Included in a Tetravalent Dengue Vaccine Efficacy Study
NCT02948933	Not specified	COMPLETED	Cohort Event Monitoring for Dengvaxia®, CYD-TDV Dengue Vaccine
NCT04048837	Not specified	COMPLETED	Prospective Study for the Evaluation of Dengue Prognostic Biomarkers in Singapore
NCT07205848	Not specified	COMPLETED	Evaluating Public Awareness and Preventive Actions for Dengue Fever in Sudan Amidst Ongoing Crises

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IVERMECTIN	4	1
RIBAVIRIN	4	1
TETANUS TOXOID	4	1
YELLOW FEVER VACCINE	3	1
CHEMBL263291	0	1
CHEMBL4082099	0	1
CHEMBL4788951	0	1