International Registry of Dengue Infection in Congenital Bleeding Disorders (DengueCBDR)

Background:

The global incidence of dengue has markedly increased over the past two decades, posing a substantial public health challenge. From 2000 to 2019, the World Health Organization (WHO) documented a tenfold surge in reported cases worldwide, increasing from 500,000 to 5.2 million, with reported instances spreading across 129 countries.

Dengue fever, a viral infection transmitted by Aedes mosquitoes, is a major health issue in tropical and subtropical regions. Dengue virus (DENV) causes systemic infection in 25% of infected individuals. The symptoms include fever, rash, and, in severe cases, hemorrhagic manifestations. Around 20-30% of symptomatic patients developed Dengue Hemorrhagic Fever (DHF), which leads to increased vascular permeability, thrombocytopenia, and coagulopathy, which are known to increase the risk of bleeding. The most serious presentation is Dengue Shock Syndrome (DSS), which can cause substantial morbidity and mortality, particularly in vulnerable populations. One such vulnerable group is individuals with congenital bleeding disorders (CBDS), such as hemophilia, von Willebrand disease (vWD), platelet disorders, and other coagulation factor deficiencies.

Individuals with CBD have an inherent predisposition to bleeding complications, which could be exacerbated by the platelet dysfunction and vascular leakage associated with dengue infection. In addition, the interaction between the pathophysiology of dengue and bleeding disorders creates significant challenges in the diagnosis, management, and treatment of these individuals. Despite the importance of this issue, there is a lack of comprehensive registries or data-collection systems that track the incidence and outcomes of dengue infection among individuals with congenital bleeding disorders.

Dengue infection in patients with hemophilia was reported. A total of six patients in a cohort of 843 patients had underlying hemophilia; five with hemophilia A and one with hemophilia B. Replacement therapy was higher in patients with bleeding disorders with dengue, compared to other febrile illnesses. All of them had bleeding during dengue infection. The mortality rate was 16%. In addition, severe hemophilia patients presented with bleeding during the febrile stage while the platelet count was normal, then required factor replacement therapy. However, there is limited data on bleeding severity, replacement or prophylaxis protocols, and outcomes for this population.

This research aims to establish a registry of dengue infections among individuals with CBDs to understand bleeding complications, management, and outcomes of these patients. The registry will gather data on the clinical course, complications, management strategies, and outcomes of dengue infection in this population.

Primary Objective:

• To develop a registry of dengue infections in individuals with CBDs.
• To evaluate the bleeding complications, replacement therapy and outcomes of dengue infections in individuals with CBDs.

Secondary Objectives (if any):

To compare bleeding severity and outcome among types of bleeding disorders

Study design/methodology:

An international multicenter, retrospective, from 1 January 2015 to 31 December 2025, and prospective cohort study, involving hospitals that treat individuals with CBDs with dengue infection. The registry format will be provided using a REDCap system

Study Population:

Inclusion criteria

Patients, aged ≥ 1 day old, diagnosed with CBDs (e.g., hemophilia, Von Willebrand disease, and other coagulation factor deficiency) who are diagnosed dengue infection, based on WHO criteria

Exclusion criteria

Patients with CBDs with dengue infection who are not willing to participate the study

Registration information (include in the document link)

PART A: General information

Age at diagnosis.......year.........month

Sex

Underlying inherited bleeding disorder: Hemophilia, Coagulation factor deficiency, Platelet disorders, von Willebrand disease Prophylaxis: Factor dose and frequency

PART B: Dengue infection

Diagnosis: Clinical, probable, definite, uncertain (criteria is defined) Onset of presentation Fever Bleeding symptoms Replacement therapy during dengue infection Febrile stage Toxic (leakage, shock) stage Recovery

Outcome Survive Improved without sequelae Improved with sequelae Death from Bleeding Organ failure Infection Other ……………………………………….

Complication None Infection-associated hemophagocytic syndrome Encephalitis/Meningitis Renal failure Liver failure Rhabdomyolysis Other infection

Statistical analysis Descriptive statistics will be used to characterize the study population, and statistical tests (e.g., the chi-square test, t-tests, logistic regression) will be employed to analyze and comparison severity of bleeding and outcomes among types of bleeding disorders

Inclusion criteria

Patients, aged ≥ 1 day old, diagnosed with CBDs (e.g., hemophilia, von Willebrand disease, and other coagulation factor deficiency) who are diagnosed with dengue infection, based on WHO criteria as follow;

Clinical dengue infection:

Symptoms of high sustained fever for 3-7 days with 2 of the following: headache, retroorbital pain, myalgia, arthralgia/bone pain, hemorrhagic manifestation, positive tourniquet test, leukopenia (WBC ≤5000/uL)

Probable dengue infection:

Positive dengue IgM

Definite dengue infection:

Seroconversion of dengue IgM between acute and convalescent serum OR Rising of dengue IgG (HAI) at least 4 folds between acute and convalescent serum OR Positive NS1 Ag or other dengue-specific antigen tests

Dengue hemorrhagic fever:

Dengue infection with signs of bleeding (including positive tourniquet test) with platelet count < 100,000/uL and with signs of leakage (one of the following):

• Increase Hct at least 15-20% from baseline
• Serum albumin < 35 g/L
• Presence of pleural effusion or ascites

Dengue shock syndrome:

• Narrow pulse pressure (< 20 mmHg)
• Hypotension
• Signs of poor tissue perfusion

Severity of DHF:

• Grade I: Positive tourniquet test
• Grade II: Spontaneous bleeding
• Grade III: Circulatory failure (narrow pulse pressure ≤20 mmHg, hypotension, or signs of poor tissue perfusion)
• Grade IV: Profound shock with undetectable blood pressure

Exclusion criteria

• Patients with CBDs with dengue infection who are not willing to participate in the study