9.

2
FEVER AND RASH ● The acutely ill patient with fever and rash poses a diagnostic challenge.
● A distinctive appearance of the rash alongside clinical symptoms aids prompt diagnosis.
● Prompt diagnosis allows for life-saving therapy or critical infection-control interventions.
● Differentiating features of the rash can guide physicians towards the underlying cause.
● Early intervention based on the rash pattern can improve patient outcomes.
● Timely identification of the rash-associated illness is crucial for effective management.

APPROACH TO THE PATIENT Thorough History:

● Immune status of the patient
● Medications taken within the previous month
● Specific travel history
● Immunization status
● Exposure to domestic pets and other animals
● History of animal (including arthropod) bites
● Recent dietary exposures
● Existence of cardiac abnormalities
● Presence of prosthetic material
● Recent exposure to ill individuals
● Sexual exposures
● Onset site of the rash
● Direction and rate of spread of the rash
●
Thorough Physical Examination:
● Close attention to the rash, noting its salient features
● Determination of the type of lesions comprising the eruption:
○ Macules: Flat lesions with changed color (blanchable erythema)
○ Papules: Raised, solid lesions, 5 mm in diameter with a flat, plateau-like surface
○ Nodules: Lesions >5 mm in diameter with a more rounded configuration
○ Wheals (urticaria, hives): Pale pink papules or plaques, may appear annular as they enlarge
○ Vesicles: Circumscribed, elevated lesions containing fluid, 5 mm in size
○ Pustules: Raised lesions containing purulent exudate
○ Nonpalpable purpura: Flat lesions due to bleeding into the skin, termed ecchymoses if 3 mm
○ Palpable purpura: Raised lesions due to vasculitis with subsequent hemorrhage
○ Ulcer: Defect in the skin extending at least into the upper layer of the dermis
○ Eschar (tâche noire): Necrotic lesion covered with a black crust
● Assessment of other pertinent features of rashes:
○ Configuration: Annular or target
○ Arrangement of lesions
○ Distribution: Central or peripheral

PETECHIAE VS PURPURA Purpura:

● Skin lesion caused by bleeding into the skin.
 ● Can be palpable or nonpalpable.
● Nonpalpable purpura:
○ Flat lesion due to bleeding into the skin.
○ If 3mm or larger, termed ecchymoses.
● Palpable purpura:
○ Raised lesion due to inflammation of vessel wall (vasculitis) with subsequent hemorrhage.
Causes of Abnormal Bleeding:
● Stem from primary or secondary defects in vessel walls, platelets, or coagulation factors.
● Proper functioning of vessel walls, platelets, and coagulation factors is essential for hemostasis.

PURPURIC ERUPTIONS ● Acute Meningococcemia:

● Classically presents in children with a petechial eruption.
● Initial lesions may appear as blanchable macules or urticaria.
● Consider Rocky Mountain spotted fever in the differential diagnosis.
● Echovirus 9 infection may mimic acute meningococcemia; prompt treatment as bacterial sepsis is
advised.
● Purpura Fulminans:
● Large ecchymotic areas reflecting severe disseminated intravascular coagulation.
● Can be due to infectious or noninfectious causes.
● Chronic Meningococcemia:
● Lesions may have various morphologies, including petechial.
● Purpuric nodules on legs resembling erythema nodosum but without exquisite tenderness.
● Disseminated Gonococcemia:
● Distinctive sparse, countable hemorrhagic pustules, often near joints.
● Viral Hemorrhagic Fever:
● Consider in patients with appropriate travel history and a petechial rash.
● Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS):
● Noninfectious causes of fever and petechiae, closely related.
● Cutaneous Small-Vessel Vasculitis (Leukocytoclastic Vasculitis):
● Typically manifests as palpable purpura with various underlying causes.
DISEASES ASSOCIATED WITH FEVER
AND PURPURIC RASH
 MENINGOCOCCEMIA

DEFINITION Definition:
● Meningococcemia refers to infection with Neisseria meningitidis.
● Commonly, it manifests as asymptomatic colonization in the nasopharynx of healthy adolescents and adults.
● Invasive disease occurs rarely but can present as:
○ Bacterial meningitis.
○ Meningococcal septicemia (septicemia caused by Neisseria meningitidis).
● Patients may also present with:
○ Occult bacteremia.
○ Pneumonia.
○ Septic arthritis.
○ Conjunctivitis.
○ Chronic meningococcemia.

EPIDEMIOLOGY Epidemiology:
● Up to 500,000 cases of meningococcal disease occur worldwide annually, with declining numbers due to
immunization programs and secular trends.
● Approximately 10% of affected individuals die.
● Several patterns of disease observed: epidemic, outbreak, hyperendemic, sporadic/endemic.
● Epidemics mainly affect the sub-Saharan meningitis belt of Africa, with tens to hundreds of thousands of
cases reported per season, primarily caused by capsular group A, W, and X.
● Capsular group A epidemics occurred in Europe and North America post-World Wars.
● Clusters of cases occur in closed communities like schools, colleges, military centers, and refugee camps.
● Capsular group W disease clusters linked with the Hajj pilgrimage led to mandatory vaccinations for travel to
Saudi Arabia.
● Hyperendemic disease involves wider and prolonged community outbreaks, mainly caused by capsular
group B meningococci.
● Sporadic cases predominate in most countries, involving various disease-causing clones without clear
epidemiologic links.
● Rates and distribution of meningococcal strains vary globally and locally over time.
● In the US, disease rates decreased due to immunization programs against capsular groups B and C.
● Capsular group Y emerged during the 1990s in the US, surpassing group C in prevalence by 2007.
● In England and Wales, rates rose in the 1990s due to the ST11 capsular group C clone, mitigated by mass
immunization against group C in 1999, leading to dominance of group B cases.
● Industrialized nations witnessed a general decrease in meningococcal disease attributed to immunization
 programs.
● Factors contributing to decreased cases include changes in population immunity, prevalent meningococcal
clones, reduction in smoking, and passive exposure to tobacco smoke.
● Emergence of hyperinvasive ST11 clone with W capsule noted in South America, Europe, and Australia,
leading to increased group W cases.
● Capsular group Y disease increases observed in various countries in Europe, Canada, and South Africa.

FACTORS ASSOCIATED WITH DISEASE Age as Principal Determinant:

RISK AND SUSCEPTIBILITY ● Peak incidence in the first year of life, attributed to absence of specific adaptive immunity and close
contact with colonized individuals.
● Infants particularly susceptible to capsular group B disease, with over 30% of cases occurring in the
first year of life.
● Second peak among adolescents and young adults (15-25 years) in Europe and North America due
to social behaviors and environmental exposures.
Individual Susceptibility Factors:
● Host's genetic constitution, environment, and contact with carrier or case contribute to susceptibility.
● Complement deficiency, especially of terminal components (C5–9), properdin, or factor D, increases
risk by up to 600-fold, primarily associated with non-B capsular groups.
● Hyposplenism and hypogammaglobulinemia also increase risk.
● Genetic associations include complement and mannose-binding lectin deficiency, Toll-like receptor
(TLR) 4 polymorphisms, complement factor H variants, and Fc gamma receptor variants.
Transmission and Acquisition:
● Close contact with carriers, overcrowding, poor socioeconomic settings, refugee camps, Hajj
pilgrimage, and college dormitories increase transmission risk.
● Social behaviors like attendance at bars, nightclubs, and kissing also elevate risk.
● Secondary cases may occur in close contacts, with risk up to 1000 times higher than background
rate.
Factors Increasing Risk of Colonization and Invasive Disease:
● Factors damaging nasopharyngeal epithelium increase risk.
● Cigarette smoking (active or passive exposure) significantly increases risk.
● Recent viral respiratory tract infection, Mycoplasma infection, and winter/dry season associated with
increased risk, likely due to enhanced meningococcal adhesion or invasion of bloodstream.

PATHOGENESIS N. meningitidis Colonization:

● Effective colonizer of human nasopharynx, with asymptomatic infection rates exceeding 25% in some series
of adolescents and young adults.
● Variation in carriage rates among different meningococci types suggests adaptations for transmission
efficiency and duration of colonization.
● Colonization involves interactions of meningococcal adhesins (e.g., Opa proteins, pili) with epithelial
mucosa.
● Meningococcus produces IgA1 protease to reduce interruption of colonization by mucosal IgA.
Pathogenesis of Invasive Disease:
 ● Invasion into bloodstream occurs rarely, usually within days of acquiring an invasive strain.
● Capsule is a crucial virulence factor, providing resistance to phagocytosis and preventing desiccation.
● Antigenic diversity and varying expression levels of surface structures contribute to maintaining
meningococcal populations.
Bloodstream Invasion:
● Bacteremia may lead to seeding of other sites (e.g., meninges, joints) or unchecked proliferation in
circulation.
● Meningococci release outer membrane blebs containing proteins and LPS, initiating inflammatory cascade.
● Inflammatory response characterized by release of various mediators, including TNF-α, ILs, and PAI-1,
leading to meningococcemia.
Endothelial Injury:
● Central to clinical features of meningococcemia, including increased vascular permeability, vascular tone
changes, thromboresistance loss, intravascular coagulation, and myocardial dysfunction.
● Increased vascular permeability results in proteinuria and capillary leak syndrome, leading to hypovolemia,
tissue edema, and pulmonary edema.
Intravascular Thrombosis:
● Activation of procoagulant pathways and downregulation of anticoagulant pathways lead to purpura
fulminans and tissue infarction.
● Impaired thrombolysis through elevated PAI-1 levels exacerbates thrombosis.
Shock:
● Hypovolemia and myocardial depression contribute to shock.
● Shock manifestations include tissue hypoperfusion, renal impairment, and decreased consciousness due to
central nervous system involvement.
Meningitis:
● Bacteria reaching meninges trigger local inflammatory response, similar to septicemia, leading to
meningitis.
● Local endothelial injury may cause cerebral edema and raised intracranial pressure.
CLINICAL MANIFESTATIONS Asymptomatic Carriage and Pharyngitis:
● Most common form of N. meningitidis infection is asymptomatic colonization in the nasopharynx.
● Rarely reported meningococcal pharyngitis, but upper respiratory symptoms common before invasive
disease.
Clinical Syndromes:
● Meningitis and meningococcal septicemia are common clinical presentations.
● Fulminant cases may lead to death within hours.
● Occult bacteremia progresses to focal infections like meningitis or septicemia if untreated.
● Other presentations include pneumonia, pyogenic arthritis, osteomyelitis, pericarditis, endophthalmitis,
conjunctivitis, primary peritonitis, and urethritis.
Rash:
● Non-blanching rash (petechial or purpuric) develops in over 80% of cases.
● Initially blanching, becoming petechial or purpuric over hours.
● Severe cases develop large purpuric lesions (purpura fulminans).
● Some patients, especially those with overwhelming sepsis, may lack rash.
Meningitis:
● Presents with nonspecific manifestations including fever, vomiting, and irritability.
● Associated petechial or purpuric rash present in two-thirds of cases.
● Headache, neck stiffness, photophobia, decreased consciousness, seizures, and focal neurologic signs may
occur.
Septicemia:
● Progresses rapidly from nonspecific symptoms to death.
● Early symptoms resemble influenza-like illness with fever, headache, myalgia, vomiting, and abdominal pain.
● Rash may initially resemble viral illness until petechiae or purpuric lesions develop.
● Purpura fulminans in severe cases, with large purpuric lesions and signs of peripheral ischemia.
Chronic Meningococcemia:
● Rarely recognized condition characterized by repeated episodes of petechial rash, fever, joint pain, arthritis,
and splenomegaly.
● May progress to acute meningococcal septicemia if untreated.
● Differential diagnosis includes bacterial endocarditis, acute rheumatic fever, Henoch-Schönlein purpura,
infectious mononucleosis, disseminated gonococcal infection, and immune-mediated vasculitis.
Post-Meningococcal Reactive Disease:
● Immune complex disease occurring 4-10 days after onset of meningococcal disease.
● Manifestations include maculopapular or vasculitic rash, arthritis, iritis, pericarditis, and polyserositis
associated with fever.
● Immune complexes involve meningococcal polysaccharide antigen, resolving spontaneously without
sequelae.
● Important to recognize to avoid unnecessary prolonged antibiotic treatment.

DIAGNOSIS Laboratory Findings:

● Meningococcal disease may cause elevations in white blood cell count, C-reactive protein, procalcitonin
 levels, or erythrocyte sedimentation rate.
● Values may be normal or low in rapidly progressive disease.
● Hypoglycemia, acidosis, electrolyte imbalances, anemia, and coagulopathy may occur in severe
meningococcal septicemia.
Culture and PCR Analysis:
● Blood culture is routine to confirm the diagnosis, positive in up to 75% of cases.
● Avoid culture media containing sodium polyanethol sulfonate.
● Real-time PCR analysis of whole-blood samples increases diagnostic yield by >40%.
● Lumbar puncture is recommended unless contraindications exist, aids in identifying and confirming
meningococcal meningitis.
● CSF features are indistinguishable from other bacterial meningitis types unless gram-negative diplococcus
is identified.
● CSF culture (sensitivity 90%) and PCR analysis should be performed.
● CSF antigen testing with latex agglutination is insensitive.
Other Focal Infections:
● Culture and PCR analysis of synovial fluid may aid in diagnosis for cases of pyogenic arthritis or
osteomyelitis.
● Urinary antigen testing and serologic testing are insensitive and inadequately studied.
Throat Swabs:
● Limited diagnostic value but may help identify the organism in the context of a probable case, as N.
meningitidis is part of normal nasopharyngeal flora.

TREATMENT Emergency Management:

● Focus on treating hypovolemic shock and raised intracranial pressure in addition to specific
antibiotic therapy.
● Delayed recognition and inadequate emergency management associated with poor outcomes.
● Airway patency may be compromised, requiring intervention.
● Pulmonary complications (e.g., pulmonary edema, hypoxia) may necessitate oxygen therapy or
elective endotracheal intubation.
● Aggressive fluid resuscitation and inotropic support may be required to maintain cardiac output in
shock.
● Correction of metabolic derangements such as hypoglycemia, acidosis, and electrolyte imbalances.
Antibiotic Therapy:
● Empirical therapy with third-generation cephalosporin (e.g., ceftriaxone, cefotaxime) to cover
potential penicillin-resistant bacteria.
● Treatment duration typically 7 days, but shorter courses may be effective.
● Single-dose options available for resource-poor settings.
● Duration of treatment for other focal infections (e.g., pneumonia, arthritis) guided by resolution of
clinical and laboratory evidence of infection.
Adjunctive Therapies:
● Use of glucocorticoids remains controversial; decision usually made before definite microbiologic
diagnosis.

INDICATIONS FOR IMMUNIZATION
Source: PIDSP Childhood Immunization
Schedule 2023
To find: 2024 updates
●Replacement glucocorticoid doses may be recommended for patients with refractory shock and
impaired adrenal gland responsiveness.
● Few adjunctive therapies subjected to clinical trials; none currently recommended.
● HA1A antibody to LPS and recombinant bactericidal/permeability-increasing protein showed no
demonstrable benefit or inconsistent results.
● Use of activated protein C considered due to reduced protein C concentrations in meningococcal
disease; adult sepsis trials showed survival benefit, but pediatric trials found no benefit and potential
bleeding risk.
Post-Meningococcal Immune-Complex Inflammatory Syndrome:
● Treatment with nonsteroidal anti-inflammatory agents until spontaneous resolution occurs.
Meningococcal Vaccines:
Indications for Immunization:
● High-risk individuals for invasive disease include:
○ Persistent complement component deficiencies.
○ Anatomic/functional asplenia (including sickle cell disease).
○ HIV.
○ Travelers to or residents of areas with hyperendemic or epidemic meningococcal disease.
○ Belonging to a defined risk group during a community or institutional meningococcal outbreak.
Given intramuscularly (IM) or subcutaneously (SC).
● Types:
○ Tetravalent meningococcal (ACYW-135) conjugate vaccine:
■ Available as MCV4-D, MCV4-TT.
○ Indicated for those at high risk for invasive disease:
■ Includes individuals with persistent complement component deficiencies,
anatomic/functional asplenia (including sickle cell disease), HIV, travelers to or residents of
areas with hyperendemic or epidemic meningococcal disease, or belonging to a defined risk
group during an outbreak.
Conjugate Vaccines:
● MCV4-D:
○ Minimum age: 9 months.
○ For children 9-23 months: 2 doses 3 months apart.
○ For children 2 years and above: 2 doses 8 weeks apart. 1 dose recommended for outbreak or travel
to endemic areas.
○ Exceptions for high-risk groups: 2 doses 8 weeks apart.
● MCV4-TT (5 ug/0.5ml):
○ Minimum age: 6 weeks.
○ Infants 6 to 12 weeks: First 2 doses at least 2 months apart; booster dose at age 12 months.
○ Children from 12 months to adolescence: 1 dose only.
● MCV4-TT (10 ug/0.5ml):
 ○ Minimum age: 1 year.
○ For children from 12 months of age to adolescence: 1 dose.
Co-administration:
● MCV4-D and PCV13:
○ If MCV4-D administered to a child with asplenia or HIV infection, delay until age 2 years and at least 4
weeks after PCV13 completion.
● MCV4-D and DTaP:
○ Recommended to give MCV4-D either before or at the same time as DTaP for high-risk children.
● MCV-TT with tetanus-toxoid (TT)-containing vaccines:
○ Whenever feasible, co-administer MCV4-TT with TT-containing vaccines, or administer 1 month
before other TT-containing vaccines.

RECOMMENDED PROPHYLAXIS Recommended Prophylaxis:

● Target Audience: Close contacts of patients with meningococcal disease.
○ Household members.
○ Hospital staff exposed to respiratory secretions of infected individuals.
○ Individuals who sat directly next to an index case on a prolonged travel of more than 8 hours.
○ Personnel with intensive close contact (e.g., mouth-to-mouth resuscitation, endotracheal
intubations) with a patient with meningococcal disease before administration of antibiotics without
proper precautions.
● Medications:
○ Rifampicin:
■ Dosage: 5-10 mg/kg/d every 12 hours for 2 days.
■ Maximum dose: 600 mg/d.
○ Ceftriaxone:
■ Dosage: 125-250 mg/d intramuscularly as a single dose.
○ Ciprofloxacin:
■ Dosage: 500 mg orally as a single dose.

CHIKUNGUNYA

DISTRIBUTION AND DISTINGUISHING Distribution of Chikungunya Virus:

CHARACTERISTIC OF CHIKUNGUNYA ● Endemic in rural areas of Africa.
VIRUS ● Intermittent epidemics occur in towns and cities of both Africa and Asia.
● Massive epidemic began in the Indian Ocean region in 2004, spreading to Réunion, Mauritius, and other
areas, likely through travelers.
● Caribbean islands experienced several thousand reported cases from 2013 to 2014, with imported cases
reported in Italy, France, and the United States.
● Threat to the continental United States due to suitable vector mosquitoes present in southern states.
Vectors:
● Yellow fever mosquitoes (Aedes aegypti) are usual vectors in urban areas.
● Asian tiger mosquito (Aedes albopictus) identified as a major vector during the Indian Ocean epidemic.
 Characteristics of Chikungunya Virus:
● Member of the Semliki Forest antigenic complex.
● Spherical, 70 nm in diameter.
● Nucleocapsid has 42 capsomeres.
● Genome: positive-sense, single-stranded RNA, 11–12 kb in size.
● Enveloped virus with three or four major structural polypeptides, two glycosylated.
● Replication occurs in the cytoplasm.
● Assembly involves budding through host cell membranes.
● Clinically resembles dengue fever but more likely to cause high fever, rash, and severe joint pain.
● Rarely causes asymptomatic infections.
Preventive Measures:
● No vaccine currently available for Chikungunya virus.

CLINICAL FEATURES Incubation Period: 2–10 days

Clinical Features:
● Abrupt Onset: Fever, often severe, with a saddleback pattern.
● Symptoms and Signs:
○ Severe arthralgia (joint pain).
○ Chills.
○ Constitutional symptoms: abdominal pain, anorexia, conjunctival injection, headache, nausea,
photophobia.
● Polyarthritis:
○ Mainly affects small joints of ankles, feet, hands, and wrists.
○ Larger joints may also be affected.
○ Migratory nature.
● Rash:
○ May appear at outset or several days into illness.
○ Often coincides with defervescence (around day 2 or 3).
○ Intense on trunk and limbs, may desquamate.
○ Bullous rash more common in children.
Maternal-Fetal Transmission: Reported, leading to fetal death in some cases.
Recovery: May require weeks; elderly patients may experience joint pain, recurrent effusions, or stiffness for several
years.
● Specific Manifestations:
○ Petechiae occasionally seen.
○ Epistaxis not uncommon.
○ Few patients develop leukopenia.
○ Elevated concentrations of aspartate aminotransferase (AST) and C-reactive protein.
○ Mildly decreased platelet counts.
MANAGEMENT
Chloroquine:
Supportive Care:
Monitoring:
Prevention:
EPIDEMIOLOGY
Source: Dengue: Guidelines for Diagnosis,
Treatment, Prevention and Control. World
Health Organization 2009, Page 3-5
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
● Mainstay of treatment.
● Used to alleviate symptoms such as fever, arthralgia, and inflammation.
● Considered for refractory arthritis cases.
● May help alleviate joint pain and inflammation.
● Rest and hydration to manage symptoms.
● Symptomatic relief for associated symptoms like headache and nausea.
● Regular monitoring of symptoms and signs of disease progression.
● Avoidance of mosquito bites through protective clothing and mosquito repellents.
DENGUE
● Dengue is the fastest spreading mosquito-borne viral disease globally, with a 30-fold increase in incidence
over the last 50 years.
● It has expanded geographically to new countries and from urban to rural areas.
● An estimated 50 million dengue infections occur annually, affecting approximately 2.5 billion people living in
endemic countries.
● WHO resolutions WHA55.17 and WHA58.3 emphasized the importance of addressing dengue as a public
health concern.
● In the WHO South-East Asia Region and Western Pacific Region:
○ More than 70% of the population at risk for dengue worldwide reside.
○ These regions bear nearly 75% of the global disease burden due to dengue.
● The Asia Pacific Dengue Strategic Plan (2008-2015) aims to reverse the rising trend of dengue by enhancing
preparedness to detect, characterize, and contain outbreaks.
● Dengue in the WHO South-East Asia Region:
○ Epidemic dengue has spread to new areas and increased in already affected areas since 2000.
○ Countries like Indonesia, Myanmar, Sri Lanka, Thailand, and Timor-Leste face significant challenges
due to widespread Aedes aegypti mosquito presence and circulation of multiple virus serotypes.
○ Cyclic epidemics are increasing in frequency, with geographic expansion observed in Bangladesh,
India, and Maldives.
○ Bhutan and Nepal in the sub-Himalayan foothills have reported epidemic dengue activity in recent
years.
● Dengue in the WHO Western Pacific Region:
○ Dengue has emerged as a serious public health problem.
○ Recurrent epidemics have been reported since the major pandemic in 1998.
○ Lack of reporting remains a challenge in prevention and control efforts.
○ Cambodia, Malaysia, Philippines, and Viet Nam have reported the highest numbers of cases and
deaths in the region.

DISEASE BURDEN
CHARACTERISTIC FEATURE OF
ARTHROPOD VECTOR DENV
TRANSMISSION PATTERN OF DENV
○ Case management improvements have led to a decrease in case fatality rates overall.
● Dengue imposes a significant health, economic, and social burden on endemic populations.
● Globally, in 2001, an estimated 528 disability-adjusted life years (DALYs) were lost to dengue.
● In Puerto Rico, between 1984 and 1994, an estimated yearly mean of 580 DALYs per million population were
lost to dengue, comparable to the cumulative total lost to malaria, tuberculosis, intestinal helminths, and
childhood diseases in all of Latin America and the Caribbean.
● Children face a higher risk of severe dengue.
● Severely ill patients require intensive care, including intravenous fluids, blood or plasma transfusion, and
medications.
● Dengue affects all levels of society, but the burden may be higher among the poorest individuals living in
communities with inadequate water supply and solid waste infrastructure, where conditions favor the
multiplication of the main vector, Aedes aegypti.
● Dengue virus serotypes are transmitted to humans through the bites of infected Aedes mosquitoes,
primarily Ae. aegypti.
● Ae. aegypti is a tropical and subtropical species widely distributed worldwide, mainly between latitudes 35°N
and 35°S.
● Geographical limits for Ae. aegypti correspond to a winter isotherm of 10°C, with invasions occurring as far
north as 45°N during warmer months.
● Ae. aegypti is relatively uncommon above 1000 meters due to lower temperatures.
● Immature stages of Ae. aegypti are found in water-filled habitats, predominantly in artificial containers
closely associated with human dwellings and often indoors.
● Studies suggest that most female Ae. aegypti spend their lifetime in or around the houses where they
emerge as adults, facilitating rapid movement of the virus within and between communities by humans
rather than mosquitoes.
● Dengue outbreaks have also been linked to other mosquito species such as Aedes albopictus, Aedes
polynesiensis, and several species of the Aedes scutellaris complex, each with distinct ecologies, behaviors,
and geographical distributions.
● Aedes albopictus has spread from Asia to Africa, the Americas, and Europe, facilitated by international trade
in used tires containing rainwater where mosquito eggs are deposited, remaining viable for many months in
the absence of water.
● Humans serve as the primary amplifying host of the dengue virus.
● Female mosquitoes, particularly Ae. aegypti, ingest the virus circulating in the blood of viraemic humans
during feeding.
● The virus then infects the mosquito mid-gut and spreads systemically over a period of 8-12 days.
● After this extrinsic incubation period, the virus can be transmitted to other humans during subsequent
probing or feeding by the mosquito.
● The extrinsic incubation period is influenced by environmental conditions, especially ambient temperature.
● Following the extrinsic incubation period, the mosquito remains infective for the rest of its life.
● Ae. aegypti is highly efficient in transmitting arboviruses due to its anthropophilic nature, frequent biting, and

DENGUE VIRUS FEATURES: GENOMIC
ORGANIZATION, STRUCTURE, AND LIFE
CYCLE
proximity to humans.
● While vertical transmission (transovarial transmission) of dengue virus has been demonstrated in the
laboratory, it is rare in the field, and its significance for virus maintenance is not well understood.
● Sylvatic dengue strains in some parts of Africa and Asia may also lead to human infection, causing mild
illness.
● Various factors, including environmental and climate conditions, host-pathogen interactions, and population
immunological factors, can influence the dynamics of virus transmission.
● Climate directly affects the biology of vectors, such as mosquitoes, influencing their abundance, distribution,
and consequently, the occurrence of vector-borne disease epidemics.
● Dengue virus (DENV) belongs to the Flavivirus genus, family Flaviviridae, with a diameter of 50 nm and a
single-stranded RNA genome.
● The genome encodes three structural proteins: capsid (C), membrane (M), envelope (E), and seven
nonstructural (NS) proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5.
● DENV comprises four serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, which share a high degree of
sequence similarity.
● Aedes mosquitoes, primarily Aedes aegypti, transmit DENV to humans, but Aedes albopictus is also
becoming a significant vector.
● Human-to-mosquito transmission occurs when mosquitoes feed on viremic individuals up to 2 days before
or after symptoms appear.
● Upon ingestion by mosquitoes, DENV replicates in the mosquito's midgut and disseminates to secondary
tissues, including salivary glands, within an average of 5.9 days.
● The virus can then be transmitted to a new host when the mosquito feeds again.
● In humans, DENV infects dendritic cells and keratinocytes in the skin, leading to viremia and dissemination
to local lymph nodes.
● The attachment and internalization of DENV into target cells involve various factors, including
glycosaminoglycans, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin
(DC-SIGN), mannose receptor (MR), CD14, and heat-shock proteins 70 and 90.
● After internalization, fusion between the viral envelope protein (E) and the endosomal membrane allows the
release of the viral genome into the cytoplasm.
● The viral RNA acts as messenger RNA, leading to the synthesis of viral polyproteins, which are subsequently
processed by cellular and viral proteases.
● Nonstructural proteins, particularly NS3, NS5, and NS2B, play crucial roles in replication complex formation,
RNA synthesis, and viral protein processing.
● The assembly of new virions occurs in the endoplasmic reticulum (ER), where viral RNA replication takes
place, and mature virions are released via exocytosis after transportation through the trans-Golgi network
(TGN) and cleavage of pre-M by cellular protease furin under acidic conditions.
LIFE CYCLE OF DENV ● Dengue virus (DENV) is a positive-sense RNA virus with a genome size of approximately 10.7 kb.
● The genome encodes for three structural proteins: capsid, premembrane/membrane (prM/M), and envelope
(E), and seven nonstructural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5.
● DENV primarily infects myeloid lineage immune cells in humans, such as monocytes, macrophages, and
dendritic cells (DCs).
● Upon receptor-mediated entry into host cells, a conformational change in the E protein is triggered by the
acidification of the endosome, leading to the release of the viral capsid into the cytoplasm.
● Uncoating of the viral genome occurs, and the RNA genome is translated into a single polyprotein, which is
cleaved into ten proteins by both viral and host proteases.
● Following the synthesis of NS5 RNA-dependent RNA polymerase and NS3 helicase, RNA replication
begins, and viral particle assembly occurs in the endoplasmic reticulum (ER).
● Mature viral particles pass through the ER and Golgi apparatus, where posttranslational modifications and
maturation occur.
● Finally, mature virions are secreted from the host cell, completing the DENV life cycle.

HOST IMMUNE RESPONSE TO DENV DENV Tropism:

INFECTION
● DENV primarily infects myeloid lineage immune cells, including monocytes, macrophages, and dendritic
cells (DCs).
● Infection begins in the epidermis and dermis, where immature Langerhans cells and keratinocytes are
infected.
● Infected cells migrate to lymph nodes, where monocytes and macrophages become targets of infection.
● Infection is amplified during primary viremia, leading to infection of various cells of the mononuclear lineage,
including blood-derived monocytes, myeloid DCs, and splenic and liver macrophages.
● Leukocytes, spleen, lymph nodes, and bone marrow are susceptible to DENV infection, with mononuclear
cells predominantly undergoing apoptosis following infection.
 ● Bone marrow stromal cells have also been shown to be susceptible to DENV infection.

Activation of the Complement System:

● Complement activation plays a role in the pathogenesis of dengue, particularly in severe cases like DSS.
● NS1 is implicated as a trigger for complement activation, either through binding of heterotypic antibodies to
NS1 expressed on infected cells or through direct activation of complement factors by NS1 released from
infected cells.
● IgG1 and IgG3 subclasses are predominant in the specific antibody response to DENV infections and
effectively activate the complement system.
● The presence of sialic acid in the glycans of IgG subclasses may affect their complement-fixing properties
and infection-enhancing activity.

Transient Immunity:

● Antibodies produced during DENV infection may cross-react with self-antigens, potentially contributing to
disease severity.
● Cross-reactive anti-NS1 antibodies may bind to cells of the liver, endothelial cells (EC), and platelets, leading
to cell damage and transient thrombocytopenia.
● Cross-reactive antibodies to self-antigens are likely short-lived IgM isotypes, but vaccination strategies
should avoid inducing memory IgG responses to such antigens.

Soluble Factors:

● Various cytokines and soluble factors elaborated by activated immune cells play roles in the development of
hemorrhage during DENV infection.
● The specific roles of these factors in DENV pathogenesis and their implications in hemorrhage are
summarized in Table 2.

FACTORS INVOLVED IN THE Factors Involved in the Development of Severe Dengue:

DEVELOPMENT OF SEVERE DENGUE
Antibody-Dependent Enhancement (ADE):

● Antibodies at sub-neutralizing concentrations can enhance DENV entry into cells expressing Fcɣ
receptors (FcɣR) through ADE.
● Low-affinity or poorly neutralizing cross-reactive antibodies generated during primary infection can
facilitate ADE during secondary infection, leading to increased viral burden and more severe disease.
 Cross-Reactive T Cell Response/Original Antigenic Sin (OAS):

● Memory T cells cross-reactive with heterologous viruses can provide partial protective immunity but
may also cause substantial immunopathology.
● CD8+ T cells may play a role in clearing infection and immunopathogenesis during DENV infection.
● During secondary infection with a heterologous DENV serotype, highly cross-reactive CD8+ T cells
with high avidity for the infecting virus are preferentially activated.
● Original Antigenic Sin (OAS) occurs when cross-reactive memory T cells for the primary infecting
virus are more efficiently activated during a secondary infection, leading to preferential expansion of
memory T cells against the priming virus.
● Narrowing of the T cell receptor (TCR) repertoire and unique TCR specificity in individuals may
contribute to variability in disease outcome upon secondary infection with heterologous DENV.

IMMUNOLOGIC & PATHOPHYSIOLOGIC Imunologic and Pathophysiologic Changes with Clinical Manifestations of Dengue:
CHANGES WITH THE CLINICAL
MANIFESTATIONS
Influence of Host Genetic Background:

● Host genetics influence the immune response to DENV infection.

Infection Pathway:

● DENV initially infects Langerhans cells and keratinocytes in the dermis.

● The virus spreads via the blood (primary viremia) and infects tissue macrophages, especially in the spleen.
● Replication efficiency in various cells, including dendritic cells (DC), monocytes, macrophages, endothelial
cells (EC), bone marrow stromal cells, and liver cells, determines the viral load in blood, which is a risk factor
for severe disease.

Cell Death and Hemostatic Response:

● Infected cells primarily undergo apoptosis, releasing toxic products that activate the coagulation and
fibrinolytic systems.
● Hemopoiesis may be suppressed due to infection of bone marrow stromal cells and elevated levels of
certain cytokines.
● Severe thrombocytopenia and platelet dysfunction, possibly due to high viral load and viral tropism for EC,
contribute to increased capillary fragility, petechiae, bruising, and gastrointestinal bleeding characteristic of
Dengue Hemorrhagic Fever (DHF).

Role of Antibodies:
 ● IgM antibodies that cross-react with EC, platelets, and plasmin amplify the loop leading to increased
vascular permeability and coagulopathy.
● Enhancing IgG antibodies bind heterologous virus during secondary infection, enhancing infection of
antigen-presenting cells (APCs), contributing to increased viral load during secondary viremia.

T Cell Response:

● High viral load stimulates both low- and high-avidity cross-reactive T cells, delaying virus clearance and
producing high levels of proinflammatory cytokines.
● Certain HLA haplotypes may influence the role of cross-reactive T cells in immunopathology.

Soluble Factors and Endothelial Changes:

● High levels of soluble factors induce changes in EC, leading to coagulopathy and plasma leakage
characteristic of Dengue Shock Syndrome (DSS).
● Many of these soluble factors remain to be identified.

CLASSIFICATION OF DENGUE INFECTION Classification of Dengue Infection:

​ Wide Spectrum of Clinical Presentations:

● Dengue exhibits various clinical presentations with unpredictable evolution and outcomes.
● Most patients experience a self-limiting non-severe course, while a small proportion progress to
severe disease, often characterized by plasma leakage with or without hemorrhage.
​ Therapy and Case Fatality Rate:
● Intravenous rehydration is the preferred therapy for severe cases, reducing the case fatality rate to
less than 1%.
● Identifying patients progressing from non-severe to severe disease is crucial for appropriate
treatment to prevent further clinical deterioration.
​ Influence on Triage and Treatment:
● Case classification for dengue influences triage, treatment decisions, and the choice of treatment
setting (healthcare facility or home), especially during outbreaks when demand surges.
​ Existing Classification Challenges:
● The existing WHO classification grouped symptomatic dengue virus infections into undifferentiated
fever, dengue fever (DF), and dengue hemorrhagic fever (DHF), further subclassified into four severity
grades with grades III and IV defined as dengue shock syndrome (DSS).
● Difficulties in applying DHF criteria in clinical settings, coupled with an increase in clinically severe
dengue cases not meeting DHF criteria, led to calls for classification reconsideration.
​ Revised Classification Approach:
● A WHO/TDR-supported multicenter study aimed to collect evidence for classifying dengue into
severity levels.
 ● Findings supported clear distinctions between severe and non-severe dengue using clinical and/or
laboratory parameters.
● For practical purposes, the large group of non-severe dengue patients was divided into those with
warning signs and those without.
● Criteria for diagnosing dengue (with or without warning signs) and severe dengue were established,
recognizing that even patients without warning signs may progress to severe disease.

PHASES OF DENGUE ILLNESS Classification of Dengue Infection:

Wide Spectrum of Clinical Presentations:

- Dengue exhibits various clinical presentations with unpredictable evolution and outcomes.
- Most patients experience a self-limiting non-severe course, while a small proportion progress to severe
disease, often characterized by plasma leakage with or without hemorrhage.

Therapy and Case Fatality Rate:

- Intravenous rehydration is the preferred therapy for severe cases, reducing the case fatality rate to less than
1%.
- Identifying patients progressing from non-severe to severe disease is crucial for appropriate treatment to
prevent further clinical deterioration.

Influence on Triage and Treatment:

- Case classification for dengue influences triage, treatment decisions, and the choice of treatment setting
(healthcare facility or home), especially during outbreaks when demand surges.

Existing Classification Challenges:

- The existing WHO classification grouped symptomatic dengue virus infections into undifferentiated fever,
dengue fever (DF), and dengue hemorrhagic fever (DHF), further subclassified into four severity grades with
grades III and IV defined as dengue shock syndrome (DSS).
- Difficulties in applying DHF criteria in clinical settings, coupled with an increase in clinically severe dengue
cases not meeting DHF criteria, led to calls for classification reconsideration.

Revised Classification Approach:

- A WHO/TDR-supported multicenter study aimed to collect evidence for classifying dengue into severity
levels.
- Findings supported clear distinctions between severe and non-severe dengue using clinical and/or
laboratory parameters.
- For practical purposes, the large group of non-severe dengue patients was divided into those with warning
signs and those without.
- Criteria for diagnosing dengue (with or without warning signs) and severe dengue were established,
recognizing that even patients without warning signs may progress to severe disease.
PHASES OF DENGUE ILLNESS Phases of Dengue Illness:

Febrile Phase:

● Typically begins abruptly with high-grade fever lasting 2–7 days.

● Accompanied by facial flushing, skin erythema, body ache, myalgia, arthralgia, headache, sore throat,
injected pharynx, and conjunctival injection.
● Anorexia, nausea, and vomiting are common.
● Petechiae and mucosal membrane bleeding may occur, along with hepatomegaly.
● Progressive decrease in total white cell count indicates a high probability of dengue.

Critical Phase:

● Occurs around defervescence (days 3–7) with decreasing temperature.

● Increased capillary permeability leads to plasma leakage, usually lasting 24–48 hours.
● Progressive leukopenia followed by rapid decrease in platelet count precedes plasma leakage.
● Pleural effusion and ascites may be clinically detectable.
● Shock may occur when critical volume of plasma is lost, preceded by warning signs.
● Organ hypoperfusion results in organ impairment, metabolic acidosis, and disseminated intravascular
coagulation.
● Warning signs may manifest, indicating progression to severe dengue.

Recovery Phase:

● Gradual reabsorption of extravascular compartment fluid occurs over 48–72 hours.

● Improvement in general well-being, appetite, gastrointestinal symptoms, and stabilization of hemodynamic
status.
● Rash and pruritus may occur.
● Bradycardia and electrocardiographic changes are common.
● Haematocrit stabilizes or may decrease due to dilutional effect.
● Respiratory distress from excessive intravenous fluids may occur if administered.

Severe Dengue:

● Defined by plasma leakage leading to shock or fluid accumulation, severe bleeding, or severe organ
impairment.
● Shock occurs around defervescence, preceded by warning signs.
● Hypotension, poor capillary perfusion, and multiple organ failure may result.
 ● Major bleeding may occur, often associated with profound shock.
● Unusual manifestations include acute liver failure, encephalopathy, cardiomyopathy, and encephalitis.
● Severe dengue should be considered in patients with fever of 2–7 days and evidence of plasma leakage,
bleeding, altered consciousness, severe gastrointestinal involvement, severe organ impairment, or other
unusual manifestations.

CLINICAL FEATURES THAT REQUIRE

HOSPITALIZATION

TESTS TO CONFIRM DIAGNOSIS Tests to Confirm Diagnosis of Dengue:

Direct Detection of Viral Components:

Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) Assay:

● Detects viral nucleic acid in serum.

● High sensitivity during the febrile phase.

Detection of Soluble Nonstructural Protein 1 (NS1):

● Detected by enzyme-linked immunosorbent assay (ELISA) or lateral-flow rapid test.

● High sensitivity (>90%) in primary infections during the febrile phase.
● Sensitivity lower (60-80%) in secondary infections due to anamnestic serologic response.
Serologic Diagnosis:

Detection of Serum IgM:

● High levels of IgM binding dengue virus antigens in ELISA or lateral-flow rapid test.
● IgM can be detected as early as 4 days after fever onset.
● IgM seroconversion between paired samples confirms diagnosis.
● Detection of IgM in a single specimen supports presumptive diagnosis.

Considerations:

● Confounded if patient recently infected or vaccinated with antigenically related flavivirus.

● Secondary infections may show rapid anamnestic IgG response, potentially dominating over IgM.

Pragmatic Diagnostic Approach:

● Investigation for elevated levels of dengue virus-reactive IgM or soluble NS1 in serum when molecular
detection methods (e.g., RT-PCR) are not available.
● Useful in suspected dengue cases where rapid confirmation is required.
CONDITIONS THAT MIMIC DENGUE FEVER
STEPWISE APPROACH TO A PATIENT
SUSPECTED OF HAVING DENGUE FEVER
Source: Dengue: guidelines for diagnosis,
treatment, prevention and control. World
Health Organization 2009 (pages 30-53)
Step I - Overall Assessment:
History:
● Date of onset of fever/illness
● Quantity of oral intake
● Assessment for warning signs (Tab. 5)
● Presence of diarrhea; change in mental state/seizure/dizziness
● Evaluation of urine output (frequency, volume, and time of last voiding)
● Other relevant histories:
● Family or neighborhood dengue
● Travel to dengue endemic areas
● Co-existing conditions (infancy, pregnancy, obesity, diabetes mellitus, hypertension)
● Jungle trekking and swimming in waterfall (consider leptospirosis, typhus, malaria)
● Recent unprotected sex or drug abuse (consider acute HIV seroconversion illness)
Physical Examination:
 ● Assessment of mental state
● Evaluation of hydration status
● Assessment of hemodynamic status (Tab. 6)
● Observation for tachypnoea/acidotic breathing/pleural effusion
● Checking for abdominal tenderness/hepatomegaly/ascites
● Examination for rash and bleeding manifestations
● Conducting tourniquet test (repeat if previously negative or in absence of bleeding manifestation)

Investigation:

● Full blood count at first visit

● Hematocrit test in early febrile phase to establish baseline
● Decreasing white blood cell count indicative of dengue
● Rapid decrease in platelet count with rising hematocrit suggests progress to plasma leakage phase
● Laboratory tests to confirm diagnosis; additional tests as indicated:
○ Liver function tests
○ Glucose level
○ Serum electrolytes
○ Urea and creatinine
○ Bicarbonate or lactate levels
○ Cardiac enzymes
○ ECG
○ Urine specific gravity

Step II - Diagnosis, Assessment of Disease Phase and Severity:

● Determine if disease is dengue and its phase (febrile, critical, or recovery)

● Assess for warning signs, hydration, hemodynamic status
● Determine need for admission based on clinical evaluation

Step III - Management:

Disease Notification:

● Notify suspected, probable, or confirmed dengue cases in endemic countries for public health measures
● Laboratory confirmation not immediately necessary but should be obtained

Management Decisions:

● Group A: Patients able to tolerate oral fluids, pass urine, and without warning signs
 ● Group B: Patients requiring in-hospital management (e.g., warning signs, co-existing conditions)
● Group C: Patients with severe dengue requiring emergency treatment and urgent referral

Group A - Patients Who May Be Sent Home:

● Encourage oral intake of oral rehydration solution (ORS), fruit juice, and other electrolyte-containing fluids
● Administer paracetamol for high fever; avoid aspirin, ibuprofen, NSAIDs
● Instruct caregivers to seek immediate medical attention if specific symptoms occur

Group B - Patients Who Should Be Referred for In-Hospital Management:

● Admit patients with warning signs or complicating factors

● Monitor closely, especially approaching critical phase
● Adjust fluid therapy based on clinical response and hematocrit levels

Group C - Patients Who Require Emergency Treatment and Urgent Referral for Severe Dengue:

● Immediate management of severe plasma leakage, severe hemorrhages, or organ impairment

● Admission to hospital with access to intensive care facilities and blood transfusion
● Judicious intravenous fluid resuscitation with isotonic solutions; blood transfusion if severe bleeding
suspected or confirmed

Treatment of Compensated Shock:

● Intravenous fluid resuscitation with isotonic crystalloid solutions

● Adjust fluid rates based on clinical response, hematocrit, and hemodynamic status
● Consider blood transfusion if hematocrit remains high or if bleeding suspected

Treatment of Hypotensive Shock:

● Vigorous intravenous fluid resuscitation with crystalloid or colloid solutions

● Monitor closely and adjust fluid rates based on clinical response and hematocrit levels
● Consider blood transfusion if bleeding suspected or confirmed

Treatment of Severe Hemorrhagic Complications:

● Blood transfusion for severe bleeding with fresh-packed red cells or fresh whole blood
● Repeat transfusion if necessary; avoid platelet concentrates and fresh-frozen plasma unless necessary
● Use caution with nasogastric tube insertion to avoid further bleeding or airway obstruction
● Monitor closely for clinical response and adjust management accordingly
SUMMARY OF THE MANAGEMENT OF Summary of Dengue Management:
PATIENTS WITH DENGUE
1. Supportive Treatment:

● No specific antiviral agents available for dengue treatment.

● Emphasis on supportive care, particularly careful fluid management.

2. Outpatient Management:

● Patients without complications and able to tolerate oral fluids may be managed at home.
● Instructions to return to hospital immediately if bleeding or warning signs suggestive of vascular leakage
develop.
● Daily evaluation in a medical clinic with complete blood count to monitor hematocrit and platelet values.

3. Hospitalization and Close Observation:

● Development of any warning sign necessitates hospitalization and close observation.

 ● Judicious use of parenteral fluids in patients with inadequate oral intake or rapidly increasing hematocrit.

4. Dengue Shock Syndrome Management:

● Prompt fluid resuscitation to restore plasma volume is imperative.

● Ongoing fluid therapy to support circulation at a level just sufficient to maintain critical organ perfusion.
● Use of isotonic crystalloid solutions; reserve isotonic colloid solutions for profound shock or non-responsive
cases.
● Limit parenteral fluid therapy to the minimum required to maintain cardiovascular stability until permeability
normalizes.

5. Blood Transfusion:

● Lifesaving for patients with severe bleeding compromising cardiovascular function.

● Undertaken with care due to risk of fluid overload.
● Platelet concentrates, fresh-frozen plasma, and cryoprecipitate may be needed based on coagulation profile.
● No evidence for prophylactic platelet transfusions in patients without clinically significant bleeding, even
with profound thrombocytopenia.
● Controlled trials needed before prophylactic platelet transfusions become standard care.

6. Adjuvant Therapy:

● In severe dengue infection, may require vasopressor and inotropic therapies, renal replacement therapy, and
further treatment of organ impairment.

Overall, management of dengue focuses on supportive care, close monitoring for complications, and timely
intervention when necessary to prevent progression to severe disease.

COMPLICATIONS FROM SEVERE DENGUE Complications from Severe Dengue:

Fluid Overload:

● Common cause of acute respiratory distress and failure.

● Causes include excessive or rapid IV fluids, incorrect fluid type, unrecognized severe bleeding, continuation
of IV fluids post-plasma leakage resolution, and comorbid conditions.
● Early clinical features: respiratory distress, rapid breathing, chest wall in-drawing, wheezing, large pleural
effusions, tense ascites, increased JVP.
● Late clinical features: pulmonary edema, irreversible shock.
● Additional investigations: chest x-ray, ECG, arterial blood gases, echocardiogram, cardiac enzymes.
● Action plan:
 ● Oxygen therapy.
● Stop or reduce IV fluid therapy when signs of cessation of plasma leakage, stable hemodynamics,
decreasing hematocrit, afebrile state, resolving symptoms, and improving urine output are observed.
● Management varies based on disease phase and hemodynamic status.

Other Complications:

● Hyperglycemia and hypoglycemia: may occur irrespective of diabetes mellitus.

● Electrolyte and acid-base imbalances: common due to vomiting, diarrhea, or use of hypotonic solutions.
● Imbalances include hyponatremia, hypokalemia, hyperkalemia, serum calcium imbalances, and metabolic
acidosis (sodium bicarbonate not recommended for pH≥7.15).
● Alert for co-infections and nosocomial infections

METHODS TO PREVENT AND/OR Methods to Prevent and/or Control Dengue Fever:

CONTROL DENGUE FEVER
1. Environmental Management:
- Environmental modification: Installing reliable piped water supply to reduce larval habitats.
- Environmental manipulation: Managing essential containers through frequent emptying, cleaning, and
proper disposal.
- Changes to human habitation or behavior: Installing mosquito screening on windows and doors, using
mosquito nets during daytime.

2. Improvement of Water Supply and Water-Storage Systems:

- Preferable use of piped water to eliminate water-storage containers.
- Installing reliable piped water supplies accompanied by discouraging traditional storage practices.

3. Mosquito-Proofing of Water-Storage Containers:

- Designing containers with tight lids or mesh screens to prevent mosquito oviposition.
- Using expanded polystyrene beads to inhibit oviposition in certain containers.

4. Solid Waste Management:

- Proper storage, collection, and disposal of solid waste to reduce larval habitats.
- Integration of dengue vector control with waste management services.

5. Street Cleansing:
- Regular cleansing to remove water-bearing containers and clean drains.
- Reduces larval habitats of mosquitoes and other urban pests.

6. Building Structures:
- Planning and construction regulations to modify or reduce potential larval habitats.
- Example: Singapore's legislation prohibiting roof gutters on buildings in new developments.
 7. Chemical Control: Larvicides:
- Considered complementary to environmental management.
- Application restricted to containers that cannot be eliminated or managed.
- Larvicides should have low toxicity to other species and not alter water taste, odor, or color.

8. Chemical Control: Adulticides:

- Residual treatment: Hand-operated compression sprayers for larval habitats.
- Space spraying: Emergency control to suppress ongoing epidemics or prevent incipient ones.

9. Biological Control:
- Introduction of organisms that prey upon or compete with mosquitoes.
- Examples include larvivorous fish and predatory copepods.
- Effective mainly in specific container habitats but have operational limitations.

10. Fish:
- Used to eliminate mosquitoes from larger containers and open freshwater wells.
- Only native larvivorous fish should be used to avoid threats to indigenous fauna.

11. Predatory Copepods:

- Effective against dengue vectors in large water-storage tanks.
- Reintroductions may be necessary for sustained control.
- Successes observed in certain regions but not widely replicated.

STATUS OF VACCINE FOR DENGUE Status of Vaccine for Dengue Fever:

FEVER Introduction
- Dengue fever, caused by the dengue virus (DENV), is a significant global health burden transmitted by
Aedes mosquitoes.
- The virus has four distinct serotypes (DENV-1, DENV-2, DENV-3, and DENV-4), increasing the risk of
severe diseases like dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).
- Vaccine development aims to prevent infection from all four serotypes to avoid antibody-dependent
enhancement (ADE).

Current Vaccine Development:

- Seven DENV vaccines based on various platforms are under development, including live attenuated viruses,
inactivated viruses, and recombinant proteins.
- The three most advanced vaccines are Dengvaxia®, TV003/TV005, and TAK-003, with promising clinical
trial results.

Clinical Evaluation:
- Dengvaxia® is the only licensed vaccine, while TV003/TV005 and TAK-003 are undergoing phase III trials.
- Age and serostatus of vaccinees impact efficacy and safety, with concerns raised from pediatric clinical
trials.
Challenges in Vaccine Development:
- Immunopathological events in DENV infections pose challenges, including overreactive immune responses
and molecular mimicry.
- Effective vaccines must induce strong neutralizing responses against all four serotypes to avoid
immunopathological events.

Safety Issues:
- Safety concerns include vaccine-induced antibody-dependent enhancement (ADE) and risk of severe
disease upon subsequent DENV infection.
- Dengvaxia® raised safety concerns, while TAK-003 has shown promising results in phase III trials.
- TV003/TV005 has demonstrated desirable immune responses but requires further evaluation.

Challenges and Opportunities:

- Vaccine developers face the challenge of achieving equal protection against all four serotypes without
causing adverse effects.
- Dengue epidemics continue to intensify, emphasizing the need for improved control measures and a
universal, highly effective vaccine.
- Safety remains a critical concern, driving the urgent need for an effective and safe dengue vaccine.