20.3 Hematopoietic & Lymphatic Infections: Dengue and Other Hemorrhagic Fevers, Malaria, Lymphatic Filariasis, Lymphogranuloma Venereum and Epstein-Barr Virus

Why this area matters

The TOS hematopoietic, lymphatic and immunologic area names:

• hemorrhagic fever;
• malaria;
• lymphogranuloma venereum;
• Epstein-Barr virus.

Dengue is the most important of these in the Philippines. It is endemic in every region, peaks in the rainy season and fills pediatric wards during outbreaks. Malaria is close to elimination but still transmitted in Palawan, and lymphatic filariasis remains a target of mass drug administration. Board questions test:

• dengue classification and fluids;
• diagnostic tests by day of illness;
• Plasmodium species features and primaquine;
• filarial periodicity;
• the EBV syndromes.

Arboviral Infections: Dengue Virus

Dengue virus (DENV) is an enveloped, single-stranded positive-sense RNA virus belonging to the family Flaviviridae, genus Flavivirus. It exists as four distinct, closely related serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. The primary vector across urban and peri-urban Philippine communities is Aedes aegypti (a day-biting, container-breeding mosquito marked by lyre-shaped thoracic stripes), with secondary transmission by Aedes albopictus.

Pathophysiology & Antibody-Dependent Enhancement (ADE)

Primary infection with one DENV serotype induces lifelong homotypic immunity to that specific serotype, but only short-lived (a few months) cross-protective heterotypic immunity to the remaining three serotypes. When an individual is infected years later by a heterologous serotype, pre-existing non-neutralizing antibodies bind to the new virions. Rather than clearing the virus, the antibody-virus complex binds via its Fc portion to Fc-gamma receptors on circulating monocytes and tissue macrophages.

This phenomenon—Antibody-Dependent Enhancement (ADE)—accelerates viral replication inside host macrophages by several logs. Infected macrophages release massive surges of inflammatory cytokines and chemical mediators (including tumor necrosis factor-alpha, interleukin-6, interleukin-8, and vascular endothelial growth factor). These mediators disrupt the endothelial glycocalyx and degrade tight junctions, precipitating sudden vascular hyperpermeability and capillary plasma leakage, which marks the transition to severe dengue.

Clinical Phases & DOH/WHO Triage Classification

Dengue characteristically evolves across three clinical phases:

1. Febrile Phase (Days 1 to 3): Sudden high fever ($39-40^\circ\text{C}$), facial flushing, retro-orbital headache, severe arthralgia ("breakbone fever"), positive tourniquet test, and leukopenia.
2. Critical Phase (Days 3 to 7, usually around defervescence): Rapid plasma leakage into pleural and peritoneal cavities. Patients are categorized under Philippine DOH and WHO guidelines into three management groups:
   • Dengue without Warning Signs: Patients with fever plus any two of: nausea/vomiting, rash, aches and pains, tourniquet test positive, leukopenia.
   • Dengue with Warning Signs: Clinical indicators signaling impending plasma leakage and shock:
     • Severe abdominal pain or tenderness
     • Persistent vomiting
     • Clinical fluid accumulation (pleural effusion, ascites)
     • Mucosal bleeding (epistaxis, gingival bleeding, menorrhagia)
     • Lethargy, restlessness, or altered sensorium
     • Hepatomegaly greater than 2 cm below the costal margin
     • Progressive increase in hematocrit concurrent with rapid decrease in platelet count
   • Severe Dengue: Manifested by:
     • Severe plasma leakage leading to Dengue Shock Syndrome (DSS) (narrow pulse pressure $\le 20\text{ mmHg}$, hypotension, prolonged capillary refill time) or respiratory distress
     • Severe bleeding (gastrointestinal hemorrhage evaluated by clinician)
     • Severe organ impairment (AST or ALT $\ge 1,000\text{ U/L}$, encephalopathy, myocarditis, acute kidney injury)
3. Recovery Phase (Days 7 to 10): Reabsorption of extravasated fluid, stabilization of hematocrit, return of appetite, and the appearance of a convalescent confluent erythematous rash with scattered round clearings ("islands of white in a sea of red") accompanied by intense pruritus.

Resuscitation & Fluid Management

For Dengue with Warning Signs, immediate hospital admission is mandatory. Intravenous fluid therapy must use isotonic crystalloids (0.9% normal saline or Ringer's lactate), initiated at $5-7\text{ mL/kg/hour}$ for 1 to 2 hours, titrating downward to $3-5\text{ mL/kg/hour}$ as perfusion and hematocrit improve. Hypotonic fluids (such as 0.45% NaCl or 5% dextrose in water) are contraindicated because they rapidly leave the vascular compartment, exacerbating third-space ascites and pleural effusions. Platelet transfusions are not recommended for thrombocytopenia alone and are reserved strictly for severe, life-threatening overt hemorrhage.

Dengue diagnosis and prevention in the Philippines

• Diagnosis by day of illness:
  • NS1 antigen and RT-PCR are positive during the first 5 days of fever;
  • IgM appears from about day 5;
  • IgG rises rapidly in secondary infection.
• Serial hematocrit and platelet counts track plasma leakage. A tourniquet test supports the diagnosis but cannot exclude it.
• Monitoring: watch closely through the critical phase. Shock often occurs as fever falls.
• What not to do:
  • do not give NSAIDs or aspirin;
  • do not give IM injections;
  • do not give steroids or prophylactic platelet transfusions.
• Prevention: the DOH promotes the 4S strategy:
  • Search and destroy mosquito breeding sites;
  • Secure self-protection (repellents, long sleeves, screens);
  • Seek early consultation;
  • Support fogging or spraying only in hotspot areas.
• Vaccine history: the school-based dengue vaccination program using CYD-TDV was stopped in 2017. Data had shown a higher risk of severe dengue in vaccinated people who had never had dengue.

Other viral hemorrhagic fevers and arboviruses

• Hantavirus:
  • carried by rodents and spread by inhaling their excreta;
  • causes hemorrhagic fever with renal syndrome, or a pulmonary syndrome.
• Chikungunya and Zika are spread by Aedes mosquitoes.
  • Chikungunya causes high fever and severe, sometimes persistent, polyarthralgia.
  • Zika is usually mild but causes congenital microcephaly and is linked to Guillain-Barré syndrome.
• Yellow fever, Ebola and Marburg are not endemic in the Philippines.
  • Travelers to yellow fever areas need vaccination and an international certificate.
  • Ebola is spread by contact with body fluids. It causes fever, vomiting, diarrhea and bleeding with high mortality, and needs strict infection control.

Blood & Tissue Protozoa: Plasmodium & Philippine Malaria Epidemiology

Malaria is caused by apicomplexan protozoa of the genus Plasmodium, transmitted to humans through the nocturnal bite of infected female Anopheles mosquitoes (the definitive hosts). In the Philippines, the primary vector is Anopheles flavirostris, which breeds in clean, slow-flowing, partly shaded foothill streams and bites mainly at night.

The Human Life Cycle

1. Exoerythrocytic (Hepatic) Phase: Mosquito inoculation introduces motile sporozoites into capillaries. Sporozoites reach the liver within 30 to 60 minutes, invading hepatocytes. Over 6 to 16 days, each sporozoite undergoes asexual multiplication (hepatic schizogony), forming an intrahepatic schizont containing thousands of merozoites. In P. vivax and P. ovale, a proportion of sporozoites differentiate into dormant hypnozoites, which remain quiescent in hepatocytes for months or years before awakening to cause true clinical relapses.
2. Erythrocytic Phase: Hepatic schizonts rupture, releasing merozoites into the bloodstream, which invade erythrocytes. Inside RBCs, merozoites develop from ring-form trophozoites into mature trophozoites, then into erythrocytic schizonts. Erythrocytic schizonts rupture, destroying the host RBC and discharging new merozoites, metabolic debris, and hemozoin pigment (malarial pigment) into the circulation. This rupture triggers massive host cytokine surges (TNF-alpha, IL-1), producing the classic malarial paroxysm (cold chills, high-spiking fever, followed by profuse diaphoresis). A subset of merozoites differentiate into sexual gametocytes, which are taken up by feeding mosquitoes during blood meals to complete sexual reproduction (sporogony).

Differential Features of Human Plasmodium Species

Pathogenesis of Severe Plasmodium falciparum Malaria

Plasmodium falciparum is the most lethal malarial parasite because it infects erythrocytes of all ages, achieving astronomical parasite densities, and expresses the surface adhesion protein PfEMP-1 (Plasmodium falciparum erythrocyte membrane protein 1). PfEMP-1 localizes to electron-dense "knobs" on the infected erythrocyte membrane, binding with high affinity to endothelial receptors—including ICAM-1 in the cerebral microvasculature, CD36, and chondroitin sulfate A in the placenta.

This binding causes cytoadherence (infected RBCs adhering to capillary endothelium) and rosetting (infected RBCs binding uninfected RBCs), resulting in microvascular sequestration and complete capillary obstruction. This drives local tissue ischemia, lactic acidosis, and endothelial breakdown, manifesting as:

• Cerebral Malaria: Severe encephalopathy, unarousable coma, generalized seizures, and cerebral edema.
• Blackwater Fever: Massive, catastrophic intravascular hemolysis resulting in severe hemoglobinuria, turning the urine dark brown or black, rapidly precipitating acute tubular necrosis and oliguric renal failure.
• Lactic Acidosis & Hypoglycemia: Lactic acidosis comes from microvascular obstruction and anaerobic glycolysis; hypoglycemia comes from parasite glucose consumption and impaired gluconeogenesis, and is worsened by quinine-induced hyperinsulinemia (especially in pregnancy).

Philippine Malaria Epidemiology & DOH Elimination Program

The Philippine malaria program has made steady progress toward elimination. By 2024, 72 of the country's 82 provinces were certified malaria-free and 9 more had recorded zero indigenous cases. Palawan remains the only province with sustained local transmission and the country's last hotspot. The Malaria Transition, Elimination and Sustainability Plan 2023 to 2028 targets zero cases in Palawan by 2026 and declaration of all provinces as malaria-free by 2030. Imported cases among overseas Filipino workers, seafarers, soldiers and travelers remain a reintroduction risk.

DOH Diagnostic & Therapeutic Guidelines

• Gold Standard Diagnostics: Microscopic evaluation of Giemsa-stained Thick and Thin Blood Smears:
  • Thick Smear: RBCs are lysed during staining, concentrating parasites 20- to 30-fold; used for detecting parasite presence and quantifying parasite density (parasites/uL).
  • Thin Smear: Preserves intact red cell morphology with methanol fixation; used for species identification and differentiating developmental stages.
  • Rapid Diagnostic Tests (RDTs) detecting P. falciparum histidine-rich protein 2 (HRP-2) and pan-species lactate dehydrogenase (pLDH) are used in peripheral clinics.
• First-Line Regimen for Uncomplicated P. falciparum: Artemisinin-based Combination Therapy (ACT). The Philippine DOH first-line regimen is Artemether-Lumefantrine (AL) (a 6-dose oral regimen given over 3 days). In addition, a single low dose of Primaquine (0.25 mg base/kg) is co-administered on Day 1 as a gametocidal agent to clear circulating gametocytes and prevent transmission to local mosquitoes (G6PD testing is not required for this single low gametocidal dose).
• First-Line Regimen for P. vivax and Radical Cure: Chloroquine (the national regimen for vivax, 25 mg base/kg over 3 days) or AL for blood schizonts, combined with Primaquine (0.25 to 0.50 mg base/kg daily for 14 days) to eliminate dormant liver hypnozoites (radical cure). MANDATORY PRECAUTION: Prior to starting the 14-day primaquine course, patients must undergo G6PD screening. In individuals with Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, primaquine generates intense intraerythrocytic oxidative stress, causing massive, life-threatening acute intravascular hemolytic anemia.
• Severe Malaria Management: Intravenous Artesunate (2.4 mg/kg IV administered at 0, 12, and 24 hours, then once daily) is the first-line treatment of choice, transitioning to a full 3-day course of oral AL once the patient tolerates oral intake.

Lymphatic Filariasis in the Philippines

Lymphatic filariasis is a mosquito-borne disease caused by tissue nematodes that reside within human lymphatic vessels and lymph nodes.

Etiologic Agents & Vector Biology

• Wuchereria bancrofti: The main cause of lymphatic filariasis in the Philippines. The primary rural vector is Aedes poicilius, an unusual night-biting mosquito that breeds preferentially in the water trapped in the axils of banana and abaca (Musa textilis) plants. Secondary vectors include Culex quinquefasciatus and Anopheles flavirostris.
• Brugia malayi: A minor cause, found in a few swampy foci; transmitted mainly by Mansonia mosquitoes, which breed in freshwater swamps among aquatic plants such as Pistia.

Microfilarial Periodicity & Morphologic Differentiation

Microfilariae demonstrate strict nocturnal periodicity in peripheral blood, remaining sequestered deep in the pulmonary microvasculature during daylight hours and peaking in the peripheral circulation between 22:00 and 02:00 (synchronizing with vector biting habits). Diagnostic blood films must be drawn during this midnight window.

Clinical Progression & DOH Mass Drug Administration (MDA)

1. Asymptomatic Phase: Subclinical microfilaremia with progressive lymphatic dilation and microscopic hematuria/proteinuria.
2. Acute Phase: Acute Adenolymphangitis (ADL) presenting with high fever, chills, painful retrograde lymphangitis (inflammation spreading centrifugally down an extremity from proximal nodes), funiculitis, and acute epididymo-orchitis.
3. Chronic Phase: Irreversible lymphatic vessel obliteration leading to profound, non-pitting lymphedema, brawny induration, verrucous hyperkeratosis, and severe elephantiasis of the lower extremities, scrota, and labia; rupture of obstructed retroperitoneal lymphatics into the renal collecting system produces chyluria (milky white, lipid-rich urine).
4. National Elimination Strategy: The Philippine DOH implements annual Mass Drug Administration (MDA) in endemic provinces: single-dose Diethylcarbamazine citrate (DEC, 6 mg/kg) combined with Albendazole (400 mg) administered once annually for at least five consecutive years, accompanied by vector control and morbidity management (scrotal hydrocelectomy and limb hygiene to prevent secondary bacterial dermato-lymphangitis).

Lymphogranuloma venereum (LGV)

• Cause: LGV is caused by the invasive Chlamydia trachomatis serovars L1, L2 and L3, which infect macrophages and lymphatic tissue rather than only mucosal epithelium.
• Primary stage: a small, painless papule or ulcer that heals quickly and is often unnoticed.
• Secondary stage: painful, matted inguinal lymphadenopathy, 2 to 6 weeks later. Nodes above and below the inguinal ligament produce the groove sign, and they may form buboes that drain through sinuses.
• Anorectal LGV: in men who have sex with men and in women it causes proctocolitis, with rectal pain, discharge and bleeding. Untreated, it can lead to strictures, fistulas and genital elephantiasis (esthiomene).
• Diagnosis is by nucleic acid testing. Treatment is doxycycline 100 mg twice daily for 21 days, with aspiration of fluctuant nodes.

Epstein-Barr virus (EBV)

• Biology: EBV is a herpesvirus that enters B cells through CD21 and remains latent in memory B cells. It spreads through saliva ("kissing disease").
• Infectious mononucleosis:
  • mainly in adolescents and young adults;
  • fever, exudative pharyngitis, posterior cervical lymphadenopathy, fatigue, splenomegaly and hepatitis.
  • Lab findings are atypical lymphocytes (reactive CD8 T cells, called Downey cells) and heterophile antibodies (Monospot test). EBV-specific antibodies such as VCA IgM are used in young children.
  • Patients given ampicillin or amoxicillin often develop a maculopapular rash.
  • Patients should avoid contact sports for at least 3 weeks because the enlarged spleen can rupture.
• EBV-associated tumors and lesions:
  • Burkitt lymphoma (t(8;14), c-myc);
  • nasopharyngeal carcinoma, common in Southeast Asia;
  • Hodgkin lymphoma;
  • primary CNS lymphoma in AIDS;
  • post-transplant lymphoproliferative disorder;
  • oral hairy leukoplakia in HIV.
• X-linked lymphoproliferative disease causes fatal mononucleosis in boys with an inherited immune defect.