L-16 Malaria and Epstein Barr Virus

Malaria and Epstein Barr Virus: Pathogens of the Hematopoietic and Lymphoreticular System

• Pathogens affecting both hematopoietic and lymph systems are covered.
• The pathogens in bold text are the pathogens covered in this self-study
• Malaria: Benign tertian is caused by Plasmodium vivax.
• Malaria: Benign quartan is caused by Plasmodium malariae.
• Malaria: Malignant tertian is caused by Plasmodium falciparum.
• Infectious mono/Lymphoma is caused by Epstein Barr Virus (EBV).

Malaria

• Malaria is caused by Plasmodium.
• Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, and Plasmodium falciparum are obligate intracellular protozoan parasites.
• It is found in tropical and subtropical locations.
• Africa, Asia, the Middle East, Central and South America, Hispaniola (Haiti and Dominican Republic), and Oceania are endemic areas.

Malaria Epidemiology

• In 2022, there were ~249 million malaria cases and 608,000 deaths worldwide.
• Approximately 76% of malaria deaths occur in children.
• About 2,000 cases are diagnosed yearly in the USA with immigration as a major factor.

Malaria: Life-cycle and transmission

• Anopheles mosquitoes are the vector.
• Mosquitoes inject plasmodium sporozoites into humans.
• Sporozoites infect liver cells and mature into schizonts.
• Schizonts rupture, which releases merozoites into the patient's blood.
• P. ovale and P. vivax can stay dormant in the liver for weeks to years.
• Merozoites infect erythrocytes (RBCs) and cycle again via the ring cell stage back to schizonts.
• Schizonts rupture RBCs.
• Hemolysis occurs during the cycle.

Malaria: Clinical Manifestations

• Benign Tertian caused by P. vivax or P. ovale, includes fever every third day.
• Benign Quartan caused by P. malariae, includes fever every fourth day.
• Incubation: Two weeks or longer.
• Brief prodromal: Fevers, headache, joint pain and myalgia.
• Cold stage: Shaking chills and high fever lasting ~24 hrs.
• Wet stage: Fever breaks with profuse sweating, patient is tired but feels ok until the next cycle begins a few days later.
• Malignant Tertian caused by P. falciparum is more severe.
• The cold stage is less pronounced or not present, but fevers are continuous.
• It causes capillary blockage potentially leading to convulsions, coma, cardiac failure, acute pulmonary insufficiency, and black-water fever, which is dark-colored urine.

Malaria: Signs and Symptoms

• The malaria pathogen affects erythrocytes.
• Anemia is a secondary effect of RBC hemolysis, phagocytosis of infected RBCs, capillary hemorrhage, thrombosis, and decreased marrow efficiency.
• Local hemorrhage and anoxia are the result of infected RBCs and immune complexes occluding capillaries, which results in local hemorrhage and anoxia in the brain, lungs, and liver.
• Pallor due to anemia
• Hepatosplenomegaly occur because of increased macrophages in the organs
• Jaundice secondary to liver damage
• Dark-colored urine (hemoglobinuria) occurs secondary to intravascular hemolysis in the kidney.

Malaria: Diagnosis

• Diagnose with a peripheral smear.
• Wright or Giemsa stain showing a parasite in RBC
• "Ring form" may be visible.
• Diagnosie with a rapid detection test or serology.
• PCR, Agar diffusion, passive hemagglutination, immunofluorescence, and ELISA may be used for serology.
• Look for malaria-specific antibodies.

Malaria: Treatment and Prevention

• Artemisinin class drug + antimalarial
• Artemisins: artesunate, artemethur
• Antimalarials: Chloroquine and Quinine sulfate + (doxycycline, tetracycline, clindamycin), Atovaquone-proguanil, and Mefloquine
• Preventing mosquito bites:
  • Nets and window screens
  • Long sleeves and bug spray
  • Insecticide
• Malaria vaccine for children in malaria-endemic areas
• Chemoprophylaxis: Medication while traveling to areas of endemic transmission, Chloroquine, or other treatment if there is endemic resistance

Epstein Barr Virus (EBV)

• EBV is a double stranded DNA virus, and is also known as Human Herpes Virus-4 (HHV-4)
• Causes infectious mononucleosis, Hodgkin and Burkitt lymphoma, CNS Lymphoma and oral hairy leukoplakia.

EBV: Epidemiology

• Found worldwide
• By the age of 25 years, about 90% in the United States are seropositive for EBV.
• United States: Most common in 15-25 year olds.
• Developing countries: More common in early childhood
• Many are asymptomatic.
• Infectious mononucleosis is the most common presentation.

EBV: Life-cycle and transmission

• EBV spreads human to human through close saliva contact, respiratory droplets, and/or blood transfusion.
• It enters Human B-cells in the oropharyngeal epithelium via the CD21 Receptors.
• Infected B-cells spread to spleen, liver, and peripheral nodes --> B- and T-cells proliferate
• Cellular immunity (suppressor/cytotoxic T-cells, NK cells) controls EBV proliferation.
• Activated B-cells produce EBV Ag antibodies and Ag antibodies from other mammals → heterophile antibodies.
• Memory B cells serve as a reservoir for EBV.

EBV Clinical Presentation: Infectious Mononucleosis

• Symptoms include a 1-2 wk prodrome of malaise, myalgia, and fatigue, followed by 2–4 weeks of fever, pharyngitis, fatigue, and rash.
• Physical Exam Findings: Hepatosplenomegaly caused by lymphocytic infiltration, and cervical lymphadenopathy caused by infected B-cells

EBV: Clinical Manifestations, Alternative Acute Presentations

• Hepatitis, Myocarditis, Pericarditis, Pneumonia, Interstitial Nephritis

EBV Clinical Manifestations: Central Nervous System Infections

• Meningitis, Encephalitis, Optic Neuritis, Transverse myelitis, Guillain-Barre Syndrome, Acute cerebellar ataxia

EBV Clinical Manifestations: Long Term Complications

• Aplastic Anemia , Cancer (Hodgkin Lymphoma and Nasopharyngeal carcinoma)
• HIV-associated Presentations: Non-Hodgkin Lymphoma, Burkitt Lymphoma, CNS lymphoma, and Oral Hairy Leukoplakia

EBV infections affect B Cell lymphocytes.

EBV Diagnosis

• "Monospot Test": a heterophile antibody test that is only positive during acute infection
• EBV Serology: EBV Anti-VCA IgM (acute), EBV Anti-VCA IgG (acute and past), and Anti-EBNA (past)
• Peripheral Smear: atypical lymphocytes

EBV Hematologic Changes

• Atypical Lymphocytes: Abundant Cytoplasm, Vacuoles, Indentations of the cell membrane
• Common: Thrombocytopenia, Neutropenia
• Very Rare: Aplastic Anemia/Pancytopenia

EBV: Treatment and Prevention

• There is no specific treatment available.
• EBV infection is self-limited.
• Treatment is supportive with fluids and rest.
• It is important to restrict activity/sports to prevent splenic injury.
• Prevention: Avoid sharing saliva by kissing, sharing glasses or food, and toothbrushes.
• Patients misdiagnosed with strep throat who are treated with Penicillin/Amoxicillin may get a diffuse maculopapular rash.

EBV Co infection with HIV

• CD4 count > 500: leads to Oral Hairy Leukoplakia .
• CD4 Count < 100: leads to Non-Hodgkin B Cell lymphoma and/or CNS Lymphoma with ring enhancing lesions on MRI.
• Important to consider a Differential Diagnosis of Toxoplasmosis.