L-16 Malaria and Blood Pathogens

Pathogens Affecting Hematopoietic and Lymph Systems

• Bold pathogens in the table are covered in the self-study, others in self-study #1 and #2.
• Lymphocytes can be infected by Epstein Barr Virus (EBV), leading to infectious mononucleosis or lymphoma.
• Macrophages can be infected by Bartonella henselae, leading to cat-scratch disease.
• Erythrocytes can be infected by Plasmodium, leading to malaria.

Malaria Epidemiology

• Malaria is found in tropical and subtropical areas.
• In 2022, there were ~249 million cases and 608,000 deaths worldwide.
• 76% of malaria deaths are in children.
• About 2,000 cases are diagnosed every year in the United States, usually from immigration not local transmission.

Malaria Pathogen

• Malaria is caused by obligate intracellular protozoan parasites.
• These parasites include Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, and Plasmodium falciparum.

Malaria: Life-Cycle and Transmission

• Anopheles mosquitoes act as vectors, injecting plasmodium sporozoites into humans.
• Sporozoites infect liver cells and mature into schizonts, which rupture and release merozoites into the blood.
• P. ovale and P. vivax can stay dormant in the liver for weeks to years.
• Merozoites infect erythrocytes (RBCs), cycling through a ring cell stage and back to schizonts.
• Schizonts rupture RBCs, continuing the cycle.

Malaria: Clinical Manifestations

• Malaria has two forms: Benign Tertian/Quartan and Malignant Tertian.
• Incubation period is two weeks or longer.
• Brief prodromal symptoms of malaria include fevers, headache, joint pain, and myalgia.
• The cold stage involves shaking chills and high fever lasting about 24 hours.
• During the wet stage, the fever breaks and there is profuse sweating.
• The patient is tired, but feels okay until the cycle repeats.
• Benign tertian fever occurs on the 3rd day and is associated with P. vivax or P. ovale.
• Benign quartan fever occurs on the 4th day and is associated with P. malariae.
• Malignant tertian tends to be more severe, is associated with P. falciparum, and has fevers that are continuous.
• Malignant tertian fever causes capillary blockage, leading to convulsions, coma, cardiac failure, and acute pulmonary insufficiency.
• Black-water fever is a symptom of malignant tertian fever, causing dark-colored urine.

Malaria: Signs and Symptoms

• Erythrocytes are the heme or lymph cells affected by malaria.
• Anemia occurs secondary to RBC hemolysis, phagocytosis of infected RBCs, capillary hemorrhage, thrombosis, and decreased marrow function.
• Local hemorrhage and anoxia occur when infected RBCs and immune complexes occlude capillaries.
• Organs affected are the brain, lungs, and liver.
• Pallor is secondary to anemia.
• Hepatosplenomegaly may be present due to increased macrophages in the organs.
• Jaundice occurs secondary to liver damage.
• Dark colored urine (hemoglobinuria) occurs secondary to intravascular hemolysis in the kidney.

Malaria Diagnosis and Treatment

• Peripheral blood smear is used for diagnosis, using Wright or Giemsa stain to show parasites with a ring form.
• Rapid detection and serological testing, including PCR, are other diagnostic tools.
• Artesimin class drugs with antimalarials are first choice for treatment.
• Artemisins include artesumate and artemethur.
• Antimalarials include chloroquine, quinine sulfate + doxycycline/tetracycline/clindamycin, atovaquone-proguanil & mefloquine.
• Prevention involves mosquito control through nets, window screens, long sleeves, and bug spray.
• Malaria vaccines are available for children in malaria endemic areas.
• Chemoprophylaxis includes medication while travelling.
• Chemoprophylaxis options are Chloroquine or other medications where there is endemic resistance.

Epstein Barr Virus (EBV)

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

EBV: Epidemiology

• It is found worldwide.
• By the age of 25, 90% of people in the United States are seropositive for EBV.
• It is most common in 15-25 years old in the United States.
• In developing countries, it is more common in early childhood.
• Many cases are asymptomatic.
• Infectious Mononucleosis is the most common presentation.

EBV: Life-Cycle and Transmission

• EBV is spread from human to human through close saliva contact ("Kissing diease").
• It can also be spread through respiratory droplets or blood transfusion.
• It enters human B-cells in the oropharyngeal epithelium via the CD21 Receptors.
• Infected B-cells spread throughout the body, including the spleen, liver, and peripheral nodes, where both B-cells and T-cells will proliferate.
• Cellular immunity (suppressor and cytotoxic T-cells, NK cells) helps to control the proliferation of EBV.
• Activated B-cells produce antibodies to EBV Ag and to Ag from other mammals, resulting in heterophile antibodies.
• Memory B cells serve as a reservoir for EBV in the body.

EBV and Infectious Mononucleosis - Symptoms, Findings, Changes

• Prodrome lasts 1-2 weeks with malaise, myalgia, and fatigue.
• Symptoms of mono may last 2-4 weeks and include fever, pharyngitis, fatigue, and rash.
• Physical findings include hepatosplenomegaly caused by lymphocytic infiltration and cervical lymphadenopathy caused by the infected B-cells.
• EBV can cause atypical lymphocytes with abundant cytoplasm, vacuoles, and indentations of the cell membrane.
• Common hematologic changes related to EBV include thrombocytopenia & neutropenia.
• Rare hematologic changes from EBV include aplastic anemia and pancytopenia.

EBV: Clinical Manifestations & Long Term Complications

• Alternative acute presentations include hepatitis, myocarditis, pericarditis, pneumonia, and interstitial nephritis.
• EBV can cause infections of the CNS including meningitis, encephalitis, optic neuritis, transverse myelitis, Guillain-Barre Syndrome, and acute cerebellar ataxia.
• Long term complications include aplastic anemia and cancer, for example Hodgkin Lymphoma and nasopharyngeal carcinoma.
• HIV-associated presentations of EBV include non-Hodgkin Lymphoma, Burkitt Lymphoma, CNS lymphoma, and oral hairy leukoplakia.

EBV: Diagnosis and Treatment

• Diagnosis can be via Monospot Test but is only positive during acute infection.
• EBV serology can be measured with EBV Anti-VCA IgM (acute), EBV Anti-VCA IgG (acute and past), and Anti-EBNA (past).
• Peripheral smear evaluation shows atypical lymphocytes.
• Treatment involves no specific medications since EBV is self-limited.
• Treatment is supportive and includes fluids and rest.
• It's important to restrict patients from sports to prevent splenic injury.
• Prevention of EBV includes avoiding saliva sharing by not kissing or sharing glasses, food, or toothbrushes.
• Misdiagnosis as strep throat and treatment with penicillin or amoxicillin may result in a diffuse maculopapular rash.
• If EBV patients also have HIV, they can develop Oral Hairy Leukoplakia with CD4 counts > 500.
• If EBV patients also have HIV with CD4 count < 100, they can develop Non-Hodgkin B Cell lymphoma, particularly Burkitt Lymphoma, and CNS Lymphoma.