Malaria 2024 Lecture Notes PDF

FOM 6: Parasites of the Blood Part 1: Malaria and Babesiosis Michelle Steinauer, Ph.D.  Learning Objectives For malaria: – Know the major species of Plasmodium that cause malaria along with their unique features, and distributions – Know the lif...

FOM 6: Parasites of the Blood Part 1: Malaria and Babesiosis Michelle Steinauer, Ph.D.  Learning Objectives For malaria: – Know the major species of Plasmodium that cause malaria along with their unique features, and distributions – Know the life cycle of malaria especially the development within the human host, and be able to relate this to the disease process and symptoms. – Be able to recognize a case of malaria given the symptoms, disease course, epidemiologic factors, and/or diagnostics. – Understand how to diagnose malaria and the key diagnostic differences of the species of Plasmodium. – Understand the difference between complicated and uncomplicated malaria and especially cerebral malaria. – Understand relapse and recrudescence. – Understand how sickle celled anemia has affected the distribution of Plasmodium species. – Understand prevention of malaria – Understand the basics of drug treatment of malaria For Babesiosis: – Understand the life cycle and transmission of Babesia parasites in humans especially compared to malaria – Know the geographic areas in the US where babesiosis is common – Understand the disease course of babesiosis and be able to recognize a case of babesiosis given the symptoms, disease course, epidemiologic factors, and/or diagnostics. – Understand how to diagnose infection – Understand treatment of babesiosis  Background Reading Despommier, Griffin, Gwadz,Hotez, Knirsch. Parasitic Diseases, 7th Edition – Free Download: http://www.parasiteswithoutborders.com/parasitic- diseases-6th-edition Harrison’s Internal Medicine. Chapter 210. Malaria. Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. Relevant sections.  Lecture Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Malaria Statistics (WHO) 2022: 249 million cases worldwide 2022: 609,000 deaths Pandemic disruptions – 13 million more malaria cases and 63,000 more deaths Distributed throughout the tropics and subtropics where vectors occur. – Africa carries a disproportionally high share of cases (94%) and deaths (95%) - Children under 5 accounted for 80% - Of all malaria deaths. https://www.who.int/news-room/fact-sheets/detail/malaria#: https://asm.org/Articles/2023/September/The-History-of-Malaria-in-the- United-States  Malaria in the U.S. Eliminated in early 1950’s – But we still have mosquito vectors ~2000 cases diagnosed in the US per year – Mostly travelers including immigrants and descendants of immigrants – outbreaks of local transmission https://emergency.cdc.gov/han/2023/han00494.asp  Species that cause malaria Plasmodium falciparum – Over 50% malaria cases, cause severe disease Plasmodium vivax – Second most common, cause relapsing episodes Plasmodium malariae – Cosmopolitan, but spotty Plasmodium ovale – West Africa, Indopacific islands, has dormant stage Plasmodium knowlesi – Indopacific and Asia. Rare but highly pathogenic.  Plasmodium falciparum The mapped variable is the age-standardised P. falciparum Parasite Rate (PfPR2-10) which describes the estimated proportion of 2-10 year olds in the general population that are infected with P. falciparum at any one time, averaged over the 12 months of 2010. http://www.map.ox.ac.uk  Plasmodium vivax The mapped variable is the age-standardised P. vivax Parasite Rate (PfPR0-99) which describes the estimated proportion of the general population that are infected with P. vivax at any one time, averaged over the 12 months of 2010. http://www.map.ox.ac.uk Plasmodium malariae and P. ovale Both relatively rare, have spotty distributions. Infections often mild and often undiagnosed. P. ovale comprises 2 sister species/subspecies Malar J 2022 May 3;21(1):138. doi: 10.1186/s12936-022-04151-4.  Lecture Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Vector Mosquitoes of the genus Anopheles – 30-40 species Note body position Hepatic cycle Erythrocytic cycle Hepatic cycle Sporozoites enter liver cell Feed and asexually reproduce Some can become dormant (P. vivax and ovale) hypnozoite) Merozoites released ~10-15 days Erythrocytic cycle Merozoites enter RBC Trophozoites – Feeding – Ring trophs Schizonts – Asexual Reproduction Merozoites – Progeny that invade cells – Repeat cycle Some merozoites develop into gametocytes – Gametes that mate in a mosquito stomach  Relapse and Recrudescence Relapse: – P. vivax and P. ovale – Hypnozoites (dormant in the liver) – Typically within 3-5 years Recrudescence – Typically P. falciparum – NO hypnozoites in liver – Low levels of parasites in RBCs Held in check by immune response Incomplete treatment – Often within months  Erythrocytic Stages: Diagnostics Ring trophozoites Gametocytes Hemozoin  Feeding ring trophozoite or ring troph Hemozoin (polymer of heme) http://www.sciencecentric.com/news/08042506-elusive-protein-protects- malaria-parasite-from-heme.html trophozoite or ring troph Schizont Microgametocyte Macrogametocyte P. vivax Schüffner’s dots P. malariae P. ovale Schüffner’s dots P. falciparum Shape of Gametocyte  P. vivax gametocyte Schuffner’s dots- bright red dots (P. vivax and P. ovale) Credits: Liverpool School of Tropical Medicine Image Collection 23  Morphology Summary Parasites inside RBC Multiple ring trophs/cell = P. falciparum Elongate gametocyte = P. falciparum Shuffners dots = P. vivax or P. ovale Infected cell larger = P. vivax  Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Clinical Malaria Risk group – High risk : travelers with no prior exposure to malaria or have lost their immunity if they left endemic area long time ago. – Low risk : In endemic area, older children and adults develop partial immunity after repeated infections. Incubation period: – P falciparum: within one month, as early as 7 days – P vivax : within 2 weeks, relapse upto 3 years.  Clinical Malaria Uncomplicated malaria – Tropical fever—classically periodic “paroxysms” Periods of chills followed by fever, with break in between “intermittent fever” Not always intermittent Complicated malaria (severe malaria) – Many manifestations, multiple organ failure – Cerebral  Uncomplicated Malaria Acute febrile illness Tropical fever Cytokine response to parasite metabolites Periodic cycles of fever = paroxysms Children can have febrile seizures Severe myalgia, headache, tachycardia Anemia-hemolysis of RBC Splenomegaly-enlargement due to hyperactivity , clearance of ruptured RBCs, and infected RBCs  Annoyed Asymptomatic to myalgia, malaise, headache, backache 10-15 days Fever paroxysms, anemia, splenomegaly, myalgia, abdominal discomfort. Can become chronic.  Paroxysm The Malarial Paroxysm cold stage hot stage sweating stage feeling of intense cold intense heat profuse sweating vigorous shivering dry burning skin declining temperature lasts 15-60 minutes throbbing headache exhausted and weak → lasts 2-6 hours sleep lasts 2-4 hours Cycles continue for 10 days to 4 weeks if untreated http://www.tulane.edu/~wiser/protozoology/notes/malaria.html  Definition of severe malaria Acidosis- rapid deep A base deficit of >8 mEq/L, a plasma bicarbonate level of 50 umol/L (3 mg/dL) with one of the following:Plasmodium Jaundice falciparum parasite count >2.5% parasitemia Plasmodium knowlesi parasite count >20,000 parasites/uL Pulmonary Radiographically confirmed or oxygen saturation 30/minute, edema/ARDS and crepitations on auscultation Including recurrent or prolonged bleeding (from the nose, gums, or venipuncture sites), hematemesis, Coagulopathy/DIC or melena Compensated shock is defined as capillary refill ≥3 seconds or temperature gradient on leg (mid to proximal limb), but no hypotension. Shock Decompensated shock is defined as systolic blood pressure 10% Hyper parasitemia P. knowlesi: Parasite density >100,000 parasites/uL Plasmodium vivax: No established parasite density thresholds  Severe or Complicated Malaria Usually due to P. falciparum Who is at risk? – Those naïve to infection – Children – Travelers Cerebral malaria – encephalopathy that presents with impaired consciousness, delirium, and/or seizures Blackwater fever – urine turns dark – intravascular hemolysis, hemoglobinuria, and acute renal failure Multiple organ failure Mortality rate 15-20% – Higher in children 8 mEq/L, a plasma bicarbonate level of 50 umol/L (3 mg/dL) with one of the following:Plasmodium Jaundice falciparum parasite count >2.5% parasitemia Plasmodium knowlesi parasite count >20,000 parasites/uL Pulmonary Radiographically confirmed or oxygen saturation 30/minute, edema/ARDS and crepitations on auscultation Including recurrent or prolonged bleeding (from the nose, gums, or venipuncture sites), hematemesis, Coagulopathy/DIC or melena Compensated shock is defined as capillary refill ≥3 seconds or temperature gradient on leg (mid to proximal limb), but no hypotension. Shock Decompensated shock is defined as systolic blood pressure 10% Hyper parasitemia P. knowlesi: Parasite density >100,000 parasites/uL Plasmodium vivax: No established parasite density thresholds  Polling qs What is the most likely etiological agent? A. P Falciparum B. P vivax C. P ovale D. P malaraei  Polling qs Which of the following would you expect on thin smear? & A. Schuffner dots B. Multiple rings C. large RBCs D. A band in RBC P. vivax Schüffner’s dots P. malariae & P. ovale Schüffner’s dots P. falciparum  Case Presentation Severe malaria was diagnosed, complicated by multi-organ failure including respiratory, renal, and hepatic failure; septic shock; and disseminated intravascular coagulation. The acute toxic-metabolic encephalopathy was most likely due to cerebral malaria. The acute hypoxemic respiratory failure evolved into acute respiratory distress syndrome driven by the shock and severe acidemia, so vasopressors and steroids were started. Infectious disease consultation was obtained and an infusion of _____________________________ was given.  Polling qs Which of the following is the best treatment? A. IV artesunate B. IV quinidine C. IV tetracycline D oral Artemether-lumefantrine Severe Malaria: Antimalarial Therapy – All species, drug susceptibility not relevant for acute treatment of severe malaria – IV artesunate: IV doses (3 in total) at 0, 12 and 24 hours – If IV artesunate not readily available, give oral antimalarials while obtaining IV artesunate. Artemether-lumefantrine (Coartem®) (preferred); or Atovaquone-proguanil (Malarone ); or Quinine sulfate; or Mefloquine (only if no other options available)  Case Presentation infusion of intravenous (IV) artesunate was started….. What is the mechanism of action? What are the common side effects?  Case Presentation Should this patient be given primaquine?  Treatment of Hypnozoites Prevent Relapse – P. vivax – P. ovale Primequine – Except patients with G6DP deficiency – https://www.ncbi.nlm.nih.gov/books/NBK592855/  Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Blood Disorders Associated with Malaria Resistance Sickle cell Duffy Blood Groups – RBCs that lack Duffy antigens are resistant to Balancing selection has invasion by P. vivax maintained alleles for Thalassemia these disorders in human populations in – Alteration of globin chain areas where malaria synthesis transmission is high G6PD Heme oxygenase polymorphism Sickle Cell and Falciparum malaria Sickle Cell Disease Inherited blood disorder Mutation in hemoglobin gene (amino acid change) Oxygen dependent Abnormal, rigid sickle shaped cells Codominant expression Codominance “Carriers” express both types of hemoglobin, but asymptomatic Two mutant alleles necessary to have the disease  Sickle cell trait: Heterozygotes: reduce malaria admission rates by 70% 90% protective against severe and complicated malaria reduces severe malarial anemia by 60% Aidoo M, Terlouw DJ, Kolczak MS et al. (2002) Protective effects of the sickle cell gene against malaria morbidity and mortality. The Lancet 359, 1311–1312. Williams TN, Mwangi TW, Wambua S et al. (2005) Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. Journal of Infectious Diseases 192, 178–186.  Blood Disorders Associated with Malaria Resistance Duffy Blood Groups – RBCs that lack Duffy antigens are resistant to invasion by P. vivax Large portion of African populations are “Duffy negative”. Selective advantage to reduced susceptibility to malaria P. vivax not common in Africa Recent reports of P. vivax parasites that have mutations that enable invasion of “Duffy negative” people. – Golassa, L., Amenga-Etego, L., Lo, E. et al.. Malar J 19, 299 (2020)  Plasmodium vivax The mapped variable is the age-standardised P. vivax Parasite Rate (PfPR0-99) which describes the estimated proportion of the general population that are infected with P. vivax at any one time, averaged over the 12 months of 2010. http://www.map.ox.ac.uk  Blood Disorders Associated with Malaria Resistance Sickle cell Duffy Blood Groups – RBCs that lack Duffy antigens are resistant to Balancing selection has invasion by P. vivax maintained alleles for Thalassemia these disorders in human populations in – Alteration of globin chain areas where malaria synthesis transmission is high G6PD Heme oxygenase polymorphism  Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Babesiosis CDC 2020 Tick Vectored Zoonosis – Common blood parasite of mammals and birds – >100 species – Distributed globally Species – Babesia microti Northeastern U.S. and upper Midwest U.S. – Babesia divergens Midwest U.S. & Europe – Babesia duncani West coast U.S. rare ~2000 cases/year reported Mild flu-like illness Elderly, asplenic or immunocompromised→ malaria like Cases of Clinical Babesiosis Who is at risk for clinical disease?  Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Babesiosis Zoonosis Domestic and wild mammals Vector: Tick – Ixodes I. scapularis I. pacificus No hepatic stage Trophs, ring shaped, pear shaped or irregular. Maltese cross is diagnositic http://smom-za.org/MalteseCross/medicine.htm  Babesiosis Parasitemia – 1-20% – 85% in asplenic No hemozoin  Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Clinical Babesiosis Often asymptomatic – Serologic surveys Symptoms are generally mild in the young and healthy Elderly, immunocompromised, or asplenic have more severe symptoms. Symptoms: 2 weeks, but can last months – Fever >38C (intermittent or persistent), shaking, chills, sweating – Malaise, myalgia, arthralgia, and shortness of breath – Anemia – Most severe in asplenic, immunocompromised and elderly  Diagnosis and Treatment Diagnosis – Microscopy Maltese cross Multiple blood smears – PCR test – Serologic indirect immunofluorescent antibody (IFA) CDC enzyme-linked immunosorbent assay (ELISA) B. microti Treatment – Azithromycin plus atovaquone or – Clindamycin plus quinine  Babesiosis Summary Zoonotic infection Looks like malaria – Elderly, asplenic, immunocompromised Tick borne/blood transfusion – Summer transmission Erythrocytic infection (no hepatic cycle) – Hemolysis and anemia Mild flu/febrile illness Epidemiology – Older folks more likely to have clinical symptoms – Geography—East coast and Upper Midwest  Outline Malaria – Species and geographic distribution – Life cycle and vector distribution – Clinical malaria Uncomplicated Complicated – Diagnostics – Pharmacology of malaria drugs – Treatment – Blood disorders and malaria Babesia – Species and distribution – Life cycle – Clinical babesiosis – Diagnostics and treatment  Review Questions 1. A 28-year-old female is planning to travel to a malaria-endemic region. She has a history of G6PD deficiency. Which of the following prophylactic drugs should be avoided in her case? A) Mefloquine B) Doxycycline C) Atovaquone/proguanil O D) Primaquine 2. A 40-year-old man is being treated for chloroquine-resistant malaria with quinine and doxycycline. He develops tinnitus and dizziness. Which adverse effect is the patient likely experiencing, and which drug is responsible? A) Retinopathy due to quinine B) Nephrotoxicity due to doxycycline G C) Cinchonism due to quinine D) Hypoglycemia due to doxycycline  A 16-year-old girl who is an exchange student from Panama is brought to the ED by her host family because of a high-grade fever and delirium. She has had 2 episodes of similar symptoms during the past 2 years. A peripheral blood smear shows punctate granulations in enlarged erythrocytes containing oval bodies. Which is the most likely cause? A. Plasmodium falciparum O B. Plasmodium vivax C. Plasmodium malariae D. Plasmodium ovale E. Dengue fever From Kaplan Test Prep 117  P. vivax gametocyte Schuffner’s dots- bright red dots (P. vivax and P. ovale) Credits: Liverpool School of Tropical Medicine Image Collection 118  Is cerebral malaria likely? A. Yes O B. No 119  A 56-yr-old man, who lived in the upper midwestern USA presented to the Emergency Department at a local hospital during August with a 2-wk history of fever up to 103°F, chills, myalgia, and 10-pound weight loss. He has never left the country. A blood smear showed the following: A. Plasmodium vivax B. Plasmodium malariae 8 C. Plasmodium falciparum D. Babesia microti  Which ontogenetic stage of Plasmodium is inoculated into humans from a mosquito? A. Schizont B. Merozoite C. Hypnozoite & D. Sporozoite E. Gametocyte  Where does the sporozoite go in the human body once inoculated by a mosquito? A. Red blood cell B. Macrophage C. Hepatocyte O D. Renal endothelial cell Hepatic cycle Sporozoites enter liver cell Feed and asexually reproduce Some can become dormant (P. vivax and ovale) hypnozoite) Merozoites released ~10-15 days  Question A 68-year-old patient presented to the ED in Massachusetts with malaise, body aches and labored breathing upon exertion. Initial labs showed elevated liver enzymes and mild pancytopenia (low blood cell and platelet count). Her clinical status worsened over the course of three days as seen by the development of severe mixed anion gap and non-anion gap metabolic acidosis complicated by significant respiratory distress and a new requirement for blood pressure support. A blood smear showed the following: What is the most likey pathogen? OA.B. Plasmodium – – Babesia microti falciparum – C. Plasmodium vivax – D. Borrelia burgdorferi – E. Anaplasma phagocytophilum Case from: https://advances.massgeneral.org/research-and-innovation/case-  Question Continued What is appropriate treatment for the patient? A. IV artesunate B. atovaquone and azithromycin C. doxycycline D. hydroxychloroquine E. artemisinin combination therapy  Question Continued How did this patient get infected? A. Bite of an Anopheles B. Bite of an Aedes g C. Bite of Ixodes D. Drinking contaminated water E. Contact with cat feces Boards and Beyond Questions & A ⑪ O & C & & ⑪ O