Malaria Mark K. Huntington, MD PhD FAAFP Sioux Falls Family Medicine Residency and University of South Dakota

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Additional Disclaimer This lecture was amply illustrated with breathtaking images – those that were selected because of their ability to make even a calloused trauma surgeon squirm! Alas, collected from myriad sources over more than a quarter of a century of teaching parasitology, copyright attribution and permission could not be established and obtained. While the Fair Use clause of the US Copyright Law permits a teacher to use small portions of a work to illustrate a point in a lecture, their reproduction in this database is generally considered to be outside the limits of the Fair Use intent. That is certainly the AAFP’s position. Too bad; guess you should have been here in person! “The 1961 Report of the Register of Copyrights on the General Revision of the U.S. Copyright Law cites examples of activities that courts have regarded as fair use: “quotation of excerpts in a review or criticism for purposes of illustration or comment; quotation of short passages in a scholarly or technical work, for illustration or clarification of the author’s observations; use in a parody of some of the content of the work parodied; summary of an address or article, with brief quotations, in a news report; reproduction by a library of a portion of a work to replace part of a damaged copy; reproduction by a teacher or student of a small part of a work to illustrate a lesson; reproduction of a work in legislative or judicial proceedings or reports; incidental and fortuitous reproduction, in a newsreel or broadcast, of a work located in the scene of an event being reported.” (emphasis added) http://www.copyright.gov/fls/fl102.html

Global Context Documented since 2700BC Asia to Africa then Europe [deleted – map of malaria in US in 1800s] Documented since 2700BC Asia to Africa then Europe Comes to Americas in 1500s Tropical and temperate! First seen in 1880 200-300 million cases annually 1-2 million deaths annually “Nearly eradicated” 1940s, 1980s, etc. [deleted – bubble map of malaria mortality worldwide] http://smokles.wordpress.com/2011/05/03/what-these-maps-imply-about-tobacco-control-in-the-developing-world/

Cases 35 year old kayaker returns from Amazon adventure with fever (103), headache, and malaise. 10 year old Rwandan girl treated at health outpost for fever (103) and altered mentaton develops renal failure.

[deleted – plot of temperature of various species of human malaria] Clinical Picture Cyclic fever [deleted – plot of temperature of various species of human malaria]

Schizogony [deleted – partial (schizogony) Plasmodium life cycle from Despommier] [deleted – colorized SEM of schizogony]

Clinical picture Cyclic fever Anemia Cerebral malaria

Cerebral malaria [deleted – multiple images of cerebral malaria: bedside, gross pathology, microscopy, electron microscopy, and pathophysiology diagrams, some available from: http://www.tcd.ie/IMM/haemostasis/projects/von-willebrand-factor-2.php http://www.nd.edu/~haldarlb/pubs/article007.pdf ] Figure legend: Mechanisms of infected erythrocyte adhesion to endothelium in cerebral malaria. Early in the blood stage of P falciparum infection, endothelial cells become activated to secrete ULVWF strands, which remain attached to the endothelial surface and rapidly bind platelets. Infected erythrocytes, coated with membrane knobs rich in PfEMP1, adhere to the platelet-decorated ULVWF strings through platelet CD36. ULVWF contributes to both the thrombocytopenia and hemolytic anemia of malaria by binding large numbers of platelets and by shearing red cells. (from Lopez J. Blood. 2010; 115; 1317 © 2010 by The American Society of Hematology). Malaria remains an important cause of morbidity and mortality in the tropics, with an estimated 400 million clinical cases, and more than 2 million deaths per annum. Although human malaria can be caused by several Plasmodium species (including P. falciparum, P. vivax, P ovale and P. malariae), P. falciparum infection is the parasite responsible for the majority of fatal malarial infections. Young children (under the age of 5 years) living in sub-Saharan Africa are at particularly high risk. Following the first 5 – 10 years of life, children living in these endemic areas typically develop partial clinical immunity. Nevertheless, more than 90% of malaria-related mortality occurs in African children. Consequently, severe P. falciparum malaria continues to constitute a leading cause of childhood death worldwide. Moreover, mortality associated with cerebral malaria has not significantly improved in the past 30 years. In spite of the significant mortality associated with P. falciparum infection, the molecular mechanisms involved in its pathophysiology remain poorly understood. However, it has been shown that red blood cells infected by malarial parasites can bind to the walls of small blood vessels. This results in blood vessel obstruction, particularly in the brain. In exciting recent studies (Bridges et al, Blood 2010; 115(7); 1472-1474), we have demonstrated for the first time that von Willebrand factor is involved in mediating the binding of malaria-infected red blood cells in the microvasculature. This research program aims to further investigate the role of played by VWF in children with cerebral malaria. http://www.tcd.ie/IMM/haemostasis/projects/von-willebrand-factor-2.php http://www.nd.edu/~haldarlb/pubs/article007.pdf

Clinical picture Cyclic fever Anemia Cerebral malaria [deleted – immunofluorescent glomerulus] Cyclic fever Anemia Cerebral malaria Renal complications [deleted – bottles of urine from patient with blackwater fever] Proteinuria is found in 20% of cases, but acute glomerulonephritis is usually transient and disappears after antimalarial treatment and appropriate fluid replacement. Some patients may progress to acute renal failure (by acute tubular necrosis). Quartan malarial nephropathy is a particular form of nephrotic syndrome found in children with chronic P. malariae infection and caused by the deposition of immune complexes. The combination of severe intravascular haemolysis, haemoglobinuria and renal failure is known as blackwater fever. The syndrome was seen more often in the past than today, usually in patients treated intermittently with quinine. The pathophysiology of the syndrome is obscure, but is believed to have an immunopathological component, as it is never seen during primo-infection and is rare in children. The mortality rate is high (20-30%) even after treatment, which explains its sinister reputation (most of the descriptions of the syndrome date back to the first half of the 20th century, when blackwater fever was common in Europeans and Asians working in colonial Africa).

Clinical picture Cyclic fever Anemia Cerebral malaria Renal complications

Clinical picture Cyclic fever Anemia Cerebral malaria Renal complications Pulmonary edema [deleted – pulmonary edema CXR from malaria] Pulmonary oedema is a grave complication of severe malaria, with a high mortality (over 80%). It may appear several days after chemotherapy has been started and at a time when the patient’s general condition is improving and the peripheral parasitaemia is diminishing. In most cases there are features of adult respiratory distress syndrome (ARDS), implying increased pulmonary capillary permeability. Pulmonary oedema may also arise iatrogenically from fluid overload. The two conditions are difficult to distinguish clinically and may coexist in the same patient. Pulmonary oedema is often associated with other complications of malaria and may also occur in vivax malaria. The first indication of impending pulmonary oedema is an increase in the respiratory rate, which precedes the development of other chest signs (Fig. 7). The arterial pO2 is reduced.

Clinical picture Cyclic fever Anemia Cerebral malaria Renal complications Pulmonary edema Diarrhea Splenic rupture

[deleted – icteric eye] Clinical picture Cyclic fever Anemia Cerebral malaria Renal complications Pulmonary edema Diarrhea Splenic rupture Jaundice [deleted – icteric eye]

Clinical picture Cyclic fever Anemia Cerebral malaria Renal complications Pulmonary edema Diarrhea Splenic rupture Jaundice Hypoglycemia

Pathophysiology [deleted – pathophysiological pathway diagram for various manifestations of malaria]

diagnostic test illustrations] Diagnosis [deleted – partial (intraerythrocytic Plasmodium lifecycle, photomicrographs, and diagnostic test illustrations] Diagnostic strategies Clinically? Antigen testing DNA testing Microscopy trophozoites gametes

Treatment Chloroquine* – standard; resistance Mefloquine* – ignore the Brits! Malarone* – $$$ , daily Fancidar – P. falciparum only Quinine/quinidine – in Africa Coartem – Chinese herb Doxycycline* – photosensitizing Primaquine – hypnozoites *also used in chemoprophylaxis

Intra-cellular Targets Deleted figure from J. Clin. Invest. 118(4): 1266-1276 (2008); http://www.jci.org/articles/view/33996

Stages targeted Deleted figure from http://parasitology.informatik.uni-wuerzburg.de/login/n/h/2237.html

Treatment Chloroquine – standard; resistance Mefloquine* – new black box warning Malarone – $$$ Fancidar – P. falciparum only Quinine/quinidine – in Africa Coartem – Chinese herb Doxycycline – photosensitizing Primaquine – hypnozoites

Hypnozoites [deleted – partial (intrahepatic) Plasmodium lifecycle from Despommier]

Transmission Via Anopheles bite Blood-borne Congenital [deleted – images of anopheles] Via Anopheles bite Based on bite frequency & infection intensity. Blood-borne Congenital

Transmission [deleted – partial (gametocyte-to-sporozoite) [deleted – image of sporozoites] [deleted – partial (gametocyte-to-sporozoite) Plasmodium lifecycle from Despommier] [deleted – image of oocyts on mosquito gut]

The Big Picture

Summary [deleted – complete Plasmodium lifecycle from Despommier]

A – Awareness B – Bed nets/ Barriers C – Chemoprophylaxis Control & prevention A – Awareness B – Bed nets/ Barriers C – Chemoprophylaxis D – rapid Diagnosis

>40 projects reached clinical stage Vaccination? >40 projects reached clinical stage Only pre-erythrocyte stage-based (RTS,S) reduce morbidity Use multiple-episodes to assess In vitro or animal studies ≠ field efficacy Malaria Journal 2012, 11:11 doi:10.1186/1475-2875-11-11

Gee-whiz material Interaction with other parasites Ascaris seems protective against malaria and its severe manifestations Hookworms increase incidence About those de-worming campaigns… Th2/Treg lymphocytes? Role of inflammation in severe malaria, balance shifted by worms: IgE-CD23 activation causes IL10 and NO release (anti-inflammatory)? Maybe?

Questions & discussion Disclaimer: The images utilized in this presentation were retrieved via Google search and wantonly plagiarized incorporated under the Fair Use clause of US Copyright Law.