1. Mark K. Huntington, MD PhD FAAFP Sioux Falls Family Medicine Residency and University of South Dakota 2015 Review and Update

2. 2 Activity Disclaimer ACTIVITY DISCLAIMER It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflicts of interest (COI), and if identified, conflicts are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or who agreed to an identified resolution process prior to their participation were involved in this CME activity. Dr. Huntington has indicated he has no relevant financial relationships to disclose.

3. 3 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. In order to comply, images have been pixilated. Apologies! “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

4. Global Context Documented since 2700 BC Asia to Africa then Europe Comes to Americas in 1500s Tropical and temperate! First seen in 1880 ~200 million cases in 2014 ~500,000 deaths in 2014 (↓47% since Y2K) “Nearly eradicated” 1940s, 1980s, etc.

5. 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.

6. Clinical Picture Cyclic fever

7. Schizogony

8. Clinical picture Cyclic fever Anemia Cerebral malaria

10. Clinical picture Cyclic fever Anemia Cerebral malaria Renal complications

11. Clinical picture Cyclic fever Anemia Cerebral malaria Renal complications

12. Clinical picture ►Cyclic fever ►Anemia ►Cerebral malaria ►Renal complications ►Pulmonary edema

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

14. Clinical picture ►Cyclic fever ►Anemia ►Cerebral malaria ►Renal complications ►Pulmonary edema ►Diarrhea ►Splenic rupture ►Jaundice

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

16. Pathophysiology

17. Diagnosis ►Diagnostic strategies –Clinically? –Antigen testing –DNA testing ►Microscopy –trophozoites –gametes Am J Trop. Med Hyg. 2012;86:192

19. Drugs Chloroquine* – standard; resistance Mefloquine* – black box warning Malarone* – $$$, daily Quinine/quinidine – in Africa Coartem – Chinese herb Doxycycline* – photosensitizing Primaquine – hypnozoites *also used in chemoprophylaxis

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

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

22. Drugs Chloroquine – standard; resistance Mefloquine – new black box warning Malarone – $$$ Quinine/quinidine – in Africa Coartem – Chinese herb Doxycycline – photosensitizing Primaquine – hypnozoites

23. Hypnozoites

24. Transmission Via Anopheles bite –Based on bite frequency & infection intensity. Blood-borne Congenital

25. Transmission

26. The Big Picture

27. Summary

28. 28

29. Treatment Uncomplicated falciparum malaria in travelers: artemether–lumefantrine atovaquone–proguanil quinine plus doxycycline or clindamycin. dihydroartemisinin–piperaquine (not in US) Note: The artemisinin combination therapies (ACT) are preferred as treatment failures are consistently lower than 5% in settings without resistance to the partner drug. 29

30. Treatment Severe falciparum malaria: Managed in the ICU Parenteral antimalarial treatment should be with artesunate (first choice), artemether or quinine. –If these medicines are not available, parenteral quinidine should be used, with careful clinical and Cardiac monitoring 30

31. Treatment Vivax malaria in travelers: Chloroquine or Coartem, combined with primaquine –Coartem (or quinine if former not available) should be given for chloroquine-resistant vivax malaria, combined with primaquine. Travelers must be tested for G6PD- deficiency before receiving primaquine 31 G6PD prevalence

32. Treatment Relapsing malaria caused by P. ovale treated like vivax malaria Malaria caused by P. malariae Treated like vivax malaria, only does not require primaquine (hypnozoites in this species) 32

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

34. 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 Vaccination? >40 projects reached clinical stage

35. Issued: Thursday 24 July 2014, London UK GSK announced today that it has submitted a regulatory application to the European Medicines Agency for its malaria vaccine candidate, RTS,S The submission will follow the Article 58 procedure, which allows the EMA to assess the quality, safety and efficacy of a candidate vaccine, or medicine, manufactured in a European Union (EU) member state, for a disease recognised by the World Health Organization (WHO) as of major public health interest, but intended exclusively for use outside the EU. RTS,S is intended exclusively for use against the Plasmodium falciparum malaria parasite, which is most prevalent in sub-Saharan Africa (SSA). Around 90 per cent of estimated deaths from malaria occur in SSA, and 77 per cent of these are in children under the age of 5. Fortune.com 35

36. Issued: Friday 24 July 2015 The European Medicines Agency in London declared Mosquirix safe for use and moderately effective against the malaria parasite, Plasmodium falciparum, in combination with established protective measures such as bednets. The World Health Organization must now formally agree to recommend its use in children. …[Mosquirix is also protective against hepatitis B. Nature 2015;523:507 36

37. Interaction with other parasites –Ascaris seems protective against malaria and its severe manifestations –Hookworms increase incidence About those de-worming campaigns… Gee-whiz material

38. 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.