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Update on Epidemiology, Practical Treatment, Travel Implications, and Public Health Strategies
Katherine Lisoni, MD, MPH June 14, 2007

 In 2004, 18.48 million laboratory confirmed cases; but estimates of actual cases run as high as 500 million.  In 2004, 99,600 confirmed deaths; estimates of actual deaths approach one million.  Most deaths are of infants, young children and pregnant women; most in Africa.  A child dies of malaria every 30 seconds.  40% of the world’s population, mostly in the world’s poorest countries, are at risk.  Most cases and deaths are in sub-Saharan Africa. However, Asia, Latin America, the Middle East and parts of Europe are also affected.

Distribution of species (%) in following areas
Asia (all) Sub-Saharan Africa

Central America
and Caribbean




West and Central

East and South

P. falciparum
P. vivax P. malariae P. ovale

1.2 2.2 8.4

9.8 3 8.4

4.2 (but in SE Asia, 48%) 95.6 0 0.2

87.1 0 0

70.6 0.2 0

Carter and Mendis, Clin Microbiol Rev 2002

 ~ 1,136,000 deaths from malaria in Africa in 2002 (The World Health Report, WHO, 2004)  Malaria causes half the deaths of African children under the age of five  Sub Saharan Africa: 275 million of total 530 million people may have malaria parasites in their blood  Up to 30% of malaria deaths in Africa related to war, local violence or other emergencies. Displaced people in makeshift housing are vulnerable: more likely to be bitten by mosquitoes, often ill with other infections, and lack access to health care.

Latin America
 Countries in region w/ greatest number of malaria cases overall (top 10 in order): Brazil, Colombia, Peru, Ecuador, Guatemala, Venezuela, Guyana, Bolivia, Honduras, Suriname  Greatest number of cases of falciparum: Colombia, Brazil, Peru, Guyana, Suriname, Ecuador, Haiti, Venezuela, French Guyana  Mortality rate:
 816 (8.3/100,000 of at-risk population) in 1994  68 (7.5/1,000,000 of high risk population) in 2003

 Population living in
 Low risk areas: 26%  Moderate risk areas: 5%  High risk areas: 4%

SE Asia
 30% of worldwide malaria morbidity; about 4% of mortality  In 2004
 2.53 million (provisional) laboratory confirmed malaria cases  3,768 malaria deaths

 In 1977, much more vivax than falciparum, now about equal; many areas w/ drug resistant falciparum  2004, % of Total Cases:
          India 75% Indonesia 12% Myanmar 6% Bangladesh 2.4% Timor 1.6% Thailand 1.1% Myanmar 52% India 25% Bangladesh 13% Thailand 6%

 2004, % of Total Deaths

Types of Transmission
 Stable Transmission
     Sub Saharan Africa and parts of Oceania Entomological inoculation rate (EIR) >10/year Worst disease in children less than 5, pregnancy Children at risk of severe disease/death Adults with partial immunity, lesser symptoms

 Epidemic or seasonal transmission
    Most of Latin America/much of Asia EIR 1-5/year All ages at risk of severe disease/death May overwhelm health system in epidemic

Protozoa Plasmodium
 Female anopheline mosquito transmits (many species)
 6-12 days after biting an infected person

 P. falciparum
 Responsible for 95% of malaria related deaths; 1 to 3% mortality rate

 P. vivax
     Most dominant species outside Africa (none in W. Africa) Affects all ages b/c common in areas of low transmission Like falciparum, reduces birth weight (but not as severely) Rare complication is splenic rupture (but mortality rate of this 80%) Can cause post-malaria cerebellar syndrome

 P. ovale
 Only P. vivax and P. ovale have hypnozoites, latent liver stage resulting in relapses weeks to months later, up to 5 years  Relapses affect local educational and economic development

 P. malariae
 May lead to glomerulonephritis and nephrotic syndrome (but uncommon)

 Co-infection of more than one species common in some regions

Uncomplicated Malaria
 First symptoms nonspecific: HA, fatigue, abdominal discomfort, muscle and joint aches, followed by fever, chills, perspiration anorexia, vomiting and worsening malaise.  Residents of endemic areas may self-diagnose.  Sometimes overdiagnosed on basis of symptoms.  No evidence of end-organ dysfunction.  P. vivax and P. ovale, more than other species have ―malarial paroxysms‖—fever spikes, chills, and rigors at regular intervals.  Fatality rate low at this stage (0.1% for falciparum, the other malarias are rarely fatal.)

Severe Malaria

(Falciparum almost always)

 If ineffective drugs given or treatment delayed in falciparum, parasite burden may increase and change to severe malaria  May progress within a few hours  Coma (cerebral malaria)  Metabolic acidosis  Severe anemia  Hypoglycemia  In adults, acute renal failure or acute pulmonary edema  In this stage, mortality in people receiving treatment is 15-20% (has increased in recent years due to resistance)  If untreated, almost always fatal.

Clinical Diagnosis:
 In settings where the risk of malaria is low:
 dx based on degree of exposure to malaria and h/o fever for 3 days or more w/out features of other severe diseases

 In setting where risk high:
 fever in previous 24 hours and/or presence of anemia  Pallor of the palms most reliable sign of anemia in young children  See WHO algorithms for IMCI (Integrated Management of Childhood Illness)

Laboratory Diagnosis:
 Light microscopy
 Low cost if case-load is high of fever Pts  High sensitivity  Need training/experience (see Oxford Tropical Medicine Handbook re preparing smears)

 Rapid Detection Tests (RDTs)
 More expensive  May be affected by heat/humidity  More feasible in community settings

 Low to moderate/unstable transmission—should confirm dx w/ laboratory before treating  Very low risk—confirm exposure before laboratory test  Stable high-transmission
 Malaria most common cause of fever in children under 5—give treatment if fever and no other obvious cause--benefits of lab dx do not outweigh benefit of not treating false negatives  Above 5 y/o and especially in pregnancy given risks of drugs should first get laboratory diagnosis  Where high prevalence of AIDS, lab dx important b/c many other causes of fever in AIDS  In severe malaria, ok to treat based on clinical dx if delay in lab dx

 Below per WHO guidelines—big emphasis on trying to avoid increased drug resistance through Artemisinin Combination Therapies (ACT)
 For Country-specific policies,
 html

Drug names
 ―Fansidar‖ (brand name) = pyrimethamine/sulfadoxine  ―Malarone‖ = atovaquone/proguanil  ―Lariam‖ = mefloquine

ACT—avoiding drug resistance
 In various areas, falciparum observed resistant to almost all antimalarials (amodiaquine, chloroquine, mefloquine, quinine, and sulfadoxine-pyrimethamine); spreading.  Except artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin)  From traditional Chinese medicine; provides rapid clearance of parasite  New WHO policy for artemisinin combination therapy (ACT) to avoid resistance (think TB, HIV)  Combination tx w/out artemisinin does not offer addtl benefit b/c high resistance to one of the compounds; not considered combination therapy b/c do not attack different targets on the parasite  Evidence of neurotoxicity in animals, but none in large human studies

Recommended ACTs
 When given with a slowly-eliminated ―partner‖ medicine, 3 day treatment possible  When given w/ rapidly eliminated compounds (tetracycline, clindamycin), 7 days needed  These 2 may have lower cure rates b/c resistance to the ―partner‖ medicine
 Artesunate + amodiaquine  Artesunate + sulfadoxine-pyrimethamine
 Resistance particularly a problem for SP where used for intermittent preventive tx in pregnancy

 These 2 less affordable and available but more recommended where multi-drug resistance (SE Asia)
 Artemether-lumefantrine
 also recommened in Africa if available  6 dose regimen

 Artesunate + mefloquine
 Insufficient data on treatment in children

 Incorrect to treat semi-immune patients with medications with known resistance or to give partial treatment  Also potentially dangerous to give only first dose of tx while waiting for lab dx; if tx started should be finished  In some areas where ACT not available, AQ and SP (amodiaquine and sulfadoxinepyrimethamine) may be used in the interim, if effective in that area
 however in some areas failure rates of this combination have increased rapidly

 Artemisins and partner medicines should not be available as monotherapies

 WHO has called for a ban on the use of oral artemisinin monotherapies worldwide
 (rectal therapy used in severe malaria cases, before transfer, if possible, for IV therapy)

 Recently proposed globally administered subsidy for ACTs
 combination therapies sold to both governments and private wholesalers at the same price as artemisinin alone  about US $0.10 per treatment course (some ACTs are more expensive, up to $2.40/treatment course)  Globally, would cost donors and development agencies US$150-200 million each year

 ACTs still first line treatment for falciparum  Antipyretic (paracetamol/acetaminophen or ibuprofen, not aspirin b/c of Reye’s syndrome) or baths in tepid water for fever reduction  Seizure management
 Overlap between febrile seizures and seizures of cerebral malaria  parenteral or rectal benzodiazepines or IM paraldehyde  No benefit for prophylactic anticonvulsants

 Beware of treating children with high levels of parasitemia outpatient, as they may deteriorate rapidly  Insufficient data on use of mefloquine in children

 Non-immune pregnant women: up to 60% fetal loss and over 10% maternal deaths; 50% mortality for severe disease  Immunity reduced during pregnancy  Associated w/ low birth weight, increased anemia, and in low transmission areas, more severe malaria

Treatment in Pregnancy
 Mefloquine should not be used in pregnancy  More and more experience w/ artemisinin derivatives in 2nd and 3rd trimester  Sulfadoxine-pyrimethamine used intermittently to clear placenta in highly endemic areas to reduce asymptomatic effects of malaria  Safe in 1st trimester:
 Quinine, chloroquine, proquanil, pyrimethamine and sulfadoxinepyrimethamine (most effective is quinine)

 First trimester: quinine plus/minus clindamycin  Second/Third trimester
 ACT being used in that country/region  Or artesunate + clindamycin  Or quinine + clindamycin

Travelers: Prophylaxis
Malaria Risk Type I--Very limited risk of malaria transmission Type II--Risk of P. vivax malaria or fully chloroquinesensitive P. falciparum only Type III--Risk of malaria transmission and emerging chloroquine resistance Type IV--High risk of falciparum malaria plus drug resistance, or moderate/low risk falciparum malaria but high drug resistance Prophylaxis Mosquito bite prevention only Mosquito bite prevention plus chloroquine chemoprophylaxis Mosquito bite prevention plus chloroquine+proguanil chemoprophylaxis Mosquito bite prevention plus either mefloquine, doxycycline or atovaquone/ proguanil (take one that no resistance is reported for in the specific areas to be visited)

 Remember, prophylaxis is NOT the same medicines/doses as treatment. Prophylaxis doses:  Chloroquine 500 mg weekly, 1-2 weeks prior to exposure (500 mg Q6hx2 if started after) to 4 weeks after exposure. Side effects: N/V/D, vision changes/HA, rarely aplastic anemia. Need periodic eye exams, CBCs if long term use. 30 tabs for $70 (in US but cheaper in other places).  Mefloquine (Lariam): 250 mg/wk starting 1 wk before and 4 wks after. N/V, dizziness, rarely depression/psychosis, seizures— much talked about but more recently several studies showed no significant difference in terms of neurologic effects. $300 for 25 tabs.  Doxycycline 100 mg daily 1-2 days before until 4 wk after. Tooth discoloration if <8 y/o, photosensitivity, headache, nausea/diarrhea, vaginal candidiasis, may affect oral contraceptives. 200 capsules for $55.  Atovaquone/proquanil (Malarone): 250/100 mg daily starting 1-2 days prior through 7 days after. N/V/D/abd pain/HA, renally excreted so consider baseline creatinine. $45 for 7 tabs.  Per one survey, the average cost of malaria prophylaxis for a twoweek trip would be $34 for doxycycline, $74 for Lariam, and $127 for Malarone.

 for country-specific information on risk level  Many major cities in endemic areas safe, except for outskirts  Many tourist destinations are safe  SBET (Stand-by Emergency Treatment): Bringing this may be recommended (in combination with mosquito bite protection)
 for frequent short trips (i.e. airline crews)  those who travel 1 week or more to remote rural areas, where multidrug-resistant malaria but very low risk of infection, and risk of side-effects of prophylaxis may outweigh risk of contracting malaria. (i.e. certain border areas of Thailand/ other countries in SE Asia, the Amazon basin.)  Travelers taking prophylaxis may bring if ―fake drugs‖ common where they are going or going to very remote areas where treatment in < 24 hours not available  still need to seek medical attention as soon as possible

Travelers: Bite-Avoidance
 Long pants/sleeves at night, avoid dark colors (which attract mosquitoes)  Insect repellant with Deet or dimethyl phthalate; higher the concentration, the longer the protection lasts:
    23.8% DEET -- an average of 5 hours protection 20% DEET -- almost 4 hours of protection 6.65% DEET -- almost 2 hours of protection 4.75% DEET or 2% soybean oil -- 1 1/2 hour

 Screens/mosquito nets

Travelers: Treatment
 Fever 1 week after and up to 3 months after exposure should be investigated  Prophylaxis should be stopped while investigating active infection  Artemether-lumefantrine (6-dose regimen)  Or atovaquone-proguanil  Or quinine + doxycycline or clindamycin

Severe Malaria
 IV artesunate or IV quinine  Quinidine w/ careful cardiac monitoring in areas (like non-malaria areas) where quinine, etc. not available  Hemodialysis early in acute renal failure or severe metabolic acidosis  Positive pressure ventilation should be started early if breathing pattern abnormality, intractable seizure, or ARDS

Pre-referral Treatment
 Artesunate or artemisinin by rectal administration  Artesunate or artemether IM  Quinine IM

 No change in treatment recommended at this time  Laboratory diagnosis of malaria or other possible causes of fever recommended b/c of many possible causes; lumbar puncture if possible  In more resource rich settings, finding out CD4 counts is very helpful to r/o some opportunistic infections if count high

P. Vivax (also P. ovale)
 Chloroquine over 3 days, w/ primaquine once daily for 14 days to eliminate liver phase  If chloroquine resistant, amodiaquine over 3 days w/ primaquine for 14 days  Testing for G6PD deficiency if possible— if moderate, reduced dose primaquine; if severe, should not be given

 For now, no longer an attempt to eliminate malaria; to decrease morbidity and mortality, especially in pregnant women and young children  Vector reduction  Better access to treatment in vulnerable populations

Vector reduction
 Indoor Residual Spraying of long-acting insecticide (IRS) – use of DDT; in this case not environmentally damaging and not shown to be dangerous to humans. Several environmental groups formerly opposed to DDT now endorse.
 Spraying not helpful in areas where ―indoor‖ mosquitoes are not the major vector

 Long-Lasting Insecticidal Nets (LLINs)
 Previous nets needed to be redipped in insecticide every 6-12 months—these new nets supposedly last for 5 years  Debate whether selling them as a commodity to increase their perceived value vs. giving them free. Current strategy a combination of both—giving free to high-risk groups (pregnant women/children). Supporting the starting of small businesses of net-making.

 Eliminating areas of standing water, etc.—depends on type of vector—obviously difficult to do in certain areas  Larvivorous fish (India, Indonesia, Myanmar, Sri Lanka and Thailand)

 Recent evidence from Africa indicates that pyrethroid and DDT resistance is becoming more widespread than anticipated. Thought to be more of a problem for IRS than LLIN. Insecticide resistance monitoring needs to be a part of control programs.  ? Changing area of stable transmission to an area of seasonal or epidemic transmission—if decreased exposure decreases immunity—could result in worse disease in adults

 Vaccine development efforts are underway, but given that people do not develop natural long-term immunity to malaria, and such efforts are underfunded, this is difficult  Malaria, TB, African trypanosomiasis, Leishmaniasis, and Chagas are the areas of greatest need for additional research and development; malaria is the most needed given the disease burden.

 Unfortunately, most top pharmaceutical companies spend 2 to 3 times a much on marketing/administration as they do on R&D; 22% of staff are employed in R&D, while 39% are in marketing.
 Almost no research is being done in malaria by pharmaceutical corporations; most is through the NSF or universities (University of Notre Dame is one).

  Oxford Handbook of Tropical Medicine  7/9789241580397_7_eng.pdf