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New Recommendations Issued for Treatment of Malaria in the United States

A systemic review of treatment of malaria in the United States, published in the May 23/30 issue of JAMA, provides recommendations to minimize morbidity and mortality of this disease.

"Even though endemic malaria has been eliminated from the United States, it remains a leading infectious disease worldwide," write Kevin S. Griffith, MD, MPH, from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and colleagues. "As a consequence, every year in the United States an average 1200 cases of malaria are reported, almost all imported, resulting in up to 13 deaths per year. The unfamiliarity of US clinicians and laboratory personnel with malaria and drug resistance patterns has contributed to delays in diagnosis and treatment, at times with adverse outcomes." To address this issue, the authors set forth practical recommendations for the diagnosis and treatment of malaria in the United States, based on published evidence; the CDC experience in assisting US clinicians; and the available drugs and diagnostic modalities used in this country.

The investigators performed a systematic MEDLINE search from 1966 to 2006 using the search term "malaria," with subheadings of "congenital," "diagnosis," "drug therapy," "epidemiology," and "therapy." They also obtained additional references from the bibliographies of pertinent articles and by reviewing articles suggested by experts in the treatment of malaria in North America.

To reduce morbidity and mortality from malaria in the United States, the authors recommend obtaining a travel history, considering malaria in the differential diagnosis of fever based on the travel history, and prompt and accurate diagnosis and treatment.

Successful management of malaria requires that treating clinicians answer the following 5 questions:

   1. What is the species?

   2. What is the density of parasitemia?

   3. What is the drug-resistant pattern where the infection was acquired?

   4. Are there signs of severe malaria?

   5. Can the patient tolerate oral medication?

Because Plasmodium falciparum infections can rapidly progress to severe illness or death in as little as 1 to 2 days, patients with malaria should be treated immediately.

In the absence of continued antigen exposure, immunity decreases. Therefore, semi-immune persons who have left an endemic area for an extended period and then return are susceptible to severe disease and death.

Unidentified species should be presumed to be P falciparum pending further identification. The travel history provides useful information about risk for drug resistance.

The need for initial hospital admission for all patients with P falciparum malaria remains controversial. Some authors have tried to define triage criteria for which patients need to be admitted and which can be followed as outpatients.

"However, since these patients can deteriorate rapidly and progress to death within 1 to 2 days, and many centers do not have the expertise to adequately triage (eg, to accurately quantify the parasite density), the CDC advises that patients infected with P falciparum or an unidentified Plasmodium species should be initially admitted to ensure that the medication is tolerated and the patient is improving clinically and parasitologically," the authors write. "Blood films should be repeated to ensure clearance of P falciparum parasitemia. Patients who are not responding clinically (with defervescence within 72 hours) need follow-up malaria blood films and may also require a search for other causes of fever."

For P falciparum acquired in areas without chloroquine-resistant strains, chloroquine remains the treatment of choice. The best treatment options for P falciparum acquired in areas with chloroquine resistance are a combination of atovaquone and proguanil; oral quinine plus tetracycline, doxycycline, or clindamycin; or mefloquine.

Chloroquine remains the treatment of choice for all other malaria species, except for Plasmodium vivax acquired in Indonesia or Papua New Guinea. In these cases, atovaquone-proguanil is recommended, with mefloquine or quinine plus tetracycline or doxycycline as suitable alternatives.

Severe malaria occurs when a patient with asexual malaria parasitemia, and no other confirmed cause of symptoms, has at least 1 designated clinical or laboratory finding. Because artemisinin drugs are not yet available in the United States, quinidine is currently the recommended treatment of severe malaria in this country. Exchange transfusion is the only adjunctive measure recommended for severe malaria.

"Malaria remains a diagnostic and treatment challenge for US clinicians as increasing numbers of persons travel to and emigrate from malarious areas," the authors write. "A strong evidence base exists to help clinicians rapidly initiate appropriate therapy and minimize the major mortality and morbidity burdens caused by this disease."

The CDC posts current treatment recommendations on its Web site (http://www.cdc.gov/malaria) and has clinicians available 24 hours daily to assist clinicians with malaria diagnosis and treatment. Malaria is a nationally notifiable disease. All cases should be reported to the appropriate state health department to facilitate monitoring of trends in disease acquisition and to provide recommendations for malaria chemoprophylaxis and treatment.

"Malaria will remain a diagnostic and treatment challenge for US clinicians as increasing numbers of persons travel to and emigrate from malarious areas," the authors conclude. "In a review of all malaria deaths in the US from 1963-2001, failure to diagnose malaria on initial presentation, promptly initiate treatment after diagnosis, and/or prescribe an appropriate antimalarial drug, were substantial contributing factors in malaria deaths. Clinicians must remain alert to the possibility of this disease and take immediate measures toward prompt accurate diagnosis and treatment."

The authors have disclosed no relevant financial relationships.

JAMA. 2007;297:2264-2277.
Clinical Context

According to the authors of the current study, every year in the United States an average of 1200 cases of malaria are reported, which result in as many as 13 deaths, and outcomes are worse with delayed diagnosis or incorrect treatment. The CDC posts current guidelines at http://www.cdc.gov/malaria and has clinicians available 24 hours daily to provide advice to clinicians on malaria diagnosis, chemoprophylaxis, and management.

This is a summary of current recommendations to clinicians for the diagnosis and treatment of malaria presenting in North America, based on articles identified from a MEDLINE search, hand search of bibliographies, and expert recommendations of reviews. Recommendations are based on randomized controlled trials, observational studies, and consensus expert opinion.
Study Highlights

    * Epidemiology and Diagnosis
          o Asexual blood stages of the malaria parasite are responsible for symptoms.
          o P falciparum infection, accounting for 50% of US cases, has the greatest potential to progress to severe illness or death and predominates in sub-Saharan Africa, Hispaniola, and Papua New Guinea.
          o Malaria prophylaxis is recommended over self-treatment.
          o The only drug recommended for self-treatment of US traveler is atovaquone-proguanil.
          o P vivax infection, accounting for 25% of US cases, is the most common predominating in South and Northern Asia, Eastern Europe, and Central and South America.
          o Chloroquine-resistant strains of P falciparum occur in all endemic areas except parts of South America and China and the Middle East.
          o Typical incubation is 9 to 18 days (longer for Plasmodium ovale [18 - 40 days] and shorter for P falciparum [7 days]).
          o Fever is the most common symptom and splenomegaly the most common physical sign.
          o Severe malaria is usually caused by P falciparum.
          o Diagnostic confirmation depends on demonstration of parasites on thick and thin films.
          o If the initial film is negative for parasites, blood films should be repeated at 12- to 24-hour intervals for 24 to 72 hours.
          o If testing is not available, empiric treatment should be started if malaria is suspected.
          o 5 questions should be answered: What is the species? What is the density of parasitemia? What is the drug-resistance pattern where acquired? Are there signs of severe malaria? And, can the patient tolerate oral medication?
    * Recommended Treatment
          o CDC recommends that patients infected with P falciparum be initially admitted for appropriate treatment.
          o Those not responding to treatment need follow-up blood films.
          o For uncomplicated P falciparum infection, chloroquine is the treatment of choice.
          o For chloroquine-resistant P falciparum infection, 3 options are recommended: oral quinine plus tetracycline, doxycycline, or clindamycin; atovaquone-proguanil; or mefloquine.
          o Quinine has a short onset of action and is associated with cinchonism with tinnitus, occurring in 13% to 94% of patients.
          o Mefloquine has neuropsychiatric adverse reactions at the rate of 1 in 215 to 1 in 1754 patients.
          o Mefloquine is not recommended for travelers returning from the borders of Thailand with Burma, Burma with China, and Thailand with Cambodia because of resistance.
          o Because of widespread resistance, the CDC no longer recommends sulfadoxine-pyrimethamine for treatment of malaria in the United States.
          o Chloroquine remains the treatment of choice for all uncomplicated Plasmodium malariae and P ovale infection, with hydroxychloroquine as second-line therapy.
          o Infections with P vivax and P ovale should be treated with primaquine to prevent relapse.
          o Most common adverse reaction to primaquine is intravascular hemolysis with glucose-6-phosphate dehydrogenase deficiency (contraindication for use).
          o Risk for relapsing infection is 20%, and chloroquine or mefloquine may be used to prevent relapse.
    * Severe Malaria
          o Most important step is initiating appropriate parenteral treatment.
          o The only parenteral drug available in the United States is quinidine gluconate.
          o Blood films should be examined every 12 hours until negative for parasites.
          o Parasite density typically decreases by 90% during the first 48 hours with quinine or quinidine.
          o Potential complications of severe malaria include hypoglycemia, hyperpyrexia, pulmonary edema, renal failure, thrombocytopenia, hyponatremia, hypocalcemia, hypophosphatemia and hyperphosphatemia.
          o For suspected cerebral malaria, a lumbar puncture should be performed.

Pearls for Practice

    * Diagnosis of malaria depends on blood film, clinical suspicion, and identification of the malaria species and of drug-resistance pattern at the source.
    * For uncomplicated P falciparum infection, chloroquine is the treatment of choice in the United States. Three treatment options for chloroquine-resistant malaria in the United States are available: oral quinine plus tetracycline, doxycycline, or clindamycin; atovaquone-proguanil; or mefloquine.



Reviewed by Dr. Ramaz Mitaishvili
Glendale, CA
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