Online Resources for Malaria Treatment

Throughout these weeks, I have referenced the CDC website extensively. Not only does it provide clear clinical recommendations for both prevention and treatment, it is also the agency responsible for malaria surveillance in the United States. The CDC website also includes treatment protocols for PO Coartem, and IV Artesunate, the artemisinin-based therapies that have been recently approved by the FDA. The CDC offers a hotline for advice for practitioners and information on how to access anti-malarials if they are not locally available:

http://www.cdc.gov/malaria/diagnosis_treatment/tx_clinicians.htm

For those working overseas, the WHO website is another excellent resource for malaria treatment guidelines. The WHO also has recommendations for malaria prophylaxis in pregnancy, and rapid diagnostic tests which are not currently in use in the US:

http://apps.who.int/malaria/treatmentguidelines.html

If people are interested in global malaria control programs, the Roll Back Malaria Partnership is a good resource:

http://www.rollbackmalaria.org/

And if people are interested in the campaign to make antimalarials accessible and affordable in developing countries, the MSF Access Campaign is another good site to check out:

http://www.msfaccess.org/main/other-diseases/msf-and-malaria/

Falciparum Malaria Treatment Side Effects

Continuing from last week, of the four treatment regimes recommended for uncomplicated (chloroquine-resistant) falciparum malaria, Artemether-lumefantrine (Coartem™), an artemesinin-combination therapy, will frequently be the treatment of choice.

The most common adverse reactions reported in adults are headache, anorexia, dizziness, physical weakness, arthralgia and myalgia, although these are difficult to separate from the symptoms of malaria. The most common adverse reactions reported in children are fever, cough, vomiting, loss of appetite, and headache.

For treatment of complicated malaria, parenteral Quinine is recommended. Adverse reactions may include: hypoglycemia, auditory and visual disturbances, and cardiac dysrhythmias. Quinine cannot be combined with coartemether, chloroquine, or halofantrine, and mefloquine should only be administered 12 hours after the last dose of quinine (risk of seizures, cardiac toxicity).

For chemoprophylaxis of falciparum malaria, there are several alternatives depending on the region of travel, and patient-specific considerations including preference of dosing frequency. It is important to choose a chemoprophylactic regime that will be well tolerated in order to optimize adherence. Choices include Atovaquone/Proguanil (Malarone™), Doxycycline, and Mefloquine (Lariam™). Chloroquine can only be used for chemoprophylaxis in the regions of the world where malaria is still chloroquine-sensitive (Central America west of Panama Canal, Haiti, the Dominican Republic, and most of the Middle East).

Malarone is generally well-tolerated, but adverse reactions can include: cough, diarrhea, dizziness, headache, anorexia, oral sores, nausea, stomach pain, vomiting, and weakness. Adverse reactions associated with Doxycycline include: gastrointestinal disturbances, esophageal ulcerations, and photosensitivity. Doxycycline is contraindicated in pregnant and breastfeeding women and in children under 8 years of age, and should not be given with dairy products.

Adverse reactions associated with Mefloquine include: gastrointestinal disturbances, dizziness, and headache. Rarely, Mefloquine can cause cardiac dysrhythmias, hypo or hypertension, and skin rash. Occasionally at treatment dose levels (less often at prophylaxis levels), Mefloquine can cause severe neuropsychiatric reactions. Patients should be screened for history of mental illness and substance abuse prior to starting Mefloquine. Mefloquine is contraindicated in patients on sodium valproate, phenytoin, carbamazepine (risk of seizures), coarthemeter, chloroquine, or halofantrine (risk of seizures, cardiac toxicity). See also above under quinine.


Sources:

Centers for Disease Control and Prevention. Reasons for Considering or Avoiding Certain Drugs for the Prevention of Malaria. Available from: http://www.cdc.gov/malaria/control_prevention/drug_avoidance.htm.

Medecins Sans Frontieres. (2006). Essential Drugs: Practical Guidelines. 3rd Ed.

Treatment of Falciparum Malaria

The most important first step in the treatment of malaria is species identification through microscopy. The morphology of various malarial parasites show distinct characteristics, but given the low incidence of imported malaria in the United States, species identification can often be difficult for laboratory technicians. In addition, microscopy (especially using thin smears) can miss low levels of parasitemia. Rapid diagnostic tests have shown to be effective in endemic areas, but only for detection falciparum malaria, and have not yet been approved for use in the United States. Rapid tests for vivax, ovale, and malariae species are still under development. Parasite nucleic acid detection using PCR is available in reference laboratories, but the CDC only recommends using PCR to confirm a diagnosis by microscopy. If the species cannot be identified, or if there is strong clinical suspicion which cannot be confirmed through laboratory testing, treatment for falciparum malaria should be initiated immediately.

Just a quick note on P. vivax and P. ovale strains: These species of malaria have prolonged liver phases, during which the parasite lies dormant in forms referred to as “hypnozoites.” In order to eliminate these parasites in the liver, and to prevent future relapses, patients require treatment with chloroquine or quinine, plus a 14 day course of primaquine (“the radical cure” for malarial infection). One more note of caution: prior to administering primaquine, patients must be evaluated for G6PD deficiency, since it can cause hemolytic anemia. Consequently, primaquine is contraindicated in pregnancy because the G6PD status of the fetus cannot be determined. Primaquine should be added to treatment regimes for patients with falciparum malaria who are co-infected with vivax or ovale species.

It is also essential to determine the patient’s travel history, and to correlate this with regional patterns of resistance. Chloroquine resistance is widespread, and as such, chloroquine should only be used in the treatment of uncomplicated falciparum malaria for travelers returning from areas with chloroquine-sensitive strains (Central America west of Panama Canal, Haiti, the Dominican Republic, and most of the Middle East). Additionally, it’s important to ask patients about chemoprophylaxis. In case of resistance, providers should choose drug regimes that do not include medications that were used for prophylaxis (even intermittently).
It is recommended that patients with uncomplicated AND severe falciparum malaria be hospitalized. Given the rapid progression of disease, and the high mortality rates among cases of severe falciparum malaria, antimalarial treatment should be initiated urgently.

In general, patients with uncomplicated falciparum malaria can be treated with oral medication. For those patients who have returned from areas with chloroquine-sensitive strains, the dose, according to the CDC guidelines, is as follows:

Chloroquine phosphate (Aralen™ and generics): 600 mg PO immediately, followed by 300 mg PO at 6, 24, and 48 hours.

The CDC recommends four possible treatment plans for uncomplicated falciparum malaria acquired in regions with chloroquine-resistance (or when patients acquired malaria in a region where the sensitivity pattern is not known). Of the four treatment plans, two utilize medications which are commonly used for chemoprophylaxis (Atovaquone-proguanil or Malarone™, and Mefloquine or Lariam™). Therefore , these treatment protocols will not be appropriate for some patients. Additionally, Mefloquine when administered at treatment doses is associated with a high risk of severe neuropsychiatric reactions. A third protocol utilizes Quinine Sulfate, plus Doxycycline, Tetracycline, or Clindamycin (for children or women who are pregnant or breastfeeding). However, this treatment plan is associated with significant adverse effects, including Quinine-induced hypoglycemia, and gastrointestinal distress related to Doxycycline.

A treatment regime which includes artemesinin-combination therapy is recommended by WHO, and is one of the four regimes recommended by the CDC. In April 2009, the FDA approved Artemether and Lumefantrine (Coartem) as an oral therapy for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least 5 kgs. The following treatment protocol is from the CDC:

Artemether-lumefantrine (Coartem™), 1 tablet = 20mg artemether and 120 mg lumefantrine

A 3-day treatment schedule with a total of 6 oral doses is recommended for both adult and pediatric patients based on weight. The patient should receive the initial dose, followed by the second dose 8 hours later, then 1 dose po bid for the following 2 days.

5 - <15 kg: 1 tablet per dose
15 - <25 kg: 2 tablets per dose
25 - <35 kg: 3 tablets per dose
≥35 kg: 4 tablets per dose

The most common adverse reactions reported in adults are headache, anorexia, dizziness, physical weakness, arthralgia and myalgia, although these are difficult to separate from the symptoms of malaria. The most common adverse reactions reported in children are fever, cough, vomiting, loss of appetite, and headache.
While some patients may tolerate Coartem better than other treatment regimes, Coartem may not be available in all areas of the United States. If there are no contraindications, patients should receive medications that are appropriate for their malarial species and sensitivity patterns, and which can be administered without delay.

For severe malaria, or in cases when oral medications cannot be used, parenteral quinine plus Doxycycline, Tetracycline, or Clindamycin should be used. Parenteral quinine is cardiotoxic and should only be administered in an ICU setting with continuous cardiac monitoring and frequent blood pressure monitoring. Regular blood glucose monitoring is also required. As another option, parenteral Artesunate is currently being considered as an investigational new drug (IND).

Supportive therapy for cases of severe malaria may include antipyretic meds, monitoring of fluid I&Os, hemodialysis in the case of renal impairment, supplemental oxygen or (in extreme cases) mechanical ventilation, transfusion, vitamin K for DIC, and diazepam for seizures. Exchange transfusion is recommended in cases of falciparum when parasitemia is greater than 10 percent, or in patients with coma, renal failure, or ARDS, regardless of the level of parasitemia.

The CDC website is a great resource, and they have a helpful treatment table to guide prescribing practice:

http://www.cdc.gov/malaria/pdf/treatmenttable.pdf

Signs and Symptoms of Falciparum Malaria

Malaria is generally transmitted by the bite of an infected female Anopheles mosquito (although rarely, cases of transfusion-related and congenital malaria can occur). The infecting sporozoite travels to the liver, and in 8 hours is undetectable in the blood. Within the hepatocytes, the sporozoites divide and form a cyst-like structure called a schizont that contains thousands of merozoites. When the schizont matures, it ruptures, releasing the merozoites into the bloodstream where it invades red blood cells.

This period between the bite of the mosquito and the invasion of RBCs by malaria parasites is called the prepatent period. Again, for the sake of simplicity, I will concentrate on P. falciparum malaria on this blog. It's important to establish the species of malaria prior to beginning treatment, and to keep in mind that patients can be infected with multiple species of malaria parasites. (Will come back to this later! Please stay tuned!)

In falciparum malaria, this process lasts from 8 to 25 days (on average, usually around 10). 90% of returning travelers with falciparum malaria present with symptoms within 30 days of departure from the malaria-endemic area.

Symptoms of malaria are often vague, and can resemble flu-like symptoms with fever, headache, and malaise. Semi-immune patients (and non-immune patients on chemoprophylaxis) generally have lower levels of parasitemia, shorter fever duration, as well as shorter parasite clearance time. Fever is the main presenting symptom, although the severe headache may also prompt patients to seek care.

Classic Paroxysm of Malaria:

Cold Stage (1-2 hours) – the patient shivers or has frank rigor; the temperature rises sharply
Hot Stage (2-6 hours) – the patient is flushed, tachycardic, and has sustained high temperature
Sweating Stage (2-4 hours) – the patient is diaphoretic, and the temperature falls rapidly

Rigors are associated with the lysis of RBCs and the release of TNF-alpha. The cycling of fever and chills is dependent on the synchronization of parasitic invasion and RBC lysis. This process can take a week to develop and in falciparum malaria, the development of disease is often too rapid to allow the classic paroxysms to develop.

Percentage of patients reporting:

Fever 92%
Headache 53%
Myalgesia/Arthralgia 34%
Fatigue 27%
Emesis 18%
Diarrhea 17%

Clinical Signs:

The Malarial Triad: Fever, Anemia, Hepato-splenomegaly. Additionally, some patients may exhibit jaundice. In complicated malaria, anemia may be severe, and patients may have acidosis and hypoglycemia. The term “Blackwater Fever” used to be used to refer to patients with discolored urine resulting from haemoglobinuria and renal failure. Disseminated Intravascular Coagulation (DIC) is an occasional complication in adults.

Cerebral Malaria is the most important complication of malaria, and even with hospitalization in modern intensive care units, the mortality rate is approximately 20 percent. The case definition is “an unrousable coma in the presence of peripheral parasitemia where other causes of encephalopathy have been excluded.” Patients make exhibit seizures (note: malaria seizures can occur at any temperatures), focal neurological signs, retinal hemorrhages, and brainstem signs such as doll’s eyes. Neurological sequelae are found in 5% of survivors (10% of children) and may include cortical blindness, hypotonia, hemiparesis, and mental retardation.

The natural history of untreated malaria differs with each species. After the first instance of infection with P. falciparum, the patient will either die in the acute attack, or survive with the development of some immunity and residual anemia. Unlike other species of malaria, falciparum does not have a dormant liver stage (hypnozoites), although small numbers of mereozoites can persist in the blood stream and cause recurrent attacks (recrudescence) for up to 12 months.


Source: "Lecture Notes: Tropical Medicine" by Geoff Gil and Nick Beeching. (2009 ed.)

Pathophysiology of Malaria

This week’s learning goal was the pathophysiology of our selected disease. Instead of focusing on the life cycle of malaria which includes the vector stages, I chose an article that concentrated on the two broad categories of severe malaria manifestations: metabolic and neurological complications.

While anemia (due to RBC destruction and reduced RBC production as a result of cytokine-mediated suppression of erythrogenesis), hypoglycemia, and renal failure (more common in adults) require urgent treatment, Planche and Krishna found that cerebral malaria and lactic acidosis were independent predictors of poor outcomes.

The (interrelated) metabolic changes that are important in severe malaria are acidosis, hyperlactatemia (serum levels >5mM), and respiratory distress. The biggest culprit appears to be increased anaerobic glycolysis due to microvascular obstruction. Interestingly, serum lactate levels were found to be higher in malaria than in sepsis, indicating impaired oxygen delivery. Dichloroacetate has been shown to safely lower blood lactate concentration, but more research is needed to assess its capacity to reduce mortality in cases of severe malaria.

In addition to the hypoglycemia induced by patients who are administered quinine (due to increased insulin secretion), hypoglycemia can also be a result of the demands of anaerobic glycolysis. Every patient should be assessed for hypoglycemia on admission, and inpatient care must include regular monitoring of blood glucose levels.

Cerebral malaria is defined as “an unrousable coma with asexual P. falciparum infection at least 30 minutes after a convulsion, when hypoglycemia has been excluded and without interference by sedative drugs or other confounding variables.” However, the authors cited studies that suggest that impaired consciousness, rather than coma, may be a more accurate predictor of death. Originally, it was believed that cerebral edema resulting from increased capillary permeability, was the cause of cerebral malaria. Post-mortem studies now suggest that sequestration of the parasites in the cerebral vasculature, and the simple mechanical obstruction that ensues, is responsible for the symptoms of cerebral malaria.


Planche T, Krishna S. The relevance of malaria pathophysiology to strategies of clinical management. Current Opinion in Infectious Diseases. 2005;18(5):369-375.

Epidemiology of Malaria

Malaria is a potentially fatal but ultimately preventable and treatable vector-borne parasitic disease that is characterized by cycling fever and chills, and generalized flu-like symptoms. Significant findings on physical exam are frequently anemia, jaundice, and hepatosplenomegaly.

According to 2008 estimates from the World Health Organization, there are 350 to 500 million cases of malaria worldwide each year, and malaria claims an estimated one million lives annually, with the majority of deaths occurring in children under 5 years of age. Spread by Anopheles mosquitoes, malaria thrives in tropical zones with warm temperatures and humid conditions. It is endemic in 100 countries in Africa, Latin America, Asia and the Middle East, and Sub-Saharan Africa is disproportionately affected with 90% of the total deaths. Malaria is strongly linked to poverty. Inadequate housing, poor water and sanitation systems, displacement, and lack of access to adequate medical care are significant risk factors for morbidity and mortality.

There are four main species of the malaria parasite (Plasmodium falciparum, P. vivax, P. ovale, and P. malariae), each with a distinct global distribution. For the sake of simplicity, I will concentrate on P. falciparum which is responsible for the majority of deaths worldwide. P. falciparium is sometimes referred to as "the malignant malaria," although the other species are certainly not benign, despite their historical classification. Travelers to endemic areas must be provided with specific counseling and chemoprophylaxis depending on the prevalent species.

Individuals at greatest risk include:

• Children under the age of 5 years
• Travellers to malarial zones from non-endemic areas who have little or no immunity
• Non-immune and semi-immune pregnant women
• People living with HIV/AIDS (PLWHA)

Malaria in pregnancy results in high rates of miscarriage and WHO estimates that it is responsible for 10% of maternal deaths worldwide. Even in the case of subclinical disease, severe anemia and impaired fetal growth can result. Additionally, the sequestration of malaria parasites in the placenta increases the risk of maternal to child transmission of HIV. Other groups at risk include individuals with sickle cell disease, although sickle cell trait provides some protection against malaria.

Due to targeted vector-control programs which relied largely on DDT, malaria has been eradicated from the US and Europe. (See map of previously malarious areas of the US. In 1914 there were 600,000 cases in the US!) While the cycle of transmission within the US has been broken, the CDC reported 1,505 cases of malaria in the US in 2007. This was not significantly different from the number of cases reported in 2006. Of these, the vast majority occurred among persons who had contracted malaria while travelling to endemic areas. However, in one case, transmission occurred through blood transfusion in a patient with transfusion-dependent sickle cell disease. (The implicated donor was identified, and while he confirmed that he had a history of malarial infection, he declined treatment.) In previous years, there have also been confirmed cases of congenital transmission. One death occurred after infection with P. vivax.

In the US, malaria is classified as a notifiable disease, and confirmed (positive blood film, rapid diagnostic test, or PCR) cases must be reported to local and state health departments which conduct the case investigation. Findings are then submitted to the CDC through the National Malaria Surveillance System, and the National Notifiable Diseases Surveillance System. My article for this week is from the CDC's MMWR series:

Centers for Disease Control and Prevention. "Malaria Surveillance - United States, 2007." MMWR 2009;58(2).

In 2007, P. falciparum was identified in a majority of cases (43.4%), while the number of cases in which the infecting species was unreported or undetermined was surprisingly high (30.2%). Of the cases with known residential status, 73.6% occurred among U.S. residents, and 26.4% occurred among residents of other countries. The majority of patients (both US residents and non-residents) reported that their reason for travel was visiting friends and relatives (VFR), highlighting the importance of this group. The highest estimated relative case rates (using estimated number of US travelers to endemic countries) appeared among travelers from West Africa. In 80.1% of cases, clinical malaria appeared within 30 days of arrival in the US.

Strikingly, it was found that among the cases of US residents (and for whom chemoprophylaxis information was available), 62.9% had not followed a chemoprophylactic drug regimen recommended by CDC for the area to which they had traveled. However, it was not clear in this report whether they had initially been prescribed an incorrect regimen, or had been non-adherent to an appropriately prescribed regimen. Of the total number of cases in women, 4.5% of those occurred in pregnant women, none of whom had adhered to a complete chemoprophylactic regimen. Problems with adherence make it difficult to identify areas of emerging drug resistance (by identifying cases that occurred in spite of chemoprophylaxis) as well as increasing the likelihood that resistance will develop.

This article did not discuss delays in treatment due to missed diagnosis, or the percentage of cases who were asked to report a travel history in their first contact with a healthcare provider. Nor was there an analysis of the appropriateness of clinical therapies once the diagnosis was made.

However, the article stressed the importance of prompt treatment, and the potentially life-threatening complications that can develop within a short period of time from the onset of symptoms. While malaria should always be considered in febrile patients with a travel history to malaria endemic areas, the CDC recommends that malaria should also be included in the differential diagnosis for all cases of FUO, regardless of the travel history. The article also drives home the importance of correct chemophrophylaxis (especially in at-risk individuals) and preventive measures to avoid contracting malaria in the first place!


From the CDC Website:

Health care providers needing assistance with diagnosis or management of suspected cases of malaria should call the CDC Malaria Hotline: 770-488-7788 (M-F, 9 am - 5 pm, eastern time). Emergency consultation after hours, call: 770-488-7100 and request to speak with a CDC Malaria Branch clinician.

First Post

Hi Everyone.

Just an initial disclaimer, I'm not particularly tech saavy, so please bear with me as I work out the kinks!

I was initially drawn to the topic of malaria by the statistics for missed diagnoses (59%) and subclinical treatment (64%) that were cited in one of the first week's readings: "Global infections: recognition, management, and prevention." Given our current setting, I thought it would be appropriate to focus on malaria and student health, both in terms of students planning to study abroad, and international students returning home to visit family and friends. This is likely to change as the quarter progresses, but at least these were my first musings!

Anyways, I thought for the first article, something general might be appropriate. The Up to Date article entitled "Epidemiology, pathogenesis, and clinical features of malaria," is a good introduction. In the section on Host Genetics, I was interested to read that while some traits may be protective against malaria, this tricky parasite is able to develop new techniques for invading previously "immune" red blood cells.

I've also included a link to the Doctors Without Borders (MSF) Campaign for Access to Essential Medicines website. http://www.msfaccess.org/main/other-diseases/msf-and-malaria/. It's a great resource for information regarding the fight to make artemisinin-based combination therapies for malaria affordable and accessible to those who need them the most. This year, efforts have been made to reduce the cost of antimalarials through the establishment of the Affordable Medicines Facility–malaria (AMF-m). However, the fund does not address other barriers to care in resource-poor settings such as user fees and geographically inaccessible health posts. Nor does the fund provide for Rapid Diagnostic Tests, or insist on the use of Fixed Dose Combinations that have been shown to improve patient adherence. If anyone's curious about these issues, there's an article entitled, “Focusing on Quality Patient Care in the New Global Subsidy for Malaria Medicines” at http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000106.

Have a great weekend, everyone, and see you on Tuesday!