Topic Editor: Becky Box, MBBS
Review Date: 12/08/2012
Definition
Malaria is a mosquito borne disease caused by protozoan parasites of the genus Plasmodium. These parasites are transmitted by infected female Anopheles mosquitoes which usually bite after dusk and before dawn. Malaria can present as a spectrum of illness severity, ranging from a mild febrile illness, to severe malaria, with a broad array of clinical features including; coma, convulsions, severe anemia, hypoglycemia, metabolic acidosis, acute pulmonary edema, septic shock, acute renal failure, severe jaundice and/or spontaneous bleeding.
Description
- Geographical distribution maps show malaria as endemic in over 90 countries located in a broad band around the equator. These countries include the Americas, many parts of Asia and much of Africa. Ninety percent of malaria fatalities occur in Sub-Saharan Africa.
- There are five recognized Plasmodium species capable of causing malaria in humans, these include P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi
- The severity of symptoms, incubation period and ability to re-activate after an initial attack depends on the infecting plasmodium species
- P. falciparum, is well recognized as the most virulent strain
- P. vivax and P. ovale can lie dormant in the liver after an initial attack, and reactivate after months or years
- P. malariae has a low prevalence and mild disease. Fever recurs at 3 day intervals, which is also known as quartan malaria
- P.knowlesi, previously only known to infect monkeys, was implicated in human disease in 2004 and has been documented to cause severe malaria in humans
- Incubation period varies from 7 to 30 days
- Travelers who are travelling to malaria-prone areas and are advised to take anti-malarial prophylaxis. In the U.S., malaria cases are mostly imported from travelers who visit malaria endemic areas
- Manifestations common in all forms are fever, headache, chills, vomiting, splenomegaly, and hepatomegaly. Malarial paroxysm will often include malaise, abrupt chills, and fever (39° to 41° C), an abnormal, rapid pulse, polyuria, worsening headache, and nausea
Epidemiology
Incidence/Prevalence
- Malaria is endemic in over 90 countries which have a combined population of ~ 40% of the total world population
- World Malaria Report 2011 reports 216 million cases of malaria. Around 655,000 deaths occurred from the disease in 2010
- Sub-Saharan Africa had the highest estimated mortality rate in 2010 ; The predominant species in Africa is P.falciparum
- Of malarial species that infect humans, P.vivax and P.falciparum are thought to be responsible for 95% of cases
- Only 1500 cases of malaria are reported annually in U.S., with approximately 40% of these being due to P. falciparum
Age - All age groups can be infected, however, severe cases tend to occur in the young in high transmission regions and in all ages in low transmission areas, due to lack of immunity
- In highly endemic regions, with high transmission, severe malaria is negatively correlated with age. Adults in such environments develop an exposure-related immunity, which results in less severe disease with advancing age
Gender- Males and females are affected equally
Genetics- In malaria-endemic areas, blood cell dyscrasias and hemoglobin-related disorders (e.g., Hemoglobin C, thalassemias, or G6PD deficiency) are prevalent and thought to protect against malaria
- Sickle cell carriers may also have relative protection against infection
- Host genetic factors are believed to contribute to the variability of malarial phenotype. Research has focused on identifying factors in the mechanisms involved in susceptibility to P. falciparum
Risk factors- Residing in tropical regions where the mosquito (Anopheles) is prevalent, and exposure to mosquitoes between dusk and dawn
- Children <5 years typically have not developed immunity and are at greater risk of severe disease
- Elderly individuals tend toward a more severe course of malaria
- Malaria during pregnancy is associated with high rates of maternal anemia, stillbirth, miscarriage, premature delivery, low birth weight, and neonatal death
- Individuals who travel from non-endemic areas to endemic areas (sub-Saharan Africa)
- Individuals with HIV/AIDS
- Refugees who are exposed to poor living conditions in malaria endemic countries
- Malaria may also be transmitted through blood transfusion, organ transplant, use of needles and syringes contaminated with blood, as well as autochthonous transmission, (indigenous or introduced from an imported case)
Etiology
- Caused by Plasmodium parasites which spread through bites of infected female Anopheles mosquitoes
- When a human is bitten, plasmodium sporozites are injected into the blood stream. They move rapidly to the liver, where they undergo asexual replication into liver shizonts. After approximately 1 week, these liver shizonts rupture, releasing merozoites into the blood stream which then infect the host's red blood cells. From there, the merozoites progress into trophozoites (ring forms) which develop into red cell shizonts and are once again released into the blood stream as merozoites to infect more red blood cells. After 1-2 weeks of the initial bite, gametocytes are produced (the sexual form) which are transmitted back to the mosquito during the next blood meal, to continue the cycle
- Different strains of plasmodium will infect younger or older aged red cells. P.falciparum and P. knowelsi can infect all ages of red cells, leading to a much higher ‘parasite density' (infected cells) and greater disease burden
- At the initial stages of infection, multiple broods infect the red bloods cells, but eventually one brood suppresses the others so that periodicity develops and the cycle of replication synchronizes. This results in simultaneous rupture of red blood cells, releasing metabolic waste products and activating the immune system, leading to commonly recognized malarial paroxysms
- Both parasite and host factors play a role in determining the severity of infection by plasmodium species. The factors include:
- Multiplication capacity – P.falciparum and P.knowelsi can infect red cells of any age leading to much greater parasitic load than its counterparts. There is a well recognized correlation between degree of parasitemia and prognosis
- Rosetting: Refers to the phenomenon where red blood cells are arranged in clusters around a central red blood cell. There is a link between rosetting and the development of cerebral malaria
- Cytoadherence: Refers to ‘stickiness' of the infected cell to the endothelium, which leads to obstruction of capillaries and reduced tissue oxygen delivery
- Cytokine release – this is activated by both parasite products and host cellular material. The degree of cytokine response is well recognized to differ amongst individuals leading to variable degrees of systemic inflammation
- Acquired immunity
- Drug resistance – which varies significantly depending on geographical distribution and strain
- Recrudence can occur when the initial parasitic infection is not cleared by either the immune system or drug therapy. The parasite continues to replicate in red blood cells leading to subsequent clinical symptoms. Relapse or recurrence occurs when the erythrocyte infection is cleared, and there is a new infection from liver merozoites. True relapse can only occur in P. vivax and P. ovale, where dormant shizogony occurs in the hepatocytes
- Species causing malaria in humans are:
- P. falciparum
- Invades red blood cells (RBCs) of all ages, and thus has a high parasitic density
- Incubation period: 9 to 14 days
- Clinically causes most severe malaria cases
- P. vivax
- Penetrates immature RBCs (reticulocytes), limiting parasitemia to 2-5%
- Incubation period: 12 to 17 days
- Relapse of P. vivax is a major cause of malaria in young children in endemic areas
- Severe complications are rare
- P. ovale
- Similar to P.vivax, infects only reticulocytes
- Incubation period: 16 to 18 days or longer
- Less severe and has less frequent relapses
- Spontaneous resolution usually occurs after ~ 6-10 paroxysms
- P. malariae
- Primarily infects aged red blood cells, limiting the number of infected cells
- Incubation period: 18 to 40 days or longer
- P. malariae infections usually cause low level parasitemia with no or minimal acute manifestations
- Proteinuria is common in children and can present clinically with nephrotic syndrome
- P. knowlesi and P. malariae are very similar at younger stages when viewed under microscope. P. knowlesi multiplies daily and can be fatal, whereas P. malariae multiplies every 3 days and does not reach high blood densities
- P.knowlesi
- Can infect all ages of red blood cells
- Only reported in areas of South East Asia
- In the early blood stages, the parasite resembles falciparum, but mature stages resemble malariae. This may lead to misdiagnosis as P.malariae, which is dangerous as P.knowlesi can be fatal and P. malariae tends to have a more benign disease course
History
- In obtaining a history, it is important to realize that patients with malaria may have a slow or fulminant course with nonspecific symptoms similar to other febrile/viral illnesses. Malaria can be classified into uncomplicated or complicated (severe). P. falciparum is most frequently responsible for the severe type whereas P. vivax and P. ovale rarely produce serious manifestations
- Obtain a travel history and review whether such travel was to an endemic region. Discuss whether the patient was taking prophylaxis during their travels. The absence of such travel history to an endemic region does not eliminate the possibility of malaria, but makes it very unlikely. There is always the possibility of an inaccurate travel history or, in rare cases infection through other sources (e.g., transfusion, congenital transmission, or local mosquito-borne transmission)
- Most of the patients present with fever (>92% of cases), chills (79%), headaches (70%) and diaphoresis (64%). Other symptoms include abdominal pain, dizziness, dry cough, malaise, mild diarrhea, myalgia, nausea, and vomiting
- In patients with severe malaria the presenting complaint may be related to complications from the acute infection:
- Cerebral malaria – reduced level of consciousness/coma
- Metabolic acidosis – due to tissue hypoperfusion with tachypnea and dizziness
- Acute renal failure – confusion, tachypnea, cardiac arrhythmias, and/or reduced urine output
- Severe anemia – breathlessness, muscle fatigue, syncope or near syncope, and weakness
Physical findings on examination
Physical findings include following:
- Fever – usually occurs in paroxysm of varying frequency
- Hepatomegaly -tender to palpation in acute phaseIcteric sclera/jaundice
- Orthostatic hypotension
- PallorSplenomegaly
- Tachycardia
Patients with severe malaria may present with following manifestations:
- Central nervous system:
- Altered level of consciousness, confusion/delirium, convulsions or signs of symmetrical upper motor neuron disease including brisk reflexes, ankle clonus, extensor plantar responses, brisk jaw reflex, jaw clenching or dysconjugate gaze
- Cardiovascular system
- Signs of cardiovascular collapse including; tachycardia, wide pulse pressure/ hyperdynamic circulation, flow murmur, poor central capillary refill
- Respiratory system
- Acute distress syndrome with tachypnea, bilateral crepitations, reduced air entry, reduced oxygen saturation
- Tachypnea in compensation for metabolic acidosis
- GIT/Renal/Heme
- Abnormal bleeding from mucosa, easy bruising, oliguria, pallor
Blood test findings
- Complete blood count (CBC):
- Anemia
- Thrombocytopenia in 60% of cases. Bleeding is uncommon due to this unless disseminated intravascular coagulation (DIC) is also present
- White blood cells (WBCs) are often low or normal, however neutrophilia (by % of WBC's) with left shift is present in most cases
- Liver function test (LFT) findings include:
- Renal function: Monitor for renal failure
- Electrolyte panel: Monitor sodium and potassium levels in cases of severe malaria and all cases of falciparum malaria.
- Bicarbonate is low in cases of acidosis due to sepsis or renal failure
- Hyperkalemia is typical in cases of acute renal failure
- Hyponatremia can occur due to dilution/salt depletion. Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH) or cerebral salt wasting may occur with severe malaria
- Coagulation profile (APTT, INR, Fibrinogen) in cases of septicemia or if DIC is suspected
- Light microscopy of thick and thin stained blood smears: Gold standard for diagnosing malaria
- Thick smears have 20 to 40 times higher sensitivity vs thin smears for detecting Plasmodium species
- Highly sensitive when performed by skilled technicians, can detect as low as 5-10 parasites per microlitre of blood Under general field conditions, estimated sensitivity is ~ 100 parasites per microlitre of blood
- Thin smears help to determine malaria species, count parasitemia, and detect the presence of schizonts, gametocytes, and malarial pigment in neutrophils and monocytes. Thin films are preferred for routine estimation of parasitemia
- In nonfalciparum malaria, parasitemia rarely exceeds 2%
- In nonimmune individuals, if parasitemia exceeds 5%, severe disease is expected
- If the results are negative and if malaria is still suspected, it is advisable to repeat smears every 6–12 hours for 48 hours
- Rapid diagnostic tests (RDT)
- Based on an immunoassay, these tests malarial antigens or enzymes of the parasite in the patient's blood
- Sensitivity varies depending on the antigen for which they are based. RDT for P.falciparum species is generally around 90% sensitive at parasite densities above 100 per microlitre of blood. The sensitivities of non-falciparum species is less well determined
- The specificity for RDT's is universally high (>90%), but false positive results do occur
- These tests are proving extremely useful in rural and remote areas where access to microscopy is not available
- Microhematocrit centrifugation with quantitative buffy coat (QBC)
- Helps to detect nuclear material of parasites using acridine orange stain. This test is unable to determine Plasmodium species or quantify the parasitemia
- This testing is expensive and requires special equipment and is thus rarely utilized
- OptiMal test
- Helps to determine lactate dehydrogenase (LDH) of parasites and may be used to diagnose malaria (good for falciparum, detects some vivax, but more false negatives) in rural areas where microscopy is not available (mostly replaced by RDT currently
- Polymerase chain reaction (PCR) assay
- Helps identify specific species, and is particularly useful in detecting low grade parasitemia
- Not available in many regions with endemic malaria due to the need for specialized equipment and reagents
Other laboratory test findings
- Urinalysis to evaluate for acute renal failure (ARF) and/or Blackwater fever:
- Findings in ARF are typically oliguria (<400 ml/day) or anuria (<50 ml/day)
- Patients with blackwater fever presents with hemoglobinuria
Radiographic finding
- Chest X-ray: Can be useful in patients presenting with respiratory symptoms
- Computed tomography (CT) : Can be used to rule out cerebral edema or hemorrhage
Other diagnostic test findings
- Lumbar puncture is recommended in patients who exhibit mental status changes to evaluate for both cerebral malaria and to evaluate for bacterial meningitis
General treatment items
- Efforts to achieve global malaria control center around two main objectives; vector control and improved recognition and treatment of patients with acute malaria
- The CDC advises that malaria treatment not be initiated until a diagnosis is confirmed in uncomplicated cases. There is concern that treatment on clinical grounds alone leads to over treatment, contributes to resistance and also leads to delayed diagnosis of other important febrile illnesses
- Presumptive treatment without confirmation of the diagnosis should be started in strongly suspected cases, in cases of severe disease, and in cases where an immediate laboratory diagnosis is unavailable
- Treatment with anti-malarial therapy should be based on species type, the patients's clinical condition and drug resistance patterns where the infection was acquired. In cases where the species remains unidentified, it is best to treat the case as though it is P. falciparum until the species is identified
- Use of acetaminophen for fever control is common. There is no evidence as to whether this is helpful or harmful, with some concerns as to whether this might prolong the illness by reducing parasite clearance
Treatment of uncomplicated malaria
P.falciparum
- Based on the WHO guidelines in 2010, Artemisinin-based combination therapies (ACTs) are the recommended treatment for uncomplicated P.falciparum malaria
- Using a combination of anti-malarials with different mechanisms of action aims to reduce the per-parasite probability of developing resistance to both drugs
- The following ACTs are recommended: artemether-lumefantrine; artesunate-amodiaquine; artesunate-mefloquine and artesunate-sulfadoxine-pyrimethamine
- Clinicians should be guided by the level of resistance within the country/region to the partner medication in the combination
- Second-line treatments are:
- An alternate ACT that has therapeutic efficacy in the area
- Artesunate + tetracycline/doxycycline or clindamycin (given for 7 days)
- Quinine + tetracycline/doxycycline or clindamycin (given for 7 days)
- Treatment in Pregnancy:
- First trimester – quinine + clindamycin for seven days, note: an ACT is indicated only if alternate treatment not available or failure of treatment after seven days
- Second & third trimester – can give ACT known to be effective in region OR artesunate + clindamycin for 7 days OR quinine + clindamycin for 7 days
- During lactation – standard treatment – but avoid dapsone, primaquine and tetracyclines
- Infants and young children
- ACT is first line of treatment, with weight based dosing. Do not use tetracycline/doxycycline in children 8yrs
P. vivax/ P. ovale
- Chloroquine combined with primaquine remains the first line treatment in chlorquine-sensitive infections
- Chloroquine-resistant infections (including all infections from Papua and New Guinea and Indonesia – with high level of resistance) should be treated with quinine sulfate + doxycycline/tetracycline or atovauone-proguanil or mefloquine
- Treatment for relapse requires Primaquine phosphate for a total of 14 days
- Treatment in Children is the same as adults, avoiding tetracycline/doxycycline
- Primaquine is contraindicated in patients with Glucose 6-Phosphate dehydrogenase deficiency (G6PD)
Treatment of Severe Malaria- Severe malaria is an emergency requiring parenteral antimalarial therapy, irrespective of the species seen on smear
- The 2011 WHO malaria treatment guidelines recommend IV/IM Artesunate as first line, in both adults and children with Artemether or Quinine as valid alternatives, depending on availability.
- Quinidine gluconate is the only parenteral antimalarial drug available and administered in the U.S.
- In severe malaria, treatment with parenteral agents should be given for a minimum of 24 hours regardless of whether or not the patient can tolerate oral medication. After this, and based upon clinical status, an oral alternative can be started
- A baseline ECG should be obtained prior to starting parenteral quinidine gluconate due to its cardiotoxic effects. This drug should be administered in an intensive care unit with frequent monitoring of blood pressure and blood glucose due to risk of developing hyperinsulinemic hypoglycemia
- In addition to expedient treatment with a parenteral agent, the complications of severe malaria must be managed effectively:
- Coma – maintain airway, identify and treat other reversible causes of coma i.e. hypoglycemia, bacterial meningitis. May require intubation and ventilation
- Hyperpyrexia – can be treated with tepid sponging, cooling blankets and anti-pyretics. Avoid NSAIDs due to risk of renal toxicity
- Convulsions – to be managed acutely with benzodiazepines and other anti-epileptics. Important to gain rapid control of seizures (may also need protection of the airway)
- Hypoglycemia – identify and treat
- Severe anemia – may require blood transfusion
- Acute pulmonary edema – manage with diuretics, positioning and oxygen. Depending on severity may require non-invasive ventilation (CPAP/BiPAP)
Medications indicated with specific doses
- Artemether/lumefantrine
- Atovaquone/proguanil
- Chloroquine
- Clindamycin [Oral]
- Clindamycin [IM/IV]
- Doxycycline [Oral]
- Doxycycline [IV]
- Hydroxychloroquine
- Mefloquine
- Primaquine
- Quinidine [IV]
- Quinine
- Tetracycline [Oral]
Disposition
Admission Criteria
- Cerebral malaria
- Complicated/Severe malaria
- Nonimmune patients with confirmed or suspected P. falciparum
- Patients showing severe dehydration
- Patients unable to tolerate oral medications
- Patient's whose diagnosis is unclear with significant systemic illness
- Severe cases of P. falciparum malaria should be admitted to the ICU
Discharge criteria - Clinical improvement, tolerance of oral medication and fluids, and a decreasing level of parasitemia
Prevention
- Exposure to mosquitoes between dusk and dawn should be avoided
- Preventive measures against mosquitoes include
- Use permethrin- or pyrethrum-containing residual insecticide sprays on clothing or in home
- Place screens on doors and windows
- Mosquito repellents containing DEET
- Use of mosquito netting impregnated with permethrin or pyrethrum around beds
- Children born to nonimmune mothers in endemic areas should receive prophylaxis from birth
- Pregnant women with P. vivax or P. ovale infection should be placed on chloroquine prophylaxis
- Travelers can use prophylactic antimalarial drugs, insect repellent, long-sleeved clothing, bednetting, and flying insect spray to protect from the disease
- Chemoprophylaxis
- Travelers with intense exposure to P. vivax or P. ovale or with splenectomy should take a 14-day prophylactic course of primaquine phosphate on return, which may reduce the risk of recurrence
- Travelers should receive chloroquine prophylaxis one to two weeks before entering an area with endemic malaria where there is no documented chloroquine resistance. However, in areas with chloroquine-resistant P. falciparum infection, travelers should be given atovaquone/proguanil, doxycycline, or primaquine 1 day before entering the area, or mefloquine 2–7 weeks before travel
Prognosis
- P. falciparum infection is the most severe form and may lead to cerebral malaria, or other complications. Untreated cases have a high mortality rate
- Cases of P. vivax and other nonfalciparum may be fatal in patients with immunosuppression or other significant comorbidities
Pregnancy/Pediatric effects on condition
- P. falciparum infection is a major risk factor in infant mortality, primarily through low birth weight
- Anemia is one the major effects of malaria in pregnant women which contributes to low birth weight
- P. falciparum and P. vivax infections during pregnancy are associated with low birth weight, but not shortened gestation
Synonyms/Abbreviations
Synonyms
- Periodic fever
- Tertian malaria
- Quartan malaria
- Tropical splenomegaly
ICD-9-CM
- 084.0 Falciparum malaria (malignant tertian)
- 084.1 Vivax malaria (benign tertian)
- 084.2 Quartan malaria
- 084.3 Ovale malaria
- 084.6 Malaria, unspecified
ICD-10-CM
- B50 Plasmodium falciparum malaria
- B51 Plasmodium vivax malaria
- B52 Plasmodium malariae malaria
- B53 Other specified malaria
- B54 Unspecified malaria
