Revised and prepared by Alexander Lazaryan, MD

Q1. What causes malaria?
A. Malaria is caused by one of four plasmodium species, affecting humans. Symptomatic malaria results from infection of red blood cells (RBCs) by malarial parasites. The parasites undergo asexual reproduction within RBCs. Their rapid growth leads to the rupture of RBCs, causing hemolysis and fresh infection of other erythrocytes.

Q2. What are the "stages of malaria"?
A. Within the RBCs the parasite matures from simple "ring forms" to form "trophozoites". The latter continue enlarging and later undergoing nuclear division to form schizonts. All three stages can be seen on peripheral blood films in P.vivax infections but schizontemia is very rare in P. falciparum infections as this stage of reproduction takes place within capillaries of the organ tissues. When P.falciparum schizonts are seen on peripheral smears, it indicates the severe disease.

Q3. How does Plasmodium falciparum malaria differ from Plasmodium vivax malaria?
A. 1. Simply speaking, falciparum malaria can be a lethal disease, while vivax malaria is generally not, although in rare cases it may also cause severe complications (i.e., splenic rupture). Plasmodium falciparum causes severe and complicated disease as a result of its capacity to make RBCs stuck to the endothelial lining of capillaries and post capillary venules. This process is known as "vascular sequestration" and causes dysfunction of organs involved, by depriving them of glucose and oxygen. Additionally, P.falciparum has the capacity to enter RBCs of any age causing infection of a significant proportion of the patient's overall RBC mass with consequently high levels of parasitemia. P.vivax infections are restricted to cells of a certain age only, thus restricting the infection to less than 5% of the overall RBC mass.
2. P.falciparum also differs from P.vivax in not causing late relapses. At the time of the initial infection, some of the P.vivax parasites hibernate and remain dormant within liver cells as hypnozoites, causing relapses many weeks (months) after the original illness.

Q4. What is the incubation period in malaria?
A. From the time of the first bite by an infected mosquito to the time of the first symptom. The incubation period is on average 10-14 days for P.falciparum and 14-21 days for P.vivax. In a host who has not been exposed to malaria in the past, the incubation period of severe disease can be very short.

Q5. What are gametocytes? How does one treat them?
A. Gametocytes are the sexual forms of the plasmodia. They develop within human RBCs and later undergo further maturation within mosquitoes. They do not cause symptoms and therefore do not need treatment unless one wishes to clear them from the blood of the patient as a public health measure to interrupt the malaria life cycle. Single dose of primaquine (45 mg stat) is sufficient. Although WHO longer recommends this.
Confusion is often caused by the fact that gametocytes persist for weeks after successful treatment of clinical malaria, and their continued detection on smears alarms doctors and patients who think they are dealing with "resistant" malaria, which is not true.

Q6. Can one get malaria without being bitten by mosquitoes?
A. Yes, malaria can be congenital (transmitted from mother to child) or it can be also acquired from blood transfusion. In both cases there is no exo-erythrocytic stage and, therefore, using primaquine is unnecessary when P.vivax is involved. Transfusion acquired malaria has no incubation period, though due to the small numbers of parasites present in each unit of blood, symptoms may take time to develop.

Q7. How is malaria diagnosed?
A. The golden standard method of diagnosis is an examination of smears taken from the peripheral blood for the presence of asexual forms of malarial parasites within RBCs. PCR is also very effective at detecting the Plasmodium species present in patients with parasitemias as low as 0.05-0.1 parasite/ÁL of blood and when malaria microscopic detection is uncertain.

Q8. When should smears be taken?
A. CDC recommends taking 1-2 blood smears per day for 2-3 days. Possibly as many as six negative smears are needed for malaria to be definitely excluded. It is also important to know that smears should not be necessarily taken at fever peak.

Q9. What is the difference between thick and thin smears? Are both necessary?
A. Thick smears are prepared from a drop of blood, which consists of many layers of RBCs and is stained by a method in which the RBCs are lysed and parasites are looked for in a stroma of hemoglobin. The advantage of this method is that it can scan for the presence of parasites through a much greater quantity of blood and is more rapid. However, a far greater degree of expertise is required for interpretation. A thin film is ideally a single layer of RBCs and, if well prepared, the RBCs should be just adjacent to each other.
A thick film is better at answering the question - "Is malaria present at all?" And a thin film is better at answering the question - "What is the infecting species of malaria - P. falciparum or P. vivax?" Thin smears are also better at estimating the percentage of RBCs infected - a figure known as the % parasitemia.

Q10. Does the routine CBC help in diagnosing malaria?
A. Yes. As a matter of fact, the CBC is sometimes can be very useful. The most important feature is that there is generally a normal or a slightly low total WBC count despite the fact that the patient has high temperature. Low or falling hemoglobin is also a useful clue to the presence of P.falciparum infection, and it is the result of hemolysis and non-specific bone marrow suppression. However, this is not a reliable feature as many patients have normal or high hemoglobin on admission, which only falls following rehydration. The platelet count is almost always reduced in malaria, and this is often the cause for undue alarm. Despite thrombocytopenia bleeding episodes are very rare and platelet counts rise rapidly with therapy.

Q11. When should I consider malaria as a diagnosis in my patient?
A. The clinical presentation of malaria is so diverse that practically any presentation could be compatible with the diagnosis of malaria. However, in order to make it easier, a few of the common presentations are as follow:
"The febrile patient" is the commonest presentation. When the patient has fever with chills and rigors on alternate days along with splenomegaly, then the diagnosis of malaria is strongly suggested. The pattern of the fever is usually unhelpful. In many instances the fever can be low grade and, on occasion, fever is almost continuous, as it would be expected in typhoid. The range of the fever also has no diagnostic value, meaning that not every patient with high fever has malaria, and patients with small blips in the temperature may also have malaria.
Many patients are initially diagnosed as having "flu" because of non-specific symptoms and malaise, until smears are checked for malaria or more severe symptoms develop.
"Gastroenteritis" with fever is present in many patients with malaria. The diarrhea is generally not as severe as in acute viral or bacterial enteritis and it is not long lasting. However, malaria should be suspected in patients with gastrointestinal symptoms who are febrile.
"Jaundice and fever" is also one of the commonest presentations. The important features in the history, which differentiate this presentation from acute viral hepatitis, are the presence of significant fever before the jaundice in malaria, and some degree of anemia. The level of bilirubin is totally not helpful and one could see patients with bilirubin levels exceeding 30 mg% that were entirely due to falciparum malaria. The level of transaminase rise is not very high in malaria and levels of ALAT and ASAT in excess of 400 IU are almost always due to viral hepatitis.
An unusual but important differential diagnosis of this type of malaria presentation is leptospirosis. It is important to remember that patients with jaundice due to other causes may have parasites of P. falciparum or P. vivax in their blood film and may be asymptomatic from the malarial infection due to the presence of partial immunity.

Q12. When do I suspect "cerebral malaria" in my patient?
A. First of all "cerebral malaria" occurs almost always in P.falsiparum. There are very rare case reports of cerebral and pulmonary complications in P.vivax. As patients with malaria develop cerebral manifestations, they develop an impairment in their conscious level, becoming confused and drowsy, and later drift into a deep coma. The manifestations of cerebral malaria are often very subtle, but in some instances can progress very rapidly. Convulsions are a common feature but tend to be associated with a significant impairment in the conscious level.
It should be noted that hypoglycemia can also produce disorientation and coma. This is a common feature in patients with cerebral malaria, especially those on quinine. Fever itself can produce convulsions in children and both chloroquine and mefloquine have been implicated as causes of seizure, especially in susceptible patients.
Neck stiffness should always be tested for in a patient with any neurological involvement and fever. When present, meningitis should be positively excluded.

Q13. Should I suspect malaria in a patient who has had fever for over a week and still has no palpable spleen?
A. Yes, there is no doubt that splenomegaly is absent in a significant proportion of patients with malaria even when the fever has been present for weeks.

Q14. When should I consider hospitalizing my patient with malaria?
A. In the first instance you should not wait for confirmation of the diagnosis before hospitalizing your patient with suspected malaria.
The patient should be transferred to the hospital on the basis of signs and symptoms of severe disease. These symptoms may include cerebral manifestations as described above, severe anemia, hyperpyrexia (> 39OC), jaundice, respiratory distress, oliguria, hypotension, bleeding etc. Hospitalization should be considered for all patients who cannot take oral medication and require parenteral therapy.

Q15. What is the correct treatment of acute P. vivax infections?
A. The drug of choice is chloroquine which should be given in a total dose of 25 mg per kg of chloroquine base split over three days.
The pharmacokinetically superior regimen consists of 10 mg of base per kg followed by 5 mg/kg 6-8 hrs later and 5 mg/kg on each of the following 2 days. A more practical regimen used in many areas consists of 10 mg/kg on the first and second days and 5 mg/kg on the third.
All these regimens provide a total dose of 25 mg/kg (e.g. 1500 mg of base for 60 kg adult). There is no advantage in giving prolonged courses of chloroquine which exceed the above total dose. However, attempts should be made to ensure that the drug is not vomited up, by giving it when the patient is afebrile and with prior priming with prokinetic agents such as domperidone.
More detailed dosage for all age groups is shown in a Table below.

Table. Dosage schedule for Chloroquine treatment (WHO)
    Number of tablets
Weight (kg) Age (years) Tablets, 100 mg of base Tablets, 150 mg of base
Day1 Day2 Day3 Day1 Day2 Day3
5-6 < 4 months 0.5 0.5 0.5 0.5 0.25 0.25
7-10 4-11 months 1 1 0.5 0.5 0.5 0.5
11-14 1-2 1.5 1.5 0.5 1 1 0.5
15-18 3-4 2 2 0.5 1 1 1
19-24 5-7 2.5 2.5 1 1.5 1.5 1
25-35 8-10 3.5 3.5 2 2.5 2.5 1
36-50 11-13 5 5 2.5 3 3 2
50+ 14+ 6 6 3 4 4 2

Q16. What other drugs can be used for acute P. vivax infections?
A. All the other antimalarials, including sulpha-pyrimethamine compounds, quinine, mefloquine will work in P. vivax infections but they should not be used unless P vivax is resistant to chloroquine, which is rare. Overall, chloroquine is probably the safest and the quickest to cause P.vivax parasite clearance.

Q17. I have given my patient with proved P. vivax malaria an adequate dose of chloroquine, which has been completed and retained well but the patient has not improved and the fever continues. Why is this?
A. It's important to check again and see the results of repeated blood smears. However, there could be many possibilities for this presentation.

  1. The original parasite could be not P. vivax but was actually a misidentified P. falciparum, which is chloroquine resistant causing the lack of clinical response.
  2. There is a mixed infection which is not uncommon, and the P. vivax clears with choloquine but the resistant P. falciparum continues to multiply, often undetected, and cause symptoms. Careful examination of repeated smears by an expert should sort out these two problems.
  3. The patients has P. vivax infection but it was not responsible for the patient's clinical symptoms, which means that there exists a state of P. vivax "infection without disease" and the fever is due to another, as yet unidentified cause, perhaps typhoid or TB. This occurrence is seen in patients who live in highly endemic areas where there is a significant degree of asymptomatic low grade parasitemia. Clues that the fever was actually due to malaria are a low platelet count, a fair to moderate degree of parasitemia and clearance of the symptoms and smears with treatment.

Q18. What is the correct treatment of P.vivax and P. falciparum infection?
Chloroquine-sensitive P.vivax & P. falciparum ADULT DOSAGE PEDIATRIC DOSAGE COMMENTS
Chloroquine (oral) 600 mg base (1000 mg phosphate salt), followed by 300 mg base (500 mg salt) 6 hours later, then 300 mg base x 2 days 10 mg base (max 600 mg base) orally, followed by 5 mg/kg 6 hours later, then 5 mg/kg base x 2 days See Table2. for the schedule!
Chloroquine-resistant P.vivax ADULT DOSAGE PEDIATRIC DOSAGE  
Mefloquine (Lariam ®, oral) 1,250 mg (split dose: 750 mg + 500 mg 8-12 hrs after) x 1day 25 mg/kg (split dose 15 mg/kg + 10 mg/kg 6 hrs after); < 45 kg NOT to be taken by aircraft pilots or drivers of public transport
Quinine sulfate + Doxycycline (oral) 650 mg every 8 hr x 3-7 days plus Doxycycline 100 mg bid x 7 days 25 mg/kg/day in 3 divided doses x 3-7 days plus Doxycycline 2 mg/kg/day up to 100 mg x 7 days Doxycycline: NOT for children < 8 years old and in pregnancy
Prevention of P. vivax relapse ADULT DOSAGE PEDIATRIC DOSAGE  
Primaquine (oral) 15 mg base (26.3 mg phosphate salt) daily x 14days 0.3 mg base (0.5 mg salt) per kg/day x 14 days NOT in pregnant or lactating women or in G6PD-deficiency
Chloroquine-resistant P. falciparum ADULT DOSAGE PEDIATRIC DOSAGE  
Quinine sulfate (oral) 600 mg every 8 hrs x 7 days 10 mg//kg/every 8 hrs x 7 days Very bitter, may causes cinchonism
* Tetracycline (oral) 250 mg every 6 hrs x 7 days NOT for children or pregnant women
* Doxycycline (oral) 100 mg daily 7 days NOT for children < 8 years old CAUTION: contraceptive pills may become less effective!
* Fancidar ® (Pyrimethamine 25mg + Sulphadoxine 500mg) oral 2-3 tablets on day 2, one dose 6 week - 1 year - ? tablet on day 2
1-3 years - ? tablet on day 2
4-8 years - 1 tablet on day 2
9-14 years - 2 tablets on day 2
CAUTION: if patient has allergy to sulfa drugs!
Mefloquine (Lariam ®, oral) 1,250 mg (split dose: 750 mg + 500 mg 6-8 hrs apart) x 1 day 25 mg/kg (split dose 15 mg/kg + 10 mg/kg 6 hrs apart); in a child < 45 kg Vivid dreams (nightmares), nausea, vomiting, dysphoria, weakness
Malarone ® (Atovaquone 250mg + Proguanil 100mg) oral 4 tabs once daily x 3 days 11-20 kg: 1 tab once daily x 3 days
21-30 kg: 2 tabs once daily x 3 days
31-40 kg: 3 tabs once daily x 3 days
Riamet ® (Artemether 20mg + Lumefantrine 120mg) 4 tabs twice a day x 3 days < 15 kg: 1 tab twice daily x 3 days
15 - < 25 kg: 2 tabs twice daily x 3 days
25 - < 35 kg: 3 tabs twice daily x 3 days
Effective in multidrug-resistant P.falciparum
* Given together with Quinine

Q19. How does one know that the patient with malaria is responding to treatment?
A. Overall, reduction in fever and then complete parasite clearance are probably the best indicators of successful therapy. A fall in the parasite count (% of erythrocytes infected by parasites) and reversal of complications also indicates successful therapy.
When hemoglobin continues to fall in the absence of bleeding and parasite density has not dropped significantly after 48 hours of therapy (normally parasite density is expected to drop by 75% in 48 hrs), the presence of drug resistance should be strongly suspected.
Gametocytes of plasmodia are unaffected by the commonly used schizonticidal drugs. They do not cause any disease symptoms and may be persist for weeks following successful therapy. Their presence does not require initiating new regimen or retreating with previously used drugs.

Q20. Which drugs can be safely used to treat malaria in pregnancy?
A. It should be noted that the risk of malaria for both mother and baby is significantly higher than the risk of drug therapy in a pregnant woman. Chloroquine and quinine are safe in pregnancy. Primaquine and sulpha-pyrimethamine compounds (Fansidar , Metakelfin ) should not be used. Tetracyclines are also contraindicated in pregnant patients. Therefore, a prolonged course of quinine as monotherapy or a combination of quinine and clindamycin is an appropriate regimen in chloroquine-resistant falciparum infection.
To prevent relapses in a pregnant woman who has had P.vivax, weekly doses of chloroquine (2 tabs-300 mg of chloroquine base) should be used until the end of pregnancy and lactation.

Q21. A 28-year-old woman was admitted to hospital with chills, fever, headache, and fatigue. Physical examination and laboratory findings revealed that the patient was 20 weeks pregnant and had a urinary infection. Blood smear showed P vivax. She was living in a big city, not in a malarious area. What is the best treatment regimen for a pregnant patient, and how to protect her from relapse?
A. Pregnant patients infected with P.vivax should be cured of blood-stage parasitemia with chloroquine using routine recommendations. The severity of disease may be increased in pregnancy, and malaria also poses a risk for the fetus. Although chloroquine is a class C drug, there are no known pregnancy-related adverse events, and this is supported by a long history of chloroquine clinical use during pregnancy. Unless the infection was acquired in an area with known chloroquine-resistant P vivax (which is rare - e.g., Irian Jaya and Papua, New Guinea, Solomon Islands, Myanmar, India, Guyana), it is initially recommended to treat with chloroquine. If clinical resistance is seen, mefloquine has been shown to be effective (FDA has not approved the use of mefloquine in pregnancy, while the CDC supports its use in all 3 trimesters). Primaquine should NOT be used during pregnancy because the G6PD status of the fetus cannot be demonstrated, even if the mother's G6PD status is known to be normal. All pregnant women should be monitored clinically for relapse and re-treated with chloroquine as needed if malaria relapses. Primaquine terminal treatment should be given only after delivery and by the end of lactation. If ongoing malaria exposure is likely and unavoidable, prophylaxis with chloroquine may be appropriate.

Q22. Can antibiotics be used to treat malaria?
A. Many antibiotics have antimalarial activity (tetracyclines, clindamycin etc.), but their activity is weak and they cannot be used as monotherapy. Antibiotics may be indicated in the treatment of severe malaria when gram negative sepsis supervenes. A combination of gentamicin (only for 48 hrs) with ceftazidime or cefuroxime and metronidazole is an effective regimen.

Q23. Which drugs can be safely used in patients with G6PD deficiency who develop malaria? A. The use of primaquine is unsafe, though depending on the level of G6PD level, 45 mg/kg x 8 weeks regimen could be possibly used under the close monitoring. Chloroquine and quinine are generally safe and acceptable in acute malaria and should be used when required.

Q24. What would be the appropriate chemoprophylaxis for P.vivax and P.falciparum?
A. Travelers to P.vivax affected areas abroad could be prescribed different chemoprophylactic regiments depending on the place of travel (is it a P.vivax-resistant area?), patient's past medical history etc. Chloroquine (Aralen ) is a good option for the chemoprophylaxis in the chloroquine-sensitive areas. The adult dosage is 500 mg of chloroquine phosphate once a week, and the first dosage should be taken 1 week before the arrival to malarious area. The traveler should regularly take chloroquine once a week on the same day of the week throughout all his stay.
Importantly, prophylaxis should be continued 4 weeks after leaving the area. Chloroquine should be taken on a full stomach to minimize nausea. Although side effects are rare, nausea and vomiting, headache, dizziness, blurred vision, and itching can occur. Chloroquine may worsen the symptoms of psoriasis.

Table. Recommendation on Malaria Chemoprophylaxis
Chloroquine-sensitive P.vivax and P. falciparum
Chloroquine (oral) 300 mg base (500 mg salt) weekly * 5 mg base/kg (8.3 mg salt/kg) *
Chloroquine-resistant P. falciparum (if traveling abroad)
Mefloquine (Lariam ®) 250 mg (228 mg base) weekly weight-dependent dosage
Doxycycline 100 mg daily ** contraindicated in < 8 years old and during pregnancy
* starting 1 week before travel and continuing weekly for the duration of stay and for 4 weeks after leaving
** starting 1 day before travel, continuing daily for the duration of stay and 4 weeks thereafter

Table. Dosage schedule for chloroquine chemoprophylaxis
  Number of tablets per week
Weight (kg) Age (years) Tablets, 100 mg base Tablets, 150 mg base
5-6 < 4 months 0.25 0.25
7-10 4-11 months 0.5 0.5
11-14 1-2 0.75 0.5
15-18 3-4 1 0.75
19-24 5-7 1.25 1
25-35 8-10 2 1
36-50 11-13 2.5 2
50+ 14+ 3 2


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