MALARIA
Introduction: Human malaria is caused by 4 species of Plasmodia: P. falciparum, P. vivax, P. ovale and P. malariae. The majority of malaria infection in Africa is caused by P. falciparum while P. vivax infection is more commonly seen in Central America, the Middle East and India. P. falciparum can be associated with severe morbidity and symptoms can progress to coma or death very rapidly. The risk of severe disease is highest among nonimmune individuals, asplenic individuals, children less than 5 and pregnant women.
Transmission: Malaria transmission is predominantly via the bite of a female Anopheles sp. mosquito however other mechanisms exist including: congenitally acquired disease, blood transfusion, sharing of contaminated needles and organ transplantation. “Autochthonous” malaria can result if a mosquito feeds on a malaria-infected individual and transmits the infection by biting someone else.
Life Cycle: Sporozoites are transmitted from the salivary glands of the infected mosquito and travel in the host’s bloodstream to the liver where they invade the hepatocytes and multiply until mature tissue schizonts, each containing thousands of daughter merozoites, are formed. The liver schizonts then rupture after 6-16 days and release thousands of merozoites into the bloodstream where they invade red blood cells and continue maturation into ring form and then to mature red cell schizonts over 48 to 72 hours. Finally, new daughter merozoites are released from the red blood cells which then infect new red cells. With P. vivax and ovale infections, some parasites may lay dormant in the liver and can cause late relapse after reactivating after many months; this does not occur with P. falciparum or malariae.
Pathogenesis: All four malaria species digest red cell proteins and hemoglobin. The parasites derive energy from anaerobic glycolysis of glucose to lactic acid and thus can cause hypoglycemia and lactic acidosis. The parasites also alter the red cell membrane making it less deformable and resulting in hemolysis and accelerated splenic clearance. P. falciparum in particular induces the formation of sticky knobs on the surface of the erythrocytes which can lead to microvascular obstruction and ultimately secondary organ dysfunction.
Immunity: Immune responses occur following infection with malaria and individuals living in endemic areas may develop partial immunity to disease following repeated infections. This does not prevent repeat infection, however the severity of symptoms is typically limited. This partial protection wanes quickly after leaving an endemic area.
Clinical Manifestations: Symptoms of malarial infections develop only with the erythrocytic stage thus patients may remain asymptomatic after being bitten by an infected mosquito anywhere from 1-4 weeks. Signs and symptoms are varied but typically include fever, chills, sweats, headache, myalgias, fatigue, nausea, vomiting, abdominal pain, diarrhea and cough. Febrile paroxysms often are daily and irregular early in infection however will typically become coordinated with the release of merozoites from the infected cells and then can typically occur every other day. Anemia, thrombocytopenia, splenomegaly, hepatomegaly and jaundice can develop and splenic rupture can occasionally occur. Cerebral malaria can present as an impaired state of consciousness and/or seizures and can result in coma and death. It is universally fatal if untreated and even with treatment has a 20% mortality rate. Up to 10% of patients who survive will have persistant neurologic abnormalities. Risk factors for cerebral malaria incule age (children and older patients), pregnancy, poor nutritional status, HIV infection, transmission intensity and h/o splenectomy.
Other complications of P. faliciparum infection include renal failure, pulmonary edema/ARDS, hypoglycemia, anemia and bleeding and gastroenteritis.
Diagnosis: The conventional method for diagnosis is light microscopy of a Giemsa-stained thick and thin blood smear. Because of the cyclical nature of the parasitemia, smears should be taken every 6-12 hours for 48 hours before the diagnosis is ruled out (however the first smear is positive in 95% of cases). The thick smear is more sensitive in diagnosis malaria and the thin smear allows examination of the morphology of the parasite (for species identification) and quantification of the percent of parasitized red cells.
Other lab abnormalities that can be seen with malaria incule evidence of anemia, hemolysis, thrombocytopenia, hyperbilirubinemia, abnormal renal function, mildly elevated transaminases, elevated LDH, and sometimes evidence of DIC.
Patients are considered to have severe malaria if they have a parasitemia of >5%, altered consciousness, oliguria, jaundice, severe normocytic anemia, hypoglycemia, or other evidence of organ failure
Treatment: Treatment of malaria involves supportive measures as well as specific anti-malarial drugs. Patients with P. falciparum malaria should have their treatment commenced without delay and generally should be admitted to the hospital so that they can be observed for any evidence of complications. Severe malaria should be managed in the ICU where close monitoring, fluid resuscitation and electrolyte balance can be achieved. Thick and thin smears should be examined routinely to monitor the efficacy of therapy until the parasitemia is below 1%. Follow-up smears at 3, 7 and 28 days should be obtained to rule out recurrence or incomplete clearance of parasitemia.
First line treatment of uncomplicated P. falciparum infections consists of one of the following:
- a quinine-based regimen (quinine sulfate 10mg/kg q8h x 7 days with either 3 tablets of pyrimethamine-sulfadoxine on day three or doxycycline 100mg po BD x 7 days)
- atovaquone-proguanil (malarone)
- mefloquine
Patients with severe malaria as well as those unable to tolerate oral therapy should be given parenteral treatment:
- IV quinidine gluconate 10mg/kg loading dose over 1-2 hours followed by a continuous infusion of .02 mg/kg/min OR
- IV quinine dihydrochloride 20mg salt/kg loading dose over 4 hours followed by 10mg/kg over 2-4 hours every 8 hours.
MALARIA CASE
A 32 yo M presents with high fevers and rigors, headache, nausea and vomiting. He states that he was born in Tanzania but moved to the US one year ago for work. He returned to Tanzania 2 weeks ago to visit his family. 1 week into his visit he began to develop his symptoms and has been progressively feeling worse. Today he noticed that his eyes seemed yellow.
1. List 5 questions that you want to ask
2. List 5 physical exam findings you will be looking for
He states that he has not been taking malaria prophylaxis during this trip. He has been unable to tolerate PO for the past day. He thinks his urine has been getting progressively darker over the past few days however he cannot remember the last time he urinated.
On exam he is an ill-appearing male. He is febrile to 40.1, BP is 95/55, HR 115, RR 26. He has no neck stiffness or meningeal signs. He is icteric. His lungs have bilateral crackles in the lower lobes. He has hepatosplenomegaly and and diffuse abdominal tenderness with no rebound or guarding. He is neurologically intact with no focal deficits.
3. Where do you want to admit him?
4. What tests do you want to order?
5. What medications do you want to start?
6. What other interventions do you want to do?
The patient is admitted to the ICU. 2 large bore IVs are placed and he is given IVF. A foley is placed with minimal urine output. You start him on antipyretics and empiric treatment for malaria with IV quinidine gluconate
You order a FBP, LFTs, BUN and creat, LDH, coags, glucose, rapid test, hepatitis panel, UA, and a thick and thin smear. A chest x-ray and abdominal ultrasound are also ordered.
His BP and HR improve with IVF and his urine output increases to about 30cc/hr
7. what side effects of quinidine do you want to watch for?
CBC reveals WBC 5, HGB 6, Plts 95. LFTs reveal a mild transaminitis with an indirect hyperbilirubinemia. LDH is 300. His BUN is 55 and his creatnine is 3.1. Coags are normal. Rapid test is negative. Hepatitis panel is negative. CXR reveals mild pulmonary edema. Abd u/s is normal. Thick and thin smear reveals P. falciparum with an estimated parasite load of 5%
8. How long do you want to keep him on IV treatment?
9. How often do you want to check his parasite load?
The patient continues to improve over the next 2 days. He is now tolerating PO. He has had no evidence of arrhythmias on cardiac monintoring and no evidence of hypoglycmeia. His repeat labs reveal that his renal failure is improving. His parasite load is now 2%. Rather than continuing the IV quinidine at a reduced dose you decide to switch his treatment to an oral regimen of quinine sulfate with a dose of pyrimethamine-sulfadoxine on day 3. The patient continues to improve and is transferred to the regular floor on day 5 to complete his treatment.
Answers:
- Character of fevers? Currently taking malaria prophylaxis? Any neck stiffness? Any respiratory symptoms? Any change in urine appearance or output?
- On exam: look for hypotension, tachycardia, pallor, jaundice/icterus, assess for nuchal rigidity, abdominal exam for hepatosplenomegaly
- Admit to ICU due to hemodynamic instability.
- Investigations: FBP with thick & thin blood smear, blood cultures, rapid HIV test, BUN, creatinine, electrolytes, bilirubin, transaminases, coags, RBG. Also check urinalysis, abdominal ultrasound, CXR.
- Start patient on IV quinine gluconate.
- Aggressive IV fluid hydration.
- Adverse effects of quinine include cardiac arrhythmias & hypoglycemia.
- Continue IV quinine for 3 days, convert to oral if patient’s condition is improved & patient is able to tolerate oral meds.
- Check parasite load again in 48-72 hours. Frequency of checking the parasite load depends on the patient’s clinical condition.
