Hematology

Malaria

Malaria

What every physician needs to know:

Malaria is the most common single agent killer of children on the planet. One child under the age of 5 years dies every 15 seconds. It has a myriad of clinical presentations. Physicians must entertain the diagnosis in exposed individuals (either travel or transfusion) to avoid high case fatality rate.

Other, rarer infectious causes of hemolysis include:

  • Pathogens that invade and directly lyse red blood cells (RBCs) such as: Babesia and Bartonella bacilliformis

  • Pathogens that precipitate microangiopathic hemolytic anemia (Escherichia coli O157 in hemolytic uremic syndrome)

  • Pathogens that produce antibody mediated hemolysis (mycoplasma and Cytomegalovirus [CMV])

Are you sure your patient has malaria? What should you expect to find?

Anemia, fever (not necessarily recurrent/periodic), headache, myalgias, central nervous system dysfunction, watery/bloody diarrhea, respiratory distress.

Beware of other conditions that can mimic malaria:

Babesia, sepsis, enteric pathogens, viral encephalitis, acute respiratory distress syndrome.

Which individuals are most at risk for developing malaria:

In endemic regions, all children under the age of 5 years and pregnant women in their first and second pregnancies are at particular risk. Pre-existing immunosuppression, such as HIV infection, exacerbates risk in these groups as well as in non-pregnant adolescents and adults.

In travelers, individuals with longer durations of stay in endemic regions and individuals who do not take effective chemoprophylaxis.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Thick and thin blood smear examination for the presence of malarial parasites. Thick films offer increased sensitivity while thin films are more useful for speciation.

The presence of parasites is always an abnormal test result.

Multiple blood smears may be necessary to detect low intensity infections.

Point-of-Care, dip-stick format, and rapid diagnostic tests are also available. These tests have similar sensitivity and specificity to blood smear examination.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of malaria?

None are typically necessary as the pathogen is directly detected in the peripheral blood.

If you decide the patient has malaria, what therapies should you initiate immediately?

Treatment varies with the species of malaria, the location where the infection was acquired and the drug-resistance status of the parasites circulating in that location, clinical severity of patient’s condition, concurrent illnesses in patient, pregnancy status of patient, drug allergies, and concurrent medications of the patient.

Most importantly, the global drug resistance patterns, as well as the availability of anti-malarials in the US changes rapidly. Physicians are strongly encouraged to contact the Center for Disease Control and Prevention (CDC) Malaria Hot Line (tel: 770-488-7788 or 770-488 7100; http://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html) to select most appropriate drug regimen.

Key issues driving treatment choices:

  • Plasmodium falciparum versus others

  • Uncomplicated versus severe malaria

- Impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of more than 5%.

  • Chloroquine sensitive region (Central America west of Panama Canal, Haiti, Dominican Republic, most of Middle East) versus chloroquine resistant region (all other areas)

If unable to access current CDC treatment guidelines consider:

Uncomplicated malaria, species and resistance pattern unknown

Adults: atovaquone-proguanil tabs (Malarone tm Adult tab = 250 mg atovaquone/ 100 mg proguanil) 4 tabs po qd x 3 days

Pediatrics: atovaquone-proguanil tabs (Malarone tm Peds tab = 62.5 mg atovaquone/ 25 mg proguanil)

  • 5-8 kg: 2 pediatric tablets po qd x 3 days

  • 9-10 kg: 3 pediatric tablets po qd x 3 days

  • 11-20 kg: 1 adult tablet po qd x 3 days

  • 21-30 kg: 2 adult tablets po qd x 3 days

  • 31-40 kg: 3 adult tablets po qd x 3 days

  • greater than 40 kg: 4 adult tablets po qd x 3 days

Severe malaria, species and resistance pattern unknown

Quinidine gluconate: 6.25 mg base/kg (=10 mg salt/kg) loading dose intravenously (IV) over 1-2 hrs, then 0.0125 mg base/kg/min (=0.02 mg salt/kg/min) continuous infusion for at least 24 hours.

Once parasite density less than 1% and patient can take oral medication, complete treatment with oral quinine sulfate (adults 650 mg salt po tid; Peds: 10 mg salt po tid). Quinidine/quinine course = 7 days in Southeast Asia; = 3 days in Africa or South America.

PLUS

Doxycycline (oral): Adults: 100 mg po bid x 7 days; Pediatrics: greater than age 8 yrs 2.2 mg/kg po bid x 7 days.

If patient not able to take oral medication, give dose IV every 12 hours and then switch to oral doxycycline (as above) as soon as patient can take oral medication. For IV use, avoid rapid administration.

OR if age less than or equal to 8 yrs

Clindamycin (oral): 20 mg base/kg/day po divided tid x 7 days.

If patient not able to take oral medication, give 10 mg base/kg loading dose IV followed by 5 mg base/kg IV every 8 hours. Switch to oral clindamycin (oral dose as above) as soon as patient can take oral medication. For IV use, avoid rapid administration. Treatment course = 7 days.

More definitive therapies?

If parasitemia is high (greater than 10%), or patient has altered mental status, acute respiratory distress syndrome (ARDS), or renal impairment, consider red cell exchange. If patient infected with Plasmodium vivax or Plasmodium ovale, should add treatment for potential hypnozoite forms (dormant liver stage parasites) as follows:

  • Adults: primaquine phosphate – 30 mg base po qd x 14 days

  • Pediatrics: primaquine phosphate - 0.5 mg base/kg po qd x 14 days

Note: Primaquine can cause hemolytic anemia in glucose-6-phosphate dehydrogenase-deficient persons. G6PD screening must occur prior to starting treatment with primaquine.

What other therapies are helpful for reducing complications?

Standard intensive care unit support for severe malaria cases.

What should you tell the patient and the family about prognosis?

Prognosis is excellent in uncomplicated malaria. Virtually all patients recover with appropriate therapy. Severe malaria carries a high case fatality rate (approximately 10%). Cerebral malaria is associated with long term (greater than 6 months) neuro-psychiatric and cognitive morbidity in up to 5% of survivors.

What if scenarios.

The most common mistake in diagnosing and treating malaria, is the failure to entertain the diagnosis in ill individuals with exposure to the parasite. This situation results from a failure to obtain a relevant travel and/or transfusion history.

Pathophysiology

Malaria is caused by members of the genus Plasmodium. Plasmodium species are apicomplexa and exhibit a complex life cycle, involving a vertebrate host and an arthropod vector. Vertebrate hosts include: reptiles, birds, rodents, monkeys, and humans. Plasmodium species are very host specific and at present there are no significant zoonoses, although Plasmodium knowlesi, a monkey malaria, is an emerging problem in humans in south east Asia. Four distinct species commonly infect humans: P. falciparum, P. vivax, P. ovale and Plasmodium malariae. The species differ in regard to their morphology, details of their life cycles, and their clinical manifestations. Mammalian Plasmodium species are transmitted by anopheline mosquitoes.

Life cycle

The female anopheline mosquito must take a blood meal for oviposition. During the blood meal, she injects sporozoites (typically 1-30 sporozoites from each infected mosquito) as she spits in to the human (saliva serves as an anti-coagulant for the mosquito’s proboscis). Sporozoites rapidly infect hepatocytes. Parasites in hepatocytes undergo asexual multiplication. After 6-18 days (depending on species) up to 10,000 merozoites rupture from each infected hepatocyte.

In some cases of P. vivax or P. ovale, a hypnozoite or dormant hepatic form develops, which can emerge to cause bloodstage infection many years later. Each merozoite infects a single red blood cell (RBC). Within the RBC, asexual reproduction produces intermediate stage parasites (rings, trophozoites, and schizonts) resulting in up to 25 merozoites, which rupture the RBC and go on to infect additional RBCs.

Occasionally, a merozoite will differentiate into a male or female gametocyte. Another mosquito takes up these gametocytes during a blood meal. In the gut of the mosquito, the gametocytes fuse to form an ookinete. The ookinete attaches to the gut wall, develops into sporozoites that migrate to the mosquito’s salivary glands to complete the cycle.

Pathogenesis

Uncomplicated malaria

The pathology and clinical manifestations associated with malaria are almost exclusively due to the asexual erythrocytic stage parasites. Tissue schizonts and gametocytes cause little, if any, pathology. Plasmodium infection causes an acute febrile illness which is most notable for its periodic fever paroxysms occurring at either 48 or 72 hour intervals in semi-immune individuals. The severity of the attack depends on the Plasmodium species, as well as other circumstances such as host age, the state of immunity, and the general health and nutritional status of the infected individual. The disease has a tendency to relapse (from hypnozoites) or recrudesce (from undetectably low levels of blood stage infection) over months or even years.

The malarial paroxysm will usually last four to eight hours and begins with a sudden onset of chills, accompanined by severe headache. Fatigue, dizziness, anorexia, myalgia, and nausea are common. After the paroxysm, the patient is exhausted, weak and will usually fall asleep. Upon awakening, the patient usually feels well, other than being tired, and does not exhibit symptoms until the onset of the next paroxysm.

In semi-immune individuals, malaria parasites tend to develop synchronously in the human host. In other words, all of the parasites within a host are at approximately the same stage (i.e., ring, trophozoite, schizont) as they proceed through schizogony. It is unclear why synchronous development does not occur in malaria naïve individuals, but naïve individuals typically do not have periodic fever paroxysms. The clinical implication is that one cannot rely on the absence of periodic fevers to exclude the diagnosis of malaria.

The malarial paroxysm corresponds to the rupture of the infected erythrocytes and the release of merozoites. The presence of malarial proteins, free merozoites and RBC ghosts, leads to the production of endogenous pyrogens: interleukin-1 beta (IL-1beta) and tumor necrosis factor (TNF) which are responsible for the clinical manifestations.

Severe malaria

Severe malaria (defined above) is largely mediated by the sequestration of infected erythrocytes in deep tissue beds. Sequestration, or cytoadherence, is a virulence factor of P.falciparum trophozoite and schizont-infected erythrocytes that allows them to bind to endothelial cells of deep vascular beds in vital organs, especially brain, lung, gut, heart, and placenta. This sequestration allows splenic avoidance and thus confers a significant survival advantage to the parasite. Sequestered parasites result in hypoxia and pro-inflammatory responses in the watershed distribution of affected organs.

These processes result in the clinical manifestations of cerebral, pulmonary, GI (gastrointestinal) and placental malaria. Importantly, as only the early ring stage parasites fail the sequester and are available for detection in blood films, peripheral parasitemia will frequently underestimate the total body burden of parasites. Thus, clinical decisions should be based on both the clinical presentation of the patient in the context of the measured parasite burden.

Cytoadherence is mediated by the interaction of parasite proteins located on the surface of infected RBCs (knob proteins encoded by plasmodium falciparum named erythrocyte membrane protein 1 [PfEMP1] or var genes) with endothelial adhesion receptors (intercellular adhesion molecules [ICAM], endothelial-leukocyte adhesion molecules [ELAM], CSA [chondroitin sulfate A], cluster of differentiation [CD36], etc.)

What other clinical manifestations may help me to diagnose malaria?

Focused questions on travel history, including remote travel (due to hypnozoites in P. vivax and P. ovale) as well as transfusion history. Note, "airport" malaria due to autochthonous transmission occurs sporadically.

Periodic fevers are not a common feature in non-immunes; the absence of periodic fever does not exclude the diagnosis of malaria.

What other additional laboratory studies may be ordered?

Both severe and uncomplicated malaria requires serial measurement of parasitemia to confirm drug efficacy. In addition, severe malaria requires laboratory based monitoring, targeted to the end organs involved, for example: blood gas analysis in the setting of pulmonary malaria with ARDS.

What’s the evidence?

Roberts, DJ. "Hematologic Changes Associated with specific Infections in the Tropics". Hematol Oncol Clin North Am. vol. 30. 2016. pp. 395-415.

(Review of mechanisms of malarial anemia.)

Wah, ST, Hananantachai, H, Kerdpin, U, Plabpleung, C, Prachayasittikul, V, Nuchnoi, P. "Molecular basis of human cerebral malaria development". Trop Med Health. vol. 44. 2016. pp. 33.

(Review of pathogenesis of cerebral malaria.)

Tilley, L, Straimer, J, Gnädig, NF, Ralph, SA, Fidock, DA. "Artemisinin Action and Resistance in Plasmodium falciparum". Trends Parasitol. vol. 32. 2016. pp. 682-96.

(Review of artemisinin mechanisms of action and resistance.)

Roth, JM, Korevaar, DA, Leeflang, AM, Mens, PF. "Molecular malaria diagnostics: A systematic review and meta-analysis". Crit Rev Clin Lab Sci. vol. 53. 2016. pp. 87-105.

(Discusses diagnostic methods for malaria.)

Taylor, WR, Hanson, J, Turner, GD, White, NJ, Dondorp, AM. "Respiratory manifestations of malaria". vol. 142. 2012. pp. 492-505.

(Review of pulmonary complications of malaria.)

Wassmer, SC, Grau, GE. "Severe malaria: what’s new on the pathogenesis front". Int J Parasitol. 2016 Sep 23. pp. 30210-7.

(Pathogenesis of severe malaria.)

Christenses, SS, Eslick, GD. "Cerebral malaria as a risk factor for the development of epilepsy and other long-term neurological conditions: a meta-analysis". Trans R Soc Trop Med Hyg. vol. 109. 2015. pp. 233-8.

(Long-term neurological sequelae of cerebral malaria.)

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