Malaria Case File

Malaria Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 48

A 50-year-old woman presents to your office with the complaints of fever, chills, nausea, and vomiting for the past 5 days. She is especially concerned because she just returned from a 3-week long church mission trip to central Africa during which she did not take the recommended malaria prophylaxis. She was careful about using insect repellent and wearing long-sleeved clothing, but she did not take the recommended weekly dose of mefloquine because it made her nauseous. Starting a few days after her return, she has had episodes of shaking chills followed by fever spikes as high as 39.7°C (103.5°F) and then profuse sweating. After these episodes she would feel so exhausted that she would sleep for hours. These severe episodes have been occurring every other day. In between these episodes, she has had low-grade fever, myalgias, nausea,vomiting, and diarrhea. On examination, she appears very fatigued and pale. Her temperature is 37.7°C (99.9°F), pulse 100 beats per minute, blood pressure 110/80 mm Hg, and respiratory rate 18 breaths per minute. Other than signs of dehydration, her examination is unremarkable. A complete blood count shows her to be anemic. She has elevated blood urea nitrogen, creatinine, and lactate dehydrogenase levels. A thin-blood smear is sent to the laboratory, which shows erythrocytes with ring forms at the periphery of the cell and multiple erythrocytes with three or four ring forms present.

◆ What is the most likely etiology of her infection?

◆ What findings on the thin blood smear are specific for this organism?

ANSWERS TO CASE 48: MALARIA

Summary: A 50-year-old woman has fever and body aches. A thin-blood smear shows erythrocytes with ring forms at the periphery of the cell and multiple erythrocytes with three or four ring forms.

◆ Most likely etiology of her infection: Plasmodium falciparum.

◆ Findings on the thin blood smear are specific for this organism: Multiple ring forms in a single erythrocyte and ring forms located at the periphery of the erythrocytes.

CLINICAL CORRELATION

Malaria is caused by one of the four species of plasmodia involved in a humanmosquito-human life cycle. Plasmodia are coccidian parasites of erythrocytes. Their life cycle involves asexual reproduction in humans and sexual reproduction in the mosquito. Human infection is initiated by the bite of an infected mosquito, which introduces sporozoites into the bloodstream. The sporozoites travel to the liver where they mature and reproduce asexually by schizogony. Plasmodium ovale and P. vivax may also establish a dormant—hypnozoite— stage in the liver; P. falciparum and P. malariae are incapable of this. On completion of the hepatic growth and reproductive stage, merozoites are released from hepatocytes and infect erythrocytes, initiating the erythrocytic cycle. Asexual reproduction continues, resulting in rupture of erythrocytes and release of more infectious merozoites. The classic symptoms of malaria relate to the paroxysm of shaking chills, fever, and sweating and correspond with the cyclical lysis of erythrocytes and release of merozoites. Plasmodium vivax, P. ovale, and P. falciparum species of malaria tend to produce paroxysms in 48-hour cycles (tertian malaria), whereas P. malariae causes paroxysms in 72-hour cycles (quartan malaria).

A series of paroxysms of decreasing intensity constitutes a primary malarial attack. After the primary attack, parasites tend to disappear from the blood. In infections with P. falciparum or P. malariae this would constitute a cure. In P. vivax and P. ovale infections, relapses may occur as a result of hypnozoites persisting in the liver.

Complicating pathologic changes such as anemia, hepatomegaly, and splenomegaly may occur. In the case of falciparum malaria, capillaries are blocked by infected erythrocytes that typically tend to become “sticky” and sequestered in capillary beds. Erythrocyte destruction leads to anemia. Capillary blockage leads to ischemia, anoxia, and subsequent organ damage. This is the basis for cerebral symptoms and kidney damage that leads to black water fever, a condition in which hemoglobin and erythrocytes appear in the urine; “blackwater fever” is associated with a poor prognosis. Falciparum malaria is the most virulent and lethal form of malaria, sometimes called malignant tertian malaria.

APPROACH TO THE SUSPECTED MALARIA INFECTION

Objectives

1. Learn the life cycle of Plasmodium species and the epidemiology and clinical course of infection.

2. Be able to describe the three basic aspects of infection: transmission, diagnosis, and treatment/prevention.

Definitions

Relapse malaria: Infection derived from hypnozoites (hypnos = sleeping; zoites = animals) or residual liver stages that persist after a primary infection with P. vivax and P. ovale.

Appliqué form: Parasite on the periphery of erythrocytes, as in P. falciparum infection.

Ring stage: Stage in the life cycle of Plasmodium in an erythrocyte consisting of a thin ring of protoplasm with a nucleus at one side.

Schizogony: Asexual division or “splitting” carried out by all Plasmodium species.

Blackwater fever: A dangerous complication of malaria, especially falciparum, characterized by passage of red to black urine and associated with high mortality.

DISCUSSION

Characteristics of Plasmodium That Impact Transmission

Plasmodium is a genus in the phylum Apicomplexa, which contains other human parasites such as Toxoplasma, Cryptosporidium, Cyclospora, and Isospora. All of these organisms belong to a phylogenetic class in which all species are parasitic.

Malaria infections are endemic in tropical developing countries. Although endogenous malaria has occurred in the United States, most cases are imported by travelers. There are numerous species of Plasmodium, but only four species cause human malaria—P. falciparum, P. vivax, P. malariae, and P. ovale. All species are transmitted by an infected anopheline mosquito. Plasmodium sporozoites are the infective forms injected into the bloodstream when the mosquito takes a blood meal. The sporozoites circulate in the bloodstream and then invade hepatocytes to initiate a preerythrocytic cycle. In the liver parenchymal cells the parasite multiplies asexually by a process called schizogony or splitting. Asexual reproduction gives rise to multiple individual stages or merozoites. These merozoites become blood-borne and invade erythrocytes to initiate the erythrocytic cycle. In the case of P. vivax and P. ovale, the liver phase can be sustained for years by sporozoite-derived dormant stages known as hypnozoites. It is the prevalence of the hypnozoites that leads to relapses of malarial symptoms, possibly occurring several years after the first acute disease has been cured.

When merozoites parasitize erythrocytes, their development takes two routes. Some merozoites develop into micro (male) and macro (female) gametocytes. When a female anopheline mosquito bites an infected person and ingests the gametocytes, fertilization of the macrogametocyte by the microgametocyte takes place in the mosquito with the subsequent and sequential formation of diploid zygotes, oocysts, and, eventually, sporozoites. Sporozoites travel to enter the salivary glands of the mosquito where they are capable of initiating a new infection when the mosquito takes a blood meal. Through the second route in the erythrocytic cycle, the parasite develops successively through ring, trophozoite and schizont stages. As a result of schizogony, the erythrocyte breaks open and releases many new merozoites. These parasites then infect more erythrocytes, repeat the development cycle, ultimately causing the destruction of massive numbers of erythrocytes. The characteristic chill, fever, and sweating paroxysm occur when the parasites are released from the erythrocytes. Because the release of parasites becomes synchronized and periodic, the paroxysms are also periodic, occurring at 48 or 72 hours depending on the species. The destruction of erythrocytes and release of cell and parasite debris elicit host responses that contribute to pathologic changes.

Diagnosis

Diagnosis is made by finding the characteristic organisms on thick and thin blood smears. Differential diagnosis rests on knowing the specific morphologic characteristics of each species, which are revealed in a thin blood smear (Table 48-1). Plasmodium vivax and P. ovale appear as ring shapes, and in other advanced stages of development in enlarged erythrocytes that contain numerous granules, known as Schüffner dots. Plasmodium malariae has characteristic “band or bar” pattern and do not enlarge the host erythrocytes. Plasmodium falciparum can be identified by the presence of multiple ring forms within a single erythrocyte, in contrast to other plasmodia that will have only one ring form per erythrocyte. Plasmodium falciparum ring forms also tend to occur at the periphery of the erythrocyte; these “appliqué” forms are distinctive for this species. Mixed infections with more than one species of Plasmodium may occur.

Table 48-1

APPEARANCE OF MALARIA PARASITES IN BLOOD SMEARS

Treatment and Prevention

From the perspective of patient management, drugs to treat malaria fall into three categories: prophylactic, schizonticidal, and antirelapse. Prophylactics are designed to prevent infection by attacking the sporozoite stages or preventing the development of clinical symptoms by preventing schizogony in the erythrocytic cycle. Schizonticidal compounds may be used in prophylactic measures and to affect a clinical cure in an acute infection. Antirelapse drugs are directed against hypnozoite stages, as in vivax infection. A radical cure in P. vivax and P. ovale infections requires the use of drugs that eradicate both the erythrocytic and exoerythrocytic schizonts in the liver.

Chloroquine is a schizonticidal compound and drug of choice in treating clinical cases of malaria. Mefloquine, referred to in the case presentation, is used in prophylaxis and also to treat chloroquine resistant strains of Plasmodium. Drug resistance of certain strains of Plasmodium is a practical problem. In this case, back-up drugs are quinine or chemically related mefloquine, or a combination of sulfadoxine (a sulfonamide) and pyrimethamine (pyrimidine derivative). Antirelapse or tissue schizonticidal drugs are aimed at hypnozoites (liver schizonts). The drug of choice in this category is primaquine.

Synopsis

The synopsis of malaria is presented in Table 48-2.

Table 48-2

COMPREHENSION QUESTIONS

[48.1] Microscopic examination of a thin blood smear from a patient suspected of having malaria reveals numerous normal size erythrocytes without stippling but with ring stages, many with multiple ring stages and appliqué forms. Several erythrocytes show developing trophozoites that are spread across the erythrocytes in a band fashion. Which of the following is the most likely cause of infection?

A. Plasmodium vivax

B. Plasmodium malariae

C. Plasmodium ovale

D. Plasmodium falciparum

E. A mixed infection with two Plasmodium species

[48.2] A patient in California was diagnosed with malaria acquired through a blood transfusion. A discussion of this case by physicians included the following statements. Which statement is correct?

A. The infected blood used in transfusion contained sporozoites.

B. The patient should be treated with chloroquine and primaquine.

C. The patient should be treated to eradicate the stages responsible for symptoms.

D. The blood donor had chloroquine-resistant malaria.

E. The patient would not be infective to mosquitoes.

[48.3] Cerebral malaria most commonly attends infection with which of the following?

A. Any two species of Plasmodium

B. Plasmodium malariae

C. Plasmodium falciparum

D. Plasmodium ovale

E. Plasmodium vivax

Answers

[48.1] E. Multiple ring stages and appliqué forms are indicative of P. falciparum; several erythrocytes show developing trophozoites that are spread across the erythrocytes in a band fashion that is indicative of P. malariae infection. Normal size erythrocytes without stippling (Schüffner dots) would exclude P. vivax and P. ovale.

[48.2] C. The primary goal should be to treat the patient to eliminate the erythrocytic cycle that is the cause of symptoms. This would constitute a radical cure because the liver phase only occurs if infection is initiated by sporozoites. Thus, treating with primaquine (B) is not necessary because the patient will not harbor hypnozoites. Likewise, (A) is not correct because sporozoites are only acquired from mosquitoes. Transfusion malaria is caused by schizonts and merozoites present in the transferred blood. There is no way to know that the malaria is chloroquine resistant until after treatment with chloroquine (D) and the patient, although not likely to occur, could transmit the infection to mosquitoes (E) because gametocytes would be present in the blood and susceptible Anopheles species occur in the United States.

[48.3] C. Cerebral malaria involves the clinical manifestations of Plasmodium falciparum malaria that induce changes in mental status and coma and is accompanied by fever. Without treatment, cerebral malaria is fatal in 24–72 hours and the mortality ratio is between 25 to 50 percent. The common histopathologic finding is the sequestration of parasitized and nonparasitized red blood cells in cerebral capillaries and venules.

MICROBIOLOGY PEARLS ❖ In a laboratory diagnosis, in which blood smears are treated with Giemsa or Wright stain plasmodia can be identified when the nucleus and cytoplasm are seen. ❖ Chemotherapy is directed at erythrocytic stages to provide a clinical cure and hypnozoites in the liver to affect a radical cure. Treatment of specific cases remains an active area of continuous investigation.

REFERENCES

Centers for Disease Control. DPDx. Laboratory identification of parasites of public concern. Malaria. 2007 http:// www.dpd.cdc.gov/dpdx/HTML/Malaria.htm 

Centers for Disease Control. DPDx. Laboratory identification of parasites of public concern. Image Library. Malaria. 2007. http://www.dpd.cdc.gov/dpdx/HTML/ ImageLibrary/Malaria_il.htm 

Medical Letter on Drugs and Therapeutics. Drugs for parasitic infections. New Rochelle, NY. 2004. http://www.medletter.com/freedocs/parasitic.pdf. This reference has been updated and “superseded by the special report Drugs for Parasitic Infections, which can be purchased (on-line) for $25.” This reference has been provided because it is a comprehensive and clinically useful reference that is regularly updated and could be of value to those who are involved in treating parasitic infections 

Centers for Disease Control. Malaria. Part 2: Treatment: General Approaches and Treatment: uncomplicated malaria.2007. http://www.cdc.gov/malaria/diagnosis_ treatment/clinicians2.htm

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