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Intermittent fevers
The Journal of Emergency Medicine, Vol. 30, No. 4, pp. 425– 428, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/06 $–see front matter
Case Presentations of the Harvard Emergency Medicine Residency
INTERMITTENT FEVERS Murray J. McLachlan,
MD,*
Kenneth Weissman, David F. M. Brown,
MD,†
Eric S. Nadel,
MD,*†‡
and
MD*†
*Division of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, †Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, and ‡Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Reprint Address: David F. M. Brown, MD, Department of Emergency Medicine, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 105, Boston, MA 02114
Dr. Murray McLachlan: Today’s case is that of a 34year-old Asian-American man who presented to the Emergency Department (ED) with complaints of 2 weeks of intermittent fevers and chills with persistent generalized malaise. The patient stated that the fevers, which were as high as 40.0°C, responded to acetaminophen. One week before presentation, the patient began vomiting and was evaluated in another ED. He was treated with intravenous hydration and was discharged with the diagnosis of viral syndrome. The nausea and vomiting resolved but the fevers persisted. The patient stated that the fevers occurred every “second day.” He was seen by his primary care physician (PCP) on the day before presentation, and laboratory testing revealed elevated liver function tests and thrombocytopenia. An ultrasound of the abdomen was scheduled. On the day of presentation, the patient had recurrent nausea, vomiting, and fever and came to our ED. The patient also complained of intermittent headaches, but denied abdominal pain, diarrhea, or rash. The past medical history was notable only for appendectomy. He had no drug allergies and took no medications. Are there any questions regarding the history? Dr. Eric Nadel: Although these symptoms are nonspecific, they are persistent enough to prompt further investigation, particularly because this represented his third visit to a health care provider in a period of a week. I think it would be important to obtain more thorough social, travel, and occupational histories.
Dr. McLachlan: The patient did not use tobacco or illicit drugs and rarely drank alcohol. He worked as an architect and was not sexually active. He had traveled to Ghana for 2 weeks 11 months prior. He had taken a full course of mefloquine prophylaxis for malaria before and during the trip. He had been vaccinated against hepatitis A, hepatitis B, meningococcus, and typhoid fever. The family history was unremarkable. Upon arrival at the ED, the vital signs were: temperature 37.9°C, heart rate 121 beats per minute, blood pressure 113/65 mm Hg, respiratory rate 18 breaths/ minute, oxygen saturation 96% on room air. The patient appeared fatigued but non-toxic. The head was normocephalic and atraumatic. The pupils were equal, round, and reactive to light. There was no scleral icterus and the oropharynx was dry without erythema or lesions. The neck was supple with no lymphadenopathy or meningismus. The lungs were clear to auscultation bilaterally. The cardiac examination was notable for tachycardia with regular heart sounds with no murmurs, gallops, or rubs. He had 2⫹ pulses throughout. The abdomen was soft and non-tender with normal active bowel sounds; there were no masses or organomegaly. The spine was non-tender and there was no costovertebral angle tenderness. The extremities were warm, had normal range of motion, and no edema. The joints were normal. The skin had no rash or petechiae. The neurological examination was normal.
Case Presentations of the Harvard Emergency Medicine Residency are coordinated by David F. M. Brown, MD, and Eric S. Nadel, MD, of Harvard University Medical School, Boston, Massachusetts 425
426
Dr. David Brown: With this additional information can someone suggest a differential diagnosis? Dr. William Binder: With such nonspecific symptoms, the differential diagnosis is quite broad at this point. Pneumonia, hepatitis, mononucleosis, endocarditis, primary human immunodeficiency virus (HIV), and undifferentiated viral infection might all present in this manner. It is also important to consider travel-related infections such as malaria and leishmaniasis as well as local infections such as Lyme disease and babesiosis (HIV) infection. How did you proceed from this point? Dr. McLachlan: Blood was drawn and sent for laboratory testing. Blood chemistry analysis revealed: sodium 132 mmol/L, potassium 3.4 mmol/L, chloride 106 mmol/L, bicarbonate 106 mmol/L, blood urea nitrogen (BUN) 28 mg/dL, creatinine 1.3 mg/dL, glucose 160 mg/dL, and magnesium 1.0 mg/dL. Liver tests were as follows: total bilirubin 1.3 mg/dL, direct bilirubin 0.4 mg/dL, alanine aminotransferase 294 U/L, aspartate aminotransferase 74 U/L. Lipase was 2.5 U/dL. Complete blood count results included white blood cell count 3.8 th/cmm (78% neutrophils), hematocrit 42.1%, platelets 40 th/cmm. A urinalysis was normal. Blood was also sent for culture, malaria smears, lyme titers, hepatitis serologies, and a monospot. A chest radiograph was normal. An abdominal ultrasound showed mild splenomegaly; and the liver appeared normal with no evidence of cholelithiasis. Dr. J. Tobias Nagurney: Although the underlying etiology here remained uncertain, the patient was exhibiting signs of dehydration, with tachycardia, dry mucus membranes, and an elevated BUN/creatinine ratio. I would hydrate this patient with crystalloid and consider admission, perhaps to the observation, until I was certain the patient could maintain his hydration status. Could you describe the remainder of the ED course here? Dr. McLachlan: The patient was given two liters of intravenous normal saline, ibuprofen 800 mg orally for a temperature that went up to 38.5°C, and ondansetron 4 mg intravenously for nausea. He was then admitted to the hospital for further hydration and assessment. The hepatitis panel revealed evidence of vaccination against hepatitis A and B; testing for hepatitis C was negative. Lyme serologies and HIV testing were negative as was the monospot test for Epstein Barr virus. Blood and urine cultures were negative. However, malaria smears were positive for plasmodium species with parasitemia of less than 1%; the laboratory was unable to determine the species. A follow-up malaria smear sent on hospital day #2 showed plasmodium species with no rings seen, as well as some gametocytes. Dr. Brown: Can you discuss the prevalence of malaria, especially as it pertains to those traveling to endemic areas?
M. J. McLachlan et al.
Figure 1. Worldwide distribution of malaria in 2006 (http:// www.cdc.gov/malaria/distribution_epi/distribution.htm).
Dr. McLachlan: Malaria is endemic in over 100 countries around the world (Figure 1). Worldwide, there are approximately 300 –500 million cases of malaria per year with approximately one million deaths (although some estimate the death rate could be as high as two to three million per year) (1,2). As approximately 50 million people from industrialized countries travel to developing countries every year, malaria may be found in travelers (3). It is estimated that more than 10,000 travelers contract malaria each year (3), and in 2002, there were 1337 reported cases in the United States (2). Thus, persistent fevers in a patient who has traveled to a country where malaria is endemic within the prior 3 months should be seen as a medical emergency. Furthermore, any patient who presents with flu-like symptoms within 12 months of traveling to an endemic area should also undergo an evaluation for malaria. Dr. Kenneth Weissman: Can you discuss the lifecycle of plasmodium species and the varied clinical presentations of malaria? Dr. McLachlan: The four main species of malaria that account for the vast majority of malaria cases are Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. The disease is transmitted by the bite of a female Anopheles mosquito and has an incubation period of at least 7 days (can be greater than 1 year). P. vivax and P. falciparum are the most commonly contracted strains of malaria, but P. falciparum is the most feared as it can be rapidly fatal. Approximately 90% of P. falciparum cases occur in sub-Saharan Africa and the majority of these cases present within 1 month of exposure. Approximately 70% of P. vivax cases are acquired in Asia or Latin American, but only 50% have symptoms within 1 month, and up to 2% have symptoms more than 1 year after exposure (3). Both P. ovale and P. vivax are more commonly associated with delayed presentation of malaria or relapse (can occur up to 4 years later), as these strains of parasites have persistent liver stages.
Intermittent Fevers
Figure 2. Life cycle of malaria (http://www.cdc.gov/malaria/ biology/life_cycle.htm).
The plasmodium parasite life cycle has two stages in the human host. The first stage (exoerythrocytic stage) involves the liver, where the parasite sporozoite proliferates in the liver cell until it ruptures and releases the parasite merozoite into the bloodstream. In the second stage (erythrocytic stage), merozoites invade erythrocytes and proliferate, forming shizonts, which can eventually rupture, spreading more parasites into the blood and causing fever in infected individuals. Some of the infected erythrocytes contain gametocytes, which can be taken up by mosquitoes, whereby the life cycle is continued in the sporogonic cycle (Figure 2). The typical symptoms of malaria are fevers, chills, headache, malaise, cough, vomiting, arthralgias, diarrhea, and abdominal pain. In severe cases, generally associated with P. falciparum infection, patients can have acute renal failure, respiratory failure, seizures, coma, severe anemia, and circulatory collapse. The fevers seen with malaria usually occur at regular intervals of 48 –72 hrs, and when this occurs it is highly suggestive of P. vivax, P. ovale, and P. malariae (3). Splenomegaly is a common physical examination finding and laboratory testing often reveals thrombocytopenia and, occasionally, leukopenia. A student: Are humans the only hosts of malaria species? Dr. McLachlan: No, there are numerous Plasmodium species that infect many different types of animals including other mammalian species, reptiles, and birds. The life cycle of these other Plasmodium species is sometimes similar to that seen in humans (4). Dr. Emily Senecal: How does one test for malaria? Dr. McLachlan: The most common method (and still the gold standard) of testing for malaria is microscopic examination of the Giemsa stain of thick and thin smears.
427
The thick smear is a drop of blood on glass slide that is used to evaluate for the presence of parasites. The density of parasites is determined by the percentage of red blood cells infected (if ⬎ 4% are infected, then the patient needs an intravenous anti-malarial agent). The thin smear refers to a drop of blood that is smeared across the slide; this test is most helpful for determining the species of malaria. If these tests are initially negative but the clinical picture is very suggestive of malaria, the smears should be repeated every 6 to 12 hours for 2 to 3 days. Other ways of testing for malaria include using polymerase chain reaction (PCR), which is expensive and has limited availability. One can also do serologic testing to look for antibodies using immunoflourescence (IFA) or enzyme-linked immunosorbent assay (ELISA), although this method detects previous as opposed to present infections. A fourth method is antigen detection, though this method is still under review. Dr. Megan Fix: Why did this patient get malaria if he was compliant with chemoprophylaxis? Dr. McLachlan: Diligent chemoprophylaxis use does not guarantee a person will not contract malaria, as resistance to the prophylactic agents is common. In a 2003 New England Journal of Medicine study, one-third of cases of malaria between 1992 and 1999 in Israel and the United States were delayed-onset malaria caused by P. vivax and P. ovale, despite adequate blood-stage prophylaxis (5). Both P. vivax and P. ovale have persistent liver stages, which can lead to relapse of the disease months to years after primary infection. Even appropriate use of a blood-stage schizonticide will not prevent these relapses and can mask the symptoms of the initial infection (5). Nonetheless, all travelers (even former residents of the area) to endemic areas should take prophylaxis. Prophylaxis usually involves taking medication 1–2 days before arriving in the endemic area and continued during time in the area and for 1– 4 weeks after departure from the area (varies with different drugs). Most of the agents are blood-stage schizonticides (and do not affect the liver stage). Chloroquine has been a commonly used agent, but P. falciparum is often resistant, and the drug may exacerbate psoriasis. Doxycycline has good efficacy against P. falciparum and P. vivax, and should be used in areas with chloroquine or mefloquine-resistant P. falciparum like Southeast Asia; however, children and pregnant women cannot take this agent. Mefloquine is another common agent that is used in areas with chloroquine resistant P. falciparum, but should be avoided in patients with psychiatric disorders, seizure disorders, or cardiac conduction problems. Halofantrine is a common agent used overseas, but has potential for serious cardiac side-effects and is not recommended by the Centers for Disease Control and Prevention (CDC).
428
Primaquine and atovaquone-proguanil provide liverstage prophylaxis. Primaquine is used only in special circumstances for primary prophylaxis, and is contraindicated in patients with G-6-PD deficiency or pregnancy or women who are breastfeeding. Atovaquone-proguanil is used as primary prophylaxis in areas with chloroquineand mefloquine-resistant P. falciparum, but should be used with caution in infants and patients with renal impairment or pregnancy (6). Dr. Brown: Can you describe the different treatment options for malaria? Dr. McLachlan: The treatment regimen depends on species, drug resistance, clinical status, where the infection was contracted, comorbidities, pregnancy, and allergies. The CDC provides a treatment table based on various clinical situations that allows the clinician to develop an appropriate plan (7). Depending on the situation, the medications that can be used to fight the parasite forms in the blood include chloroquine, sulfadoxine-pyrimethamine (Fansidar®), mefloquine (Lariam®), atovaquone-proguanil (Malarone®), quinine, doxycycline, tetracycline, clindamycin, and artemisin derivatives (not licensed for use in the United States, but often found overseas). For the dormant parasite liver forms, primaquine can be used, but should not be used in patients who are pregnant, breastfeeding, or who have G-6-PD deficiency. Intravenous anti-malarial agents (quinidine ⫹ doxycycline) are indicated in patients with severe clinical courses (renal failure, severe anemia, respiratory distress, altered mental status) or P. falciparum ⬎ 4% parasitemia (8). In non-endemic areas, the CDC recommends that patients with uncomplicated or severe cases of malaria should be kept under clinical observation and patients with P. falciparum malaria definitely should be admitted (9). Our patient was admitted and treated with a 3-day course of chloroquine and then a 14-day course of primaquine, after his G-6-PD deficiency test was negative.
M. J. McLachlan et al.
He was discharged after 3 days with a diagnosis of probable P. ovale or P. malariae, both of which are common in West Africa where, presumably, he had been exposed 11 months previously. P. vivax is rare in West Africa and P. falciparum rarely has gametocytes seen on a smear, as was the case here, and generally follows a more virulent course than seen here. The patient made a complete recovery. In summary, the key points to remember are that one should always consider malaria in a febrile patient who has been to a region of the world endemic with malaria within the past year, and that although drug prophylaxis is recommended for patients traveling to locations where malaria exists, these agents do not guarantee that a person will not acquire malaria.
REFERENCES 1. Teklehaimanot A, Keusch G, Binder S. Malaria (panel summary from the 2000 Emerging Infectious Diseases Conference in Atlanta, Georgia). Emerg Infect Dis 2001;7(Suppl 3):S546 –7. 2. Centers for Disease Control and Prevention. Malaria facts. Available at. http://www.cdc.gov/malaria/facts.htm. 3. Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med 2002;347:505–16. 4. Baldacci P, Menard R. The elusive malaria sporozite in the mammalian host. Mol Microbiol 2004;54:298 –306. 5. Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of malaria—implications for chemoprophylaxis in travelers. N Engl J Med 2003;349:1510 – 6. 6. Centers for Disease Control and Prevention. Travelers’ health. Information for health care providers. prescription drugs for malaria. Available at: http://www.cdc.gov/travel/malariadrugs2.htm. 7. Centers for Disease Control and Prevention. Treatment of malaria (guidelines for physicians). Available at. http://www.cdc.gov/malaria/diagnosis_treatment/tx_clinicians.htm. 8. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 2000;94(Suppl 1):S1–90. 9. Centers for Disease Control and Prevention. Malaria. treatment. Available at: http://www.cdc.gov/malaria/diagnosis_treatment/ treatment.htm.
Case Presentations of the Harvard Emergency Medicine Residency
INTERMITTENT FEVERS Murray J. McLachlan,
MD,*
Kenneth Weissman, David F. M. Brown,
MD,†
Eric S. Nadel,
MD,*†‡
and
MD*†
*Division of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, †Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, and ‡Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Reprint Address: David F. M. Brown, MD, Department of Emergency Medicine, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 105, Boston, MA 02114
Dr. Murray McLachlan: Today’s case is that of a 34year-old Asian-American man who presented to the Emergency Department (ED) with complaints of 2 weeks of intermittent fevers and chills with persistent generalized malaise. The patient stated that the fevers, which were as high as 40.0°C, responded to acetaminophen. One week before presentation, the patient began vomiting and was evaluated in another ED. He was treated with intravenous hydration and was discharged with the diagnosis of viral syndrome. The nausea and vomiting resolved but the fevers persisted. The patient stated that the fevers occurred every “second day.” He was seen by his primary care physician (PCP) on the day before presentation, and laboratory testing revealed elevated liver function tests and thrombocytopenia. An ultrasound of the abdomen was scheduled. On the day of presentation, the patient had recurrent nausea, vomiting, and fever and came to our ED. The patient also complained of intermittent headaches, but denied abdominal pain, diarrhea, or rash. The past medical history was notable only for appendectomy. He had no drug allergies and took no medications. Are there any questions regarding the history? Dr. Eric Nadel: Although these symptoms are nonspecific, they are persistent enough to prompt further investigation, particularly because this represented his third visit to a health care provider in a period of a week. I think it would be important to obtain more thorough social, travel, and occupational histories.
Dr. McLachlan: The patient did not use tobacco or illicit drugs and rarely drank alcohol. He worked as an architect and was not sexually active. He had traveled to Ghana for 2 weeks 11 months prior. He had taken a full course of mefloquine prophylaxis for malaria before and during the trip. He had been vaccinated against hepatitis A, hepatitis B, meningococcus, and typhoid fever. The family history was unremarkable. Upon arrival at the ED, the vital signs were: temperature 37.9°C, heart rate 121 beats per minute, blood pressure 113/65 mm Hg, respiratory rate 18 breaths/ minute, oxygen saturation 96% on room air. The patient appeared fatigued but non-toxic. The head was normocephalic and atraumatic. The pupils were equal, round, and reactive to light. There was no scleral icterus and the oropharynx was dry without erythema or lesions. The neck was supple with no lymphadenopathy or meningismus. The lungs were clear to auscultation bilaterally. The cardiac examination was notable for tachycardia with regular heart sounds with no murmurs, gallops, or rubs. He had 2⫹ pulses throughout. The abdomen was soft and non-tender with normal active bowel sounds; there were no masses or organomegaly. The spine was non-tender and there was no costovertebral angle tenderness. The extremities were warm, had normal range of motion, and no edema. The joints were normal. The skin had no rash or petechiae. The neurological examination was normal.
Case Presentations of the Harvard Emergency Medicine Residency are coordinated by David F. M. Brown, MD, and Eric S. Nadel, MD, of Harvard University Medical School, Boston, Massachusetts 425
426
Dr. David Brown: With this additional information can someone suggest a differential diagnosis? Dr. William Binder: With such nonspecific symptoms, the differential diagnosis is quite broad at this point. Pneumonia, hepatitis, mononucleosis, endocarditis, primary human immunodeficiency virus (HIV), and undifferentiated viral infection might all present in this manner. It is also important to consider travel-related infections such as malaria and leishmaniasis as well as local infections such as Lyme disease and babesiosis (HIV) infection. How did you proceed from this point? Dr. McLachlan: Blood was drawn and sent for laboratory testing. Blood chemistry analysis revealed: sodium 132 mmol/L, potassium 3.4 mmol/L, chloride 106 mmol/L, bicarbonate 106 mmol/L, blood urea nitrogen (BUN) 28 mg/dL, creatinine 1.3 mg/dL, glucose 160 mg/dL, and magnesium 1.0 mg/dL. Liver tests were as follows: total bilirubin 1.3 mg/dL, direct bilirubin 0.4 mg/dL, alanine aminotransferase 294 U/L, aspartate aminotransferase 74 U/L. Lipase was 2.5 U/dL. Complete blood count results included white blood cell count 3.8 th/cmm (78% neutrophils), hematocrit 42.1%, platelets 40 th/cmm. A urinalysis was normal. Blood was also sent for culture, malaria smears, lyme titers, hepatitis serologies, and a monospot. A chest radiograph was normal. An abdominal ultrasound showed mild splenomegaly; and the liver appeared normal with no evidence of cholelithiasis. Dr. J. Tobias Nagurney: Although the underlying etiology here remained uncertain, the patient was exhibiting signs of dehydration, with tachycardia, dry mucus membranes, and an elevated BUN/creatinine ratio. I would hydrate this patient with crystalloid and consider admission, perhaps to the observation, until I was certain the patient could maintain his hydration status. Could you describe the remainder of the ED course here? Dr. McLachlan: The patient was given two liters of intravenous normal saline, ibuprofen 800 mg orally for a temperature that went up to 38.5°C, and ondansetron 4 mg intravenously for nausea. He was then admitted to the hospital for further hydration and assessment. The hepatitis panel revealed evidence of vaccination against hepatitis A and B; testing for hepatitis C was negative. Lyme serologies and HIV testing were negative as was the monospot test for Epstein Barr virus. Blood and urine cultures were negative. However, malaria smears were positive for plasmodium species with parasitemia of less than 1%; the laboratory was unable to determine the species. A follow-up malaria smear sent on hospital day #2 showed plasmodium species with no rings seen, as well as some gametocytes. Dr. Brown: Can you discuss the prevalence of malaria, especially as it pertains to those traveling to endemic areas?
M. J. McLachlan et al.
Figure 1. Worldwide distribution of malaria in 2006 (http:// www.cdc.gov/malaria/distribution_epi/distribution.htm).
Dr. McLachlan: Malaria is endemic in over 100 countries around the world (Figure 1). Worldwide, there are approximately 300 –500 million cases of malaria per year with approximately one million deaths (although some estimate the death rate could be as high as two to three million per year) (1,2). As approximately 50 million people from industrialized countries travel to developing countries every year, malaria may be found in travelers (3). It is estimated that more than 10,000 travelers contract malaria each year (3), and in 2002, there were 1337 reported cases in the United States (2). Thus, persistent fevers in a patient who has traveled to a country where malaria is endemic within the prior 3 months should be seen as a medical emergency. Furthermore, any patient who presents with flu-like symptoms within 12 months of traveling to an endemic area should also undergo an evaluation for malaria. Dr. Kenneth Weissman: Can you discuss the lifecycle of plasmodium species and the varied clinical presentations of malaria? Dr. McLachlan: The four main species of malaria that account for the vast majority of malaria cases are Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. The disease is transmitted by the bite of a female Anopheles mosquito and has an incubation period of at least 7 days (can be greater than 1 year). P. vivax and P. falciparum are the most commonly contracted strains of malaria, but P. falciparum is the most feared as it can be rapidly fatal. Approximately 90% of P. falciparum cases occur in sub-Saharan Africa and the majority of these cases present within 1 month of exposure. Approximately 70% of P. vivax cases are acquired in Asia or Latin American, but only 50% have symptoms within 1 month, and up to 2% have symptoms more than 1 year after exposure (3). Both P. ovale and P. vivax are more commonly associated with delayed presentation of malaria or relapse (can occur up to 4 years later), as these strains of parasites have persistent liver stages.
Intermittent Fevers
Figure 2. Life cycle of malaria (http://www.cdc.gov/malaria/ biology/life_cycle.htm).
The plasmodium parasite life cycle has two stages in the human host. The first stage (exoerythrocytic stage) involves the liver, where the parasite sporozoite proliferates in the liver cell until it ruptures and releases the parasite merozoite into the bloodstream. In the second stage (erythrocytic stage), merozoites invade erythrocytes and proliferate, forming shizonts, which can eventually rupture, spreading more parasites into the blood and causing fever in infected individuals. Some of the infected erythrocytes contain gametocytes, which can be taken up by mosquitoes, whereby the life cycle is continued in the sporogonic cycle (Figure 2). The typical symptoms of malaria are fevers, chills, headache, malaise, cough, vomiting, arthralgias, diarrhea, and abdominal pain. In severe cases, generally associated with P. falciparum infection, patients can have acute renal failure, respiratory failure, seizures, coma, severe anemia, and circulatory collapse. The fevers seen with malaria usually occur at regular intervals of 48 –72 hrs, and when this occurs it is highly suggestive of P. vivax, P. ovale, and P. malariae (3). Splenomegaly is a common physical examination finding and laboratory testing often reveals thrombocytopenia and, occasionally, leukopenia. A student: Are humans the only hosts of malaria species? Dr. McLachlan: No, there are numerous Plasmodium species that infect many different types of animals including other mammalian species, reptiles, and birds. The life cycle of these other Plasmodium species is sometimes similar to that seen in humans (4). Dr. Emily Senecal: How does one test for malaria? Dr. McLachlan: The most common method (and still the gold standard) of testing for malaria is microscopic examination of the Giemsa stain of thick and thin smears.
427
The thick smear is a drop of blood on glass slide that is used to evaluate for the presence of parasites. The density of parasites is determined by the percentage of red blood cells infected (if ⬎ 4% are infected, then the patient needs an intravenous anti-malarial agent). The thin smear refers to a drop of blood that is smeared across the slide; this test is most helpful for determining the species of malaria. If these tests are initially negative but the clinical picture is very suggestive of malaria, the smears should be repeated every 6 to 12 hours for 2 to 3 days. Other ways of testing for malaria include using polymerase chain reaction (PCR), which is expensive and has limited availability. One can also do serologic testing to look for antibodies using immunoflourescence (IFA) or enzyme-linked immunosorbent assay (ELISA), although this method detects previous as opposed to present infections. A fourth method is antigen detection, though this method is still under review. Dr. Megan Fix: Why did this patient get malaria if he was compliant with chemoprophylaxis? Dr. McLachlan: Diligent chemoprophylaxis use does not guarantee a person will not contract malaria, as resistance to the prophylactic agents is common. In a 2003 New England Journal of Medicine study, one-third of cases of malaria between 1992 and 1999 in Israel and the United States were delayed-onset malaria caused by P. vivax and P. ovale, despite adequate blood-stage prophylaxis (5). Both P. vivax and P. ovale have persistent liver stages, which can lead to relapse of the disease months to years after primary infection. Even appropriate use of a blood-stage schizonticide will not prevent these relapses and can mask the symptoms of the initial infection (5). Nonetheless, all travelers (even former residents of the area) to endemic areas should take prophylaxis. Prophylaxis usually involves taking medication 1–2 days before arriving in the endemic area and continued during time in the area and for 1– 4 weeks after departure from the area (varies with different drugs). Most of the agents are blood-stage schizonticides (and do not affect the liver stage). Chloroquine has been a commonly used agent, but P. falciparum is often resistant, and the drug may exacerbate psoriasis. Doxycycline has good efficacy against P. falciparum and P. vivax, and should be used in areas with chloroquine or mefloquine-resistant P. falciparum like Southeast Asia; however, children and pregnant women cannot take this agent. Mefloquine is another common agent that is used in areas with chloroquine resistant P. falciparum, but should be avoided in patients with psychiatric disorders, seizure disorders, or cardiac conduction problems. Halofantrine is a common agent used overseas, but has potential for serious cardiac side-effects and is not recommended by the Centers for Disease Control and Prevention (CDC).
428
Primaquine and atovaquone-proguanil provide liverstage prophylaxis. Primaquine is used only in special circumstances for primary prophylaxis, and is contraindicated in patients with G-6-PD deficiency or pregnancy or women who are breastfeeding. Atovaquone-proguanil is used as primary prophylaxis in areas with chloroquineand mefloquine-resistant P. falciparum, but should be used with caution in infants and patients with renal impairment or pregnancy (6). Dr. Brown: Can you describe the different treatment options for malaria? Dr. McLachlan: The treatment regimen depends on species, drug resistance, clinical status, where the infection was contracted, comorbidities, pregnancy, and allergies. The CDC provides a treatment table based on various clinical situations that allows the clinician to develop an appropriate plan (7). Depending on the situation, the medications that can be used to fight the parasite forms in the blood include chloroquine, sulfadoxine-pyrimethamine (Fansidar®), mefloquine (Lariam®), atovaquone-proguanil (Malarone®), quinine, doxycycline, tetracycline, clindamycin, and artemisin derivatives (not licensed for use in the United States, but often found overseas). For the dormant parasite liver forms, primaquine can be used, but should not be used in patients who are pregnant, breastfeeding, or who have G-6-PD deficiency. Intravenous anti-malarial agents (quinidine ⫹ doxycycline) are indicated in patients with severe clinical courses (renal failure, severe anemia, respiratory distress, altered mental status) or P. falciparum ⬎ 4% parasitemia (8). In non-endemic areas, the CDC recommends that patients with uncomplicated or severe cases of malaria should be kept under clinical observation and patients with P. falciparum malaria definitely should be admitted (9). Our patient was admitted and treated with a 3-day course of chloroquine and then a 14-day course of primaquine, after his G-6-PD deficiency test was negative.
M. J. McLachlan et al.
He was discharged after 3 days with a diagnosis of probable P. ovale or P. malariae, both of which are common in West Africa where, presumably, he had been exposed 11 months previously. P. vivax is rare in West Africa and P. falciparum rarely has gametocytes seen on a smear, as was the case here, and generally follows a more virulent course than seen here. The patient made a complete recovery. In summary, the key points to remember are that one should always consider malaria in a febrile patient who has been to a region of the world endemic with malaria within the past year, and that although drug prophylaxis is recommended for patients traveling to locations where malaria exists, these agents do not guarantee that a person will not acquire malaria.
REFERENCES 1. Teklehaimanot A, Keusch G, Binder S. Malaria (panel summary from the 2000 Emerging Infectious Diseases Conference in Atlanta, Georgia). Emerg Infect Dis 2001;7(Suppl 3):S546 –7. 2. Centers for Disease Control and Prevention. Malaria facts. Available at. http://www.cdc.gov/malaria/facts.htm. 3. Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med 2002;347:505–16. 4. Baldacci P, Menard R. The elusive malaria sporozite in the mammalian host. Mol Microbiol 2004;54:298 –306. 5. Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of malaria—implications for chemoprophylaxis in travelers. N Engl J Med 2003;349:1510 – 6. 6. Centers for Disease Control and Prevention. Travelers’ health. Information for health care providers. prescription drugs for malaria. Available at: http://www.cdc.gov/travel/malariadrugs2.htm. 7. Centers for Disease Control and Prevention. Treatment of malaria (guidelines for physicians). Available at. http://www.cdc.gov/malaria/diagnosis_treatment/tx_clinicians.htm. 8. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 2000;94(Suppl 1):S1–90. 9. Centers for Disease Control and Prevention. Malaria. treatment. Available at: http://www.cdc.gov/malaria/diagnosis_treatment/ treatment.htm.