Robert D. Newman, MD, MPH; Monica E. Parise, MD; Ann M. Barber, BA; Richard W. Steketee, MD, MPH
Acknowledgments: The authors thank Meghna Desai and Jacqueline Roberts for assistance with data management.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Robert D. Newman, MD, MPH, Malaria Branch, Centers for Disease Control and Prevention, 4770 Buford Highway NE, Mailstop F-22, Atlanta, GA 30341; e-mail, email@example.com.
Current Author Addresses: Dr. Newman, Dr. Parise, Ms. Barber, and Dr. Steketee: Malaria Branch, Centers for Disease Control and Prevention, 4770 Buford Highway NE, Mailstop F-22, Atlanta, GA 30341.
Nearly 1500 malaria cases occur each year in the United States; approximately 60% are among U.S. travelers. Despite the availability of sophisticated medical care, malaria-related deaths continue to occur. The authors reviewed all 185 fatal cases between 1963 and 2001 that were reported to the National Malaria Surveillance System: 123 (66.5%) occurred among U.S. travelers, and of these, 114 (92.7%) were attributed to Plasmodium falciparum. Failure to take or adhere to recommended chemoprophylaxis, to promptly seek medical care for post-travel illness, and to promptly diagnose and treat suspected malaria all contributed to fatal outcomes. Health care providers need to take a travel history, obtain a blood film for suspected malaria, and use the 24-hour malaria management advice available through the Centers for Disease Control and Prevention (CDC) Malaria Hotline (770-488-7788) or the CDC Malaria Web site (www.cdc.gov/Malaria). Hospitals must maintain intravenous quinidine gluconate on formulary because it is the only drug available to treat severe malaria in the United States.
Number of malaria deaths among travelers, refugees or visitors, and military in the United States, 1963–2001.
Table 1. Drugs Used in the Prophylaxis of Malaria
Table 2. Presenting Symptoms of 123 U.S. Travelers Who Died of Malaria, 1963–2001
Potential contributing factors to malaria-related fatalities among U.S. travelers.
Table 3. Summary of Key Findings of Review of Malaria Deaths among U.S. Travelers, 1963–2001, and Recommended Action Items To Reduce Mortality
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Burke A. Cunha
October 27, 2004
The Importance of Non-Specific Laboratory Tests in Suspecting Malaria in Returning Travelers
TO THE EDITOR: I read with interest the recent Annals article by Dr. Newman, et al describing various factors associated with U.S. traveler malaria related deaths. (1)
The authors reported fatal malaria could result if travelers failed to take malaria prophylaxis or took inappropriate malaria prophylaxis for the region of travel i.e., presence of chloroquine-resistant Plasmodium falciparum. They also noted a delay in returned travelers seeking medical attention (range = 2-28 days). The main point of their study was that in 67.8% of returned U.S. travelers, the diagnosis of malaria was missed on initial medical evaluation. After initial evaluation, there was a delay of four days (median) to the time of malaria (range 1-17 days) diagnosis. The author's review the factors responsible for missed malaria diagnosis that contributed to malaria related deaths. The single most important cause of a missed diagnosis was failure to obtain a recent travel history and or failure to consider malaria in the differential diagnosis. Obviously, if the diagnosis of malaria is not made or not made early, there will be a delay in initiating appropriate anti-malarial treatment, this increases the likelihood of a fatal outcome. Failure by physicians to consider the possibility of malaria by not obtaining a recent travel history to a malarious area resulted in their failure to order a malarial smear to confirm the diagnosis of malaria. (1 "“ 7) The single most important difficulty in malaria diagnosis is failure to consider malaria in the differential diagnosis. If malaria is considered in the differential diagnosis, physicians will order malarial smears, make the diagnosis, initiate appropriate anti-malarial therapy. The authors also describe the laboratory misidentification of Plasmodium sp., which resulted in incorrect or delayed treatment of malaria, particularly with P. falciparum strains. Inexperienced laboratory personnel may also mistake staining artifacts for malaria which could also lead to therapy inappropriately directed at the misidentified species. (6, 7) The importance of non-specific laboratory tests in suggesting the diagnosis of malaria was not mentioned in the article (1). In returning U.S. travelers presenting with a non-specific febrile illness, there is a characteristic pattern of non-specific laboratory abnormalities is invariably present in malaria. Even if the travel history was missed and malaria was not suspected, the characteristic pattern of non-specific laboratory findings in acute malaria should suggest the diagnosis and prompt the physician to obtain malarial smears to confirm the diagnosis and initial treatment. (7, 8) My experience over the past thirty years is that aside from failure to ask about recent foreign travel, the most avoidable pitfall in missing the diagnosis of malaria is failing to suspect the possibility of malaria from routine laboratory tests. These non-specific laboratory tests considered individually but together should suggest acute malaria.
Returning U. S. travelers with acute malaria invariably present with some degree of hemolytic anemia. If the malarial infection is mild, the hemoglobin and hematocrit may not be decreased early. However, an otherwise unexplained, even mild, elevation of the serum lactate dehydrogenase (LDH) in a returning U.S. traveler regardless of history of mosquito bite or inadequate/inappropriate prophylaxis, should suggest the diagnosis of malaria and prompt the physician to order a peripheral smear for malaria. Many physicians overlook the diagnostic importance of atypical lymphocytes in acute malaria. Acute malaria is invariably accompanied by equal to or greater than 1% of atypical lymphocytes in the peripheral smear. However, atypical lymphocytes may not be present in sufficient numbers to be reported as elevated (>5%) i.e., atypical lymphocytosis. In manually interpreted stained malarial smears, the absence of even 1% atypical lymphocytes should cause the physician to question the diagnosis of malaria. Atypical lymphocytes in the peripheral smear in patients with acute malaria do not relate to Plasmodium species or degree of parasitemia. (8, 9) Besides an elevated serum LDH and atypical lymphocytes, otherwise unexplained thrombocytopenia is a feature of acute malaria. Virtually all U.S. returning travelers with acute malaria present with a combination of a normal/low-normal WBC count with atypical lymphocytes, an increased serum LDH level, and thrombocytopenia. The diagnostic specificity of these combined non-specific laboratory findings of a normal/low normal WBC count with atypical lymphocytes, an increased LDH, and thrombocytopenia in recently returned U.S. travelers should suggest the possibility malaria and prompt an to order for a malarial smear to confirm the diagnosis. (8 "“ 10)
The authors have performed a valuable service in reminding practicing physicians that malaria should be included in the differential diagnosis of U.S. travelers returning from malarious areas in this era of international travel. Clearly, prior to travel, patients should be given appropriate malarial prophylaxis and be counseled to promptly seek medical attention if ill after returning to the U.S. The correct identification of Plasmodial species on malarial smears combined with knowledge of the presence/absence of chloroquine resistance in the area of travel are fundamental to selecting appropriate anti-malarial prophylaxis/therapy which may be life saving. (1 "“ 5) The most readily reversible problem of missed or delayed malaria diagnosis in returning U.S. travelers, may be largely remedied by taking a travel history and, as importantly, by not missing the characteristic combination of non-specific laboratory clues present in acute malaria. The absence of an elevated WBC count, absence of or even 1% atypical lymphocytes, normal serum LDH level, and a normal platelet count should cause the clinician to question the diagnosis of acute malaria in returning U.S. travelers. In a febrile returning U.S. traveler, even if the travel history is missed, a normal/low normal WBC count, with atypical lymphocytes with even modest elevations of serum LDH levels and thrombocytopenia should suggest the possibility of malaria and prompt the clinician to order a malarial smear which will be diagnostic and lead to appropriate therapy which will decrease malaria related deaths.
Burke A. Cunha, MD Infectious Disease Division Winthrop-University Hospital Mineola, New York and State University of New York School of Medicine Stony Brook, New York
References 1. Newman RD, Parise ME, Barber AM, Steketee RW. Malaria-Related Deaths among U.S. Travelers, 1963-2001. Ann Intern Med. 2004;141:547-555.
2. Kriacou DN, Spira AM, Talan DA, Mabey DC. Emergency department presentation and misdiagnosis of imported falciparum malaria. Ann Emerg Med. 1996;27:696-699.
3. Dorsey G, Gandhi M, Oyugi JH, Rosenthal PJ. Difficulties in the prevention, diagnosis, and treatment of imported malaria. Arch Intern Med. 2000;160:2505-2510.
4. Winters RA, Murray HW. Malaria "“the mime revisited: fifteen more years of experience at a New York City teaching hospital. Am J Med. 1992;93:243-246.
5. O'Brien D, Tobin S, Brown GV, Torresi J. Fever in returned travelers: review of hospital admissions for a 3-year period. Clin Infect Dis. 2001;33:603-609.
6. Cunha BA: The Microscopic Mimics of Malaria. Infectious Disease Practice 2002;26:89-90.
7. Gilles HM. The differential diagnosis of malaria. In: Wernsdorfer WH, McGregor IA. Malaria. Churchill Livingstone, London, 1988, pp. 769-780.
8. Cunha BA. Diagnostic significance of non-specific laboratory abnormalities in infectious diseases. In: Gorbach SL, Bartlett JG, Blacklow NR: Infectious Diseases, Lippinoctt Williams & Wilkens, Philadelphia, 2004, pp. 158-165.
9. Cunha BA, Bonoan JT, Schlossberg D. Atypical lymphocytes in acute malaria. Arch Intern Med. 1997;157:1140-1141.
10. Cunha BA. The diagnosis of imported malaria. Arch Intern Med. 2001;161:1926-1928.
Newman RD, Parise ME, Barber AM, Steketee RW. Malaria-Related Deaths among U.S. Travelers, 1963–2001. Ann Intern Med. 2004;141:547-555. doi: 10.7326/0003-4819-141-7-200410050-00012
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Published: Ann Intern Med. 2004;141(7):547-555.
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