—  SPECIALTY CONFERENCE  —

Infectious Disease Pathology

Case 5 - Pediatric Malaria

Jeannette Guarner
Emory University
Decatur, GA





Click on slide thumbnail images for an enlarged view.

If you have any difficulties viewing these slides, email the webmaster.



Clinical History
A 7-year-old female presented with 5 days of fever, headache, abdominal pain, and vomiting, without diarrhea. On admission, her hemoglobin was 9.1 mg/dl and platelets were 41,000 platelets/ microliter. Liver function tests were mildly elevated, with an aspartate amino transferase of 107 U/lt and an alanine amino transferase of 112 U/lt. What is your diagnosis? What is the percent parasitemia?


Case 5 - Figure 1


About 1500 cases of imported malaria are reported annually in the United States, [1] and the true number of cases is likely higher. [2] Although malaria is one of the most common causes of fever in returned travelers, [3, 4] it is misdiagnosed as often as 90% of the time on initial presentation, especially in children. [5] This may be because parents do not perceive malaria as a true threat thus prophylaxis is generally not considered for these young travelers. [6, 7, 8, 9, 10, 11] In addition, parents may fail to provide adequate travel history to the health care provider.

Mortality due to malaria in the US (among all ages) is generally low (~1%), but delays in diagnosis and treatment may lead to fatalities. [12] Of 123 fatal cases seen in the US from 1963-2001, 109 had seen a doctor prior to death but 33 received no or inadequate treatment, either because the diagnosis was not made, there was a delay in initiating treatment, or the treatment was inadequate for the species or region where the traveler had been. [12]

US clinicians and laboratories need to be familiar with the epidemiology, signs and symptoms, laboratory diagnosis, and treatment of the disease since travelers are at risk of acquiring malaria when visiting family and friends. Here we present the epidemiology, clinical and laboratory presentation, and treatment of 50 children with malaria that were seen at Children's Healthcare of Atlanta and we compare our results to what has been published in the literature.

Our Cases
We identified a total of 50 children with blood smear confirmed malaria out of a total of 385 children who had malaria smears performed from 2000 to 2008. Three children had smears sent twice, several years apart. Only 3% (10 children) without malaria had more than one slide sent. The mean age of infected children was 8.1 years (1.1-16.8 years, interquartile range 6-10 years), 60% were boys.

The primary reason for travel was to visit friends and relatives in the country of the parents' origin, accounting for 26 (62%) of those for whom a travel reason was recorded. Fifteen patients (37%) had been living abroad (8 immigrants, 5 refugees, 2 visitors from abroad). Among the 17 patients traveling from the US for whom there was data, the median duration of travel was 30 days (14- 75 days). The median time from arrival in the US until presentation was 10 days, with 25% of children presenting within 7 days (1-365 days, N=37). Most cases presented in the summer months (May to August). None of the cases presenting after 28 days had P. falciparum malaria. Two cases presented a year after returning to the US, one was diagnosed as P. ovale, the other was diagnosed as non-falciparum malaria. A previous history of malaria was reported in 73% of patients for whom information was available (22/ 30 patients); some were diagnosed in Africa, but it was unclear whether these represent presumptive or microscopic diagnoses.

93% of the children reported travel to Africa, in particular to either Central or West Africa. The most common country visited was Nigeria (51%), followed by Cameroon (14%); all other countries accounted for only 1-2 cases. Only 2 patients had traveled to Central America or the Caribbean.

Countries Visited by 43 Children with Malaria

n %
Africa 40 93
Africa 1 2
Central Africa 6 14
Cameroon 6 14
West Africa 30 60
Senegal 1 2
Guinea 1 2
Sierra Leone 1 2
Liberia 2 5
Ivory Coast 2 5
Nigeria 22 51
Togo 1 2
East Africa 3 6
Uganda 1 2
Kenya 1 2
Tanzania 1 2
Central America/ Caribbean 2 4
Haiti 1 2
Guatemala 1 2
Asia 1 2
Thai/ Burmese border 1 2

Fever was the most common symptom, present in 97.6%. Fever was present for a mean of 4 days (1-11 days) prior to presentation. Vomiting was the second most commonly reported symptom, present in 34% of cases. Hepatomegaly was present in 28%, splenomegaly in 20%. Headache was reported in 20% of patients, all of the patients with headache also reported fever. Abdominal pain was reported in 20%; one patient reported abdominal pain without fever. Diarrhea was present in 3 cases, all had fever but only one reported vomiting, none reported abdominal pain. Myalgias were reported in 10% and malaise or fatigue in 6%. Three patients presented with sore throat and fever, one of whom also had vomiting; these patients denied headache, cough, and malaise. Three patients had jaundice. One patient had altered mental status. Thrombocytopenia and anemia were the most commonly observed laboratory abnormalities. Mild hyponatremia was also relatively common (36% had sodium ≤135 mEq/L and 12% had sodium ≤130 mEq/L). G6PD levels were measured in 10 children, in case primaquine treatment was necessary. Only one was G6PD deficient. Six patients were tested for sickle cell disease, all were negative. Two patients had known sickle trait.

Clinical and Laboratory Characteristics of Patients with Malaria

Variable Normal Range N tested Mean Standard Deviation Minimum Maximum
Age (years) 50 8.1 4.1 1 16
Fever Duration (days) 31 4.0 2.5 1 11
Time to presentation (days post travel) 37 37.1 88.4 1 365
Days Hospitalized 50 0.4 0.5 0 1
Parasitemia (%) 0 46 2.8 5.2 0.03 28.6
White blood cells on admission (thousand/ ul) 4.5- 13.5 40 6.8 3.0 2.6 13.84
Absolute neutrophil count on admission (thousand/ ul) 1.8- 8.0 37 4.0 2.4 0.99 9.78
Platelets on Admission (thousand/ ul) 150- 450 40 151 123 24 611
Admission Hemoglobin (mg/dl) 13- 16 49 10.4 1.8 5.4 13.8
Mean corpuscular volume 78- 98 47 76.6 7.3 46.1 90.6
Reticulocyte count (%) 0.5- 3 11 2.6 2.1 0.6 8.4
Reticulocyte production index (%) 0.5- 1.5 11 0.7 0.5 0.2 2
C-reactive protein (mg/dl) <1.0 31 8.0 6.3 1.2 25.4
Erythrocyte sedimentation rate (mm/hr) 0- 20 9 41.3 24.2 10 97
Creatinine (mg/dl) 0.3- 1.0 36 0.6 0.2 0.3 1.4
Albumin (gm/dl) 3.1- 4.8 33 3.2 0.6 2.3 4.6
Aspartate amino transferase (U/lt) 13- 38 35 98.5 229.1 17 1311
Alanine amino transferase (U/lt) 8- 36 35 53.5 96.5 7 547
Bilirubin (total, mg/dl) 0-2 34 1.9 2.9 0.2 16.5
Sodium (mmol/lt) 133- 143 41 135.3 3.7 122 143

Only 10 patients (20%) had taken any prophylaxis to prevent malaria. Five of these took a drug that was inappropriate for the country to which they traveled.

Plasmodium falciparum was most common (72%). P. vivax, P. ovale, and P. malariae were present in 4, 3, and 1 case, respectively. In 6 cases, the species was not identified. No co-infections were seen. The majority of patients (52%) had parasitemia <1%; only 7 patients had hyperparasitemia (>5%). The maximum parasitemia was 28.6%. All cases with >5% parasitemia were P. falciparum, except for one in which species was unidentified. Non-falciparum forms made up 42% of patients with ≤1% parasitemia and 12% of those with 1-5% parasitemia. Gametocytes were rarely identified.

Thirty-four children (68%) were hospitalized for treatment of malaria. Among those with P. falciparum malaria, 25% were not hospitalized, and another 17% stayed for only one day. The longest stay was 9 days. 36% [18] were treated with quinine and doxycycline and 16% [8] were treated with quinine/ quinidine and clindamycin. Six more were treated with quinine alone [3] or in combination with another drug, one of these patients also received quinidine. Four were treated with atovaquone- proguanil, one in combination with primaquine. Several children received antibiotic therapy due to concern for additional diagnoses. Sixteen patients had received antimalarial therapy previously, although in some cases this was several months prior.

One patient received a blood transfusion for anemia (hemoglobin 5.4 mg/dl). No exchange transfusions were performed. One patient received platelet transfusion for a platelet count of 32,000. All of the patients recovered without serious complications.

Comparison with Other Case-series
This case series demonstrates the wide spectrum of possible clinical presentations which may be seen with malaria- including vomiting, diarrhea, headache, abdominal pain, etc. Gastrointestinal symptoms can be so severe that an intestinal infection may be suspected. Hepatosplenomegaly may be seen; this was less common in our series than in other reports. [14, 15] In contrast to the report by Viani et al, hyponatremia was not a common finding. [14] One almost universal symptom is fever, either by history or at presentation. Because malaria may present with a wide variety of clinical symptoms, a high index of suspicion is required to ensure prompt diagnosis. Primary care providers seeing patients with a history of fever should always ask about a history of recent travel and request the appropriate diagnostic tests. Because of the cases which presented a year after travel, we believe that in evaluation of a patient with fever, a history of ever having visited a foreign country should be elicited. It is important to note that although patients presenting with a remote travel history may have malaria, it would be non-falciparum malaria and is therefore not life-threatening. P. falciparum generally presents within a month of exposure.

Diagnosis of malaria relies on trained microscopists finding parasites in Giemsa stained blood smears. Laboratories use 2 types of preparations for different purposes: the thin smear is used for speciation and quantification of parasitemia while the thick smear concentrates the parasites and may be helpful in detecting low level parasitemias. Three smears are recommended to confirm that the patient does not have malaria; it is interesting to note that in our case series, repeated testing was obtained on only 3% of children. Newer, more expensive assays that do not rely on microscopy have been developed, but their use is not wide spread. All these tests detect the presence of the Plasmodium but do not provide a parasitemia level. Rapid diagnostic tests rely on the detection using ELISA of either histidine-rich protein 2 (HRP-2), which is P. falciparum specific, or parasite lactate dehydrogenase (pLDH) enzyme, which is present in all Plasmodium species which infect humans. In general, rapid diagnostic tests are adequate for detection of P. falciparum and P. vivax, but have not been very successful for detection of P. ovale and P. malarie. In addition, these tests provide rapid results, but are insensitive if there are less than 500 parasites/ microliter of blood, and are more expensive than blood smear. Only one, the Binax NOW Malaria Test, is currently FDA-approved. State Health Departments and CDC also have available PCR-based methods. These can detect all Plasmodium species using a variety of platforms (Luminex, nucleic acid sequence based amplification –NASBA-, loop mediated isothermal amplification –LAMP-). Nucleic acid detection does not permit quantification of parasitemia.

In our series, more than half of the children had parasitemia below 1%, and 87% had parasitemia of 5% or less. The very low level parasitemia (<1%) makes the diagnosis of malaria more challenging, because not only does one need to consider the diagnosis, but the laboratory must examine the slides very carefully for the presence of ring forms. Gametocytes were rarely observed; speciation was usually based on other morphological aspects.

All of the patients in our series recovered with no long term sequelae; only one presented with findings concerning for possible cerebral malaria. This is most likely related to the primarily low density parasitemias observed in our study. Possible explanations for this include some degree of immunity as approximately half of all patients gave a history of previous malaria or the fact that some of the children had been partially treated prior to presentation.

In Atlanta, there is a large community of people from Nigeria and families visit friends and relatives as well as having relatives visit their families in the US (at least 2 cases in our series), thus it was not surprising that most of our patient had acquired malaria in Nigeria. A similar finding was seen in a recent review from the UK, with 54% of cases acquiring malaria in Nigeria or Ghana. [16] It is important for health care providers to know the immigrant composition in the community they serve. To our surprise, we had very few patients from Latin America, even though immigration from Latin America is higher than that from Africa. Another consideration is that travelers that visited friends and relatives are more likely to visit high risk areas and stay longer. Similar to what has been noted previously, most of our patients had visited Africa during the summer (May through August), we believe that predominance in the summer months is due to children's vacation schedule, rather than there being higher transmission during this time. [16, 17, 18]

Very little information was available about prophylaxis in our cases. We suspect that the majority of children were not receiving any prophylaxis. Prophylaxis was reported in less than 20% of our cases, and of those, 50% took a medication that was ineffective for the area of travel (chloroquine in areas with chloroquine resistant P. falciparum), similar to findings of other studies. [15, 19] Furthermore, no one took the prophylaxis in the manner in which it supposed to be taken- many families stopped prophylaxis halfway through their stay- rather than completing prophylaxis one week (atovaquone- proguanil) to one month (mefloquine and doxycycline) after having completed their travel. This may be because parents returning to their country of origin are less likely to perceive malaria as a true threat, therefore are less likely to seek pre-travel health consultation and give their children prophylactic medicines. [6, 7, 8, 9, 10]

All travelers to endemic areas should be counseled about malaria prevention, including using insect repellant containing DEET, insecticide treated bednets, keeping arms and legs covered, sleeping in an air-conditioned room, [20] and appropriately using a prophylactic anti-malarial drug. Up to date information on areas where malaria transmission occurs and CDC recommended prophylaxis may be found at: http://www.cdc.gov/malaria/risk_map/ or http://wwwn.cdc.gov/travel/yellowBookCh4-Malaria.aspx.

Chloroquine plus primaquine remains the appropriate choice for P. vivax acquired everywhere except Papua New Guinea or Indonesia, where chloroquine resistant P. vivax is common. For any malaria acquired in these areas, or for P. falciparum acquired in an area where chloroquine resistance is found, there are 4 options for treating non-severe malaria: (1) atovaquone-proguanil (Malarone™, GlaxoSmithKline, Middlesex, United Kingdom), (2) Artemether-Lumefantrine (Coartem™ , Novartis Pharmaceuticals Corporation, Basel, Switzerland), (3) quinine plus doxycycline or tetracycline (for children over 8 years old) or clindamycin, or (4) mefloquine (Lariam™, Hoffmann-La Roche Inc. Nutley, NJ). Atovaquone- proguanil is very well tolerated, with a short treatment course of only 3 days; however, it was not available as a formulary medication until very recently which likely explains the infrequent use of this drug in our series. For malaria acquired in an area where chloroquine resistance is found, presumptive treatment for P. falciparum should be given until a species identification is made. Speciation is necessary to determine whether infection was due to P. vivax or P. ovale which have latent liver forms (hypnozoites) requiring treatment with primaquine to prevent relapse. As primaquine can cause hemolytic anemia in patients with G6PD deficiency, it is important to rule this out prior to starting treatment with primaquine. In our series, one patient was apparently successfully treated for P. falciparum with primaquine alone, but primaquine is never recommended as single treatment for P. falciparum malaria, although it may be used for prophylaxis in selected patients. Although several patients in our series were treated as outpatients, this can not be routinely recommended, as serious complications can arise.

Severe malaria in children occurs in less than 20% of cases (see Table 3). Severe malaria is most commonly caused by P. falciparum and is characterized by neurological involvement (impaired consciousness, seizures, coma), severe anemia, pulmonary edema or acute respiratory distress syndrome (ARDS), thrombocytopenia, shock, acute renal failure, metabolic acidosis, or hyperparasitemia (>5% parasitized red blood cells). Patients with severe malaria should always be treated with intravenous quinidine. In endemic countries, artemisinin combination therapies (artesunate or artemether combined with another anti-malarial) are widely used for severe malaria. Artemisinins were discovered in China in 1972 and are the most effective antimalarial compounds available today. In April 2009, Coartem became the first artemisinin combination therapy to be licensed in the US. Coartem is administered orally as 6 doses over 3 days at 0, 6, 24, 36, 48, and 60 hours; dosing is weight based. Artesunate can be obtained for the treatment of cases of severe malaria through an investigational new drug protocol by calling the CDC malaria hotline at 770-488-7788. Current CDC recommendations for treatment of malaria may be found at http://www.cdc.gov/malaria/pdf/treatmenttable.pdf.

In summary, this series of cases shows that children with malaria present with a variety of signs and symptoms, have usually received incomplete prophylaxis if any at all, and have been diagnosed up to one year after travel. In addition, we have provided information about diagnosis, treatment and prophylaxis of malaria in the pediatric population which should be useful for physicians seeing patients that present with fever and have visited relatives and friends in other country.

Comparison of 50 Cases in Atlanta to Previous Reports

Our series Emmanuel 1993 Rivera-Matos 1997 Brabin 1997 Viani 1999 Huerga 2001 Ladhani 2003 Miller 2004 Driessen 2007 Mascarello 2008
Number of cases 50 20 34 1445 20 49 211 40 32 49
Location of study Atlanta, GA Chicago, IL Houston, TX UK New York, NY Madrid, Spain East London, UK British Colombia Netherlands Verona, Italy
P. falciparum (%) 72% 25% 56% 56% 70% 78% 91% 7.1% 81% 95.3%
P. vivax (%) 8% 55% 23% 35.7% NA 2% 5.7% 88.1% 4.7%
Parasitemia > 5% (% of patients) 14% NA NA NA NA NA 2.4% had >10% parasitemia NA 19% NA
Acquired disease in Africa 93% 50% NA 32.5% 80% 98% 94.3% NA NA 95.3%
Traveled to visit family/ friends 62% 85% immigrants 77% NA NA 10.2% 82% NA 47% 53.5%
Took any prophylaxis <20% NA 45% 13.3% 5% 60.% 42% 33%
(10/ 30 residents) 		40.0% 16.3%
Took appropriate prophylaxis 10% NA 13.6% 12.0% 0% 0% 15% 13% 25% 0%
Hyponatremia (sodium ? 130) 12.2% NA NA NA 25% NA NA NA NA NA
Abnormal liver function tests (AST or ALT >40) 42.8% 25% NA NA 40% NA NA NA 19% NA
Severe malaria 14% NA 9% NA 15% 4% 7.1% NA 9% 18.6%
Fatal cases 0 NA 0 NA 0 0 0 NA NA NA

References
  1. Thwing J SJ, Newman RD, Barber AM, Mali S, Roberts JM, Slutsker L, Arguin PM. Malaria Surveillance — United States, 2005. . MMWR. 2007;56(SS-6):23-42.

  2. Barat LM BB, Smolinski MS, Espey DK, Levy CE, Zucker JR. Evaluation of malaria surveillance using retrospective, laboratory-based active case detection in four southwestern states, 1995. Am J Trop Med Hyg. 1999;60(6):910-914.

  3. Strickland G. Fever in the returned traveler. . Med Clin North Am. . 1992;76:1375–1392.

  4. O'Brien D, Tobin S, Brown GV, and Torresi J. Fever in Returned Travelers: Review of Hospital Admissions for a 3-Year Period. Clinical Infectious Diseases. 2001;33(5):603-609.

  5. Emanuel B, Aronson N, Shulman S. Malaria in children in Chicago. Pediatrics. 1993;92(1):83-85.

  6. Kain K, Harrington MA, Tennyson S and Keystone JS. Imported malaria: prospective analysis of problems in diagnosis and management. Clin Infect Dis. 1998;27:142-149.

  7. Chalumeau M, Holvoet L, Chéron G, Minodier P, Foix-L'Hélias L, Ovetchkine P, Moulin F, Nouyrigat V, Bréart G, Gendrel D. Delay in diagnosis of imported Plasmodium falciparum malaria in children. Eur J Clin Microbiol Infect Dis. 2006;25:186-189.

  8. Vicas A, Albrecht H, Lennox JL, del Rio C. Imported malaria at an inner-city hospital in the United States. . Am J Med Sci 2005;329:6-12.

  9. Baird J. Effectiveness of antimalarial drugs. N Engl J Med. 2005;325:1565-1574.

  10. Leder K, Black J, O'Brien D, et al. Malaria in Travelers: A Review of the GeoSentinel Surveillance Network. Clinical Infectious Diseases. 2004;39(8):1104-1112.

  11. Stäger K, Legros F, Krause G, Low N, Bradley D, Desai M, Graf S, D'Amato S, Mizuno Y, Janzon R, Petersen E, Kester J, Steffen R, Schlagenhauf P. Imported malaria in children in industrialized countries, 1992–2002. Emerg Infect Dis. 2009;15(2):[serial on the Internet] [June 20,2009]. Available from http://www.cdc.gov/EID/content/2015/2002/2185.htm.

  12. Newman R, Parise ME, Barber AM, Steketee RW. Malaria-Related Deaths among U.S. Travelers, 1963–2001. Ann Intern Med. 2004;141:547-555.

  13. US Census. http://www.census.gov/Press-Release/www/releases/archives/population/009865.html.

  14. Viani RM BK. Pediatric imported malaria in New York: delayed diagnosis. Clinical Pediatrics. 1999;38(6):333-337.

  15. Huerga H L-VR. Imported malaria in immigrant and traveling children in Madrid. European Journal Clinical Microbiology & Infectious Diseases. 2001;20(8):591-593.

  16. Smith AD, Bradley DJ, Smith V, et al. Imported malaria and high risk groups: observational study using UK surveillance data 1987-2006. BMJ. July 3, 2008 2008;337(jul03_2):a120-.

  17. Ladhani S, El Bashir H, Patel VS, Shingadia D. Childhood malaria in East London. Pediatric Infectious Disease Journal. 2003;22(9):814-818.

  18. Rivera-Matos IR AJ, Doerr CA, White AC, Jr. Pediatric Malaria in Houston, Texas. Am. J. Trop. Med. Hyg. 1997;57(5):560-563.

  19. Brabin BJ GY. Imported malaria in children in the UK. Archives of Disease in Childhood. 1997;77:76-81.

  20. Andreas Schoepke RSNG. Effectiveness of Personal Protection Measures against Mosquito Bites for Malaria Prophylaxis in Travelers. Journal of Travel Medicine. 1998;5(4):188-192.

  21. Ndao M. Diagnosis of parasitic diseases: old and new approaches. Interdiscip Perspect Infect Dis . 2009; 2009:278246.