Infectious Disease Pathology
Case 5 -
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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?
About 1500 cases of imported malaria are reported annually in the United States,  and the
true number of cases is likely higher.  Although malaria is one of the most common causes of
fever in returned travelers,
it is misdiagnosed as often as 90% of
the time on initial presentation, especially in children.  This may be because parents do not
perceive malaria as a true threat thus prophylaxis is generally not considered for these young
In addition, parents may fail to provide adequate travel history to the health
Mortality due to malaria in the US (among all ages) is generally low (~1%), but delays in
diagnosis and treatment may lead to fatalities.  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. 
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.
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% 
were treated with quinine and doxycycline and 16% 
were treated with quinine/ quinidine and clindamycin. Six more were treated with quinine alone  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.
In contrast to the report by Viani et
al, hyponatremia was not a common finding.  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.  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.
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
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.
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,  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:
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
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)
|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|
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