American Journal of Emergency Medicine (2012) 30, 972-980

Review

Imported malaria: an update^?

Eric J. Nilles MD ^a,?, Paul M. Arguin MD ^b

^aDepartment of Emergency Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa,

Iowa City, IA, USA

^bMalaria Branch, Centers for Disease Control and Prevention, MS F-22, Atlanta, GA 30341, USA

Received 23 April 2011; revised 10 June 2011; accepted 15 June 2011

Abstract Evidence suggests that imported malaria is a diagnostic challenge with initial misdiagnosis rates of 40% or greater. Given that Prompt diagnosis and appropriate treatment are the only intervention proven to prevent progression to severe malaria and death, these figures are concerning. The purpose of this clinical review is to provide the most up-to-date and practical information on the diagnosis and treatment of imported malaria for the emergency health care provider. We highlight common pitfalls, errors, and mistakes in arriving at the correct diagnosis. We also emphasize the 3 key aspects to avoid progression to severe disease: rapid diagnosis, prompt initiation of treatment, and appropriate choice of antimalarial treatment.

(C) 2012

Introduction

Malaria continues to present one of the major global public health challenges with an estimated 225 million Clinical cases and 781 000 deaths in 2009, mostly in children less than 5 years of age living in sub-Saharan Africa [1].

Malaria is transmitted by the bite of an infective female anopheline mosquito; and in rare cases, transmission results from blood transfusions, organ transplantation, or congenital or occupational exposures [2-5]. Most malaria in humans is caused by the protozoan parasite of 4 Plasmodium species: P falciparum, P vivax, P ovale, and P malariae. A fifth species, P knowlesi, primarily infects primates; but there are an increasing number of reports of this species infecting humans in Southeast Asia [6-8]. Severe and life-threatening

^? This project received no funding or outside support. The authors have no financial interests in any of the topics presented in this manuscript.

* Corresponding author. Tel.: +1 608 592 5706.

E-mail addresses: [email protected] (E.J. Nilles), [email protected] (P.M. Arguin).

malaria occurs mainly from P falciparum infections, although serious morbidity and death can also occur with the other species [9-11]. A subset of P vivax and P ovale sporozoites does not immediately mature in the liver into blood-stage parasites causing the clinical syndrome of malaria, but develops into the dormant hepatic hypnozoite forms. The hypnozoites cause, in malaria terminology, re- lapse, which is the recurrence of clinical disease in P vivax or P ovale infections after clearance of the blood-stage form. This relapse phenomenon occurs because the standard antimalarial drugs treat only the blood-stage form and not the dormant hypnozoite forms. For this reason, primaquine, which is used specifically to treat the hepatic hypnozoites, is added to the Treatment regimen of P vivax and P ovale infections. In the absence of primaquine treatment, patients with P vivax or P ovale infections may experience a relapse of clinical malaria months or even years later. Neither P falciparum nor P malariae have hypnozoites; and as such, they do not cause relapsing infections. However, “recrudescence,” another form of clinical disease recurrence, does exist in all malaria species. Recrudescence typically

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2011.06.016

results after incomplete treatment of the blood-stage, or erythrocytic, form of the parasite. Patients with P malariae infections may remain asymptomatic for decades before recrudescence and clinical illness, sometimes associated with immunosuppression [12]. In P falciparum infections, recrudescence typically occurs 2 to 4 weeks after prophylaxis or inappropriate or incomplete treatment.

The risk of contracting malaria is determined by a number of factors. Of these, the intensity of transmission of malaria in the area visited is the most important. Travel to sub- Saharan Africa confers the highest risk. The risk for travelers to southern America and much of Asia is substantially lower, although pockets of high transmission occur [13]. In many regions, there is a significant seasonal component to transmission intensity, with increasing rates of clinical malaria seen shortly after the start of the rainy seasons [14,15]. The likelihood of contracting malaria can be substantially modified by pretravel medical advice, use of and adherence to appropriate chemoprophylaxis, and mosquito protection measures [16]. Most infections in travelers occur in those who do not take prophylaxis, take prophylaxis erratically, or take an inappropriate prophylactic regimen [17-19]. However, it is important to note that no antimalarial regimen is 100% effective, even when taken appropriately [20].

The reported incidence of imported malaria varies widely in nonendemic countries. This appears to be due to variability in disease recognition, diagnostic capabilities, reporting protocols, adherence to those reporting protocols and population travel patterns. For example, with large numbers of travelers returning from West Africa, France reports the highest numbers of imported malaria cases in Europe, with approximately 6000 cases per year [21]. The most recent US data are from 2009 when 1484 cases were reported [22]. However, the reliability and consistency of surveillance data are variable; and underreporting is considered to be common. This was demonstrated in one US study that showed underreporting of 25% [23]. In Europe and North America, most of the imported malaria is caused by the most serious of the malarial species, P falciparum

[24]; it should be emphasized, however, that non-falciparum infections, particularly P vivax infections, are not benign and can also cause Serious disease.

From the 1970s to the mid-2000s, imported malaria increased significantly in many countries in the developed world. Over the past 5 years, this trend has slowed and, in some countries, has started to reverse [19,21]. However, imported malaria is still common and continues to cause significant morbidity and mortality in many developed regions [19,25]. Furthermore, with ongoing imported malaria into countries, like the United States, which have retained the anopheline mosquito vector, local transmission of malaria can, and does, exist, usually in small localized outbreaks [26]. However, the greatest burden, by far, of malaria in nonendemic countries remains imported cases. The increased international travel to malaria-endemic areas

continues to expose very large numbers of travelers to potential infection and disease by the malaria parasite (Fig. 1). A review of travelers returning from the developing world identified malaria as the most frequent cause of fever in patients without localizing-organ findings, and most of these cases were P falciparum [24].

Diagnostic and management challenge

With very large numbers of travelers visiting malaria- endemic regions, emergency physicians are likely to encounter these infections. The nonspecific clinical picture of malaria, combined with a low incidence rate in most nonendemic countries, makes the Initial diagnosis of malaria difficult. Consequently, misdiagnosis is common [27]. One emergency department (ED)-based study from the United States highlights the magnitude of this problem: malaria was considered in the initial diagnosis in only 60% of the malaria cases, despite the fact that all the patients had been in malaria-endemic countries within the prior 2 months and all cases reported a history of fever [28]. A review of imported pediatric malaria demonstrated initial misdiagnosis rates of 2% to 53% in Europe and 35% to 90% in North America [29]. Once diagnosed, malaria is often managed subopti- mally, with long delays before starting treatment [30-34]. The findings in these studies are very concerning given that prompt diagnosis and appropriate management are vital to minimize complications and mortality [35]. The conse- quences of this suboptimal management is highlighted in a review of malaria deaths in the United States between 1963 and 2001: 67% of the deaths for whom sufficient information was available were associated with Medical errors including failure to prescribe the correct chemoprophylaxis regimen, failure to diagnose malaria on initial presentation, failure to initiate treatment promptly on diagnosis, or treatment with an antimalarial drug that was inappropriate for the infecting species or region of acquisition [36].

Incubation period, immunity, and pregnancy

Although the incubation period for malaria is highly variable, symptomatic presentation is typically between 10 days and 4 weeks after inoculation by the anopheline mosquito [12]. On occasion, symptoms may develop as early as 8 days or, rarely, as late as 1 year after infection. Late presentation is generally considered to be associated with the dormant hypnozoite form of P vivax and P ovale; but late presentation may occur with all malaria species, particularly in the semi-immune or those taking chemoprophylaxis [17]. Almost all Western travelers are nonimmune and thus at considerable risk for progression from uncomplicated to severe malaria. Conversely, because of the development of antibody-mediated humoral immunity, malaria in highly endemic regions is rarely life threatening after 5 years of age. Yet, despite the development of acquired immunity,

Fig. 1 Map of malaria endemic countries.

Red represents countries with ongoing local malaria transmission [27]. An entire country is shaded even if malaria transmission occurs only in a part of that country. Updates to the global distribution of endemic malaria can be obtained from the CDC, WHO, Pan American Health Organization, and Health Canada Web sites.

residents of malaria-endemic regions never develop com- plete protection; and when removed from the malarious environment, acquired immunity wanes [37]. Furthermore, acquired immunity is generally considered species and strain specific, although some degree of protection may be attained by prior infection by a different species [38]. The clinical implication is that immigrants or refugees with a history of- or even current-protective immunity may be susceptible to severe disease either by loss of acquired immunity or by exposure to a nonfamiliar species or strain.

In the United States, pregnant women comprise between 3% and 7% of all cases of malaria in women [1,39]. This is of particular concern given that both the pregnant woman and her fetus are at increased risk for the development of complications [40]. Because of P falciparum‘s pronounced affinity for the maternal placental vascular space, premature deliveries, intrauterine growth retardation, and neonatal mortality are common perinatal complications, whereas the pregnant women herself is at an increased risk for the development of severe malaria [41-43]. However, despite these well-recognized complications, pregnant US travelers appear less inclined to take antimalarial chemoprophylaxis than their nonpregnant counterparts [1]. Given the potential serious consequences of malaria to the pregnant woman and her fetus, travel to malarious areas is not recommended and should be avoided; if this is not possible, there are safe chemoprophylactic regimens that should be carefully

followed [1,44]. It should be emphasized that malaria in a pregnant woman is an acute medical emergency.

Clinical features and considerations

The cornerstone of any malaria diagnosis in the ED is a high degree of suspicion in a patient with fever or history of fever returning from a malaria-endemic region [45]. This is such an important component in making the diagnosis that these authors strongly recommend all emergency physicians develop the reflex to include Travel history, within the past year, in the routine history of any febrile patient. If negative, the health care provider can proceed with the standard evaluation. If there has been a history of travel, more detailed information regarding the location and dates of possible exposure will help focus the differential diagnosis, which in returning travelers with nonlocalizing systemic febrile illnesses includes (in addition to malaria) dengue, other Viral illnesses, rickettsial infections, and typhoid or paraty- phoid infections.

The Centers for Disease Control and Prevention (CDC) Web site has an interactive malaria map that can help health care providers determine if malaria transmission occurs in the region of travel (www.cdc-malaria.ncsa.uiuc.edu). Other historical information including use of mosquito protection measures and type of, and adherence to, chemoprophylaxis is

Manifestation	Features	Frequency in adults	Frequency in children
Cerebral malaria	Technically, unarousable coma without other cause,	Common	Very common
	GCS b9. In practice, any patient with impaired consciousness
Repeated seizures	or neurological dysfunction should be treated emergently. >=3 within a 24-h period	Less common	Very common
Severe anemia	Hematocrit b15% or hemoglobin b5 g/dL	Less common	Very common
Renal failure	in presence of parasite count N10 000/uL UOP b400 mL/24 h in adults or b12 mL/(kg 24 h)	Common	Unusual
	in children and serum creatinine N3.0 mg/dL
	despite volume repletion
ARDS	Radiological and/or clinical criteria	Common	Unusual
Acidemia	arterial pH b7.25 or plasma bicarbonate b15 mmol/L	Less common	Very common
Macroscopic	Massive hemolysis, not due to G6PD deficiency	Less common	Unusual
hemoglobinuria
Jaundice	Total bilirubin N2.5 mg/dL	Very common	Less common
Abnormal bleeding	Spontaneous bleeding from GI tract or mucous membranes	Less common	Unusual
and/or DIC	or laboratory evidence of DIC
circulatory collapse	Systolic BP b70 mm Hg in age N5 y or b50 mm Hg	Less common	Less common
	in children aged 1-5 y
Hyperlactatemia	N5.0 mmol/L	Less common	Very common
Hypoglycemia	b40 mg/dL	Less common	Very common
Hyperparasitemia	N5% of red blood cells infected	Common	Common
Modified from the WHO criteria. [58]. a A positive malaria blood smear with any of the above manifestations fulfills the case definition of severe malaria.

useful for risk stratification, although this information can never definitively rule out malaria and, if the suspicion exists, further investigation is mandatory.

Table 1 Case definitions of severe malaria ^a

The symptoms of malaria are nonspecific; fever, head- ache, and malaise are commonly the first manifestations. An important consideration is that up to half of patients may not be febrile when they present to the ED, although 78% to 100% of patients will have a history of fever [16]. The Classic symptoms of cyclic fevers, rigors, and cold sweats are often not present. Historically, fever cycles were used to diagnose and-to a lesser degree-differentiate malarial species; but the sensitivity and specificity of this method are poor [46,47]. Diarrhea, vomiting, back pain, myalgias, sore throat, or cough may predominate, frequently distracting clinicians from the diagnosis. With the exception of fever, there are no signs that consistently help with the diagnosis in mild, uncomplicated disease. Splenomegaly is seen in 24% to 40% of cases of uncomplicated malaria and is probably more common as disease severity increases [16,48,49]. With Disease progression, clinical signs of thrombocytopenia, anemia, and jaundice may become apparent, although these are not universal [12]. There is evidence that some laboratory markers-most notably thrombocytopenia [50,51], but also elevated C-reactive protein, bilirubin, and lactate dehydro- genase-may be suggestive of malaria [52]. However, given the lack of sensitivity and specificity of these tests, all suspected cases need definitive laboratory diagnosis, usually using microscopy of blood.

Once a diagnosis of malaria has been made, clinicians need to promptly assess severity. Untreated, approximately 10% of imported malaria will progress to complicated or severe malaria [53] (Table 1) (Tables 2 and 3). The presentation of severe malaria depends on several factors, of which age is the most important [54]. Severe malaria in children and infants is usually caused by severe anemia, cerebral malaria and seizures, respiratory distress, acidosis, and hypoglycemia [55]. In adults, cerebral malaria, renal failure, Liver failure, and acute respiratory distress syndrome are important presenta- tions [56]. Although less common in either population, disseminated intravascular coagulation or circulatory collapse may be complicating presentations.

Diagnosis of malaria

Examining a sample of the patient’s blood by a trained microscopist remains the criterion standard of diagnosis for malaria. Two types of blood preparations should be used: thin films (very similar to the methods used to perform a complete blood count with manual differential in hematol- ogy) and thick films. Thin blood films are more useful for determining the species and the parasitemia. Thick blood films are more sensitive in detecting malaria parasites because a greater volume of blood is examined per field compared with the thin film. The parasite density, or parasitemia, should always be estimated by counting the

Drug	Loading dose a	Maintenance dose	Comments
One of the following b Quinine dihydrochloride salt in 5% glucose or isotonic sodium chloride solution Quinidine gluconate reconstituted in 5% glucose or isotonic sodium chloride solution Plus one of the following Doxycycline Tetracycline	7 mg salt/kg IV over 30 min followed immediately by maintenance dose OR 20 mg salt/kg IV over 4 h followed 8 h later by maintenance dose 10 mg salt per kilogram (=6.25 mg base/kg) IV over 1-2 h, followed immediately by maintenance dose None None	10 mg salt/kg diluted in 10 mg/kg isotonic fluid IV over 4 h. Repeat Q 8 h 0.02 mg salt per kilogram per minute (= 0.0125 mg base per kilogram per minute) continuous infusion for at least 24 h 100 mg (children b45 kg: 2 mg/kg) PO/IV BID 250 mg (children b45 kg: 12.5 mg/kg) PO/IV QID If unable to tolerate PO, follow load with 5 mg/kg IV Q 8 h. When able to take PO, switch to 20 mg/(kg d) PO divided TID	Cardiotoxic. Requires EKG monitoring. If QRS lengthens N25% from baseline or QTc is N500 ms, slow or stop infusion. May cause hypoglycemia. Monitor blood glucose closely As above c Should not be given to pregnant or breast feeding women or children b8 y As above
Clindamycin	If unable to tolerate PO, give 10-mg/kg loading dose IV		None
Adapted from recommendations by the CDC and Trampuz et al [66]. a Loading dose should not be given if patients have received quinine, quinidine, halofantrine, or mefloquine in the preceding 12 hours. b Quinine dihydrochloride is the first-line recommended treatment for severe malaria in most regions of the world. Quinine dihydrochloride is not available for general clinical use in the United States. The first-line recommended treatment for severe malaria in the United States is quinidine gluconate. Under an investigational new drug protocol, artesunate is available in the United States through the CDC. c Quinidine dihydrochloride is 4 times more cardiotoxic than quinine.

percentage of red blood cells infected under an oil immersion lens on a thin film.

Table 2 Recommendations for initial parenteral treatment of severe malaria

It is important to recognize that many hospital laboratories may not have microscopists with experience reading and interpreting blood films for malaria, particularly overnight or during the weekend. This may cause a significant delay in arriving at the correct diagnosis. Under such circumstances, senior laboratory or pathology personnel should be consulted to rapidly determine the most appropriate course of action, which may include prompt transfer of the patient to a center with the necessary skilled personnel. These delays are thought to contribute to the disturbing findings of one US- based study that showed an average delay of 2.5 days from the time a malaria smear was ordered until the time of malaria diagnosis [27].

Persons suspected of having malaria, but whose blood films do not indicate the presence of parasites, should have blood films repeated every 12 to 24 hours for a total of 3 sets. If films remain negative, then the diagnosis of malaria is essentially ruled out.

Rapid diagnostic tests (RDTs) have been developed that can detect antigens derived from malaria parasites. Such tests most often use a dipstick or cassette format, and provide results in 2 to 15 minutes. Rapid diagnostic tests offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not immediately available [57].

Although there are many types of RDTs, with varying degrees of reliability and accuracy [58], there is currently just one, BinaxNOW, approved for use by hospitals and commercial laboratories in the United States. It is not approved for use by individual clinicians or by patients themselves. In the United States, it is required that this RDT is followed up with microscopy to confirm the result and, if positive, assess the parasitemia [59].

In general, the use of an RDT should decrease the time to preliminary diagnosis, particularly in non-Tertiary care centers. Polymerase chain reaction tests also exist, but are only available in reference laboratories and are used mainly for speciation and confirmation and not for initial diagnostic testing [60]. Similarly, serology, or indirect fluorescent Antibody testing is not appropriate for the Acute diagnosis of malaria [61]. There is a delay before the development of antibodies; and if antibodies are present, this indicates only that there has been a prior malaria infection.

It is important that emergency physicians be familiar with the appropriate diagnostic tests to order. The results of these tests should be reliable and available within hours so that decisions can be made regarding hospitalization and choice of medications. Hospital laboratories should not simply send these tests to reference laboratories or batch them for their most qualified staff. Even if a definitive species diagnosis cannot be made immediately, knowing that the patient is

Error Action to address error

Not inquiring about travel history in febrile patients or patients Reflex travel history for all patient with fever or without fever with a history of fever Not considering malaria on the differential diagnosis in a febrile Understanding that malaria continues to exist in most tropical, returned traveler and many subtropical, regions of the world Thinking that patients with malaria will always be febrile on Recognition that 30%-50% of patients will not have a fever presentation to the ED when they present to the ED Distraction by presenting symptoms that commonly include diarrhea, Recognition that presenting symptoms can be highly variable vomiting, Abdominal or back pain, myalgias, sore throat, or cough and nonspecific (frequently mimicking viral infections), thus reinforcing the importance of the travel history and High clinical suspicion Thinking that malaria prevention methods, including prophylactic Recognition that no preventative method is 100% effective medications, are 100% effective Not understanding, and thus not ordering, the correct tests Understanding that smear microscopy remains the criterion standard for malaria diagnosis, but when not immediately available, antigen detection tests (RDTs) should be used Not ensuring a rapid turnaround time for definitive diagnostic testing Prior coordination with laboratory services and, potentially, infectious disease physicians to ensure these test results can be obtained within several hours Not prescribing the correct treatment Knowing that accurate and reliable treatment guidelines for malaria exist, which should be referenced to help choose the best regimen

infected with malaria is essential for the initial management of the patient. If a delay in obtaining a reliable microscopic diagnosis is likely and an RDT is not available, expeditious transfer to a medical center equipped to provide this service is recommended.

Table 3 Common errors in the diagnosis and management of imported malaria

Additional workup

In addition to establishing the diagnosis and degree of parasitemia by microscopy, additional laboratory tests should be obtained to determine the severity of the malaria infection. A complete blood count should be obtained to assess for anemia or thrombocytopenia. A chemistry panel should be ordered to assess for electrolyte or renal abnormalities, hypoglycemia, acidosis, and hyperbilirubine- mia. If signs of respiratory distress are present, a chest radiograph, blood gas analysis, and lactate should be obtained. Given that bacterial infections and malaria can coexist, if clinical signs of sepsis or meningitis are present, appropriate antibiotics should be administered; and a lumbar puncture should be performed [62,63]. If clinical suspicion is high that the malaria infection is a relapsing species (eg, based on a history of recurrence of symptoms or travel history), a test to assess for G6PD deficiency should be ordered. These patients require evidence of a normal G6PD level before receiving primaquine for relapse prevention.

In well-appearing patients, laboratory-confirmed diagno- sis of malaria should be established before initiation of drug treatment. Exceptions to this rule include a high degree of suspicion and a lack of laboratory diagnostic facilities: given these criteria, treatment should be initiated and continued

until the diagnosis can be reliably ruled out with a minimum of 3 negative blood smears obtained 12 to 24 hours apart [45]. In patients for whom there is a strong suspicion of severe malaria, treatment may be started empirically if immediate malaria diagnostic testing is unavailable. In these instances, it is advisable to collect appropriate specimens for diagnostic testing before initiation of treatment to assist with the subsequent management.

Treatment

Once the diagnosis is established, the choice of appropri- ate drug treatment is dependent upon several factors: uncomplicated vs severe disease, age and pregnancy status of the patient, region of acquisition, and malarial species. Severe malaria requires parenteral therapy; pediatric patients and pregnant women have drug treatment restrictions; region of acquisition, malarial species, and chemoprophylactic agent used influence drug resistance considerations; and treatment of the hepatic hypnozoite form of P vivax and P ovale necessitates therapy with primaquine phosphate following treatment of the acute phase of the illness. For uncomplicated malaria, several CDC-recommended drug regimens are available depending upon the clinical scenario. These include chloroquine phosphate (Aralen); quinine sulfate (Qualaquin) in combination with either doxycycline, tetracycline, or clindamycin; atovaquone-proguanil (Malarone); artemether- lumefantrine (Coartem); or mefloquine (Lariam). Chloro- quine should only be used to treat non-falciparum infections or malaria acquired in areas without chloroquine resistance. The CDC malaria Web site (www.cdc.gov/malaria) is an

excellent source of information on drug resistance in specific countries. This site also provides detailed treatment dosages and schedules.

Considerations in severe malaria

For the treatment of severe malaria, intravenous quinidine gluconate is currently the only Food and Drug Administration- approved medicine available in the United States. However, under an investigational new drug protocol for severe malaria, the parenteral drug artesunate-which evidence suggests is a highly effective treatment option for severe malaria [64-67]-is now available in the United States through the CDC. Health care providers caring for patients with severe malaria should contact the CDC for management advice, including whether artesunate should be administered. However, it is critical to recognize that delays in the initiation of treatment for severe malaria, whether with quinidine, quinine, or artesunate, need to be avoided at all costs. The CDC Malaria Hotline is (855) 856- 4713 during weekday hours and (770) 488-7100 during evenings, weekends, and holidays.

fluid management in severe malaria is controversial. Given that lactic acidosis in severe malaria is correlated with morbidity and that elevated lactate levels typically resolve with improved tissue perfusion, aggressive fluid resuscitation, as with severe bacterial sepsis or septic shock, is theoretically sound. However, concerns about precipitating congestive heart failure or cerebral edema, particularly in the comatose pediatric population, have historically limited aggressive fluid resusci- tation guidelines. Good, high-quality data on this topic have been limited. However, a recent landmark, multicenter, randomized clinical trial in African children with shock and life-threatening infections-but not severe hypotension- demonstrated increased mortality in children resuscitated with initial intravenous fluid boluses vs conservative mainte- nance-only fluid therapy, despite these children all showing evidence of impaired perfusion [68]. Almost 60% of the children were malaria positive, and the increased mortality risk with intravenous fluid boluses was demonstrated equally in the malaria-positive and malaria-negative groups. Intriguingly, there was no evidence of increased mortality secondary to pulmonary edema or increased intracranial pressure. While recognizing the difficulties in extrapolating these trial findings to the management of imported malaria in the developed world, this trial does support the conservative World Health Organization (WHO) guidelines for intrave- nous fluids in malaria: in the absence of clear intravascular depletion, recommendations for fluid administration are maintenance only; in decompensated shock, fluid manage- ment is based on estimations of dehydration with standard 20- to 40-ml/kg boluses of 0.9% isotonic sodium chloride solution or Ringer’s lactate solution for children and 1 to 2 L of the same fluids for adults [69].

Urine output is a good measure of organ perfusion; but oliguric renal failure does occur, more commonly in adults,

in severe malaria, and if suspected, central venous pressure monitoring-maintaining central venous pressure at 0 to 5 mm Hg-is indicated [68]. Finally, splenic rupture and severe gastrointestinal bleeding may occur in severe malaria and should be considered in any patient with acute Hemodynamic deterioration.

Blood glucose testing is of paramount importance in the early evaluation of any patient with malaria or suspected malaria. This is particularly important in children or pregnant women, who frequently present with hypoglycemia; in any patient with an Altered level of consciousness; or in any patient who deteriorates rapidly. In addition, quinine and quinidine, the mainstay drugs in the treatment of severe malaria, stimulate pancreatic insulin secretion, which may lead to recurrent hypoglycemia [69]; pregnant women are particularly susceptible to hypoglycemia by this mechanism and require regular blood glucose monitoring [70]. Hypo- glycemia should be treated with Standard therapy, and dextrose-supplemented intravenous fluids may be necessary in patients receiving quinine or quinidine.

Other therapeutic options in severe malaria including blood transfusion and Exchange transfusions should be considered in consultation with a tropical medical or infectious disease specialist. If a patient presents with malaria and severe anemia, blood transfusion is indicated. However, beyond this basic principle, clear evidence-based criteria for when to transfuse are lacking. Similarly, there are multiple reports of the successful use of exchange transfusions in patients with severe malaria and high parasitemia [71-75]; but one meta- analysis and one systematic review examined this question and failed to show a clear Survival benefit [76,77]. Dexamethasone and other corticosteroids have been shown to be harmful in severe or cerebral malaria and should not be administered [78,79].

Admission criteria

Although a diagnosis of malaria in the ED may presume hospitalization, it is not always necessary [48]. When considering admission criteria, there are 3 categories of patients:

1. Nonsevere P malariae, P ovale, and P vivax, which, if the diagnosis is certain, can usually be safely managed as outpatients on oral therapy
2. Nonsevere P falciparum, which should be admitted to an inpatient ward and treated with oral therapy
3. Severe malaria of any species or any patient unable to tolerate oral treatment needs intensive care unit admission and Intravenous treatment.

The subset of patients with nonsevere falciparum malaria who are admitted to the ward should be closely monitored for signs or symptoms of severe disease. However, most of these patients demonstrate a favorable response to treatment within 24 hours, after which they can usually be managed as outpatients.

Summary

The clinical presentation of malaria is typically charac- terized by the acute onset of symptoms including fevers, chills, and malaise. These patients feel ill and often seek immediate medical care. Furthermore, pretravel advice provided by Travel medicine clinics instructs patients to go to EDs should they develop fevers in the months following their return. Unlike outpatient Primary care clinics, EDs often have the resources necessary to diagnose, or rule out, malaria. Thus, it is to EDs that these patients should, and will, often turn. For these reasons, emergency physicians are likely to see imported malaria; and emergency physicians can make a significant impact on malaria-associated morbidity and mortality.

To limit the progression of uncomplicated malaria to severe malaria and death, we emphasize 3 critical steps: (1) early diagnosis, (2) prompt institution of therapy, and (3) appropriate choices for antimalarial therapy. If in doubt about the appropriate management of a patient with malaria or suspected malaria, consult an infectious disease or tropical medicine specialist early.

To ensure an early diagnosis, emergency physicians need to obtain a travel history from all febrile patients, and understand and order appropriate laboratory studies. Emer- gency physicians need to ensure a timely laboratory turnaround time, ensure pharmacy formularies include an appropriate array of antimalarial medications, and ensure the pharmacy keeps an acceptable supply of these medications. These final 3 points may require proactive advocacy to make sure that deficiencies are not discovered in the middle of the night when a severe malaria case presents in need of immediate diagnosis and treatment.

References

1. WHO: world malaria report: 2010. Geneva: WHO; 2010.
2. Probable transfusion-transmitted malaria-Houston, Texas, 2003. MMWR Morb Mortal Wkly Rep 2003;52(44):1075-6.
3. Mungai M, Tegtmeier G, Chamberland M, Parise M. Transfusion- transmitted malaria in the United States from 1963 through 1999. N Engl J Med 2001;344(26):1973-8.
4. Lesko CR, Arguin PM, Newman RD. Congenital malaria in the United States: a review of cases from 1966 to 2005. Arch Pediatr Adolesc Med 2007;161(11):1062-7.
5. Tarantola A, Rachline A, Konto C, Houze S, Sabah-Mondan C, Vrillon H, et al. Occupational Plasmodium falciparum malaria following accidental blood exposure: a case, published reports and considerations for post-exposure prophylaxis. Scand J Infect Dis 2005;37(2):131-40.
6. Cox-Singh J, Davis TM, Lee KS, Shamsul SS, Matusop A, Ratnam S, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis 2008;46(2):165-71.
7. Singh B, Kim Sung L, Matusop A, Radhakrishnan A, Shamsul SS, Cox-Singh J, et al. A large focus of naturally acquired Plasmo- dium knowlesi infections in human beings. Lancet 2004;363(9414): 1017-24.
8. Chin W, Contacos PG, Coatney GR, Kimball HR. A naturally acquired quotidian-type malaria in man transferable to monkeys. Science 1965;149:865.
9. Elliott JH, O’Brien D, Leder K, Kitchener S, Schwartz E, Weld L, et al. Imported Plasmodium vivax malaria: demographic and clinical features in nonimmune travelers. J Travel Med 2004;11(4):213-7.
10. Price L, Planche T, Rayner C, Krishna S. Acute respiratory distress syndrome in Plasmodium vivax malaria: case report and review of the literature. Trans R Soc Trop Med Hyg 2007;101(7):655-9.
11. Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV, Das A.

Plasmodium vivax malaria. Emerg Infect Dis 2005;11(1):132-4.

1. White N. Malaria. In: Cook GC, Zumla A, Weir J, editors. Manson’s tropical diseases, 21st ed.Philadelphia (Pa): WB Saunders; 2003.
2. Carter R, Mendis KN, Roberts D. Spatial targeting of interventions against malaria. Bull World Health Organ 2000;78(12):1401-11.
3. Craig MH, Snow RW, le Sueur D. A climate-based distribution model of malaria transmission in sub-Saharan Africa. Parasitol Today 1999;15(3):105-11.
4. Laneri K, Bhadra A, Ionides EL, Bouma M, Dhiman RC, Yadav RS, et al. Forcing versus feedback: epidemic malaria and monsoon rains in northwest India. PLoS Comput Biol 2010;6(9):e1000898.
5. Svenson JE, MacLean JD, Gyorkos TW, Keystone J. Imported malaria. Clinical presentation and examination of symptomatic travelers. Arch Intern Med 1995;155(8):861-8.
6. Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of malaria-implications for chemoprophylaxis in travelers. N Engl J Med 2003;349(16):1510-6.
7. Krause G, Schoneberg I, Altmann D, Stark K. Chemoprophylaxis and malaria Death rates. Emerg Infect Dis 2006;12(3):447-51.
8. Mali S, Steele S, Slutsker L, Arguin PM. Malaria surveillance- United States, 2008. MMWR Surveill Summ 2010;59(7):1-15.
9. Baird JK. Effectiveness of antimalarial drugs. N Engl J Med 2005;352(15):1565-77.
10. WHO: centralized information system for infectious diseases (CISID)/- malaria. World Health Organisation Regional Office for Europe; 2011.
11. Mali STK, Arguin PM. Malaria surveillance-United States, 2009. MMWR Surveill Summ 2011 [In Press].
12. Hwang J, McClintock S, Kachur SP, Slutsker L, Arguin P. Comparison of national malaria surveillance system with the national notifiable diseases surveillance system in the United States. J Public Health Manag Pract 2009;15(4):345-51.
13. Freedman DO, Weld LH, Kozarsky PE, Fisk T, Robins R, von Sonnenburg F, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006;354(2):119-30.
14. Field V, Gautret P, Schlagenhauf P, Burchard GD, Caumes E, Jensenius M, Castelli F, Gkrania-Klotsas E, Weld L, Lopez-Velez R, et al. Travel and migration associated infectious diseases morbidity in Europe, 2008. BMC Infect Dis 2010;10:330.
15. From the Centers for Disease Control and Prevention. Local transmission of Plasmodium vivax malaria-Virginia 2002. JAMA 2002;288(17):2113-4.
16. Kain KC, Harrington MA, Tennyson S, Keystone JS. Imported malaria: Prospective analysis of problems in diagnosis and manage- ment. Clin Infect Dis 1998;27(1):142-9.
17. Kyriacou DN, Spira AM, Talan DA, Mabey DC. Emergency department presentation and misdiagnosis of imported falciparum malaria. Ann Emerg Med 1996;27(6):696-9.
18. Ladhani S, Aibara RJ, Riordan FA, Shingadia D. Imported malaria in children: a review of clinical studies. Lancet Infect Dis 2007;7(5):349-57.
19. Singh K, Wester WC, Trenholme GM. Problems in the therapy for imported malaria in the United States. Arch Intern Med 2003;163(17): 2027-30.
20. Freedman DO. Imported malaria-here to stay. Am J Med 1992;93(3): 239-42.
21. Moore TA, Tomayko Jr JF, Wierman AM, Rensimer ER, White Jr AC. Imported malaria in the 1990s. A report of 59 cases from Houston, Tex. Arch Fam Med 1994;3(2):130-6.
22. Vicas AE, Albrecht H, Lennox JL, del Rio C. Imported malaria at an inner-city hospital in the United States. Am J Med Sci 2005;329(1):6-12.
23. Elmansouf L, Dubos F, Dauriac A, Courouble C, Pruvost I, Dervaux B, et al. Evaluation of imported pediatric malaria management in northern France. Med Mal Infect 2011.
24. Greenberg AE, Lobel HO. Mortality from Plasmodium falciparum malaria in travelers from the United States, 1959 to 1987. Ann Intern Med 1990;113(4):326-7.
25. Newman RD, Parise ME, Barber AM, Steketee RW. Malaria-related deaths among U.S. travelers, 1963-2001. Ann Intern Med 2004;141(7):547-55.
26. Schofield L, Grau GE. Immunological processes in malaria pathogen- esis. Nat Rev Immunol 2005;5(9):722-35.
27. Achtman AH, Bull PC, Stephens R, Langhorne J. Longevity of the immune response and memory to blood-stage malaria infection. Curr Top Microbiol Immunol 2005;297:71-102.
28. Eliades MJ, Shah S, Nguyen-Dinh P, Newman RD, Barber AM, Roberts JM, et al. Malaria surveillance-United States, 2003. MMWR Surveill Summ 2005;54(2):25-40.
29. Subramanian D, Moise Jr KJ, White Jr AC. Imported malaria in pregnancy: report of four cases and review of management. Clin Infect Dis 1992;15(3):408-13.
30. Jelliffe EF. Low birth-weight and malarial infection of the placenta. Bull World Health Organ 1968;38(1):69-78.
31. Guyatt HL, Snow RW. Impact of malaria during pregnancy on low birth weight in sub-Saharan Africa. Clin Microbiol Rev 2004;17(4): 760-9 table of contents.
32. Brabin BJ, Romagosa C, Abdelgalil S, Menendez C, Verhoeff FH, McGready R, Fletcher KA, Owens S, D’Alessandro U, Nosten F, et al. The sick placenta-the role of malaria. Placenta 2004;25(5): 359-78.
33. Garner P. GlAM: drugs for preventing malaria in pregnant women. Cochrane Database Syst Rev 2006;4:CD000169.
34. Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria in the United States: a systematic review. JAMA 2007;297(20):2264-77.
35. Dorsey G, Gandhi M, Oyugi JH, Rosenthal PJ. Difficulties in the prevention, diagnosis, and treatment of imported malaria. Arch Intern Med 2000;160(16):2505-10.
36. Lynk A, Gold R. Review of 40 children with imported malaria. Pediatr Infect Dis J 1989;8(11):745-50.
37. D’Acremont V, Landry P, Darioli R, Stuerchler D, Pecoud A, Genton

B. Treatment of imported malaria in an ambulatory setting: prospective study. BMJ 2002;324(7342):875-7.

1. D’Acremont V, Landry P, Mueller I, Pecoud A, Genton B. Clinical and laboratory predictors of imported malaria in an outpatient setting: an aid to medical decision making in returning travelers with fever. Am J Trop Med Hyg 2002;66(5):481-6.
2. Hanscheid T, Melo-Cristino J, Grobusch MP, Pinto BG. Avoiding misdiagnosis of imported malaria: screening of emergency department samples with thrombocytopenia detects clinically unsuspected cases. J Travel Med 2003;10(3):155-9.
3. Nilles E. [Epidemiological and clinical characteristics of imported malaria in Dubai: a cohort study of 660 cases from 2008 to 2010] Unpublished raw data. In. Dubai; 2011.
4. Gjorup IE, Vestergaard LS, Moller K, Ronn AM, Bygbjerg IC. Laboratory indicators of the diagnosis and course of imported malaria. Scand J Infect Dis 2007;39(8):707-13.
5. Parise MLL. Severe malaria: North American perspective. In: Feldman C, Sarosi GA, editors. Tropical and parasitic infections in the ICU. New York (N.Y.): Springer Science + Business Media Inc; 2005. p. 17-37.
6. Dondorp AM, Lee SJ, Faiz MA, Mishra S, Price R, Tjitra E, et al. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin Infect Dis 2008;47(2):151-7.
7. Maitland K, Marsh K. Pathophysiology of severe malaria in children. Acta Trop 2004;90(2):131-40.
8. Mackintosh CL, Beeson JG, Marsh K. Clinical features and pathogen- esis of severe malaria. Trends Parasitol 2004;20(12):597-603.
9. Moody A. Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev 2002;15(1):66-78.
10. Murray CK, Bennett JW. Rapid diagnosis of malaria. Interdiscip Perspect Infect Dis 2009;2009:415953.
11. BinaxNOW(R) package insert. The Hague: Inverness Medical; 2007.
12. Perandin F, Manca N, Calderaro A, Piccolo G, Galati L, Ricci L, et al. Development of a real-time PCR assay for detection of Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale for routine clinical diagnosis. J Clin Microbiol 2004;42(3):1214-9.
13. WHO: new perspectives-malaria diagnosis. In: WHO, editor. Joint Report WHO/USAID. Geneva: WHO; 2000.
14. Ukaga CN, Orji CN, Orogwu S, Nwoke BE, Anosike JC, Udujih OS, et al. Concomitant bacteria in the blood of malaria patients in Owerri, southeastern Nigeria. Tanzan Health Res Bull 2006;8(3):186-8.
15. Berkley JA, Maitland K, Mwangi I, Ngetsa C, Mwarumba S, Lowe BS, et al. Use of clinical syndromes to target Antibiotic prescribing in seriously ill children in malaria endemic area: observational study. BMJ 2005;330(7498):995.
16. Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005;366(9487):717-25.
17. Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open- label, randomised trial. Lancet 2010;376(9753):1647-57.
18. Sinclair D, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2011;3:CD005967.
19. Phillips RE, Warrell DA, White NJ, Looareesuwan S, Karbwang J. Intravenous quinidine for the treatment of severe falciparum malaria. Clinical and pharmacokinetic studies. N Engl J Med 1985;312(20): 1273-8.
20. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, et al. Mortality after Fluid Bolus in African Children with severe infection. N Engl J Med 2011;364:2483-95.
21. WHO: guidelines for the treatment of malaria, 2nd ed. 2010.
22. Phillips RE. Hypoglycaemia is an important complication of falciparum malaria. Q J Med 1989;71(266):477-83.
23. Chung HS, Peck KR, Kim DW. Two case reports of successful therapeutic erythrocytapheresis as an adjunctive therapy in severe falciparum malaria. Ther Apher Dial 2010;14(2):230-3.
24. Shanbag P, Juvekar M, More V, Vaidya M. Exchange transfusion in children with severe falciparum malaria and heavy parasitaemia. Ann Trop Paediatr 2006;26(3):199-204.
25. Virdi VS, Goraya JS, Khadwal A, Seth A. Neonatal transfusion malaria requiring exchange transfusion. Ann Trop Paediatr 2003;23(3):205-7.
26. Tejura B, Sass DA, Fischer RA, Daskal I, Eiger G. Transfusion- associated falciparum malaria successfully treated with red blood cell exchange transfusion. Am J Med Sci 2000;320(5):337-41.
27. van Genderen PJ, Hesselink DA, Bezemer JM, Wismans PJ, Overbosch D. Efficacy and safety of exchange transfusion as an adjunct therapy for severe Plasmodium falciparum malaria in nonimmune travelers: a 10-year single-center experience with a standardized treatment protocol. Transfusion 2010;50(4):787-94.
28. Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 2002;34(9):1192-8.
29. Omari AA, Garner P. Malaria: severe, life-threatening. Clin Evid (Online) 2007:2007.
30. Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, et al. Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J Med 1982;306(6):313-9.
31. Prasad K, Garner P. Steroids for treating cerebral malaria. Cochrane Database Syst Rev 2000(2):CD000972.