Difficulties in the Prevention, Diagnosis, and Treatment of Imported Malaria FREE

MALARIA REMAINS one of the most important infectious diseases in the world.¹ An estimated 300 to 500 million cases occur each year, causing 1.5 to 2.7 million deaths.² In the United States, the incidence of imported malaria began to rise in the 1970s, and recent reports have documented well over 1000 cases per year.³ These reports likely understate the true incidence of malaria, as it is estimated that 40% to 70% of cases are not reported.^4- 6 Many cases of imported malaria appear to be preventable, as travelers often fail to follow appropriate guidelines for prevention,^7- 11 and this failure has been associated with an increased risk for malaria.¹² Delays in diagnosis and therapy have also been common^7- 8,10 and have been associated with increases in morbidity and mortality.^8,13- 14

The rise in the incidence of imported malaria is probably attributable to the increase in travel by Americans to countries where malaria is endemic¹⁵ and to increases in immigration and travel to the United States by persons living in endemic countries. Also, the resistance of malaria parasites to available antimalarial agents is increasing.^1,16 Owing to the spread of antimalarial drug resistance and the availability of new drugs, standard recommendations for chemoprophylaxis and treatment have changed over the last decade.^11,17- 19 To evaluate the impact of changes in travel patterns and chemoprophylaxis on the epidemiology of imported malaria and to highlight the difficulties encountered in prevention, diagnosis, and therapy, we reviewed 121 cases of imported malaria diagnosed at 2 urban university hospitals.

All smear-positive malaria cases diagnosed between 1988 and 1997 by the microbiology laboratories at San Francisco General Hospital, a city hospital serving a largely indigent population, and Moffit-Long Hospital, San Francisco, Calif, a tertiary referral center, were reviewed. Diagnoses were based on thin and thick smears stained with 5% Giemsa stain (Moffit-Long Hospital and San Francisco General Hospital) or 0.4% Wright stain (San Francisco General Hospital) and examined by experienced laboratory personnel. Cases were defined as patients with thin or thick malaria-positive smears who were seen at either hospital during the acute phase of illness. Patients with relapsing or recrudescent infections were counted only once. Medical records were reviewed, and data were collected on a standardized form. Severe malaria was defined according to World Health Organization criteria.²⁰ For the purpose of our analysis, US residents were defined as patients living in nonendemic areas who acquired malaria through travel to endemic areas. Foreign residents were defined as patients who were living in malaria-endemic areas when they acquired the disease. Statistical analysis of categorical data was performed using χ² or Fisher exact test for dichotomous variables and the Mann-Whitney test of means. Significance was defined as P≤.05 (2-tailed).

Of 123 malaria cases diagnosed between 1988 and 1997, 121 cases (81 at San Francisco General Hospital and 40 at Moffit-Long Hospital) were available for review and included in the study. Cases presented to the emergency department (69%), pediatric clinics (13%), general medical clinics (10%), infectious diseases clinics (7%), and obstetric clinics (1%).

Patient demographics are summarized in Table 1. All patients acquired malaria while traveling or living in endemic areas. Approximately 50% of the patients (classified as US residents) had been living in nonendemic areas and had acquired the disease through travel; the other 50% (classified as foreign residents) had been living in endemic areas before coming to the United States. The median duration of travel for US residents was 60 days (range, 10 days to 2 years). The purpose of travel for US residents included tourism (84%), foreign employment (14%), and missionary work (2%). The median length of stay for foreign residents in the United States prior to their presentation was 90 days (range, 1 day to 4 years). Areas of travel or prior residence are detailed in Table 2. US residents were most likely to have traveled to Africa or Southeast Asia, while more than 80% of foreign residents had come from Central America or the Indian subcontinent.

Of 57 US residents, 33 (58%) reported using some form of chemoprophylaxis. Only 2 (3%) of 64 foreign residents used chemoprophylaxis; 1 of these 2 was pregnant. Among the 33 US residents who reported taking chemoprophylaxis, 28 (85%) took medications recommended by the Centers for Disease Control and Prevention, Atlanta, Ga, at the time of travel,^11,17- 19 and 13 (48%) of these individuals reported compliance with chemoprophylaxis. Thus, overall, only 13 (23%) of the 57 US residents were compliant with a currently recommended chemoprophylactic regimen.

Previous evaluations during which the diagnosis of malaria was not considered were performed in 19 patients (16%), 16 of whom had been seen at 1 of our 2 institutions. Eight of these patients had 2 prior visits before the correct diagnosis was made. Missed diagnosis led to a mean delay in therapy of 5.6 days (range, 1-23 days). Incorrect diagnoses included viral syndrome, fever of unknown origin, upper respiratory tract infection, bronchitis, hepatitis, drug fever, urinary tract infection, and iron deficiency anemia. There were 2 dramatic misdiagnoses. The first misdiagnosis involved a 26-year-old man who had traveled to Mexico 9 months earlier and who had presented to an outside hospital with fever, headache, abdominal pain, diarrhea, and myalgias. Pancytopenia was identified and acute leukemia was diagnosed based on a peripheral blood smear. The patient was transferred to our hospital for a bone marrow biopsy, but review of the peripheral blood smear identified Plasmodium vivax infection. The second misdiagnosis involved a 53-year-old Nicaraguan man who had been living in the United States for many years and who had undergone liver transplantation 9 years earlier. He returned from a trip to Nicaragua with a 1-day history of fever, headache, and mildly elevated liver function test results. He was treated with pulse-dose methylprednisolone for presumptive rejection, and underwent a liver biopsy. On the following day, a routine manual blood smear revealed P vivax.

Before presenting to our institutions, 11 patients (9%) had been diagnosed with malaria at an outside hospital in the United States. Three were persons with Plasmodium falciparum infection who presented within 4 days after they did not respond to their initial therapy (1 discontinued quinine sulfate therapy owing to tinitis; 1 was treated with chloroquine phosphate; and 1 was treated with mefloquine after traveling in Southeast Asia). The remaining 8 patients presented with apparent relapses due to P vivax (at least 1 month after an apparently successful response to therapy).

The causes of each case of malaria and the endemic areas of exposure are listed in Table 3. Patients with P falciparum infections were much more likely to have had an exposure in Africa than were patients with nonfalciparum infections (81% vs 17%, P<.001). In 119 (98%) of 121 cases, the initial smear was positive. The remaining 2 cases were diagnosed on a second smear (1 of the 2 patients was receiving a chemophrophylactic regimen of chloroquine and proguanil at the time of evaluation). In 8 (7%) of 121 cases, there was a discrepancy between the initial smear reading and the final smear reading (5 cases initially read as possible P falciparum were determined to be P vivax or P ovale; 2 cases initially read as negative were determined to be P vivax; and 1 case initially read as P vivax or P ovale was determined to be P ovale).

The most common signs and symptoms reported at the time of the initial positive smear are listed in Table 4. The only symptoms present in a majority of cases were fever, chills, and headache. While nearly all patients had a history of fever, in only 60% of the cases was the patient febrile (≥ 38.0°C) at the time of presentation. More than 60% of the patients presented with no significant physical findings other than fever. There were no significant differences in the prevalence of symptoms and physical findings between falciparum and nonfalciparum infections except that anorexia was more common with falciparum infection (50% vs 19%, P<.001).

The average duration between the departure from an endemic area and the onset of symptoms was considerably longer in nonfalciparum infections than in falciparum infections (143 days vs 8.3 days, P<.001). The average duration of symptoms before presentation was 7.9 ± 11 (mean ± SD) days (range, 1-60 days). The patient with the longest duration of symptoms (60 days) had the only Plasmodium malariae monoinfection in the study. There was no difference in the duration of symptoms between patients with falciparum infections and patients with nonfalciparum infections or between US residents and foreign residents.

The most common laboratory abnormalities were thrombocytopenia, elevated bilirubin levels, and anemia (Table 5). There were no significant differences in laboratory values between patients with falciparum infections and patients with nonfalciparum infections except that patients with falciparum infections were more likely to have elevated creatinine levels (20% vs 4%, P = .03). There were no significant differences in laboratory values between US residents and foreign residents, except that US residents were more likely to have elevated aspartate aminotransferase levels (30% vs 8%, P = .009).

Patients were admitted to the hospital in 37% of cases; 5% were admitted to the intensive care unit for intravenous quinidine therapy and cardiac monitoring for presumed falciparum malaria. Patients with falciparum malaria were more likely to be admitted than were those with nonfalciparum malaria (65% vs 38%, P<.001). There was no difference in the admission rates between US residents and foreign residents either overall or stratified for plasmodial species. The median duration of hospitalization was 2 days (range, 1-17 days). Only 1 patient developed severe malaria (P falciparum infection complicated by acute respiratory distress syndrome, disseminated intravascular coagulation, hypoglycemia, hyperbilirubinemia, and renal insufficiency), and there were no deaths.

Errors in antimalarial treatment occurred in 11 patients (9%) in our series. Five patients with P falciparum infections acquired in areas with chloroquine resistance were treated with chloroquine or chloroquine plus primaquine phosphate. Two of these 5 patients developed recrudescence owing to treatment failure 8 and 25 days after their initial therapy. Other treatment failures included 5 patients who received unnecessary antimalarial medications (2 cases of P vivax infection acquired in India were treated with antimalarial agents other than chloroquine or primaquine; 2 cases of P falciparum infection were treated with 3 active drugs; and 1 case of P falciparum infection was treated with primaquine), 1 patient with P vivax infection who did not receive primaquine, and 1 patient with P vivax infection who received no documented therapy because the smear was initially read as negative. Only 1 patient developed toxic effects that required a change in antimalarial therapy (neutropenia, possibly due to quinine use). In 7 patients (6%), there was a delay of 1 to 10 days in the initiation of therapy because the patient was sent home before the initial blood smear results were reported. Relapses following appropriate therapy occurred in 3 patients. Two of the 3 patients had received chloroquine and primaquine for vivax malaria and had recurrences of the same infection 2 and 3 months later. One of the infections was acquired in Indonesia, where chloroquine-resistant P vivax and failures of primaquine therapy have been described.^11,21 One patient who was treated with oral quinine and doxycycline for P falciparum infection relapsed with P ovale infection 1 month later.

Imported malaria was neither rare nor exotic at our 2 institutions, as 123 cases were diagnosed over a 10-year period. The epidemiological distribution in our cases was consistent with recent national malaria surveillance statistics³ except that we saw a higher percentage of P vivax infections, owing to excess cases in immigrants from Central America.

Chemoprophylaxis is recommended for all American travelers to malaria-endemic areas. Only 23% of US residents in our series reported compliance with the chemoprophylactic regimens recommended by the Centers for Disease Control and Prevention. The most common errors were failure to initiate any chemoprophylactic regimen and noncompliance with a chosen regimen, as has consistently been reported over the last 20 years.^{7- 8,10,22- 23} U.S. residents traveling back to their country of birth were significantly less likely than US-born travelers to have used any chemoprophylaxis (25% vs. 69%, P = .009), identifying a high-risk group that often fails to seek pretravel advice.⁹

In contrast to some previous studies,^10,22,24 our study found that P falciparum infections were uncommon after appropriate chemoprophylaxis: there were only 2 cases, both of which occurred in the 1980s, before mefloquine was available. All the remaining 11 US residents who developed malaria despite appropriate chemoprophylactic therapy had P vivax or P ovale infections, and their symptoms began a mean of 125 days after they left the malaria-endemic area (range, 1 month to 1 year). These cases illustrate the fact that even with effective chemoprophylaxis, patients remain at risk for relapsing P vivax and P ovale infections. Although not truly a failure of chemoprophylaxis, this phenomenon has recently been recognized as an increasingly important limitation of all currently recommended prophylactic drugs, which target the erythocytic phase of the parasite.²⁵ In our series, no patients reported terminal prophylaxis with primaquine, which is recommended by some authorities, especially for patients with heavy exposure or prolonged travel.¹¹ In no cases in our series did falciparum malaria develop after chemoprophylactic therapy with mefloquine. These results and other recent published observations support the effectiveness of mefloquine chemoprophylaxis in preventing the most lethal form of the disease.^3,12 However, these results should be interpreted with caution owing to recent reports of increasing mefloquine resistance in Southeast Asia and elsewhere.^26- 28

Overall, 19 (16%) of our patients had previously been seen by a physician who failed to consider a diagnosis of malaria. This error rate is consistent with rates reported by other hospitals with experience in the diagnosis of imported malaria, but considerably lower than those at less experienced centers.^7,10,22 Among patients in whom the diagnosis was missed, there was a significantly longer duration between exposure and onset of symptoms than among patients who received a correct diagnosis (mean 222 days vs 84 days, P = .003), suggesting that physicians failed to obtain an adequate travel history or failed to appreciate the significance of fairly remote malaria exposure.

In our series, the clinical presentation of imported malaria was nonspecific and did not differ between falciparum and nonfalciparum malaria or between US residents and foreign residents. A history of fever was present in virtually all patients, although fever periodicity was uncommon and normal temperatures at presentation were common. Physical findings and laboratory test results were generally unhelpful as diagnostic aids, although anemia and thrombocytopenia were present in a majority of patients.

The sensitivity of microscopy in our series was excellent: 119 of 121 cases were diagnosed on the first blood smear. In 8 cases (7%), there was a discrepancy between the initial smear reading and the final reading. In most of these cases, smears were read as possible P falciparum until final species identification could be made. Results from our study and others⁷ suggest that in the hands of experienced microscopists, the sensitivity of a single blood smear for the diagnosis of malaria is excellent. However, when the suspicion of malaria is high, especially if a patient has recently taken antimalarial agents, serial smears can increase sensitivity. In our series, errors were made in antimalarial therapy in 11 (9%) of 119 patients for whom this information was recorded. In a recent study of imported malaria in Canada, 8% of the patients who were treated at a tropical disease specialty unit received inappropriate initial therapy, compared with 48% of patients treated at outside hospitals.⁷ Treatment errors in our series were more common in falciparum malaria than in nonfalciparum malaria (26% vs 3%, P<.001). Although 7 US residents with falciparum malaria were treated successfully as outpatients, this number is too small to disprove the current dictum of admitting all nonimmune patients with falciparum malaria to the hospital.

In summary, imported malaria remains a significant problem in the United States. It has the potential to become increasingly common as the frequency of international travel continues to grow and antimalarial drug resistance increases. Effective chemoprophylactic regimens exist, but failure to use recommended regimens continues to be a frequent problem in travelers to endemic areas. Also, even when appropriate chemoprophylaxis is used, patients may develop malaria owing to drug resistance or relapsing infection. The clinical presentation of malaria was nonspecific and remarkably similar in US and foreign residents, as well as in cases of falciparum and nonfalciparum infections. Therefore, physicians should consider the diagnosis in any patient who has an exposure history, even if it is remote. The decision to order a simple blood smear remains the most important factor in the management of this disease. Imported malaria, especially falciparum malaria, has the potential to cause life-threatening illness, but with timely diagnosis and appropriate treatment, the outcome of this disease is generally quite good.

Accepted for publication January 28, 2000.

This study was supported in part by a Emerging Infections Postdoctoral Training Program grant from the Centers for Disease Control and Prevention.

The authors thank Margaret Wong and Marguerite Roemer of the San Francisco General Hospital Department of Microbiology for their assistance.

Corresponding author: Grant Dorsey, MD, Box 0811, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 (e-mail: grantd@itsa.ucsf.edu).