Uncommon Manifestation of a Mixed-Species Malaria Infection: Cryptic Falciparum Malaria in a Traveler With Successfully Treated Tertian Malaria
Professor Frank P. Mockenhaupt, MD, Institute of Tropical Medicine and International Health, Charité—Universitätsmedizin Berlin, Spandauer Damm 130, D-14050 Berlin, Germany. E-mail: firstname.lastname@example.org
We report a case of falciparum malaria in a traveler 9 days after successful treatment of ovale malaria. The underlying, cryptic mixed-species infection was primarily undetectable with standard laboratory diagnostics. This case highlights the limitations of these tests and the unpredictability of typical incubation periods in the individual case.
The number of imported malaria cases in the WHO European region has declined in recent years but still amounts to several thousand episodes annually. According to the GeoSentinel analysis of data from international travelers from 1997 to 2002, 74% of imported malaria infections were acquired in sub-Saharan Africa. Travelers visiting friends and relatives (VFRs) made up the biggest proportion (35%) of imported cases, were less likely than others to receive pre-travel counseling from a health care provider, and often did not take antimalarial chemoprophylaxis. Only 2.1% of imported malaria infections were mixed species, but 90% of those involved potentially fatal Plasmodium falciparum. The typical interval between returning from travel and presentation to a health care provider was 7 to 14 days for P falciparum and 2 to 6 months for Plasmodium ovale.1
We report a case of a traveler VFR, who did not take antimalarial chemoprophylaxis and developed P falciparum malaria 9 days after a successfully treated first malaria episode with P ovale.
A 58-year-old man of Nigerian origin, living in Germany for 37 years, presented to the outpatient clinic of the Institute of Tropical Medicine and International Health in Berlin. He reported a 3-day history of fever and chills. Four days before that, he had returned from a 3-week visit to Lagos, Nigeria, where he had not taken antimalarial chemoprophylaxis. At presentation, he was afebrile and in good clinical condition. The laboratory tests showed normal values for hemoglobin, white blood cell (WBC) and platelet counts, liver enzymes, bilirubin, lactate dehydrogenase, and creatinine. The C-reactive protein (CRP) was increased at 14.7 mg/L (normal value <5 mg/L). Dengue fever was ruled out by negative NS1-antigen test. Thick and thin blood films revealed the presence of P ovale (parasite density, <0.01%) but no other malaria parasites were detected. The immunochromatographic test (ICT, Binax NOW; Binax, Inc., Scarborough, ME, USA) was negative for P falciparum-specific histidine-rich protein-2 (HRP-2) and the pan-malarial aldolase antigen. Because of the diagnosis of ovale malaria, the patient was treated with chloroquine (25 mg/kg body weight).
Two days later, the patient's condition had improved. Blood films and ICT were negative. Apart from a WBC of 3.1 G/L, and a raised CRP (34.8 mg/L), all other laboratory parameters were normal. After excluding glucose-6-phospate-dehydrogenase deficiency he received a prescription for primaquine (30 mg/d for 14 days), which he started to take 9 days after initial presentation.
On the 12th day following initial examination, 9 days after completion of chloroquine treatment, and 3 days after starting primaquine treatment, the patient presented with a 3-day history of chills, sweating, malaise, headache, and loss of appetite, but no history of fever. Since he suspected side effects of primaquine, he had stopped taking it. Thick and thin blood films were now positive for P falciparum (parasite density, 0.2%). The ICT was positive for both, HRP-2 and aldolase. CRP was 89.7 mg/L and creatinine 110 µmol/L. All other laboratory tests were normal. The patient was hospitalized and treated with artemether–lumefantrine. He recovered quickly and was discharged after 3 days. Blood films on days 3 and 7 following treatment were negative.
Two blood samples were available for retrospective polymerase chain reaction (PCR) analysis,2–5 ie, one collected at the initial presentation and one from the second disease episode 12 days later. Species-specific PCR assays confirmed the presence of P ovale in the initial sample, but also revealed P falciparum-specific DNA. The second sample was negative for P ovale but positive for P falciparum. Comparing the P falciparum isolates from the initial and the second sample by typing the polymorphic msp1/2 genes indicated the persistence of one parasite clone over time and the presence of at least one other clone in the second sample. Lastly, typing for parasite alleles associated with P falciparum chloroquine resistance showed their presence (pfmdr 86Y-184Y-1246Y; pfcrt 76T) in both the initial and the subsequent isolate.
We describe a case of P falciparum malaria in a returned traveler from Nigeria, 9 days after completing chloroquine treatment for confirmed tertian malaria caused by P ovale. Mixed-species infections are a frequent phenomenon in malaria, but due to its shorter incubation period, P falciparum in most cases becomes manifest first. Also, rather P ovale tends to be missed in mixed infections because of its notoriously low parasite density.
In our re-presenting patient, the absence of fever, the history of a recently completed malaria therapy, the initial absence of P falciparum in microscopy, and the initially negative ICT could have led to missing the diagnosis of the potentially fatal falciparum malaria. Consecutive infections in the 3-week travel period, first with P ovale, then with P falciparum, are the most likely explanation for laboratory findings and clinical course of this case. Considering that the patient had annually traveled to Nigeria during the preceding 10 years, a late relapse from a previous P ovale infection coinciding with a newly acquired P falciparum infection could be an alternative possibility.
All microscopic examinations and laboratory tests were performed by highly experienced personnel. The ICT produces reliable results,6 and the combination of blood film microscopy and ICT is widely used in the diagnosis of malaria. At initial presentation of our patient, blood film microscopy and ICT failed to detect P falciparum, probably because of very low parasitemia and antigen concentration. The ICT failed to detect P ovale in the first blood sample as well, but the test is known for its low sensitivity for this parasite (approximately 60%).6 The PCR has a 50% higher sensitivity for detecting submicroscopic P falciparum infection,7 and higher detection rates for mixed-species infections.8 With higher parasitemia and concentration of antigen in the second sample, P falciparum was easily detectable by microscopy and ICT. In the second sample, one additional P falciparum clone was suggested by PCR to be present, probably due to the release of new parasites from the liver to the blood.
Another explanation for the late manifestation of P falciparum is the suppression of P falciparum by P ovale after simultaneous infection. In some reports, non-falciparum strains were described as dominating P falciparum in number and clinical manifestation in mixed-species infections in non-immune travelers,9 although most reports describe the opposite.10 Alternatively, preexisting P falciparum-specific immune responses could have led to a delayed onset of falciparum malaria, and antibodies to P falciparum were present at low titers determined by indirect immunofluorescence test (1 : 80; cutoff, 1 : 20) on the first day of presentation. However, it seems more likely that an initially low-level P falciparum infection during 12 days grew to the threshold of microscopic detection and clinical manifestation. Thereby, chloroquine treatment may have temporarily suppressed multiplication without eliminating the parasite, in line with its chloroquine-resistance genotype. Primaquine treatment started simultaneously with the (presumed) onset of falciparum malaria and thus could not exert its preerythrocytic activity. On the blood stages of P falciparum, primaquine has hardly any effect.11
Diagnosing malaria is and will remain a challenge despite technical progress. Microscopy and ICT need a certain parasite density and antigen concentration, respectively. PCR can detect cryptic mixed infections including P falciparum earlier but is inapplicable for the first-line routine diagnostic procedure. From the clinical perspective, infections with P falciparum are much more frequent than those with P ovale.1 Therefore, a single infection with P ovale is rather unlikely in a traveler and needs to attract the clinician's attention when there are signs of a possible recrudescence. The individual presenting with malaria was obviously at risk of infection with all Plasmodium species prevalent at the travel destination. Thus, recrudescent malaria in travelers may be falciparum malaria despite initial diagnosis of malaria by a Plasmodium species with a normally longer incubation period.
In conclusion, this case stresses the need for pre-travel counseling and effective antimalarial chemoprophylaxis, but especially the importance of both physicians and patients being aware of the variable clinical courses of malaria. Expert blood film microscopy remains the mainstay in the diagnosis of malaria but molecular tools may provide important additional information. Importantly, this case emphasizes the necessity of routine checkups of parasitemia following treatment and whenever indicated by the clinical course.
We thank S. Zander for excellent technical assistance.
Declaration of Interests
The authors state that they have no conflicts of interest to declare.