ABSTRACT.
Malaria in child travelers caused by Plasmodium ovale spp. is less well characterized than malaria due to other Plasmodium species. Commonly used diagnostic tests often lack adequate sensitivity to identify P. ovale spp., and a missed diagnosis may have serious consequences. We present a case series of eight children in the United States with P. ovale malaria, all of whom had traveled to or immigrated from malaria-endemic areas. Two children developed clinical malaria, including one with severe malaria; two had isolated splenomegaly; and four were asymptomatic siblings of the children with splenomegaly. Seven of the eight children had negative blood smear readings, and the diagnosis was made by polymerase chain reaction testing. Two children had concurrent P. malariae infection despite presumptive antimalarial treatment before immigration. These findings suggest a need for reconsideration of screening and diagnostic evaluation for P. ovale malaria in high-risk groups.
INTRODUCTION
Through the efforts overseen by the Office of Malaria Control in War Areas in the 1940s, the United States was declared free of malaria in 1949, and nearly all cases today occur in the context of travel or immigration.1 Given the life-threatening nature of malaria, particularly Plasmodium falciparum, the disease remains an important consideration for clinicians in the United States. Malaria is a leading cause of fever in the returning traveler and requires prompt diagnosis and treatment to prevent morbidity and mortality.2 Recent reports of local transmission of malaria in the United States are concerning,3 and it is important for clinicians to understand when to consider malaria as a diagnosis and which diagnostic tests to perform, including for non-falciparum species.
Plasmodium ovale spp. are a less common but important cause of malaria. Plasmodium ovale malaria is caused by two distinct but related species of human malaria, P. ovale curtisi and P. ovale wallikeri.4 These species cause similar disease phenotypes and cannot be distinguished morphologically.4 Increased utilization of polymerase chain reaction (PCR) has highlighted the growing significance of P. ovale malaria in travelers, particularly from West Africa, and to a lesser extent East Africa and Southeast Asia.5,6 Commercially available PCR tests do not routinely distinguish between the two species of P. ovale malaria. Historically, P. ovale malaria has been relegated to the “benign” malarias, but severe disease, and in rare cases death, have been reported.6 Plasmodium ovale spp. have a lower pyrogenic threshold than P. falciparum and cause disease at lower parasitemia,7 leading to a potential missed diagnosis when microscopy alone is used.8,9 Additionally, P. ovale spp. have a dormant liver stage, and clinical manifestations may be delayed for years after the initial infection.10,11 An improved understanding of P. ovale malaria in travelers and of diagnostic pitfalls is important to ensure timely treatment of this infection. We present a case series of eight child travelers or immigrants to the United States with P. ovale spp. infection, including one child with severe malaria, in whom the diagnosis was aided by PCR. We also provide a literature review on severe P. ovale malaria cases.
MATERIALS AND METHODS
We used ICD-10 diagnosis codes to identify children less than 18 years old treated for P. ovale malaria from 2018 to 2023 at Indiana University Health medical facilities. Electronic medical records were reviewed to confirm the diagnosis of malaria and document the clinical presentation, treatment, and outcomes of affected individuals. The study was conducted under an institutional review board–exempt status through Indiana University Health. Published indexed articles found in PubMed and Google Scholar searches using the terms Plasmodium ovale, acute respiratory distress syndrome (ARDS), and severe Plasmodium ovale through April 2024 were reviewed to identify cases of severe P. ovale spp. infection.
CASE SERIES
Patient 1.
A 15-year-old female with sickle cell disease (SCD) developed fever and abdominal pain 17 days after returning from a 5-week trip to Nigeria. She was admitted for antibiotic therapy and discharged after 48 hours of negative blood culture results. She was readmitted within 24 hours with return of fever and worsening abdominal pain. She had not been on malaria chemoprophylaxis in Nigeria, and malaria evaluation was not pursued until she developed hypotensive shock and respiratory failure with ARDS and bilateral pleural effusions. Two blood smears on consecutive days were interpreted as negative for malaria, and alternative infectious etiologies were considered. On day 4 of the second hospitalization, a malaria PCR test resulted positive for P. ovale spp. Her prior smears were reassessed, and P. ovale spp. were identified at <0.01% parasitemia. However, P. ovale malaria was not initially suspected to be the primary cause of her critical illness. Artemether-lumefantrine was initiated rather than intravenous artesunate, the treatment of choice for severe malaria, while alternative etiologies were pursued.
Her fever resolved on the second day of antimalarial therapy. An extensive evaluation failed to identify another source of her illness. She had a positive chikungunya IgM (an unlikely etiology based on her symptom complex and onset >14 days after return from travel), Coccidioides IgM (suspected false positive), and enteropathogenic Escherichia coli on a stool multiplex nucleic acid test. Next-generation sequencing of serum for parasites, bacteria, fungi, and viruses through the U.S. CDC was only positive for P. ovale spp. It was subsequently discovered that her father had given her a dose of chloroquine between hospitalizations, which may have contributed to the low parasitemia. By this time, she had demonstrated improvement on artemether-lumefantrine and completed a 7-day course with full recovery. She was intubated for a total of 8 days. She had a normal glucose-6 phosphate dehydrogenase (G6PD) activity level and received 14 days of primaquine.
Patient 2.
A 9-year-old female developed fever, chills, myalgias, headache, and vomiting 19 days after returning from a 10-month trip to Liberia. She had been on mefloquine prophylaxis until the final few weeks of her trip before returning to the United States. She was started on amoxicillin on day 2 of her fever without a specific diagnosis. On day 6 of symptoms, a blood smear was obtained in the ambulatory setting. She was evaluated in the infectious diseases clinic 4 days later when her outside blood smear was reported positive for malaria (species and percent parasitemia were not documented). A repeat blood smear was negative, but malaria PCR was positive for P. ovale spp., and she was treated with atovaquone-proguanil followed by primaquine (normal G6PD levels) with resolution of symptoms.
Patients 3 through 8.
A family of children born in Uganda to Congolese refugee parents received presumptive malaria treatment with artemether-lumefantrine before resettlement in the United States.12 Each of them had negative blood smears before treatment. Two of the children, patients 4 and 6, had isolated splenomegaly on their initial exam in the United States, but this resolved in patient 6 on repeat assessment. Patient 4 had a negative repeat malaria smear 4 months after immigration but a positive smear for P. ovale spp. at 0.04% parasitemia the following month. Social factors prevented follow-up and treatment for 3 months during which time no new symptoms developed. Malaria PCR after this time was positive for P. malariae and negative for P. ovale spp., and the blood smear was negative. His positive test led to the screening of his siblings for malaria with blood smears and PCR testing. Blood smears were negative in all siblings, but four had P. ovale spp., and one had P. ovale spp. and P. malariae on blood PCR. The PCR-positive children were treated with hydroxychloroquine followed by primaquine (G6PD levels normal in all patients). The siblings with negative PCR results were empirically treated with primaquine. Table 1 summarizes the clinical presentation of the 8 children with malaria.
Table 1.
Clinical features of eight children with Plasmodium ovale malaria
| Patient | Age | Sex | Country of Exposure | Clinical Presentation | Medical History | Malaria Diagnostics | Treatment | Outcome |
|---|---|---|---|---|---|---|---|---|
| 1 | 15 | F | Nigeria | Fever, abdominal pain, ARDS, hypotensive shock | SCD | Blood smears—initially negative, <0.01% on repeat assessment PCR—P. ovale spp. NGS—P. ovale spp. |
Artemether-lumefantrine Primaquine |
Recovered |
| 2 | 9 | F | Liberia | Fever, headache, vomiting, myalgias | Healthy | Blood smear—initial positive, repeat negative before treatment PCR—P. ovale spp. |
Atovaquone-proguanil Primaquine |
Recovered |
| 3 | 4 | M | Uganda | Asymptomatic | Healthy | Blood smear—negative PCR—P. ovale spp., P. malariae |
Hydroxychloroquine Primaquine |
Remained asymptomatic |
| 4 | 6 | M | Uganda | Splenomegaly | Healthy | Blood smear—P. ovale spp.* PCR—P. malariae |
Hydroxychloroquine Primaquine |
Unknown outcome of splenomegaly |
| 5 | 9 | M | Uganda | Asymptomatic | Healthy | Blood smear—negative PCR—P. ovale spp. |
Hydroxychloroquine Primaquine |
Remained asymptomatic |
| 6 | 11 | M | Uganda | Splenomegaly† | Healthy | Blood smear—negative PCR—P. ovale spp. |
Hydroxychloroquine Primaquine |
Remained asymptomatic |
| 7 | 16 | M | Uganda | Asymptomatic | Healthy | Blood smear—negative PCR—P. ovale spp. |
Hydroxychloroquine Primaquine |
Remained asymptomatic |
| 8 | 17 | F | Uganda | Asymptomatic | Healthy | Blood smear—negative PCR—P. ovale spp. |
Hydroxychloroquine Primaquine |
Remained asymptomatic |
ARDS = acute respiratory distress syndrome; NGS = next-generation sequencing; PCR = polymerase chain reaction; SCD = sickle cell disease.
Patient 4 had a positive blood smear that was reported as either P. vivax or P. ovale spp. at 0.04% parasitemia; P. ovale spp. is most likely considering the other siblings also had P. ovale spp. and P. vivax is less prevalent in sub-Saharan Africa. Three months later, and before treatment, malaria PCR was positive only for P. malariae.
Splenomegaly had resolved before the diagnosis of malaria.
DISCUSSION
Plasmodium malaria has a lower pyrogenic threshold than P. falciparum, resulting in symptoms at lower parasitemia, and commonly used diagnostic tests, including blood smears and rapid diagnostic tests, have inadequate sensitivity to detect all infections.6,13,14 Multiple blood smears are recommended to improve sensitivity,12 but this may be insufficient with low parasitemia. When P. ovale malaria is a potential cause of fever in a child, malaria smears may require more extensive evaluation (e.g., counting through fields with a minimum of 500 white blood cell count) to detect the low-level parasitemia that often occurs with P. ovale spp. The sensitivity of rapid diagnostic tests for non-falciparum species is also low (61%, range 0–100%), especially for P. ovale spp.15 Molecular techniques are 10–100 times more sensitive than microscopy, depending on the method used.16
The present case series highlights the role of PCR in the diagnosis of P. ovale malaria and demonstrates the potential severity of this infection.2,13,15,17,18 In adults with severe P. falciparum malaria, ARDS is well described and may occur after treatment initiation and parasite clearance,19–22 but ARDS is uncommon in pediatric malaria. Respiratory distress in children with severe malaria is typically a manifestation of metabolic acidosis.23 In adults, ARDS has been described in severe P. vivax24 and rarely P. ovale malaria,8,21,25–30 but no prior case of ARDS in children with P. ovale malaria has been reported. ARDS is a defining criterion for severe malaria31 and carries a high mortality rate.21,22,32,33 Antimalarial treatment may precipitate an inflammatory response that worsens alveolar-capillary injury and gas exchange, resulting in noncardiogenic pulmonary edema.22 Pulmonary vascular sequestration may contribute to respiratory manifestations in P. falciparum,21,33 and, to a lesser extent, in P. vivax,18,34 although this has not been demonstrated with P. ovale spp.
Risk factors for severe P. ovale malaria include extremes of age, nonimmune status, immunocompromising conditions, and pregnancy.33 Sickle cell trait appears to increase the susceptibility to disease from P. ovale spp.,14 and one study observed a higher than expected prevalence of SCD in imported cases of P. ovale malaria.35 One case of severe P. ovale malaria in a child with SCD has previously been documented.36 Table 2 summarizes reported cases of severe P. ovale malaria. When respiratory status worsened after starting antimalarials, patients were treated with chloroquine or quinine, with some improving after starting artesunate.25,27
Table 2.
Literature review of reported cases of severe P. ovale malaria
| Age | Sex | Country of Residence/Country of Travel | Parasitemia | Initial Therapy | Therapy Change | Complications |
|---|---|---|---|---|---|---|
| 3725 | M | Italy/Angola | 0.1%* | Chloroquine, primaquine | Artesunate, doxycycline† | ARDS 2 days after starting therapy |
| 3126 | M | Morocco/DRC | <0.2% | Quinine | – | ARDS after treatment, died |
| 5927 | M | Malaysia/Nigeria‡ | 0.18%* | Chloroquine, primaquine | Quinine followed by artesunate† | ARDS 4 days after starting therapy; acute renal failure, nosocomial sepsis; died on day 23 of hospital admission |
| 4328 | M | Spain/Nigeria | 6,000/µL | Chloroquine | –† | AKI followed by ARDS on day 2 after therapy |
| 468 | F | Beirut (transfusion) | 1.11%§ | Quinine, doxycycline | –† | ARDS on day 2 after starting therapy |
| 4621 | F | USA/Uganda‡ | 0.5% | Quinine, doxycycline | Quinidine, doxycycline‖ | ARDS requiring ECMO 4 days after starting therapy |
| 5629 | M | France/Liberia or Côte d’Ivoire, and Senegal | 0.19%¶ | Quinine | Artesunate† | ARDS 2 days after starting therapy |
| 6430# | M | Italy/South Korea and Guinea | 0.001%¶ | Chloroquine | –† | ARDS 1 day after starting therapy; splenic infarct |
| 2437 | M | France/Chad, Côte d’Ivoire‡ | 0.2% | Chloroquine | Quinine† | ARDS 3 days after starting therapy |
| 3138 | F | USA/Ghana‡ | 0.10% | Chloroquine | –† | Respiratory distress 1.5 days after starting therapy |
| 5139 | F | UK/Ghana | 1.8% | None | – | Splenic rupture; died |
| 4240 (reviewed in18) | M | –/South and Central Africa | – | Chloroquine | –† | Splenic rupture |
| 4241 | NS | Spain/Central Africa‡ | 0.01% | Artemether-lumefantrine | – | Splenic rupture |
| 2942 | M | UK/DRC | – | Chloroquine | – | Splenic rupture |
| 3443 | M | France/Côte d’Ivoire‡ | 2% | Chloroquine | – | Splenic rupture |
| 3944 | F | USA/Botswana, Zimbabwe, and South Africa‡ | – | Quinine, doxycycline | Quinidine | Cardiac arrest on day 3 of admission with splenic rupture, severe anemia; died |
| 3445 | M | France/Senegal and Côte d’Ivoire | 0.001% | Quinine | – | Splenic infarct |
| 38 (reviewed in46) | M | –/Niger‡ | – | Chloroquine | – | Cardiomyopathy |
| 2047 (reviewed in46) | –/Western Africa and Cameroon‡ | – | Mepacrine | – | Cardiac arrhythmia | |
| 2347 (reviewed in46) | –/Western Africa and Cameroon‡ | – | Mepacrine | – | Severe anemia | |
| 3135,46** | M | – | –†† | – | – | Severe anemia |
| –35** | – | – | – | – | – | Severe anemia |
| 7548 | M | India/India | – | Artesunate | – | Hypotension, jaundice |
| 5227 | M | Malaysia/Nigeria*‡ | 0.10% | Artemether-lumefantrine, primaquine | – | Jaundice |
| 4218 | M | South Africa/Guinea and Mozambique | 1.4% | Quinine, doxycycline | –† | Hypotension, jaundice, AKI |
| 2349 | M | –/Nigeria | 0.2% | Quinine, doxycycline† | – | Jaundice |
| 2850 | M | –/Nigeria, Ghana, Gambia, and Sierra Leone‡ | – | Mepacrine, quinine | – | Hemoglobinuria, Jaundice |
| 589 | F | Spain/Angola | 6,000/µL¶‡‡ | Dihydroartemisinin/piperaquine | –† | HLH |
| 1735,46** | F | – | –†† | – | – | Severe anemia |
| 536§§ | M | USA/Nigeria | 0.9% | Quinidine, doxycycline | – | Hypotension, autoimmune hemolytic anemia, high-output cardiac failure |
| 5 weeks51 | F | Mother from Nigeria; birthed in Italy | 0.01% | Quinine | – | Congenital infection; severe anemia |
| 21 days52 | M | Mother from East Africa; birthed in UK‡ | – | Proguanil | Chloroquine | Congenital infection; severe anemia |
| 5 weeks11 | F | Mother from Nigeria; birthed in Canada | 0.1% | Artesunate | Quinine, clindamycin | Congenital infection; severe anemia, possible seizures |
= data not available; AKI = acute kidney injury; ARDS = acute respiratory distress syndrome; DRC = Democratic Republic of Congo; ECMO = extracorporeal membrane oxygenation; HLH = hemophagocytic lymphohistiocytosis.
Plasmodium ovale curtisi.
Documented receipt of primaquine during or after therapy.
On malaria chemoprophylaxis.
Initial smear negative; a repeat smear on readmission 2 days later was positive.
Changed to intravenous quinidine and clindamycin due to per oral intolerance; transitioned to chloroquine after Plasmodium ovale and Plasmodium vivax coinfection diagnosis and then intravenous again after development of ARDS.
Plasmodium ovale wallikeri.
In the original published report, the age is listed incorrectly as 4 years old. The correct age is 64 years old (personal communication with the author).
The report by Rojo-Marcos et al. mentions three cases of severe anemia (two of which were associated with sickle cell disease); patient-specific details are not provided in the article otherwise for these patients. The report by Groger et al. includes unpublished information on two of these patients obtained directly from the author of the primary report.
Microscopy negative, polymerase chain reaction positive.
Initial smear negative; a repeat smear 7 days after initial evaluation was positive.
Comorbid sickle cell disease.
Since 1999, the CDC has recommended routine presumptive antimalarial therapy for all U.S.-bound refugees from sub-Saharan Africa (SSA),12 and artemisinin combination treatments (ACT) are preferred. The guidelines focus on the control of P. falciparum malaria, and the success of this intervention has been well documented.53 Testing for non-falciparum species, especially P. vivax and P. ovale spp, in asymptomatic individuals is not currently recommended for most travelers, with the acknowledgment that current diagnostic tests, including blood smears, RDTs, and even PCR, are inadequately sensitive to detect all asymptomatic infections.12
An exception to this recommendation is in Congolese refugees with splenomegaly, in whom primaquine is recommended if G6PD activity levels are normal, regardless of malaria test results.12,54 Patients 3 through 8 were Congolese refugees living in Uganda. A potential lack of awareness of the recommendations for empiric primaquine therapy for splenomegaly in this population was demonstrated in patients 4 and 6.54 Additionally, missed malarial diagnoses may be common, as was seen in the other siblings. A positive blood smear in patient 4 with splenomegaly led to the testing and treatment of his siblings. If this low parasitemia had not been detected (he had negative smears 1 month earlier and 3 months later before treatment), an opportunity to identify and treat malaria in the family members would have been missed. With concerns for increasing prevalence of P. ovale malaria in SSA,55 it may be important to consider a PCR-based screening approach to detect malaria parasitemia in febrile children or asymptomatic immigrants and refugees who have traveled to or lived in areas in which P. ovale spp. are endemic.
The finding of P. malariae in patients 3 and 4 is important. Plasmodium malariae does not have a hepatic hypnozoite stage like P. ovale malaria but may cause chronic infection.56 Presumptive therapy with ACT may be insufficient to eradicate P. malariae, and recurrence after treatment has been described.57,58 Plasmodium malariae has a longer intraerythrocytic cycle than other species of malaria that infect humans, and it has been postulated that this may allow it to survive the three-day course of ACT,58 despite the longer half-life of the non-artemisinin combination drug. Further investigation into the mechanisms of persistence after artemisinin-based combination treatment of P. malariae is needed to assist in elimination efforts and decrease the risk of recrudescence.
In conclusion, P. ovale malaria is a challenging diagnosis because of low parasitemia and insensitivity of RDTs15,59,60 but should be considered in febrile travelers returning from endemic areas, particularly West Africa.5,6 Multiple studies have highlighted increased prevalence of P. ovale spp. when tested by PCR compared with microscopy,14,38,55,61 and this case series supports the need for more sensitive diagnostic tools for detection in symptomatic, asymptomatic, or subclinical infections to prevent morbidity and aid in malaria elimination. Increased awareness of non-falciparum species locally, including P. ovale spp, is necessary to avoid missed diagnoses, prevent development of severe illness, and avoid local transmission.62
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