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Laboratório de Doenças Febris Agudas, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, CEP 21.040-900, Manguinhos, Rio de Janeiro, RJ, BrazilCentro de Pesquisa, Diagnóstico e Treinamento em Malária, FIOCRUZ, Rio de Janeiro, RJ, Brazil
Laboratório de Doenças Febris Agudas, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, CEP 21.040-900, Manguinhos, Rio de Janeiro, RJ, Brazil
Centro de Pesquisa, Diagnóstico e Treinamento em Malária, FIOCRUZ, Rio de Janeiro, RJ, BrazilLaboratório de Parasitologia, Instituto Nacional de Infectologia Evandro Chagas, Rio de Janeiro, RJ, Brazil
Centro de Pesquisa, Diagnóstico e Treinamento em Malária, FIOCRUZ, Rio de Janeiro, RJ, BrazilLaboratório de Parasitologia, Instituto Nacional de Infectologia Evandro Chagas, Rio de Janeiro, RJ, Brazil
Centro de Pesquisa, Diagnóstico e Treinamento em Malária, FIOCRUZ, Rio de Janeiro, RJ, BrazilLaboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, FIOCRUZ, Pavilhão Leônidas Deane, RJ, Brazil
Centro de Pesquisa, Diagnóstico e Treinamento em Malária, FIOCRUZ, Rio de Janeiro, RJ, BrazilLaboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, FIOCRUZ, Pavilhão Leônidas Deane, RJ, Brazil
Centro de Pesquisa, Diagnóstico e Treinamento em Malária, FIOCRUZ, Rio de Janeiro, RJ, BrazilLaboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, FIOCRUZ, Pavilhão Leônidas Deane, RJ, Brazil
Laboratório de Doenças Febris Agudas, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, CEP 21.040-900, Manguinhos, Rio de Janeiro, RJ, BrazilCentro de Pesquisa, Diagnóstico e Treinamento em Malária, FIOCRUZ, Rio de Janeiro, RJ, Brazil
This is the first case report of concurrent dengue and Plasmodium ovale infections.
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Dengue fever (DF) seems to be able to trigger an ovale malaria relapse or a patent ovale malaria.
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DF, as a co-morbidity for malaria, could impact the fluid electrolyte management.
Summary
Objectives
To report that dengue fever (DF) could have triggered Plasmodium ovale wallikeri malaria.
Methods
A retrospective case report of P. ovale malaria and DF in a single patient in Rio de Janeiro, Brazil, who had lived in Angola, is presented.
Results
On the second week of illness, the patient was referred to our research service. As symptoms had persisted up to day 14, malaria was also considered, based on the patient's long-standing epidemiological history. On day 16 of illness, a thick blood smear was positive for P. ovale (3480 parasites/mm3), PCR for malaria was positive for P. ovale wallikeri, and the kinetics of dengue virus (DENV) antibodies suggested a recent primary dengue infection.
Conclusions
Concurrent infections of DENV and malaria have rarely been reported; the actual impact of these sequential or simultaneous infections remains unknown. Therefore, DF must be considered as a potential co-morbidity for malaria, because of its influence on fluid electrolyte management. The case presented showed consistent temporal, clinical, and laboratory evidence that the relapse or the long incubation period of P. ovale malaria may have been triggered by a recent DF episode. To the authors’ knowledge, this is the first report of DENV and P. ovale co-infection.
Concurrent infections of dengue virus (DENV) and Plasmodium vivax or Plasmodium falciparum have rarely been reported. Thus, despite a wide geographical overlap of the two diseases in endemic areas, the actual impact of these sequential or co-infections is unknown. In fact, there are only a few reports of the simultaneous observation of dengue and malaria.
To the authors’ knowledge, this is the first report of DENV and Plasmodium ovale co-infection.
The incidence of P. ovale malaria is low. Since its description in 1922, P. ovale malaria has typically remained restricted to tropical Africa and a few islands in Southeast Asia and the Middle East.
The real burden of P. ovale malaria is probably underestimated. Recent studies using molecular techniques have reported a prevalence of 15% in rural zones of Nigeria and Papua New Guinea and of 9.3% in children under 6 years of age in Equatorial Guinea.
In a recent Spanish report, P. ovale was diagnosed in approximately 7% of imported malaria cases, representing the second most frequently found species after P. falciparum, probably reflecting immigration from West Africa.
P. ovale malaria, usually clinically benign compared with malaria arising from other common species, has been well-studied because of its traditional use in the malaria therapy of neurosyphilis.
The existence of two species (or subspecies) of P. ovale occurring sympatrically in Asia and Africa – P. ovale curtisi and P. ovale wallikeri – is correlated with different patterns of relapse.
The prepatent period usually ranges from 12 to 20 days, with a median of 14.4 days. There are descriptions of incubation periods as long as 4 years, with maximum parasite counts registered around the ninth day of disease. The restriction of P. ovale to young erythrocytes could explain the low parasitemia usually found in infections (approximately 6000 parasites/μl). Relapses of P. ovale are less common than for P. vivax, with an estimated risk of 1:200, and relapses can arise as early as 17 days or as late as 4 years after effective therapy.
In Brazil, a total of 39 cases of P. ovale malaria have been recorded, showing a gradually increasing trend in recent years as a result of the migration of travelers from P. ovale-endemic regions.
The low prevalence of this parasite, combined with its morphological similarity to P. vivax and the low sensitivity of currently available rapid diagnostic tests, could increase the rates of P. ovale misdiagnosis.
Dengue is a mosquito-borne infection caused by four serotypes of the dengue Flavivirus (DENV1–DENV4) and is the most common arboviral disease worldwide.
Since the 1980s, dengue has become a major public health issue in Brazil, where all four serotypes have been isolated. Seven percent of dengue cases worldwide are reported from Brazil. In 2013, 921 716 dengue cases were registered by the Brazilian health surveillance system.
The incubation period ranges from 3 to 10 days, 30–50% of infections are asymptomatic, and 10% of cases may have a poor prognosis, with a 1–3% mortality rate even in the presence of ideal assistance care services.
Even in overlapping regions, little is known about the reciprocal influence of malaria and dengue. A case of dengue in a patient from the city of Rio de Janeiro, Brazil, 2 years after leaving Luanda, Angola, is reported here. As there is no autochthonous P. ovale malaria in the Americas, the authors raise the possibility that dengue could have triggered a P. ovale malaria relapse or the expression of a latent infection not yet manifested.
2. Methods
The study was performed at the Laboratório de Doenças Febris Agudas at the Instituto Nacional de Infectologia Evandro Chagas (INI-FIOCRUZ), a regional dengue center that integrates the Center for Malaria Research and Training (CPD-Mal) of FIOCRUZ, Rio de Janeiro, Brazil. CPD-Mal covered 25% to 30% of attendant care of all confirmed malaria cases registered in the state of Rio de Janeiro from 2005 to 2014 (unpublished data). During the period December 2010 to June 2014, 24 patients were diagnosed with dengue and malaria co-infection (unpublished data). All of these patients had a history of recent travel to a malaria endemic area. The patients had never used chemoprophylaxis for malaria and all had been immunized for yellow fever.
The diagnosis of malaria cases at CPD-Mal is usually made on the basis of direct microscopic identification of the hematozoa on thick and thin blood smears stained with Giemsa, rapid diagnostic tests (RDT), and a single conventional PCR for Plasmodium
Standardization of a very specific and sensitive single PCR for detection of Plasmodium vivax in low parasitized individuals and its usefulness for screening blood donors.
Malaria diagnosis: standardization of a polymerase chain reaction for the detection of Plasmodium falciparum parasites in individuals with low-grade parasitemia.
In the case of P. ovale diagnosis, a first reaction with the genus-specific primer set rPLU1–rPLU5 is used, followed by the second reaction using two pairs of primers: rOVA1–rOVA2 for P. ovale curtisi amplification
At CPD-Mal, a dengue diagnosis is considered routinely in the protocol for the investigation of fever, as well as in suspected cases of malaria, and dengue is screened for in serum samples obtained at admission. A dengue diagnosis is confirmed by standard serological tests, IgM-Panbio in paired samples, conventional PCR, and NS1 antigen test (NS-1 Ag) within the first 5 days of symptom onset. In the case presented here, the IgG-CDC titled assay was also performed to confirm the recent dengue infection,
since the patient was referred to our service only after day 14 of fever. The previous samples collected in the basic health service units were not recovered, because during the epidemic season, the storage period is limited to 1 week, with the exception of samples from critical patients and those who have died.
3. Case report
In April 2013, a 52-year-old man was referred to CPD-Mal, FIOCRUZ, with a history of chills, fever, headache, arthralgia, myalgia, choluria, discrete jaundice, anorexia, diffuse abdominal pain, nausea, and one episode of vomiting. The illness had begun 16 days before, and the patient had already received medical care at a basic health unit, where he had been monitored every 2 days in accordance with the Brazilian protocol as a suspected dengue patient. IgM ELISA confirmed the infection on day 7 of disease, and laboratory examinations revealed leukopenia and thrombocytopenia. The patient had no criteria for severe dengue disease during the first week. He received supportive treatment, but as his fever persisted at day 14, his epidemiological history of travel was reviewed. Malaria was considered, as well the possibility of hepatitis, typhoid fever, and unusual forms of dengue, after confirmation of a long stay in Luanda, Angola.
The patient had high blood pressure and reported previous episodes of P. falciparum malaria in 2009 and 2011 in Angola, both treated successfully with only therapeutic schemes effective for P. falciparum malaria, without the use of primaquine. Epidemiologically important facts were his residence in Angola between 2007 and 2011, with short visits to a non-endemic malarial area in Brazil every 3 months. In December 2011, he moved back to Brazil and did not return to Angola or visit another malaria endemic area.
On admission to the outpatient service of FIOCRUZ on day 16 of disease, the patient presented moderate anemia, fever, mild jaundice, and dehydration, without signs of circulatory collapse. There was no tachycardia, no respiratory distress, and no coagulation disturbance. A thick blood smear was positive for P. ovale and the parasitemia was 3480 parasites/mm3, with the presence of gametocytes, schizonts, and trophozoites (Figure 1). The PCR for malaria was positive for Plasmodium and negative for P. vivax, P. falciparum, and P. malariae. An RDT was negative. In view of these results, a blood sample was submitted to P. ovale PCR using primers specifically designed for the diagnosis of P. ovale curtisi
The patient had no glucose 6-phosphate enzyme deficiency. The results of a complete blood count were as follows: hemoglobin 10.0 g/dl, hematocrit 32.4%, platelets 145 ×109/l , and white blood cell count 8.98 ×109/l (with differential 0/0/0/1/15/53/21/10). Other values included alkaline phosphatase of 130.0 U/l, gamma-glutamyl transferase of 382.0 U/l, aspartate aminotransferase of 80.0 U/l, alanine aminotransferase of 36.0 U/l, C-reactive protein of 10.5 mg/dl, total bilirubin of 1.96 mg/dl, and creatinine of 1.67 mg/dl. Table 1, shows a summary of the most relevant laboratory results and clinical signs for the complete patient follow-up.
Table 1Clinical and laboratory data, according to the patient's follow-up
Hb, hemoglobin; Hct, hematocrit; WBC, white blood cell count; RDT, rapid diagnostic test; Ag, antigen; CDC, US Centers for Disease Control and Prevention; NP, not performed; NA, not available.
a Results that support the hypothesis of the study.
The serology for dengue panel was repeated on day 16, and the serum was reactive for IgM and IgG. NS-1 Ag and dengue PCR results were negative, as expected. This step was performed in order to differentiate between sequential and simultaneous infections. There was a significant dengue IgG-CDC titer increase (seroconversion), and dengue IgM-Panbio was still reactive on day 60 and negative on day 90 of follow-up, suggesting a recent primary dengue infection, although a previous DENV infection could not be ruled out completely (Table 1). Acute viral hepatitis and typhoid fever were ruled out by serological tests and cultures.
Malaria treatment was initiated immediately using chloroquine and primaquine (total cumulative dose 3.2 mg/kg), after which the patient became apyretic. The parasitemia decreased rapidly and became negative on day 3 of treatment. Follow-up was performed weekly until day 90, and the patient was considered cured, with complete clinical recovery after this period.
4. Discussion
This is the first report of concurrent or sequential dengue and ovale malaria. Considering that it would be difficult to discriminate a malaria relapse or a delayed incubation period from a new P. ovale infection in endemic regions and that there is no transmission of this species in the Americas, it was considered that this case deserved to be reported. Unfortunately, as a result of the lack of initial samples, the demonstration of recent DF had to be investigated with only the specific antibody kinetics. Nevertheless, the profile and chronology of the clinical presentation of the disease clearly points to the temporal precedence of dengue in relation to the P. ovale wallikeri malaria episode. This raises the possibility that the dengue may have triggered the emergence of a latent previous P. ovale infection or the relapse of a very old ovale malaria. The intense inflammatory reaction, classically recognized in symptomatic dengue and well-described in severe cases,
Detection of circulant tumor necrosis factor-alpha, soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever.
could have caused a stress response resulting in the re-emergence of P. ovale in the circulation.
Because malaria is classically recognized to be a disease caused by an agent endowed with important mitogenic and polyclonal B-lymphocyte activation (PBA) properties,
Malaria, a difficult diagnosis in a febrile patient with sub-microscopic parasitaemia and polyclonal lymphocyte activation outside the endemic region, in Brazil.
However, some evidence indicates that this was not the case in the present patient: (1) clinically, there were two clear disease patterns; (2) false-positive serological results related to the malaria-associated PBA usually present low titers and decrease early after treatment,
Malaria, a difficult diagnosis in a febrile patient with sub-microscopic parasitaemia and polyclonal lymphocyte activation outside the endemic region, in Brazil.
unlike the situation described here in which there were significant antibody dengue titers at up to day 90 of the disease; and (3) although the anti-DENV IgM test was negative on day 90, the specific IgG titers continued to rise after malaria treatment on day 16, despite parasite clearance (confirmed by negative PCR on day 19) and it was still high on day 90.
The outcome of the concurrence of a non-severe dengue with P. ovale malaria reported here was positive, possibly as a result of a co-infection of the DENV with a relatively benign Plasmodium. However, this outcome should not always be expected, as both diseases may present severe forms and co-infection could enhance their respective morbidities. This has already been reported in DENV and P. falciparum and in DENV and P. vivax co-infections.
Severe falciparum malaria with dengue coinfection complicated by rhabdomyolysis and acute kidney injury: an unusual case with myoglobinemia, myoglobinuria but normal serum creatine kinase.
Some authors have recently reported that usually benign forms of P. vivax malaria are becoming more severe in some regions of South America and Asia. Because dengue and malaria overlap in some of these regions,
Discriminating malaria from dengue fever in endemic areas: clinical and biological criteria, prognostic score and utility of the C-reactive protein: a retrospective matched-pair study in French Guiana.
the data presented here emphasize the need for the accurate recognition of dengue as a co-morbidity of malaria to avoid the false diagnosis of severe disease caused by a relatively benign Plasmodium such as P. vivax.
The clinical case presented here showed temporal, clinical, and laboratory evidence consistent with a relapse or a long incubation period of a P. ovale wallikeri malaria being triggered by a dengue episode. Clinicians must therefore keep this possibility in mind when facing cases with a clinical evolution similar to that described here. The results also highlight the importance of adequate training for malaria diagnosis, allowing the detection of imported cases caused by species of Plasmodium that are not prevalent in the country, such as P. ovale in Brazil.
Finally, this is the first description of P. ovale wallikeri in Angola. Further studies should be done using P. ovale-specific PCR to assess the prevalence of P. ovale curtisi and P. ovale wallikeri in endemic areas of Angola.
Acknowledgements
RMRN, MFFC, and CTDR are supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) through a Research Fellowship and by the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado de Rio de Janeiro (FAPERJ) as Cientistas do Nosso Estado. RMRN received financial support from FAPERJ (E-26/010.001558/2014). The present study received no specific financial support. We thank Dr Clarissa Menezes Maya Monteiro, IOC/FIOCRUZ, for the photographic records.
Ethics statement: Written consent was obtained from the patient under a research project approved by the Ethic Committees of IPEC/FIOCRUZ: “Detecção de formas não usuais de dengue a partir da vigilância de síndrome febris agudas”, CAAE 0026.0.009.000-07.
Conflict of interest: The authors have no competing interests to declare.
Author contributions: OL and FR liaised with the clinic regarding the management of the patient, collected the clinical information, and drafted the manuscript; SS and GMZ established the parasitological diagnosis of P. ovale malaria; AL performed the malaria molecular diagnosis; RMRN performed the antigenic research and the serological and molecular tests for the diagnosis of dengue; MFFC supervised the molecular malaria diagnosis and reviewed the manuscript; CTDR and PB discussed and reviewed the manuscript. All authors read and approved the final manuscript.
Standardization of a very specific and sensitive single PCR for detection of Plasmodium vivax in low parasitized individuals and its usefulness for screening blood donors.
Malaria diagnosis: standardization of a polymerase chain reaction for the detection of Plasmodium falciparum parasites in individuals with low-grade parasitemia.
Detection of circulant tumor necrosis factor-alpha, soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever.
Malaria, a difficult diagnosis in a febrile patient with sub-microscopic parasitaemia and polyclonal lymphocyte activation outside the endemic region, in Brazil.
Severe falciparum malaria with dengue coinfection complicated by rhabdomyolysis and acute kidney injury: an unusual case with myoglobinemia, myoglobinuria but normal serum creatine kinase.
Discriminating malaria from dengue fever in endemic areas: clinical and biological criteria, prognostic score and utility of the C-reactive protein: a retrospective matched-pair study in French Guiana.
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