Clinical relevance of low-densityPlasmodium falciparumparasitemia in untreated febrile children: A cohort study

Background Low-density (LD)Plasmodiuminfections are missed by standard malaria rapid diagnostic tests (standard mRDT) when the blood antigen concentration is below the detection threshold. The clinical impact of these LD infections is unknown. This study investigates the clinical presentation and outcome of untreated febrile children with LD infections attending primary care facilities in a moderately endemic area of Tanzania. Methods/findings This cohort study includes 2,801 febrile pediatric outpatients (median age 13.5 months [range 2-59], female:male ratio 0.8:1.0) recruited in Dar es Salaam, Tanzania between 01 December 2014 and 28 February 2016. Treatment decisions were guided by a clinical decision support algorithm run on a mobile app, which also collected clinical data. Only standard mRDT+ cases received antimalarials. Outcomes (clinical failure, secondary hospitalization, and death) were collected in follow-up visits or interviews on days 3, 7, and 28. After patient recruitment had ended, frozen blood from all 2,801 patients was tested forPlasmodium falciparum(Pf) by ultrasensitive-quantitative polymerase chain reaction (qPCR), standard mRDT, and "ultrasensitive" mRDT. As the latter did not improve sensitivity beyond standard mRDT, it is hereafter excluded. Clinical features and outcomes in LD patients (standard mRDT-/ultrasensitive-qPCR+, not given antimalarials) were compared with those with no detectable (ND) parasitemia (standard mRDT-/ultrasensitive-qPCR-) or high-density (HD) infections (standard mRDT+/ultrasensitive-qPCR+, antimalarial-treated). Pfpositivity rate was 7.1% (n= 199/2,801) and 9.8% (n= 274/2,801) by standard mRDT and ultrasensitive qPCR, respectively. Thus, 28.0% (n = 76/274) of ultrasensitive qPCR+ cases were not detected by standard mRDT and labeled "LD". LD patients were, on average, 10.6 months younger than those with HD infections (95% CI 7.0-14.3 months,p< 0.001). Compared with ND, LD patients more frequently had the diagnosis of undifferentiated fever of presumed viral origin (risk ratio [RR] = 2.0, 95% CI 1.3-3.1,p= 0.003) and were more often suffering from severe malnutrition (RR = 3.2, 95% CI 1.1-7.5,p= 0.03). Despite not receiving antimalarials, outcomes for the LD group did not differ from ND regarding clinical failures (2.6% [n= 2/76] versus 4.0% [n= 101/2,527], RR = 0.7, 95% CI 0.2-3.5,p= 0.7) or secondary hospitalizations (2.6% [n= 2/76] versus 2.8% [n= 72/2,527], RR = 0.7,95% CI 0.2-3.2,p= 0.9), and no deaths were reported in anyPf-positive groups. HD patients experienced more secondary hospitalizations (10.1% [n= 20/198], RR = 0.3, 95% CI 0.1-1.0,p= 0.005) than LD patients. All the patients in this cohort were febrile children; thus, the association between parasitemia and fever cannot be investigated, nor can the conclusions be extrapolated to neonates and adults. Conclusions During a 28-day follow-up period, we did not find evidence of a difference in negative outcomes between febrile children with untreated LDPfparasitemia and those withoutPfparasitemia. These findings suggest LD parasitemia may either be a self-resolving fever or an incidental finding in children with other infections, including those of viral origin. These findings do not support a clinical benefit nor additional risk (e.g. because of missed bacterial infections) to using ultrasensitive malaria diagnostics at a primary care level. Author summaryWhy was this study done? Every infection has a symptomatic threshold, above which the magnitude of infection burden triggers fever and other clinical symptoms that distinguishes ill individuals from those who remain asymptomatic. In malaria, this is called the "pyrogenic (fever) threshold." The standard malaria rapid diagnostic tests (sd-mRDTs), which have been in use for decades, can detect parasite loads of up to 10-fold below this threshold. New ultrasensitive malaria tests are now able to detect genetic traces of parasites that go 1,000-fold further. However, the clinical relevance of these minute levels of parasitemia is unknown. Does it detect a previously unappreciated cause of clinical failure? Or does it risk reporting a clinically irrelevant signal that may distract the clinician from other causes of fever? What did the researchers do and find? We assessed the clinical consequences of untreated low-density (LD) parasitemia that is only detectable with the ultrasensitive malaria test. In a cohort of 2,801 pediatric outpatients in Tanzania, we observed that of all patients in whom parasites were detected using ultrasensitive tests, over a quarter were not detected by standard mRDTs. However, despite not receiving antimalarials, patients with LD parasitemia did not differ from those without any detectable parasites regarding clinical outcomes during a 28-day follow-up. What do these findings mean? These findings suggest LD parasitemia may either be a self-resolving fever or an incidental finding in children with other infections. These findings neither support a specific utility nor risk (other than the obvious wasted resources) to using ultrasensitive malaria diagnostics at a primary care level.