Clinical relevance of low-density Plasmodium falciparum parasitemia in untreated febrile children: A cohort study


Autoři: Mary-Anne Hartley aff001;  Natalie Hofmann aff003;  Kristina Keitel aff003;  Frank Kagoro aff004;  Clara Antunes Moniz aff003;  Tarsis Mlaganile aff004;  Josephine Samaka aff004;  John Masimba aff004;  Zamzam Said aff004;  Hosiana Temba aff004;  Iveth Gonzalez aff006;  Ingrid Felger aff003;  Blaise Genton aff001;  Valérie D’Acremont aff001
Působiště autorů: Centre for Primary Care and Public Health, University of Lausanne, Lausanne Switzerland aff001;  EPFL, Machine Learning and Optimization Laboratory, Lausanne, Switzerland aff002;  Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland aff003;  Ifakara Health Institute, Dar es Salaam, United Republic of Tanzania aff004;  Amana hospital, Dar es Salaam, United Republic of Tanzania aff005;  Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland aff006
Vyšlo v časopise: Clinical relevance of low-density Plasmodium falciparum parasitemia in untreated febrile children: A cohort study. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003318
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003318

Souhrn

Background

Low-density (LD) Plasmodium infections 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 for Plasmodium 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).

Pf positivity 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 any Pf-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 LD Pf parasitemia and those without Pf parasitemia. 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.

Klíčová slova:

Antimalarials – Diagnostic medicine – Fevers – Malaria – Malarial parasites – Medical risk factors – Parasitemia – Parasitic diseases


Zdroje

1. Okell LC, Ghani AC, Lyons E, Drakeley CJ. Submicroscopic infection in Plasmodium falciparum-endemic populations: a systematic review and meta-analysis. J Infect Dis. 2009 Nov 15;200(10):1509–17. doi: 10.1086/644781 19848588. Epub 2009/10/24.

2. Smith T, Ross A, Maire N, Rogier C, Trape JF, Molineaux L. An epidemiologic model of the incidence of acute illness in Plasmodium falciparum malaria. The American journal of tropical medicine and hygiene. 2006 Aug;75(2 Suppl):56–62. doi: 10.4269/ajtmh.2006.75.56 16931816. Epub 2006/08/26.

3. Ranadive N, Kunene S, Darteh S, Ntshalintshali N, Nhlabathi N, Dlamini N, et al. Limitations of Rapid Diagnostic Testing in Patients with Suspected Malaria: A Diagnostic Accuracy Evaluation from Swaziland, a Low-Endemicity Country Aiming for Malaria Elimination. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2017 May 1;64(9):1221–7. doi: 10.1093/cid/cix131 28369268. Pubmed Central PMCID: PMC5399938. Epub 2017/04/04.

4. Rossi G, De Smet M, Khim N, Kindermans JM, Menard D. Performance of Rapid Diagnostic Testing in Patients with Suspected Malaria in Cambodia, a Low-Endemicity Country Aiming for Malaria Elimination. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2017 Oct 30;65(10):1769–70. doi: 10.1093/cid/cix625 29020315. Epub 2017/10/12.

5. Hofmann NE, Gruenberg M, Nate E, Ura A, Rodriguez-Rodriguez D, Salib M, et al. Assessment of ultra-sensitive malaria diagnosis versus standard molecular diagnostics for malaria elimination: an in-depth molecular community cross-sectional study. The Lancet infectious diseases. 2018 Oct;18(10):1108–16. doi: 10.1016/S1473-3099(18)30411-0 30170986. Epub 2018/09/02.

6. Hofmann N, Mwingira F, Shekalaghe S, Robinson LJ, Mueller I, Felger I. Ultra-sensitive detection of Plasmodium falciparum by amplification of multi-copy subtelomeric targets. PLoS Med. 2015 Mar;12(3):e1001788. doi: 10.1371/journal.pmed.1001788 25734259. Pubmed Central PMCID: PMC4348198. Epub 2015/03/04.

7. World Health Organization. WHO technical consultation on research requirements to support policy recommendations on highly sensitive point-of-care diagnostics for P. falciparum malaria. Geneva, Switzerland: 2018.

8. Das S, Jang IK, Barney B, Peck R, Rek JC, Arinaitwe E, et al. Performance of a High-Sensitivity Rapid Diagnostic Test for Plasmodium falciparum Malaria in Asymptomatic Individuals from Uganda and Myanmar and Naive Human Challenge Infections. The American journal of tropical medicine and hygiene. 2017 Nov;97(5):1540–50. doi: 10.4269/ajtmh.17-0245 28820709. Epub 2017/08/19.

9. World Health Organization. IMCI chart booklet. Geneva: World Health Organization March 2014. [cited 2020 Mar 3]. Available from: http://www.who.int/maternal_child_adolescent/documents/IMCI_chartbooklet/en/.

10. D'Acremont V, Kahama-Maro J, Swai N, Mtasiwa D, Genton B, Lengeler C. Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study. Malar J. 2011 Apr 29;10:107. doi: 10.1186/1475-2875-10-107 21529365. Pubmed Central PMCID: PMC3108934. Epub 2011/05/03.

11. d'Acremont V, Malila A, Swai N, Tillya R, Kahama-Maro J, Lengeler C, et al. Withholding antimalarials in febrile children who have a negative result for a rapid diagnostic test. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2010 Sep 1;51(5):506–11. doi: 10.1086/655688 20642354. Epub 2010/07/21.

12. Rossi IA, D'Acremont V, Prod'Hom G, Genton B. Safety of falciparum malaria diagnostic strategy based on rapid diagnostic tests in returning travellers and migrants: a retrospective study. Malar J. 2012 Nov 16;11:377. doi: 10.1186/1475-2875-11-377 23158019. Pubmed Central PMCID: PMC3528469. Epub 2012/11/20.

13. Keitel K, Kagoro F, Samaka J, Masimba J, Said Z, Temba H, et al. A novel electronic algorithm using host biomarker point-of-care tests for the management of febrile illnesses in Tanzanian children (e-POCT): A randomized, controlled non-inferiority trial. PLoS Med. 2017 Oct;14(10):e1002411. doi: 10.1371/journal.pmed.1002411 29059253. Pubmed Central PMCID: PMC5653205. Epub 2017/10/24.

14. Hofmann NE, Moniz CA, Holzschuh A, Keitel K, Boillat-Blanco N, Kagoro F, et al. Diagnostic performance of conventional RDT and ultra-sensitive RDT for malaria diagnosis in febrile outpatients in Tanzania. The Journal of infectious diseases. 2018 Nov 24. doi: 10.1093/infdis/jiy676 30476111. Epub 2018/11/27.

15. Shao AF, Rambaud-Althaus C, Samaka J, Faustine AF, Perri-Moore S, Swai N, et al. New Algorithm for Managing Childhood Illness Using Mobile Technology (ALMANACH): A Controlled Non-Inferiority Study on Clinical Outcome and Antibiotic Use in Tanzania. PloS ONE. 2015;10(7):e0132316. doi: 10.1371/journal.pone.0132316 26161535. Pubmed Central PMCID: PMC4498627. Epub 2015/07/15.

16. Zhang J, Yu KF. What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA: the journal of the American Medical Association. 1998 Nov 18;280(19):1690–1. doi: 10.1001/jama.280.19.1690 9832001. Epub 1998/12/01.

17. Okell LC, Bousema T, Griffin JT, Ouedraogo AL, Ghani AC, Drakeley CJ. Factors determining the occurrence of submicroscopic malaria infections and their relevance for control. Nat Commun. 2012;3:1237. doi: 10.1038/ncomms2241 23212366. Pubmed Central PMCID: PMC3535331. Epub 2012/12/06.

18. Bjorkman AB. Asymptomatic low-density malaria infections: a parasite survival strategy? The Lancet infectious diseases. 2018 May;18(5):485–6. doi: 10.1016/S1473-3099(18)30047-1 29398387. Epub 2018/02/06.

19. Felger I, Maire M, Bretscher MT, Falk N, Tiaden A, Sama W, et al. The dynamics of natural Plasmodium falciparum infections. PLoS ONE. 2012;7(9):e45542. doi: 10.1371/journal.pone.0045542 23029082. Pubmed Central PMCID: PMC3445515. Epub 2012/10/03.

20. Dobbs KR, Dent AE. Plasmodium malaria and antimalarial antibodies in the first year of life. Parasitology. 2016 Feb;143(2):129–38. doi: 10.1017/S0031182015001626 26743626. Pubmed Central PMCID: PMC4825094. Epub 2016/01/09.

21. Roca-Feltrer A, Carneiro I, Smith L, Schellenberg JR, Greenwood B, Schellenberg D. The age patterns of severe malaria syndromes in sub-Saharan Africa across a range of transmission intensities and seasonality settings. Malar J. 2010 Oct 13;9:282. doi: 10.1186/1475-2875-9-282 20939931. Pubmed Central PMCID: PMC2992028. Epub 2010/10/14.

22. Amaratunga C, Lopera-Mesa TM, Brittain NJ, Cholera R, Arie T, Fujioka H, et al. A role for fetal hemoglobin and maternal immune IgG in infant resistance to Plasmodium falciparum malaria. PLoS One. 2011 Apr 12;6(4):e14798. doi: 10.1371/journal.pone.0014798 21532754. Pubmed Central PMCID: PMC3075246. Epub 2011/05/03.

23. Makani J, Komba AN, Cox SE, Oruo J, Mwamtemi K, Kitundu J, et al. Malaria in patients with sickle cell anemia: burden, risk factors, and outcome at the outpatient clinic and during hospitalization. Blood. 2010 Jan 14;115(2):215–20. doi: 10.1182/blood-2009-07-233528 19901265. Pubmed Central PMCID: PMC2843825. Epub 2009/11/11.

24. Ouedraogo A, Tiono AB, Diarra A, Nebie IO, Konate AT, Sirima SB. The effects of a pre-season treatment with effective antimalarials on subsequent malaria morbidity in under five-year-old children living in high and seasonal malaria transmission area of Burkina Faso. Trop Med Int Health. 2010 Nov;15(11):1315–21. doi: 10.1111/j.1365-3156.2010.02618.x 20958888. Epub 2010/10/21.

25. Tiono AB, Guelbeogo MW, Sagnon NF, Nebie I, Sirima SB, Mukhopadhyay A, et al. Dynamics of malaria transmission and susceptibility to clinical malaria episodes following treatment of Plasmodium falciparum asymptomatic carriers: results of a cluster-randomized study of community-wide screening and treatment, and a parallel entomology study. BMC Infect Dis. 2013 Nov 12;13:535. doi: 10.1186/1471-2334-13-535 24215306. Pubmed Central PMCID: PMC4225764. Epub 2013/11/13.

26. Smith T, Felger I, Beck HP, Tanner M. Consequences of multiple infection with Plasmodium falciparum in an area of high endemicity. Parassitologia. 1999 Sep;41(1–3):247–50. 10697863. Epub 2000/03/04.

27. Chen I, Clarke SE, Gosling R, Hamainza B, Killeen G, Magill A, et al. "Asymptomatic" Malaria: A Chronic and Debilitating Infection That Should Be Treated. PLoS Med. 2016 Jan;13(1):e1001942. doi: 10.1371/journal.pmed.1001942 26783752. Pubmed Central PMCID: PMC4718522. Epub 2016/01/20.

28. Faure E. Malarial pathocoenosis: beneficial and deleterious interactions between malaria and other human diseases. Front Physiol. 2014;5:441. doi: 10.3389/fphys.2014.00441 25484866. Pubmed Central PMCID: PMC4240042. Epub 2014/12/09.

29. Villarino NF, LeCleir GR, Denny JE, Dearth SP, Harding CL, Sloan SS, et al. Composition of the gut microbiota modulates the severity of malaria. Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2235–40. doi: 10.1073/pnas.1504887113 26858424. Pubmed Central PMCID: PMC4776451. Epub 2016/02/10.

30. Rooth I, Bjorkman A. Fever episodes in a holoendemic malaria area of Tanzania: parasitological and clinical findings and diagnostic aspects related to malaria. Trans R Soc Trop Med Hyg. 1992 Sep-Oct;86(5):479–82. doi: 10.1016/0035-9203(92)90076-o 1475809. Epub 1992/09/01.

31. World Health Organization. WHO malaria terminology. Global Malaria Programme, 2018. 2018. [cited 2020 Mar 3]. Available from: https://apps.who.int/iris/bitstream/handle/10665/208815/WHO_HTM_GMP_2016.6_eng.pdf;jsessionid=77CF54CB61C7F38D7622202778207E19?sequence=1

32. Keitel K D'Acremont V. Electronic clinical decision algorithms for the integrated primary care management of febrile children in low-resource settings: review of existing tools. Clin Microbiol Infect. 2018 Aug;24(8):845–55. doi: 10.1016/j.cmi.2018.04.014 29684634. Epub 2018/04/24.

33. Bousema T, Okell L, Felger I, Drakeley C. Asymptomatic malaria infections: detectability, transmissibility and public health relevance. Nat Rev Microbiol. 2014 Dec;12(12):833–40. doi: 10.1038/nrmicro3364 25329408. Epub 2014/10/21.

34. Msellem MI, Martensson A, Rotllant G, Bhattarai A, Stromberg J, Kahigwa E, et al. Influence of rapid malaria diagnostic tests on treatment and health outcome in fever patients, Zanzibar: a crossover validation study. PLoS Med. 2009 Apr 28;6(4):e1000070. doi: 10.1371/journal.pmed.1000070 19399156. Pubmed Central PMCID: PMC2667629. Epub 2009/04/29.


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