Host Immunity, Plasmodium and Pathogens Co-Infections (HIPPI)

Few studies have focused on malaria co-infections, mainly caused by Plasmodium falciparum, occurring mainly in children under 5 years of age in sub-Saharan Africa. These studies have focused on malaria-associated bacterial sepsis, with an estimated prevalence of 9.1% and associated mortality of 15.0%. However, no study has documented infectious sites other than the blood compartment, considered viruses and parasites as possible causes of infection in addition to bacteria, and used molecular diagnostic methods based on PCRs, which are more sensitive. Thus, the prevalence of these co-infections and the spectrum of pathogens involved are probably underestimated, as is the impact of these co-infections on mortality. Furthermore, it has been shown that malaria infections can condition the immune cells of naturally exposed individuals, potentially leading to greater susceptibility to all types of infection. But these mechanisms have never been documented in the context of co-infections.

The WHO recommends the use of broad-spectrum antibiotics in cases of severe malaria, in addition to antimalarial drugs, as it can be difficult to differentiate clinically between severe malaria and severe bacterial infection (bacteremia, pneumonia and meningitis). Yet this empirical use of antibiotics could be contributing to an increase in antibiotic resistance. Identifying the determinants of co-infection with malaria and severe bacterial infection would enable this treatment to be better targeted.

These determinants remain undetermined as no study has considered other causes of severe bacterial infection other than bacteremia, used appropriate statistical methodology (univariate analysis only) and explored important determinants, notably the capacity of children's innate immunity to respond to severe bacterial infection.

Study Overview

• Status: Not yet recruiting
• Conditions: Malaria; Bacterial Co-infection
• Intervention / Treatment: Other: Blood sample; Other: Urine sample; Other: oropharyngeal sample; Other: Optionnal : stool sample; Other: Optionnal : cerebrospinal fluid; Other: placental biopsy

Detailed Description

This is a prospective multicenter longitudinal study.

The study will focus on several populations:

• febrile children: aged between 6 and 60 months consulting ;
• non-febrile children: aged between 6 and 60 months consulting.
• Pregnant women.
• newborns: those born to mothers included in the study with or without pregnancy-associated malaria.

The study will be based on :

• Clinical and microbiological documentation of acute febrile episodes in recruited children
• Documentation of vital status in children 3 months after recruitment
• Ability of host cells to respond to infections.

• Study Type: Interventional
• Enrollment (Estimated): 2000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bich-Tram Huynh, PhD; Phone Number: +33 1 53 55 18 50; Email: bich-tram.huynh@pasteur.fr
• Study Contact Backup: Name: Celia Dechavanne, PhD; Phone Number: +229 99 35 05 98; Email: celia.dechavanne@ird.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Febrile children:

• aged between 6 and 60 months
• with a febrile episode lasting less than 7 days (axillary temperature >=37.5° Celsius)
• whose state of health is compatible with a minimum single blood sample volume of 6.25 ml

Non-febrile children:

• aged between 6 and 60 months
• with axillary temperature <37.5° Celsius
• no clinical signs of infection at the time of inclusion
• no infectious episode or fever for 7 days

Pregnant women :

• giving birth in the project's partner health center
• intending to reside in the study area during the newborn follow-up period
• with a mono-fetal pregnancy
• With an apparently uncomplicated delivery not requiring referral to a higher-level health facility

Newborns at delivery:

• Born at term (determined by Ballard score)
• whose parents or legal guardians reside in the study area during the newborn's follow-up period

Exclusion Criteria:

For all :

- person already participating in another biomedical research project.

For febrile and non-febrile children:

- chronic non-infectious pathology (cancer, malnutrition, etc.)

For pregnant women

• scheduled caesarean section for current pregnancy
• Caesarean section in previous pregnancies
• chronic non-infectious pathology during pregnancy (diabetes, hypertension, pre-eclampsia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Febrile and non febrile children, pregnant women and new borns; The study population is composed of children under the age of 5, which is also the population most at risk of malaria, living in the endemic areas of Lomé and Tsévié in Togo.

Other: Blood sample; For febrile children at the time of inclusion : 6.25 ml to 8.25 ml of blood ; For non febrile children at the time of inclusion : 4 ml of blood ; For pregnant women at the time of inclusion : 5 ml of peripheral blood, 5 ml of placental blood, 20 to 40 ml of umbilical cord blood ; For new borns : drop of blood on child's heel each month and 5 ml of blood the 12th and last month.; Other: Urine sample; For febrile children : 10 ml of urine; Other: oropharyngeal sample; For febrile children : oropharyngeal swab sampling; Other: Optionnal : stool sample; For febrile children (only as part of the care of the child) : 5g stool; Other: Optionnal : cerebrospinal fluid; For febrile children (only as part of the care of the child in case of suspected meningitis) : 4 additional drops of cerebrospinal fluid; Other: placental biopsy; For pregnant women : placental biopsy the size of 2 rice grains

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the extent and microbiological spectrum of malaria co-infections in children under 5.	the number of malaria co-infection events in febrile children.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the impact of malaria co-infections on mortality	Number of deaths in children under 5 with malaria co-infection	2 years
Identify the underlying immunological mechanisms mediating malaria co-infections	Concentration of cytokines IL6, IL1β and TNFα and IL 10 in children under 5 years of age	2 years
Identify determinants of malaria co-infections and severe bacterial infections.	The number of malaria co-infection events associated with severe bacterial infection in febrile children under 5 years of age.	2 years
Identify epigenetic and transcriptomic modifications in infant, maternal and placental blood cells mediating malaria co-infections	Expression level of transcripts according to the populations studied will be measured by RNA-seq	2 years
Identify molecules associated with epigenetic modifications (metabolome, proteome).	Expression level of proteins and metabolites according to the populations studied will be measured by RNA-seq	2 years

Collaborators and Investigators

• Sponsor: Institut Pasteur
• Collaborators: Institut de Recherche pour le Developpement
• Investigators: Study Director: Bich-Tram Huynh, PhD, Institut Pasteur; Principal Investigator: Luc Douti, MD, CHU-Campus de Lomé; Principal Investigator: Serge Ekoué Gbadoe, MD, Hôpital de district Polyclinique de Zio-Tsévié

Study record dates

Study Major Dates

• Study Start (Estimated): February 15, 2025
• Primary Completion (Estimated): February 15, 2027
• Study Completion (Estimated): August 15, 2027

Study Registration Dates

• First Submitted: January 6, 2025
• First Submitted That Met QC Criteria: January 6, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 21, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: children; malaria; immune response; co-infection; Togo; epigenetic mechanisms
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Pathologic Processes; Disease Attributes; Protozoan Infections; Parasitic Diseases; Malaria; Infections; Communicable Diseases; Coinfection
• Other Study ID Numbers: 2023-079; IRB2024-01 (Other Identifier: IRB00006966 Institut Pasteur IRB #1); 043/2024/CBRS (Other Identifier: Comité de Bioéthique pour la Recherche en Santé)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No