Host Immunity, Plasmodium and Pathogens Co-Infections

Overview

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.

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.

Interventions

• 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

Primary outcome measures

• Determine the extent and microbiological spectrum of malaria co-infections in children under 5. [Time frame: 3 years]

Secondary outcome measures (5)

• Assess the impact of malaria co-infections on mortality [Time frame: 2 years]
• Identify the underlying immunological mechanisms mediating malaria co-infections [Time frame: 2 years]
• Identify epigenetic and transcriptomic modifications in infant, maternal and placental blood cells mediating malaria co-infections [Time frame: 2 years]
• Identify molecules associated with epigenetic modifications (metabolome, proteome). [Time frame: 2 years]
• Identify determinants of malaria co-infections and severe bacterial infections. [Time frame: 2 years]

Eligibility criteria

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06769815 · 2023-079 · IRB2024-01 · 043/2024/CBRS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗