Whole blood genome-wide transcriptome profiling and metagenomics next-generation sequencing in young infants with suspected sepsis in a low-and middle-income country: A study protocol

Popescu, Constantin R.; Tembo, Bentry; Chifisi, Rhoda; Cavanagh, Miranda M.M.; Lee, Ahwon; Chiluzi, Blessings; Ciccone, Emily J.; Tegha, Gerald; Alonso-Prieto, Esther; Claydon, Jennifer; Dunsmuir, Dustin; Irvine, Michael A.; Dumont, Guy A.; Ansermino, J. Mark; Wiens, Matthew O.; Juliano, Jonathan J.; Kissoon, Niranjan; Mvalo, Tisungane; Lufesi, Norman; Chiume-Kayuni, Msandeni; Lavoie, Pascal M.

doi:10.12688/gatesopenres.13172.2

Cited by 4 publications

(10 citation statements)

References 42 publications

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“…To date, this pioneering research has found numerous instances of expected human rhinoviruses, enteroviruses, influenza A virus, coronavirus OC43, and respiratory syncytial virus, rotavirus, Torque-teno virus, human papillomavirus, human beta herpesvirus 7, along with novel cyclovirus, vientovirus, gemycircularvirus, and statovirus (17)(18)(19)(20)(21)(22)(23). The blood DNA virome in several thousand asymptomatic humans has been reported by researchers in the USA and Singapore (Human Longevity Ltd.) 94 different viruses including DNA viruses, parvovirus and RNA viruses were identified in 42% of patients studied (34). RNA viruses included herpesviruses, anelloviruses, papillomaviruses, polyomaviruses, adenovirus, HIV, HTLV, hepatitis B and C, parvovirus B19 and influenza.…”

Section: Discussionmentioning

confidence: 84%

Molecular Microbiology in Clinical Practice: Current and Future Applications

Biney-Assan

Kron

2022

Al-Kindy Col. Med. J

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Technological advances have yielded new molecular biology-based methods for the diagnosis of infectious diseases. The newest and most powerful molecular diagnostic tests are available at regional and national reference laboratories, as well as at specialized centers that are certified to conduct metagenomic testing. Metagenomic assays utilize advances in DNA extraction technology, DNA sequence library construction, high throughput DNA sequencing and automated data analysis to identify millions of individual strands of DNA extracted from clinical samples. At present, metagenomic assays are only possible at a small number of special research, academic and commercial laboratories. Continued research in human and pathogen genomic organization and host-pathogen interactions, represent important future goals that will maximize the information obtained from metagenomic assays. To illustrate the power and limitations of metagenomics, we report on a previously healthy 27 year old woman with work related exposure to ill animals, and who developed a rapidly progressive, severe diffuse interstitial pneumonitis that ultimately ended in the need for a double lung transplant. Metagenomic testing on DNA extracted from pleural fluid and nasopharyngeal swabs demonstrated the presence of expected normal bacterial flora along with some unexpected herpesvirus and non-HIV retroviral elements integrated into the patients DNA. Although no specific pathogen was ultimately identified to explain this patient’s severe disease, the sample preparation and data analysis methods detailed herein illustrate the powerful benefits and limitations of metagenomic testing.

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Section: Discussionmentioning

confidence: 84%

Molecular Microbiology in Clinical Practice: Current and Future Applications

Biney-Assan

Kron

2022

Al-Kindy Col. Med. J

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“…Study design, setting & population: This study was a pragmatic cohort study, and secondary analysis of data from a parent study that aimed to identify molecular signatures of bacterial sepsis in young infants with suspected sepsis (12). In the parent study, infants below 3 months of age were sequentially enrolled "around the clock" at the time they presented with suspected sepsis before, to the neonatal or pediatric units at Kamuzu Central Hospital in Lilongwe, Malawi between June 5 th , 2018, and April 6 th , 2020.…”

Section: Methodsmentioning

confidence: 99%

“…All infants also had a standardized aerobic blood culture (minimum 2 mL of blood) collected within 4 hours of presentation, using a rigorously implemented aseptic protocol (with in-training of all front-line healthcare providers prior to study initiation), as detailed (13). Infants also had cerebrospinal fluid (CSF) and urine cultures collected as clinically indicated.…”

Section: Severe Chest Recession Central Cyanosis and Convulsions (Def...mentioning

confidence: 99%

“…Blood cultures were processed into BACTEC PEDS Plus culture bottles incubated in a BD BACTEC 9050 instrument.In keeping with a pragmatic design, the study did not attempt to enforce strict criteria to define DS or illness status. Identification of organisms from blood or CSF cultures was completed in-house using bioMerieux API, and BD Crystal kits at a local University of North Carolina-affiliated research facility, as described (12). Culture results were made available to clinicians within 5 days.…”

Section: Severe Chest Recession Central Cyanosis and Convulsions (Def...mentioning

confidence: 99%

“…Another study in community settings in Madagascar, Senegal and Cambodia reported 8.2% culture-confirmed sepsis among 514 infants assessed for "possible serious bacterial infection" out of 3,688 neonates (18). One large study followed 12,622 842 infants assessed, excluding potential contaminants), for a population-level incidence of cultureconfirmed sepsis of 6.7 per 1,000 births (19). Taken together, these findings suggest that bacterial sepsis may be uncommon in this age group even in LMICs, when sepsis is clinically suspected.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

See 2 more Smart Citations

World Health Organization Danger Signs to predict bacterial sepsis in newborns: A pragmatic prospective cohort study

Akinseye

Popescu

Chiume-Kayuni

et al. 2023

Preprint

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Background: The World Health Organization (WHO) has developed danger signs (DS) to help front-line health workers triage interventions in children with severe illnesses. Our objective was to evaluate the extent to which DS predict bacterial sepsis in young infants presenting with acute illness. Methodology/Principal Findings: This prospective study evaluated nine DS in infants younger than 3 months with suspected sepsis in a large regional hospital in Lilongwe, Malawi, between June 2018 and April 2020. The main outcomes were positive blood or cerebrospinal fluid (CSF) cultures and mortality. Blood (n=85/401) and CSF (n=2/204) cultures were positive in 21.2% and 1% of infants, respectively (N=401; gestational age mean ± SD: 37.1±3.3 weeks, birth weight 2865±785 grams). In-hospital deaths occurred in 9.7% (N=39/401) of infants (61.5% within 48h of admission). In univariate analyses, all DS were associated with mortality except for temperature instability and tachypnea, whereas “infant was unable to feed” was the only DS significantly associated with bacterial sepsis. After co-variable adjustments, number of DS predicted mortality (OR: 1.75; 95%CI: 1.43–2.16; p<0.001; AUC-ROC: 0.756) but not positive cultures (OR 1.08; 95%CI: 0.92–1.30; p=0.336). Whether potential bacterial contaminants were included or not did not change results meaningfully. Conclusion/Significance: DS predicted fatal outcomes but not positive cultures in a large regional hospital setting. These data imply that the incidence of bacterial sepsis and attributable mortality are unlikely to be accurate based on clinical signs alone, in infants in LMIC settings.

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Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes

Fidanza,

Hibbert,

Acton

et al. 2024

Sci Rep

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Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

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Whole blood genome-wide transcriptome profiling and metagenomics next-generation sequencing in young infants with suspected sepsis in a low-and middle-income country: A study protocol

Cited by 4 publications

References 42 publications

Molecular Microbiology in Clinical Practice: Current and Future Applications

Molecular Microbiology in Clinical Practice: Current and Future Applications

World Health Organization Danger Signs to predict bacterial sepsis in newborns: A pragmatic prospective cohort study

Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes

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