A recent study published in the Journal of Fungi used a novel OrbitrapTM high-resolution mass spectrometric technology coupled with liquid chromatography to identify geographically different clades of Candida auris(C. auris) isolates. This proof-of-concept methodology could accurately detect C. auris in the microbiology laboratory.
Over a decade ago, C. auris was first found in East Asia, causing bloodstream infections. Although this fungal infection was initially found in India, South America, South Africa, and the Middle East, it soon prevailed globally.
C. auris soon became a common nosocomial fungal pathogen, particularly among intensive care unit (ICU) patients. As a result, the Centers for Disease Control and Prevention (CDC) has classified C. auris as an urgent threat pathogen.
An important factor that allows C. auris outbreaks worldwide is the improper identification of yeast pathogens in hospital laboratories. Hence, there is an urgent need for accurate and rapid identification of C. auris in hospital laboratories, which can reduce their transmission in healthcare facilities.
Genomic analysis of worldwide C. auris isolates has indicated that around five clades have emerged in the last 20 years, independently and simultaneously. These five distinct geographically restricted clades are clade I: South Asia, clade II: East Asia, clade III: Africa, clade IV: South America, and clade V: Iran. Each clade differs from the other by around ten thousand single-nucleotide polymorphisms.
Each clade has differential resistance to antifungal agents; for example, clade I is more resistant to fluconazole, while clade II exhibits susceptibility. Currently, C. auris isolates belonging to these clades have been introduced to many countries worldwide. Scientists have highlighted the importance of quickly identifying and monitoring these clades to restrict further spread.
C. auris possesses several structurally unique sphingolipids and mannoproteins, enabling it to adhere to medical devices and hospital environments persistently. These proteins also aid in biofilm formation and prevent elimination by common disinfectants.
Several studies have indicated that molecular techniques fail to identify C. auris, whereas matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) technology can accurately identify this fungus at the species level.
The Study and its Findings
102 clinical C. auris strains were selected, representing all five clades. These clades were determined based on a short tandem repeat (STR) typing assay, which was subsequently compared to whole-genome sequencing results.
The current study applied OrbitrapTM high-resolution mass spectrometric technology to identify C. auris based on protein analysis methods. This technique was combined with liquid chromatography (LC) for initial separation. In this method, electrospray ionization (ESI) transfers proteins into the gas phase for ionization and is subsequently introduced to the mass spectrometer (LC-MS).
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Mass analysis is conducted by either fragment ions or intact mass (MS) through tandem mass spectrometry (MS/MS). Some of the key features of the OrbitrapTM mass analyzer are a high resolution of up to 200,000, a high mass-to-charge ratio of 6,000, high mass accuracy between 2 and 5 ppm, and a dynamic range greater than 104.
C. auris clade differentiation using monoisotopic mass measurements depicted as heat map. Color scale ranges from blue (max signal) to dark red (no signal), representing abundance of measured monoisotopic masses in each strain. Clade specific differential protein masses are visible from the rectangular vertical boxes indicating the geographic affiliation and clade assignment and its vertically associated dendrogram indicating observed protein masses (columns vs. rows). X-axis indicating clade assignment and y-axis indicating observed MS1 protein masses.
In addition, this method is highly sensitive and can measure the exact mass of a compound. It can also identify minor structural changes due to a translated single nucleotide polymorphism into an amino acid change.
Importantly, this newly developed technology could identify all C. auris isolates with high confidence. Furthermore, it could differentiate C. auris across clades. Even though a limited number of isolates were present from each clade, this spectrometric technology identified C. auris clades with 99.6% identification accuracy.
Based on a principal component analysis (PCA) and a subsequent affinity clustering study, the South Asian, East Asian, and Iranian C. auris clades were more proteomically closely related. Long branches in the affinity clustering analysis suggested that the C. auris strains were present as outliers that required more attention, regardless of the detection technique.
Proteomic typing results indicated the capacity to track strains of the same origin isolated from diverse geographical locations. In the future, more precise matching and alignment of typing schemes (based on next-generation sequencing) is required to build on these results. This would significantly reduce false identifications and classifications of unknown strains associated with new clades or lineage.
Conclusions
Although the workflow linked to mass spectrometry and next-generation sequencing are not directly comparable, their results are similar, i.e., identifying unknown clinical microbes. The standard next-generation sequencing method is a highly time-consuming process that requires many delicate time-intensive quality-control steps, particularly during multiplexed sample runs.
In contrast, the newly developed methodology can provide results within 60 minutes. Therefore, applying the high-resolution OrbitrapTM mass spectrometer to accurately and rapidly identify C. auris clades is an attractive alternative to conventional platforms.
Journal reference:
Jamalian, A. et al. (2023) “Fast and Accurate Identification of Candida auris by High Resolution Mass Spectrometry”, Journal of Fungi, 9(2), p. 267. doi: 10.3390/jof9020267, https://www.mdpi.com/2309-608X/9/2/267
Global data shows nearly 10 per cent of severe COVID-19 cases involve a secondary bacterial co-infection – with Staphylococcus aureus, also known as Staph A., being the most common organism responsible for co-existing infections with SARS-CoV-2. Researchers at Western have found if you add a ‘superbug’ – methicillin-resistant Staphylococcus aureus (MRSA) – into the mix, the COVID-19 outcome could be even more deadly.
The mystery of how and why these two pathogens, when combined, contribute to the severity of the disease remains unsolved. However, a team of Western researchers has made significant progress toward solving this “whodunit”.
New research by Mariya Goncheva, Richard M. Gibson, Ainslie C. Shouldice, Jimmy D. Dikeakos and David E. Heinrichs, has revealed that IsdA, a protein found in all strains of Staph A., enhanced SARS-CoV-2 replication by 10- to 15-fold. The findings of this study are significant and could help inform the development of new therapeutic approaches for COVID-19 patients with bacterial co-infections.
Interestingly, the study, which was recently published in iScience, also showed that SARS-CoV-2 did not affect the bacteria’s growth. This was contrary to what the researchers had initially expected.
We started with an assumption that SARS-CoV-2 and hospitalization due to COVID-19 possibly caused patients to be more susceptible to bacterial infections which eventually resulted in worse outcomes.”
Mariya Goncheva
Goncheva is a former postdoctoral associate, previously with the department of microbiology and immunology at Schulich School of Medicine & Dentistry.
Goncheva said bacterial infections are most commonly acquired in hospital settings and hospitalization increases the risk of co-infection. “Bacterial infections are one of the most significant complications of respiratory viral infections such as COVID-19 and Influenza A. Despite the use of antibiotics, 25 per cent of patients co-infected with SARS-CoV-2 and bacteria, die as a result. This is especially true for patients who are hospitalized, and even more so for those in intensive care units. We were interested in finding why this happens,” said Goncheva, lead investigator of the study.
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Goncheva, currently Canada Research Chair in virology and professor of biochemistry and microbiology at the University of Victoria, studied the pathogenesis of multi-drug resistant bacteria (such as MRSA) supervised by Heinrichs, professor of microbiology and immunology at Schulich Medicine & Dentistry.
When the COVID-19 pandemic hit, she pivoted to study interactions between MRSA and SARS-CoV-2.
For this study, conducted at Western’s level 3 biocontainment lab, Imaging Pathogens for Knowledge Translation (ImPaKT), Goncheva’s work created an out-of-organism laboratory model to study the interactions between SARS-CoV-2 and MRSA, a difficult-to-treat multi-drug resistant bacteria.
“At the beginning of the pandemic, the then newly opened ImPaKT facility made it possible for us to study the interactions between live SARS-CoV-2 virus and MRSA. We were able to get these insights into molecular-level interactions due to the technology at ImPaKT,” said Heinrichs, whose lab focuses on MRSA and finding drugs to treat MRSA infections. “The next step would be to replicate this study in relevant animal models.”
Goncheva, M. I., et al. (2023). The Staphylococcus aureus protein IsdA increases SARS CoV-2 replication by modulating JAK-STAT signaling. IScience. doi.org/10.1016/j.isci.2023.105975.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
In a recent study posted in the medRxiv* preprint server, scientists assessed the efficacy of sotrovimab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) treatment.
Emerging SARS-CoV-2 variants have lowered the fold change in half maximal effective concentration (EC50) for the SARS-CoV-2 Omicron BA.2 sublineage and subsequent sublineages. Yet, the association between this decrease and clinical efficacy outcomes is unknown. With a lack of clinical trials evaluating the efficacy of sotrovimab against novel variants, real-world evidence becomes an essential data source.
In the present study, researchers assessed the efficacy of sotrovimab on severe coronavirus disease 2019 (COVID-19) outcomes throughout the period of the prevalence of the SARS-CoV-2 Omicron BA.2 subvariant.
This systematic literature review (SLR) comprised observational papers assessing clinical outcomes as well as the viral load in sotrovimab-treated patients, which were published between 1 January 2022 and 3 November 2022 in preprint articles, peer-reviewed journal publications, and conference abstracts. To identify data related to Omicron BA.2 and the following subvariants, the team chose a suitable publication period for the systematic review.
The following electronic databases were searched on 3 November 2022: MEDLINE, LitCovid, Embase, EcoLit, and Cochrane COVID-19 Study Registry. Further searches were undertaken in medRvix, bioRvix, arRvix, xhemRvix, Preprints.org, SSRN, and ResearchSquare for relevant preprints. In addition, relevant abstracts from the following conferences were indexed beginning in January 2022: Infectious Diseases Week, International Conference on Emerging Infectious Diseases, European Respiratory Society, and European Congress of Clinical Microbiology and Infectious Diseases.
Data extraction from the listed studies was conducted by a single extractor using a Microsoft Excel-designed data extraction file. Information extracted included the study’s title and citation, data source, study design and details, country, number of patients, study population, data collection period and circulating SARS-CoV-2 variants, duration of follow-up, key baseline features, and clinical outcomes. The clinical outcomes taken into account for the study included hospital admission, intensive care admission, respiratory support, emergency department visits, mortality, COVID-19 progression, the relative and absolute change in viral load observed during the acute phase after sotrovimab therapy, and the number of patients having undetectable viral load after sotrovimab treatment.
Results
Initial searches of electronic databases generated 257 studies. Another 263 studies were found by searching preprints, conference abstracts, and citation chasing from appropriate SLRs. After removing duplicates, 343 unique abstracts and titles were evaluated, of which 89 were deemed eligible for full-text review. Five observational trials reporting viral load or clinical outcome data associated with sotrovimab during the era of BA.2 predominance were deemed appropriate for inclusion in the present SLR.
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Point estimates for hospitalization or mortality (as a composite endpoint) or clinical progression for sotrovimab-treated patients. a95 CIs calculated via Clopper-Pearson methods using reported data. bDefined as March through April 2022 in source and assumes homogeneity in the distribution of SARS-CoV-2 variants across all US states. cOnly COVID-19-specific outcome shown; all-cause outcome also reported in source. dHospitalizations were COVID-19-specific; deaths could be due to any cause. CI confidence interval
The number of patients reporting hospitalization or fatality due to COVID-19 was consistently low for all investigations and periods of the prevalence of Omicron BA.1 and BA.2 variants. COVID-19-related hospital admission or mortality rates were between 1.0% and 3.1% for sotrovimab-treated patients during Omicron BA.1 prevalence and from 1.0% and 3.6% when BA.2 was predominant. The number of patients who reported hospitalization and mortality due to all causes ranged from 2.1% to 2.7% for the BA.1 predominance era, and from 1.7% to 2.0% for the BA.2 era. During Omicron BA.1 predominance, COVID-19-related mortality was projected to be 0.21% for the sotrovimab group versus 0.67% for the molnupiravir group, and 0.15% versus 0.96% for the BA.2 era, respectively.
During the BA.1 and BA.2 subvariant surges, sotrovimab was associated with a significantly decreased incidence of 28-day SARS-CoV-2-related hospital admission or fatality compared to molnupiravir. After statistical adjustment for demographics, vaccination status, high-risk cohort categories, body mass index, calendar time, and other comorbidities, the findings indicated that sotrovimab was associated with a significantly lower risk of COVID-19-related hospital admission or mortality compared to molnupiravir during the BA.1 and BA.2 periods.
During the BA.2 subvariant surge, sotrovimab was linked with a decreased risk of 30-day hospitalization or mortality from all causes compared to no mAb treatment. In March 2022, sotrovimab was considerably more successful than non-mAb-treated patients, with an adjusted reduction of 59% in relative risk and a propensity score-matched relative risk reduction of 64% with respect to 30-day all-cause hospital admission or mortality. Similar risks of hospitalization were associated with BA.1 and BA.2 patients treated with sotrovimab.
Conclusion
The study findings showed that sotrovimab continued to be clinically effective in mitigating severe clinical outcomes associated with SARS-CoV-2 infections during the period of SARS-CoV-2 Omicron BA.2 predominance compared to the control/comparator and relative to Omicron BA.1 predominance. During Omicron BA.1 and BA.2 subvariant predominance, the studies consistently reported low rates of poor clinical outcomes in individuals treated with sotrovimab.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Journal reference:
Preliminary scientific report.
Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 subvariant predominance: a systematic literature review, Myriam Drysdale, Daniel C. Gibbons, Moushmi Singh, Catherine Rolland, Louis Lavoie, Andrew Skingsley, Emily J. Lloyd, medRxiv 2023.03.09.23287034, DOI: https://doi.org/10.1101/2023.03.09.23287034, https://www.medrxiv.org/content/10.1101/2023.03.09.23287034v1
In a recent study published in Open Forum Infectious Diseases, researchers evaluated the use of empiric antibiotics to determine the prevalence rates of community-acquired bacterial coinfections among hospitalized pediatric critical coronavirus disease 2019 (COVID-19) patients and to identify opportunities for de-escalating antibiotic usage in case of no bacteria-caused sepsis among high-risk individuals, and those presenting with shock.
Community-acquired bacterial coinfections among hospitalized adult coronavirus disease 2019 (COVID-19) patients are uncommon; however, empiric antibiotic usage is reportedly high. Data on empiric antibiotic usage and bacterial coinfections among pediatric individuals with critical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are limited.
The clinical manifestations of severe SARS-CoV-2 infections often include pulmonary distress and fever, findings that could be difficult to discriminate from serious bacterial infections, which might prompt the use of empiric antibiotics in the initial days of hospitalization, particularly among high-risk individuals.
About the study
In the present study, researchers investigated whether any radiographic, laboratory, or clinical features ascertainable during hospitalization were related to empiric antibiotic usage or were estimative of bacterial coinfections acquired in community settings.
The team evaluated individuals below 19.0 years and admitted to pediatric high-acuity units (HAU) or intensive care units (ICU) due to SARS-CoV-2 infections from March 2020 to December 2020. On the basis of microbiology reports from the initial 72 hours of hospitalization, the team adjudicated if patients had community-acquired bacterial coinfections.
Clinical and demographic variables of individuals with and without antibiotic prescriptions and bacterial coinfections in the initial days of hospitalization were compared. Poisson regression modeling was performed to assess factors related to the outcome, and the adjusted relative risk (aRR) values were calculated.
Data were obtained from patient electronic medical records and data from the nationwide overcoming COVID-19 population health active surveillance registry of patients hospitalized due to COVID-19-associated complications between 15 March 2020 and 31 December 2020 across >70.0 pediatric hospitals in 25 states.
COVID-19 diagnosis was confirmed using polymerase chain reaction (PCR). The team excluded multisystem inflammatory syndrome among children (MIS-C) patients diagnosed using the Centers for Disease Control and Prevention (CDC) criteria. Data were obtained on demographic parameters, clinical symptoms and signs, comorbidities, radiographical and laboratory investigations, and data on antibiotics prescribed at admission and the course of critical COVID-19, including clinical outcomes and hemodynamic and respiratory support needed.
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The primary study outcome assessed was the prescriptions of empirical antimicrobials, for which enteral or intravenous antimicrobials administered in the initial two days of hospital admission were assessed. The second outcome evaluated community-acquired bacterial infection presence, for which relevant case report form (CRF) information from individuals with SARS-CoV-2-positive microbiological cultures, and PCR, were analyzed in the initial 72 hours of hospital admission.
Results
Out of 532 individuals, 63.0% were administered empiric antibiotics; however, only seven percent developed bacterial coinfections, of which only three percent were respiratory-type. Empirical antibiotics had a greater likelihood of being prescribed to immunosuppressed individuals (aRR of 1.3), requiring non-mechanical ventilator-type respiratory aid (aRR of 1.4), or requiring invasive-type mechanical ventilators (aRR of 1.8), than no respiratory aid.
The most frequently prescribed antimicrobials were ceftriaxone (41%) and vancomycin (28%), followed by cefepime (20%). Most individuals were prescribed multiple antimicrobials, with 21%, 10%, and 18% receiving 2.0, 3.0, and ≥4.0 antibiotics in the initial two days of hospital admission. More than 33% of individuals received antibiotics for ≥5.0 days, despite no evidence of bacterial coinfections. The median social vulnerability index (SVI) values were significantly greater among those who received antibiotics than those who did not.
The median C-reactive protein (CRP) levels were greater among those who received antibiotics versus those who did not (4.6 mg per dL vs. 2.2 mg per dL), as were the median procalcitonin levels (0.4 ng per mL vs. 0.1 ng per mL). The median leukocyte counts showed no significant differences between the two groups. Antibiotic usage was related to COVID-19 severity, indicated by greater median values for PEdiatric Logistic Organ Dysfunction-2 (PELOD-2) scores at hospitalization among individuals who received antibiotics than those who did not.
Seven percent (n=38) of individuals had true community-onset bacterial coinfections, of which 13, 16, 8.0, and 4.0 were bloodstream infections, respiratory infections, urinary tract infections, and bacterial infections at other sites (peritonitis, colitis, meningitis, and pharyngitis), respectively.
No particular pathogenic organism predominantly caused bacterial coinfections, although most pulmonary coinfections were caused by Staphylococcus aureus and/or Pseudomonas aeruginosa. Greater PELOD-2 scores at admission were associated with bacterial coinfections (aRR of 1.2), in addition to age, sex, and pulmonary conditions other than asthma (aRR 2.3).
Conclusion
Overall, the study findings showed that community-onset bacterial coinfections among children with critical COVID-19 are not frequent; however, empiric antibiotics are usually prescribed. The study findings inform antibiotic use and underpin swift de-escalation in case assessments indicating that coinfections are not likely.
In a recent study published in the Clinical Microbiology and Infection, researchers assessed the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on pregnant women during the Omicron wave.
During the coronavirus disease 2019 (COVID-19) pandemic, pregnant women were more likely than the general population to develop severe COVID-19. In utero mother-to-child viral transmission was shown to be uncommon, and infected mothers demonstrated a strong immune response with anti-SARS-CoV-2 antibodies passed on to newborns.
Despite many studies indicating a substantial maternal antibody response to SARS-CoV-2 immunization and the absence of safety issues, the vaccination rate among pregnant women remained lower than that of the general population. Only a few studies have been undertaken to date on the impact of the SARS-CoV-2 Omicron variant on unvaccinated and vaccinated pregnant women.
About the study
In the present study, researchers compared the perinatal and maternal outcomes of SARS-CoV-2-infected women in Italy during the SARS-CoV-2 Omicron variant wave based on their vaccination protection.
The current national prospective cohort research involved pregnant women who tested COVID-19-positive within seven days of hospitalization in any Italian maternity unit between January 1 and May 31 2022. In addition, women reported whether they had received the SARS-CoV-2 vaccine, as well as the when (before and/or at the time of pregnancy) and how many doses were received.
The primary outcome measure was SARS-CoV-2 disease severity, classified as mild, moderate, or severe. The two most severe severity categories, determined by pneumonia diagnosis, were grouped together for statistical analysis as “moderate or severe COVID-19 disease” (MSCD). Secondary outcomes comprised preterm birth, stillbirth, delivery mode, admission to the neonatal intensive care unit (NICU), and early neonatal mortality before hospital release.
MSCD protection was taken into account as an exposure variable. Women vaccinated with a minimum of one vaccine dose at the time of pregnancy, and those vaccinated with the full vaccine schedule and the first booster vaccine were protected against MSCD. On the other hand, unvaccinated women and participants who were vaccinated with either one or two vaccine doses prior to pregnancy and tested positive for SARS-CoV-2 at 22 or more gestational weeks were deemed unprotected. Women with incomplete vaccination information and those who were vaccinated with one or two doses prior to pregnancy and who tested positive for SARS-CoV-2 at less than 22 gestational weeks were deemed “unknown in terms of protective status.”
Results
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Between January 1 and May 31, 2022, a total of 2,774 women who tested positive for SARS-CoV-2 within seven days of hospitalization were enrolled. Information was available about the protection status of 2147 women, while no significant clinical or socio-demographic variations were noted between these women and the entire cohort.
According to the study’s definition, almost 1,069 (49.8%) individuals were protected against MSCD. Of them, 74 were vaccinated with one vaccine during pregnancy, while 596 received two, including a minimum of one dose administered during pregnancy, while 327 received their first booster. In contrast, 1,078 women were deemed unprotected, including 989 women who were unvaccinated and 89 who tested positive for SARS-CoV-2 at 22 or more weeks of gestation after receiving one or two doses before pregnancy. All except 26 women were immunized with the conventional vaccinations alone or in conjunction with messenger ribonucleic acid (mRNA) vaccines.
Compared to protected women, unprotected women displayed a higher likelihood of being younger, less educated, of foreign nationality, and symptomatic. Also, 96.4% were hospitalized for childbirth or obstetrical causes, whereas 3.6% were hospitalized due to COVID-19. Eight of the latter acquired severe disease, 12 developed a moderate disease, and 58 developed a mild disease.
MSCD illness was uncommon overall but more prevalent among unprotected women than among protected women. Among the 41 MSCD cases, 27 of 29 unprotected women had not received any vaccine, while two were vaccinated with two doses prior to pregnancy. Three of the 12 protected women received the booster, while nine received two doses, among which the first was received before and the second was received during pregnancy.
Among unprotected women, seven out of eight severe infection cases and one maternal fatality occurred. COVID-19 pneumonia was deemed the cause of death, reported two weeks after delivery. Unprotected women had a greater incidence of MSCD compared to protected women, Asian women, and those with a history of comorbidities.
Sensitivity analysis revealed that unprotected women had considerably higher MSCD risk than protected women. Furthermore, 8.7% of newborns were born preterm, predominantly late preterm, with no significant variations between unprotected and protected women, but C-section was reported in 34.4% and 29.3% of women, respectively. The rate of preterm birth was greater among MSCD-infected women compared to those with milder cases and those with CS. Also, out of 619 CS cases, five were urgent/emergent due to COVID-19, and all involved MSCD-affected women.
Conclusion
Overall, the study findings documented a low prevalence of severe SARS-CoV-2 infection in pregnant women and considerable efficacy of the COVID-19 vaccine in providing protection. These statistics can serve as the foundation for informing pregnant women uncertain about the vaccine’s efficacy and demonstrating the importance of vaccination in protecting their newborns.
In a recent article published in Clinical Microbiology and Infection, researchers reviewed all registered trials currently investigating potential treatment options for post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS).
Additionally, the scientists examined the limitations of the current clinical trials to inform future research.
Over 663 million people contracted COVID-19 globally, of which 10% to 20% suffered from PACS, a complex systemic post-COVID-19 disease with substantial morbidity, per the World Health Organization (WHO) COVID-19 dashboard. Though studies have identified over 100 persistent symptoms associated with COVID-19, most studies have documented fatigue, followed by dyspnea, as the most reported PACS symptom.
There is a shortage of medical interventions to treat PACS patients. The data indicate that PACS patients will continue to spike globally in the coming future, increasing the burden on healthcare facilities. With just four multi-center clinical trials in the pipeline, there is an urgent need for more research investigating potential therapeutic options for PACS.
About the study
In the present study, researchers screened the WHO Internal Clinical Trials Registry Platform (ICTRP) on September 16th, 2022, to identify PACS trial registry entries. The ICTRP gathers records from 17 trial registries collecting information globally.
For trial selection, they adhered to the Patient Intervention Comparison Outcomes Study type (PICOS) framework, which mandated any patient sample size with patients of any age diagnosed with COVID-19 and related persistent symptoms for over four weeks or PACS. Additionally, these trials mentioned treatment of PACS, not prevention, and covered any outcome.
In total, 12 reviewers extracted data from the selected trials in duplicate and reviewed them as per the PRISMA guidelines. Later, two reviewers merged the overlapping primary outcomes and grouped them into appropriate outcome domains. Further, they used experimental arm(s) to identify all interventions under investigation for PACS for each trial. Furthermore, the team recorded trial numbers, patients enrolled, nations, and their specific clinical use per the trial source for each intervention under investigation. Finally, they organized all interventions into different classes, sorted into seven human organ systems. Also, they used the WHO definition to organize interventions under the rehabilitation classes. They used percentages to summarize trial characteristics.
Study findings
The study identified 388 trials exploring 144 interventions for PACS. From all, 108 and 133 clinical trials specifically targeted fatigue and the pulmonary system, respectively. Among the interventions targeting a single human organ system, most were not specific to an organ system, and 70 trials adopted an all-inclusive approach to weaken PACS symptoms. It raises the issue of the reproducibility of these trials and the efforts to determine their clinical benefits later.
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Further, the researchers noted that most trials investigated PACS treatment strategies repurposed from similar conditions; for instance, the rehabilitation interventions are currently exploring treatment strategies for cancer-related fatigue syndrome.
In addition, most interventions targeted multiple PACS symptoms concurrently or proposed the same intervention for different symptoms. Furthermore, these trials investigated barely a few novel therapeutic agents specifically for PACS (e.g., RSLV-132, AXA1125).
The clinical category of the patient, in or outpatient, admitted to the intensive care unit (ICU) under treatment is crucial. However, over 60% of these trials barely indicated the hospitalization status of the trial population in their inclusion/exclusion criteria.
Most importantly, all the included trials used a different PACS definition. So, the researchers noted a considerable heterogeneity among the included trials in this aspect, and the reported primary outcomes were also often not standardized. Additionally, they did not refer to time zero, with around 66 clinical trials mentioning PACS patients as having a positive and then a negative COVID-19 test. It made it difficult to ascertain whether the patient trial population recovered from COVID-19 exhibited PACS symptoms.
The cohort size of almost three-fourths of the trials was under 100. Moreover, over one-third of the participants were open-label. Accordingly, several interventions reported in these trials likely yielded only preliminary evidence of the safety and effectiveness of the PACS treatment options. Additionally, these trials used subjective and patient-reported scales that increased the risk of outcome assessment bias.
Conclusions
To conclude, the study highlighted the issue of the need for proper diagnostic tests for PACS, which hindered the systematic identification of patients with PACS and the assembling of a control group. Remarkably, of the four international multi-center trials, two trials neither explicitly mentioned PACS nor defined a time reference. A clinical trial mentioned PACS patients but did not define a time reference.
Moreover, many registered trials needed to have more effectively defined their inclusion criteria. They did not indicate the acute phase of illness, which made it impossible to ascertain whether all the included patients were experiencing symptoms due to some other chronic/infectious diseases (e.g., post-intensive care syndrome) or PACS.
The healthcare demands of PACS patients will continue to rise. Thus, there is an urgent need for robust PACS treatment research with standardized outcome reporting adhering to WHO’s recommendations. Data from the current study could inform future PACS research for developing robust treatment options. Though repurposing existing treatments could work, for now, the focus should be on developing novel therapies, specifically targeting PACS pathophysiology. In this regard, International collaborations, such as the National Institutes of Health’s RECOVER initiative for PACS, should be encouraged.
Furthermore, it is crucial to include trials investigating alternative medicine, which currently has low registration quality. The authors also advocated improving the quality of research protocols reporting and sharing them for public access. All these endeavors could greatly benefit all the handlers of clinical trial evidence, including PACS patients.
Journal reference:
Nader A. Fawzy, Bader Abou Shaar, RandM. Taha, Tarek Z. Arabi b, Belal N. Sabbah, Mohamad S. Alkodaymi, Osama A. Omrani, Tariq Makhzoum, Najwa E. Almahfoudh, Qasem A. Al-Hammad, Wed Hejazi, Yasin Obeidat, Naden Osman, Khaled M. Al-Kattan, Elie F. Berbari, Imad M. Tleyjeh. (2023). A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform. Clinical Microbiology and Infection. doi:https://doi.org/10.1016/j.cmi.2023.01.007https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(23)00009-5/fulltext
In a recent scientific paper published in the journal Nature Microbiology, researchers reproduced two target trials using electronic health records (EHRs) of the Department of Veterans Affairs (VA) to compare the effectiveness of the third dose of BNT162b2 or messenger ribonucleic acid (mRNA)-1273 vaccine among United States (US) veterans.
There is a lack of head-to-head comparative studies of the effectiveness of a third booster dose of different mRNA-technology-based coronavirus disease 2019 (COVID-19) vaccines. An ideal comparative effectiveness study of mRNA vaccines should cover racially diverse populations and evaluate possible differences in vaccine efficacy based on the time when an individual completed the primary vaccination series. Most importantly, these studies should account for the time windows of the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants.
During the current SARS-CoV-2-induced pandemic, vaccination effectively reduced the burden of severe disease and death from COVID-19. Especially, booster doses of BNT162b2 and mRNA-1273 vaccines countered waning immunity and broadened protection against novel, highly transmissible SARS-CoV-2 variants. In one of their previous work covering 439,684 US veterans, researchers found that both mRNA-1273 and BNT162b2 lowered the risk of SARS-CoV-2 infection and severe disease outcomes during SARS-CoV-2 Alpha variant prevalence.
About the study
In the present study, researchers matched recipients of BNT162b2 or mRNA-1273 vaccines in a 1:1 ratio based on their risk factors to estimate their comparative effectiveness over 16 and nine weeks in the Delta-Omicron and Omicron period, respectively, for five COVID-19 outcomes:
reported SARS-CoV-2 infection,
reported symptomatic SARS-CoV-2 infection,
SARS-CoV-2 infection-related hospitalization,
intensive care unit (ICU) admission, and
death.
The veterans in the first emulated trial received the third dose of BNT162b2 or mRNA-1273 vaccines between 20 October 2021 and 8 February 2022. This period corresponded to SARS-CoV-2 Delta and Omicron variants prevalence. For each veteran in the primary analysis, the team started follow-up on the day of the third vaccination (baseline). It ended 16 weeks after baseline, death, or the end of study duration, i.e., 15 February 2022, as applicable.
The veteran population of the second emulated trial received the third dose of any of the two mRNA COVID-19 vaccines between 1 January and 1 March 2022, the period of only Omicron predominance. The median follow-up continued over nine weeks, during which the team documented 214 SARS-CoV-2 infections.
Study findings
In the first emulated trial, 147,553 and 214,728 veterans received the third dose of BNT162b2 and mRNA-1273, respectively. The baseline characteristics of 65,196 BNT162b2 recipients matched to an equal number of mRNA-1273 recipients were comparable compared to the eligible population. The median age of this veteran population was 70 years, 96% were males, and 24% were Blacks.
During the 16-week follow-up spanning Delta and Omicron prevalence, the researchers documented 2,994 SARS-CoV-2 infections, of which 200 were symptomatic COVID-19 cases, 194 sought hospitalization, 52 needed ICU admission, and 22 culminated in death. During this time, the estimated risk of reported infection for the BNT162b2 and mRNA-1273 third dose was 353.9 and 308.5 events per 10,000 individuals, respectively.
In the second emulated trial, 25,557 and 36,809 eligible veterans received the third dose of BNT162b2 mRNA-1273, respectively. Like in the first trial, the matched population comprised 7,894 BNT162b2 and an equal number of mRNA-1273 recipients with comparable baseline demographic and clinical characteristics relative to the eligible population. They had a higher proportion of men and White people.
During nine weeks of follow-up amid Omicron predominance, the estimated risk of documented SARS-CoV-2 infection was higher with a third dose of the BNT162b2 vaccine vs. mRNA-1273. Accordingly, the estimated risk ratio was 1.57, presented as events per 10,000 individuals.
Conclusions
The present study remarkably showed the comparative effect of the third (booster) dose of two mRNA vaccines, BNT162b2 and mRNA-1272, among a nationwide cohort of US veterans. Both vaccines reduced the absolute risks of breakthrough SARS-CoV-2 infections and severe COVID-19 outcomes. However, mRNA-1273 recipients had a lower risk of COVID-19-related adverse events over 16 weeks of follow-up than the mRNA-1273 vaccine recipients, particularly for reported SARS-CoV-2 infections. The findings remained comparable across periods spanning Delta and Omicron predominance and only Omicron predominance. The authors advocated continuous evaluation of the comparative effectiveness and safety of additional (booster) doses of COVID-19 mRNA vaccines in the future.
Journal reference:
Barbra A. Dickerman, Hanna Gerlovin, Arin L. Madenci, Michael J. Figueroa Muñiz, Jessica K. Wise, Nimish Adhikari, Brian R. Ferolito, Katherine E. Kurgansky, David R. Gagnon, Kelly Cho, Juan P. Casas & Miguel A. Hernán, Comparative effectiveness of third doses of mRNA-based COVID-19 vaccines in US veterans. Nat Microbiol (2023). DOI: https://doi.org/10.1038/s41564-022-01272-z, https://www.nature.com/articles/s41564-022-01272-z
Thought LeadersProfessor Roberto La RagioneChair of TrusteesHumanimal Trust
In this interview, News-Medical speaks to Professor Roberto La Ragione, Chair of Trustees at Humanimal Trust, about the concept of One Medicine and how human and veterinary medicine can collaborate, share knowledge, and initiate research for the benefit of both humans and animals.
Please can you introduce yourself, tell us about your professional background, and your role at Humanimal Trust?
I am Professor Roberto La Ragione, Chair of Trustees at Humanimal Trust.
I graduated in 1995 and then studied for a postgraduate degree in veterinary microbiology at the Royal Veterinary College (University of London). In 1996, I moved to the government’s Veterinary Laboratories Agency (VLA) to undertake a Ph.D. on the pathogenesis of E. coli in poultry. Upon completing my Ph.D. studies, I commenced a post-doctoral position at Royal Holloway, University of London, studying E. coli virulence factors and vaccine development.
Since 2001, my work has focused largely on understanding the pathogenesis of zoonotic bacterial pathogens to develop control strategies. I have led several commercial, Defra, research councils (BBSRC, MRC, EPSRC, AHRC, Innovate) and EU projects in this area.
My current research interests focus on the pathogenesis of food-borne pathogens with a particular interest in Antimicrobial Resistance (AMR) and the development of intervention strategies, including vaccines, rapid diagnostic, pre, and probiotics. I have published over 190 papers in the area of host-microbe interaction, with a particular emphasis on E. coli,Salmonella, vaccines, probiotics, and AMR.
In 2005, I was appointed Head of Pathogenesis and Control at the AHVLA, and in 2010, I was appointed Professor of Veterinary Microbiology and Pathology at the University of Surrey. I gained the FRCPath in 2010, and in 2012, I was appointed the Associate Dean for Veterinary Strategy in the new School of Veterinary Medicine at the University of Surrey. In 2014, I was appointed to the position of Head of the Department of Pathology and Infectious Diseases and Director of the Veterinary Pathology Centre. In 2019 I was appointed Deputy Head of the School of Veterinary Medicine at the University of Surrey, and then in 2021, I was appointed Head of the School of Biosciences and Medicine.
I am the past president of the Med-Vet-Net Association and the Veterinary Research Club, the current Chair of Humanimal Trust, a member of the FSA ACMSF AMR sub-committee, a Trustee of the Houghton Trust, a member of the APHA Science Advisory Board and Chair of the Royal College of Pathologists Veterinary Pathology SAC. I am an Associate member of the European College of Veterinary Microbiology, and in 2020, I was awarded an Honorary Associateship of the Royal College of Veterinary Surgeons.
Humanimal Trust is a unique organization. Please could you tell us about the organization’s origin, purpose, and values?
Humanimal Trust is the only organization in the UK with the sole and specific purpose of progressing One Medicine.
It was founded in May 2014 by world-renowned orthopedic-neuro veterinary surgeon Professor Noel Fitzpatrick – otherwise known as the TV Supervet. As a vet, Noel Fitzpatrick experienced personally the deep divide between human and animal medicine and saw how unfair this was.
Image Credit: LightField Studios/Shutterstock.com
Frustrated by the lack of opportunities to share what he was learning from veterinary practice or to benefit from relevant learning from human medicine, he decided to create the platform himself. This laid the foundations for the work Humanimal Trust does today, removing barriers and seeking to close the divide between human and animal medicine.
Our five areas of work spell out I-CARE, which sums up the way we feel, our supporters feel, and we hope everybody will one day feel about One Medicine:
Influence – we care about bringing together everyone who cares about One Medicine to create a road map for change in public policy, education, and at the clinical coalface.
Collaboration – we care about creating opportunities for human and veterinary professionals and students to learn from one another (in person and virtually) by demonstrating One Medicine at work.
Awareness – we care that people should know and understand the benefits of One Medicine for humans and animals, about non-animal alternatives to laboratory models, and how much human and animal medicine can learn from one another’s clinical practice – saving time, money, and lives.
Research – we care about research – funding it, facilitating it, shouting about it – that could benefit humans and animals without using laboratory animal models.
Education – we care about learning – every child learning about the connections between humans and animals; veterinary and human medical students learning with and from one another; practitioners learning continuously from their peers.
Humanimal Trust advocates for One Medicine. What is One Medicine, when did this concept originate, and how has the understanding of it evolved in recent years?
The origins of One Medicine date back to the nineteenth century when Rudolf Virchow linked human and animal health. Sir William Osler, Dr. Calvin Schwabe, Lord Lawson Soulsby, and others have since continued to expand the One Medicine concept, identifying the connections, commonalities, and synergies between human and veterinary medicine.
It was whilst studying the history of medicine that Professor Fitzpatrick came upon a term used to describe human and veterinary medicine working with one another: One Medicine. The third edition of Dr. Calvin Schwabe’s seminal publication in 1984 of ‘Veterinary Medicine and Human Health’ which spoke of One Medicine, laid the foundation for what we now know as One Health, but in considering this text, Fitzpatrick identified a need to move away from a public health agenda to a common health agenda focusing on infectious and non-infectious diseases.
Moreover, when reviewing the three Rs (refinement, reduction, and replacement) in relation to animal use in research, it became clear that a fourth R was missing from the 3Rs principle – the principle of reciprocity so that not only do medical practitioners and allied researchers benefit, but also patients, regardless of their species.
By considering the contribution that animals can make to research by studying their lives and their responses to naturally occurring, spontaneous diseases rather than using experimental animal models in research, the use of animals in research can be significantly reduced.
One Medicine and the ‘Biology of the Future’ (Biology Week 2020)
Why is it currently the case that human and veterinary medicine are kept separate, and why would it be beneficial to change this?
Although the practice of bringing veterinary and human medical and research professionals together is thought to stimulate new and innovative research, historically, this has been challenging. A number of studies have investigated why this could be, and different levels of awareness and priorities may be one reason. A 2020 study, which surveyed vets and GPs in Australia, found that vets generally had more awareness and felt more confident in engaging in zoonoses management compared to GPs, and were also more likely to initiate cross-professional referrals.
The Trust believes that education is key to One Medicine. Only by learning about the similarities between humans and animals from the earliest stage to collaboration in the most advanced science and clinical practice will we promote change. Therefore, we must ensure that the best research, clinical practice and learning, benefiting both humans and animals, are accessible, funded, encouraged, and promoted.
A study published in 2017 by a group of scientists in The Netherlands noted that having a clear common goal (like One Medicine) can help to stimulate collaboration. The study also suggested that professional organizations could be important facilitators of collaboration in this area.
With this in mind, in 2020, the Trust launched the Humanimal Hub, a free online platform for all human and animal medical and veterinary professionals to meet, collaborate, share knowledge, and initiate research for the benefit of both humans and animals.
While still in its infancy, the Hub already has over 250 members. It provides a much-needed virtual space for connections to be made and conversations to be initiated, which the Trust actively seeks to nurture. For example, Anna Radford, a Consultant in Paediatric Surgery at Hull University NHS Trust and Leeds Children’s Hospital, was looking to collaborate with an individual or group in veterinary medicine with a specialty in problems with urinary tract or kidneys and/or antimicrobial resistance. Through the Hub, we were able to identify a suitable professional, and as a result, an interdisciplinary group has been set up to identify common urological conditions affecting both humans and companion animals.
Anna was also introduced to a diagnostics company working in the animal medical care field at the Trust’s inaugural global ‘One Medicine Symposium: Stronger Together’ in May 2021. Through them, Anna has set up a new collaboration to determine whether this diagnostic technology developed with companion animal medicine in mind could potentially also be useful to help diagnose urinary, joint, and cerebrospinal fluid infections in a busy NHS hospital setting.
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These are just two examples of how we know that great things can happen when animal and human health professionals and scientists come together.
Which areas of medicine do you currently focus on, and what benefits does One Medicine provide to this particular area?
I believe One Medicine has transformative potential across all areas of medicine where physiological and genetic similarities exist between humans and animals. There are five main pillars of research that the Trust currently seeks to fund, namely infection control and antimicrobial resistance; cancer; bone and joint disease; brain and spinal disease; and regenerative medicine.
In line with this, the Trust began an important collaboration with the children’s charity Action Medical Research in 2020 to help support two child-focused medical research projects. The first study, led by Professor Hall-Scraggs at University College London, focuses on juvenile idiopathic arthritis (JIA). Patients with JIA have a disease that causes inflammation of their joints. This leads to pain, joint deformity, disability, and reduced quality of life. There are newer drugs now available that suppress joint inflammation, but these are expensive and can have side effects, the most serious being life-threatening infection. Magnetic resonance imaging (MRI) scans can show inflammation of joints. By measuring inflammation in patients with juvenile idiopathic arthritis, the study could help optimize their treatment by showing how much inflammation is present and whether it changes with treatment.
Image Credit: Amir Bajric/Shutterstock.com
The second study, which is ongoing, is investigating infection prevention and its impact on antimicrobial resistance in critically ill children, led by Dr. Nazima Pathan, Lecturer in Paediatric Intensive Care at the University of Cambridge. The transferable data from both studies has real potential to help improve the lives of humans and animals with similar conditions.
Another example of research the Trust has funded concerns liquid biopsies for canine patients. This research was undertaken by Professor Joanna Morris and Dr. Tomoko Iwata at the University of Glasgow and is a great example of reciprocity whereby human and animal bladder cancer patients may benefit from this research.
Are there any particular examples of where either human or veterinary medicine has led to advances in the other?
Cancer research is perhaps the area for which One Medicine is most well-known. For example, dogs, long considered our best friends, don’t just share our lives but also risk factors for certain diseases. Many diseases also share genetic similarities between humans and dogs. Canine lymphoma, the second most common cancer in dogs, has relatively similar characteristics to human non-Hodgkin lymphoma. Around 1 in 8 golden retrievers will develop canine lymphoma, and CRUK estimates that 1 in 39 males and 1 in 51 females are at risk of being diagnosed with non-Hodgkin lymphoma. Both species need better, more effective ways to treat the disease, and clinical trials with canine veterinary patients have been helping to fast-track the development of new treatments in this area for several years.
Image Credit: Varvara Serebrova/Shutterstock.com
The US-based DISCO initiative recognizes the value of aligning veterinary and human drug development projects and explains why it can be worthwhile to include veterinary patients at an early stage in cancer drug development trials. From shortening drug development times to encouraging cross-collaboration between the disciplines for the benefit of both human and veterinary patients, the potential advantages of this approach are clearly laid out in a landmark 2019 paper, which came about from a workshop of the World Small Animal Veterinary Association’s One Health committee.
What is the one thing you wish people knew about One Medicine?
One Medicine is about human and animal healthcare advancing hand in hand, in an equitable and sustainable way, and not at the expense of an animal’s life.
How can people, both medical professionals and the general public, get involved with Humanimal Trust and support the One Medicine cause?
Human and animal medical professionals, students, and researchers can join the Humanimal Hub for free and use it as an opportunity to collaborate, share knowledge, and initiate research with other like-minded individuals. The Trust also holds an annual One Medicine Day event that brings together researchers, doctors, vets, allied healthcare professionals, and students from around the world to discuss practical ways forward for One Medicine. The year’s ‘One Medicine Day Seminar: One Medicine in Action’ talks can be found here.
There are also opportunities to join our team as a volunteer Ambassador, write articles for us, present at events or act as a moderator for the Hub.
There are many ways that members of the public interested in One Medicine can get involved too, from signing The Humanimal Pledge or organizing a Paws for a Picnic fundraiser with family and friends to leaving a gift in your will or becoming a volunteer speaker in your local community.
What is next for yourself and Humanimal Trust?
We recognize the need to present One Medicine consistently through an education lens. Our absolute priority is to improve understanding at every level – from pre-school to professional training (veterinary and medical undergraduates) and development – of the relationship between human and animal health and the need for collaboration and reciprocity of benefit to humans and animals.
With this in mind, our focus for the next twelve months is on four key areas of activity:
Focused awareness building among key audiences
Developing partnerships, networks, and collaborations
Education
Research funding, engagement, and influencing activity
To help drive this, we have appointed a new CEO, Joe Bailey, who will be joining us in November from RSPCA Assured, together with a new Trustee, Anna Radford, whom I referred to earlier. I have no doubt that their understanding of and passion for our purpose will help take Humanimal Trust to the next level.
We are expanding our Science Committee, which will strengthen our ability to draw on the best available expertise to make better-informed decisions about which research activities we prioritize for funding or support. In addition, to support the strategic development of our educational program, we have created a new role – Schools Education Manager – which will enable us to initiate the long-term development of a One Medicine curriculum.
We will soon launch our new Podcast series, which I’m very excited about. This will follow the Trust’s previous series, Humanimal Connection, but with a very different feel to it, so watch this space.
About Professor Roberto La Ragione, BSc (Hons) MSc Ph.D. FRSB CBiol FIBMS CSci AECVM FRCPath HonAssocRCVS
I am a Professor of Veterinary Microbiology and Pathology in the School of Veterinary Medicine and the Head of the School of Biosciences and Medicine at the University of Surrey. My role includes delivering and overseeing teaching and research in the School and running my own research group, which consists of vets, doctors, and scientists. My current research interests focus on Antimicrobial Resistance (AMR) and understanding the pathogenesis of zoonotic bacterial pathogens (those that can be transmitted from animals to humans and, in some cases, from humans to animals). I also have a particular interest in developing control and intervention strategies, including rapid diagnostics, vaccines and probiotics for controlling bacterial pathogens in companion and food-producing animals. I have published over 190 peer-reviewed papers in the area of microbiology and pathology.
Sepsis accounts for 20% of all fatalities worldwide and 20% to 50% of hospital deaths in the United States. For timely and effective antibiotic therapy crucial for sepsis survival, initial detection and identification of microbial infections are required. However, no etiologic pathogens are identified in more than 30% of cases. Distinguishing sepsis from non-infectious systemic disorders is essential since they frequently appear clinically similar during hospitalization.
About the study
In the present study, researchers created a sepsis diagnostic tool that combined host transcriptional profiling along with broad-range pathogen identification.
At two tertiary care hospitals, the team conducted a prospective observational examination of critically ill adult patients admitted to the intensive care unit (ICU) from the emergency department (ED). Patients were divided into five subgroups based on the presence or absence of sepsis. These patients included those who had: (1) clinically adjudicated sepsis as well as confirmed bacterial bloodstream infection (SepsisBSI); (2) clinically adjudicated sepsis as well as a confirmed non-bloodstream infection (Sepsisnon-BSI); (3) suspected sepsis characterized with negative clinical microbiological testing (Sepsissuspected); (4) patients having no evidence of sepsis and an explanation for their critical disease (No-sepsis); or (5) patients with an indeterminate status (Indeterm).
By conducting ribonucleic acid (RNA) sequencing on whole blood samples, the team first examined transcriptional variations between patients having clinically and microbiologically proven sepsis and those without symptoms of infection. A technique called gene set enrichment analysis (GSEA) detects clusters of genes within a dataset with related biological functions.
A differential gene expression (DE) study across the SepsisBSI and Sepsisnon-BSI groups was conducted to identify further variations between sepsis patients with infections in the bloodstream versus peripheral sites. The team developed a universal sepsis diagnostic classifier based on whole-blood gene expression patterns in response to the practical requirement to diagnose sepsis in SepsisBSI as well as Sepsisnon-BSI patients. The team utilized a bagged support vector machine (bSVM) learning strategy to choose the genes that most successfully differentiated patients with sepsis (SepsisBSI and Sepsisnon-BSI) and those without sepsis (No-sepsis).
A median of 2.3 × 107 reads was acquired after sequencing the RNA from obtained patients whose plasma specimens were available. Furthermore, DE analysis was performed to determine if a biologically plausible signal could be used to differentiate patients who did and did not have sepsis.
Results
Heart failure exacerbation, overdose/poisoning, cardiac arrest, and pulmonary embolism were the most frequently diagnosed conditions in the No-sepsis group. Irrespective of the subgroup, most patients required vasopressor support and mechanical ventilation. Patients in the SepsisBSI and Sepsisnon-BSI who had proven sepsis did not show any difference from No-sepsis patients with respect to age, sex, race, ethnicity, APACHE III score, immunocompromise, intubation status, maximal white blood cell count, or 28-day mortality. In the group of patients without sepsis, all but one patient demonstrated two or more systemic inflammatory response syndrome (SIRS) criteria.
The study also revealed the downregulation of pathways linked to ribosomal RNA processing and translation along with the upregulation of genes involved in innate immune signaling and neutrophil degranulation in sepsis patients. Using DE analysis, the team found 5,227 genes. The Sepsisnon-BSI cohort displayed enrichment in genes associated with defensins, antimicrobial peptides, and G alpha signaling as well as other pathways. On the other hand, the SepsisBSI cohort showed enrichment in genes associated with immunoregulatory interactions between non-lymphoid and lymphoid cells and CD28 signaling, among other functions.
The bSVM model displayed a mean cross-validation area under the receiver operating characteristic (ROC) curve (AUC) of 0.81. Samples with transcript counts lower than the quality control (QC) threshold had a lower mean input mass than samples with sufficient counts.
Interestingly, a number of differentially expressed genes have been identified as sepsis biomarkers, including increased CD177, repressed human leukocyte antigen – DR isotype (HLA-DRA), indicating a biologically significant transcriptome signature from plasma RNA. In the Sepsisnon-BSI group, plasma deoxyribonucleic acid (DNA) metagenomic next-generation sequencing (mNGS) revealed three out of eight bacterial urinary tract infection (UTI) pathogens and two out of 25 bacterial lower respiratory tract infection (LRTI) pathogens. None of the three patients with severe colitis caused by C. difficile had this pathogen. In eight out of 73 patients with proven sepsis, additional potential bacterial pathogens not identified by culture were found.
Conclusion
Overall, the study findings showed that reliable sepsis diagnosis is facilitated by the combination of host gene expression profiling with metagenomic pathogen identification from plasma nucleic acid. Future research is required to verify and gauge the therapeutic utility of this culture-independent diagnostic strategy.
Journal reference:
Kalantar, K., Neyton, L., Abdelghany, M., Mick, E., Jauregui, A., & Caldera, S. et al. (2022). Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults. Nature Microbiology. doi: 10.1038/s41564-022-01237-2https://www.nature.com/articles/s41564-022-01237-2
Microbiome: From Research and Innovation to Market
Study: Fast and Accurate Identification of Candida auris by High Resolution Mass Spectrometry. Image Credit: Jens Goepfert / Shutterstock
C. auris clade differentiation using monoisotopic mass measurements depicted as heat map. Color scale ranges from blue (max signal) to dark red (no signal), representing abundance of measured monoisotopic masses in each strain. Clade specific differential protein masses are visible from the rectangular vertical boxes indicating the geographic affiliation and clade assignment and its vertically associated dendrogram indicating observed protein masses (columns vs. rows). X-axis indicating clade assignment and y-axis indicating observed MS1 protein masses.
My role includes delivering and overseeing teaching and research in the School and running my own research group, which consists of vets, doctors, and scientists. My current research interests focus on Antimicrobial Resistance (AMR) and understanding the pathogenesis of zoonotic bacterial pathogens (those that can be transmitted from animals to humans and, in some cases, from humans to animals). I also have a particular interest in developing control and intervention strategies, including rapid diagnostics, vaccines and probiotics for controlling bacterial pathogens in companion and food-producing animals. I have published over 190 peer-reviewed papers in the area of microbiology and pathology.
