Tag Archives: Syndrome

Microbiology

Candida auris infection without epidemiologic links to a prior outbreak

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Dr. Priyom Bose, Ph.D.By Dr. Priyom Bose, Ph.D.Mar 23 2023Reviewed by Danielle Ellis, B.Sc.

The Centers for Disease Control and Prevention (CDC) has classified Candida auris (C. auris) as an urgent public threat due to its role in elevating mortality, its ability to persist in hospital environments, and the high possibility of developing pan-drug resistance.

Notably, a recent study published in the journal Open Forum Infectious Diseases has pointed out that surfaces near patients with C. auris quickly become re-contaminated after cleaning.

Existing research has not adequately elucidated the environmental reservoirs of C. auris. Further, few studies have reported epidemiologic links associated with C. auris infection. 

Study: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship?. Image Credit: Kateryna Kon / ShutterstockStudy: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship? Image Credit: Kateryna Kon / Shutterstock

Background

C. auris is a species of fungus that grows as yeast. It is one of the few species of the genus Candida which cause candidiasis in humans. In the past, C. auris infection was primarily found in cancer patients or those subjected to feeding tubes.

In the United States (US), the emergence of C. auris was traced to New York, and surveillance for this fungal infection was focused mainly on New York City to detect outbreaks. Recently, scientists investigated the association between genomic epidemiology and C. auris infection in Western New York.

A Case Study

The study describes the emergence of C. auris in a patient hospitalized at a small community hospital in Genesee County, New York (NY). In January 2022, C. auris was isolated from the urine culture of a 68-year-old male on the 51st day of hospitalization.

This patient had no known epidemiological connections outside his immediate community. Before his hospitalization, he was not exposed to other patients or family members associated with C. auris infection.

This patient had no history of organ transplantation, decubitus ulcers, hemodialysis, feeding tubes, or nursing home stays. He had an active lifestyle with a history of mild vascular dementia. He was hospitalized due to pneumonia and was prescribed azithromycin treatment.

Post hospitalization, he tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and was treated with dexamethasone (6 mg) daily for 10 days and remdesivir (200 mg) once, followed by 100 mg daily for five days.

Since the patient’s chest radiograph showed left lobar consolidation, he was further treated with empiric ceftriaxone and azithromycin. As the respiratory symptoms deteriorated, he received non-invasive positive pressure ventilation, with subsequent endotracheal intubation for eight days. He was successfully extubated. He developed a fever and received antimicrobial therapy for 73 days. The patient had a urinary catheter and a peripherally inserted central line in his arm for 35 days. 

Microbiology culture test and serum procalcitonin levels remained negative and within normal levels. On the 22nd day of hospitalization, Candida albicans were isolated from respiratory samples. On the 51st day, the urine culture revealed the presence of azole-resistant C. auris.

The isolated C. auris (MRSN101498) was forwarded to the Multidrug-resistant organism Repository and Surveillance Network (MRSN), where genomic sequencing was performed. After the patient was discharged, the hospital room was cleaned using hydrogen peroxide and peracetic acid, followed by ultraviolet-C light. Other patients who shared rooms with the patient with C. auris were tested for infection.

Study Outcomes

C. auris was not detected in the Western NY community hospital in the past year. Physicians stated that the patient received excessive antibiotic treatment for a prolonged period. Genomic studies revealed that the MRSN101498 genome sequence was closely related to the 2013 Indian strain with minor genomic differences. Interestingly, the K143R mutation in ERG11 was found in MRSN101498, which is associated with triazole resistance in Candida albicans.

Whole genome single nucleotide polymorphism (SNP) analysis also highlighted that MRSN101498 was strongly genetically related to four other isolates, with marginal differences.

These isolates were linked to an outbreak in March 2017 in a hospital 47 miles northeast of Rochester, NY. Based on the current findings, it is highly likely that isolates from Western NY share a recent common ancestor.

Study Importance

This case study is important for several reasons, including the absence of epidemiologic links to C.auris infection. Since reports from rural sectors are rare, this study addresses a vital surveillance ‘blind spot.’ 

However, the current study failed to identify the potential reservoirs of MRSN101498 in Western NY. Sporicidal disinfectants were inefficient for both Clostridioides difficile and C. auris. However, terminal cleaning protocols that included UV irradiation and sporicidal cleaning agents were able to eradicate C. auris effectively.

The current study highlights the role of excessive antibiotic exposure in the emergence of C. auris. It also indicates the challenges in eliminating fungi from hospital settings. The authors recommend proper antibiotic treatment and cleaning procedures for drug-resistant pathogens.

Journal reference:
Microbiology

Low-cost, universal oral COVID-19 vaccine prevents severe respiratory illness in hamsters

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Reviewed by Emily Henderson, B.Sc.Mar 22 2023

A UCLA-led team has developed an inexpensive, universal oral COVID-19 vaccine that prevented severe respiratory illness and weight loss when tested in hamsters, which are naturally susceptible to SARS-CoV-2. It proved as effective as vaccines administered by injection or intranasally in the research.

If ultimately approved for human use, it could be a weapon against all COVID-19 variants and boost uptake, particularly in low- and middle-income countries, and among those with an aversion to needles.

The study is published in the peer-reviewed journal Microbiology Spectrum.

The oral vaccine is based primarily on the nucleocapsid protein, which is the most abundantly expressed of the virus’s four major structural proteins and evolves at a much slower rate than the frequently mutating spike protein. The vaccine utilizes a highly weakened bacterium to produce the nucleocapsid protein in infected cells as well as the membrane protein, which is another highly abundant viral structural protein.

Being a universal vaccine based primarily upon the nucleocapsid protein, the vaccine is resistant to the incessant mutations of the SARS-CoV-2 spike protein upon which virtually all current vaccines are based. As a result, current vaccines rapidly become obsolete, requiring that they repeatedly be re-engineered. Hence, our vaccine should protect against new and emerging variants of SARS-CoV-2.”

Dr. Marcus Horwitz, senior author, distinguished professor of medicine in the Division of Infectious Diseases and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA

Oral delivery also makes it easier to distribute the vaccine in resource poor areas of the world by eliminating the need for needles, syringes, and trained personnel to deliver injectable vaccines, he added. “An oral vaccine may also be attractive to many people with vaccine hesitancy on account of fear of needles.”

The researchers noted that while it worked exceptionally well in preventing severe respiratory illness, it did not provide full protection against high viral loads in the hamsters. Also, they did not test it against the Omicron strain, which contains a nearly identical nucleocapsid protein, because of this strain’s low virulence in the golden Syrian hamsters they used.

But the vaccine, they write, “is efficacious when administered via the oral route against COVID-19-like disease in a highly demanding animal model. This conveniently administered, easily manufactured, inexpensive, and readily stored and transported vaccine could play a major role in ending the COVID-19 pandemic by protecting immunized individuals from serious disease from current and future strains of SARS-CoV-2.”

The next step in the process will be to manufacture the vaccine for oral administration via an acid-resistant enteric capsule that will allow the vaccine to be safely released in the small intestine, Horwitz said. It will then be tested for safety, immunogenicity, and efficacy in humans.

“We also plan to expand the vaccine to protect against infections caused by other types of potentially pandemic coronaviruses such as the virus that causes Middle Eastern Respiratory Syndrome (MERS),” he added.

Additional authors are Qingmei Jia and Saša Masleša-Galić of UCLA; Helle Bielefeldt-Ohmann of the University of Queensland, Australia; and Rachel Maison, Airn Hartwig, and Richard Bowen of Colorado State University.

This study was supported by a Corona Virus Seed grant from the UCLA AIDS Institute and Charity Treks and by the National Institutes of Health (AI141390).

Source:

UCLA Health

Journal reference:

Jia, Q., et al. (2023). Oral Administration of Universal Bacterium-Vectored Nucleocapsid-Expressing COVID-19 Vaccine is Efficacious in Hamsters. Microbiology Spectrum. doi.org/10.1128/spectrum.05035-22.

Microbiology

New SARS-CoV-2 Omicron XBB.1.5 variant has high transmissibility and infectivity, study finds

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Mar 20 2023Reviewed by Danielle Ellis, B.Sc.

COVID-19 has caused significant global panic after its rapid emergence more than 3 years ago. Although we now have highly effective vaccines against the SARS-CoV-2 virus, which causes COVID-19, scientists continue to study emerging SARS-CoV-2 variants in order to safeguard public health and devise global preventive strategies against emerging variants. A team led by Japanese researchers has recently discovered that the SARS-CoV-2 Omicron XBB.1.5 variant, prevalent in the Western hemisphere, has high transmissibility and infectivity.

New SARS-CoV-2 Omicron XBB.1.5 variant has high transmissibility and infectivity, study finds
New SARS-CoV-2 variant may jeopardize public health across the globe. The SARS-CoV-2 Omicron XBB.1.5 variant spreads rapidly and is more infectious than its historic precursor. Image Credit: The University of Tokyo

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for millions of deaths worldwide. Although scientists have designed novel vaccines to counter COVID-19, they are constantly on the lookout for emerging variants that can bypass vaccine resistance and potentially jeopardize global public health. A team led by Japanese researchers has recently been successful in characterizing the new SARS-CoV-2 Omicron XBB.1.5 variant, which was first detected in October 2022. Their findings were published on January 31, 2023 in volume 23 of The Lancet Infectious Diseases.​​​

Says senior author Prof. Kei Sato from the Division of Systems Virology, The Institute of Medical Science, The University of Tokyo, Japan, “Because the Omicron XBB.1.5 variant can spread more rapidly than previous variants and has a potential to cause the next epidemic surge, we should carefully monitor it to safeguard public health.”

While studying emerging variants of the SARs-CoV-2 Omicron lineage, the research team made a startling discovery: the SARS-CoV-2 Omicron XBB.1.5 variant has a novel mutation in the spike (S) protein—the protein that anchors the virus firmly to the human angiotensin converting enzyme-2 (ACE2) receptor, thus facilitating the invasion of human cells. The serine-to-proline amino acid mutation noted at residue no. 486 in the S protein is virologically concerning because of a variety of reasons.

Sharing his concerns, first author Keiya Uriu from the Division of Systems Virology, Department of Microbiology and Immunology, The University of Tokyo, Japan, says, “In late 2022, the SARS-CoV-2 Omicron BQ.1 and XBB lineages, characterized by amino acid substitutions in the S protein and increased viral fitness, had become predominant in the Western and Eastern Hemisphere, respectively. In 2022, we elucidated the characteristics of a variety of newly emerging SARS-CoV-2 Omicron subvariants. At the end of 2022, the XBB.1.5 variant, a descendant of XBB.1 that acquired the S:S486P substitution, emerged and was rapidly spreading in the USA.”

To gain mechanistic insights into the infectivity, transmissibility, and immune response associated with XBB.1.5, the team conducted a series of experiments. For instance, upon conducting epidemic dynamics analysis—statistical modeling that facilitates the analysis of the general characteristics of any epidemic—the team realized that the relative effective reproduction number (Re) of XBB.1.5 was 1.2-fold greater than that of the parental XBB.1. This indicated that an individual with the XBB.1.5 variant could infect 1.2 times more people in the population than someone with the parental XBB.1 variant. Moreover, the team also realized that, as of December 2022, XBB.1.5 was rapidly outcompeting BQ.1.1, the predominant lineage in the United States.

Co-first-author Jumpei Ito from the Division of Systems Virology, remarks, “Our data suggest that XBB.1.5 will rapidly spread worldwide in the near future.”

The team also studied the virological features of XBB.1.5 to determine how tightly the S protein of the new variant interacts with the human ACE2 receptor. To this end, the researchers conducted a yeast surface display assay. The results showed that the dissociation constant (KD) corresponding to the physical interaction between the XBB.1.5 S receptor-binding domain (RBD) and the human ACE2 receptor is significantly (4.3-fold) lower than that for XBB.1 S RBD. “In other words, the XBB.1.5 variant binds to human ACE2 receptor with very high affinity,” explains Shigeru Fujita from the Division of Systems Virology.

Further experiments using lentivirus-based pseudoviruses also showed that XBB.1.5 had approximately 3-fold higher infectivity than XBB.1. These results suggest that XBB.1.5 exhibits a remarkably strong affinity to the human ACE2 receptor, which can be attributed to the S486P substitution.

The study by Prof. Sato and his team led to another important discovery from an immunization perspective. The XBB.1.5 S protein was found to be highly resistant to neutralization antibodies elicited by breakthrough infection with the BA.2/BA.5 subvariants. In other words, patients with prior infection from the BA.2/BA.5 subvariants may not show robust immunity against XBB.1.5, increasing their chances of infection and disease.

The results of our virological experiments explain why the Omicron XBB.1.5 variant has a higher transmissibility than past variants: This variant acquired strong binding ability to human ACE2 while maintaining a higher ability to escape from neutralizing antibodies.”

​​​​​​​Yusuke Kosugi, Division of Systems Virology, Department of Microbiology and Immunology, The University of Tokyo, Japan

Contributing members of The Genotype to Phenotype Japan (G2P-Japan) Consortium conclude, “The SARS-CoV-2 Omicron XBB.1.5 variant does show enhanced transmissibility. Although few cases have been detected in the Eastern hemisphere, it could become a looming threat. Imminent prevention measures are needed.”

​​​​​​​Thanks to the research team for the early warning! Meanwhile, we must continue adopting safe practices to defend ourselves from XBB.1.5. 

Source:

The University of Tokyo

Journal reference:

Uriu, K., et al. (2023) Enhanced transmissibility, infectivity, and immune resistance of the SARS-CoV-2 omicron XBB.1.5 variant. The Lancet Infectious Diseases. doi.org/10.1016/S1473-3099(23)00051-8.

Microbiology

Real-world data on the effectiveness of Sotrovimab as a prophylactic against COVID-19

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Bhavana KunkalikarBy Bhavana KunkalikarMar 16 2023Reviewed by Danielle Ellis, B.Sc.

*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.

Study: Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 subvariant predominance: a systematic literature review. Image Credit: Cryptographer / ShutterstockStudy: Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 subvariant predominance: a systematic literature review. Image Credit: Cryptographer / Shutterstock

About the study

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.

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

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:
Microbiology

Study finds community-onset bacterial coinfection in children with critical COVID-19 is infrequent but empiric antibiotics are commonly prescribed

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Pooja Toshniwal PahariaBy Pooja Toshniwal PahariaMar 8 2023Reviewed by Danielle Ellis, B.Sc.

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.

Study: Community-onset bacterial coinfection in children critically ill with SARS-CoV-2 infection. Image Credit: nokwalai/Shutterstock
Study: Community-onset bacterial coinfection in children critically ill with SARS-CoV-2 infection. Image Credit: nokwalai/Shutterstock

Background

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.

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.

Journal reference:
Microbiology

Study finds unique epigenetic biosignature in individuals with post-COVID syndrome

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Reviewed by Emily Henderson, B.Sc.Feb 28 2023

A reprogramming of which genes are active, and which are not, is visible in post-COVID sufferers. This is shown in a study from Linköping University, Sweden, on a small group of individuals. The researchers can see that genes associated with taste and smell, as well as cell metabolism, are affected in individuals with post-COVID syndrome. These findings may ultimately contribute to the development of new diagnostic tools for this and similar diseases.

There are many external factors that can affect which of all the genes in a cell are used at a certain point in time. The body’s ability to switch genes on and off contributes to our ability to adapt to various conditions. This gene use regulation is called epigenetics.

One of the regulation mechanisms entails that a small chemical group, a methyl group, is switched on and removed from the DNA strand. Reduced methylation of a gene may be a sign of it becoming easier for the cell to read and use, whereas high methylation most often means that the gene is not used. The researchers in Maria Lerm’s research group at Linköping University have previously found that exposure to the tuberculosis bacteria is visible in individuals’ DNA by looking at certain epigenetic changes.

In their new study, published in Clinical Epigenetics, the researchers studied blood samples from ten individuals having had persistent post-COVID symptoms for more than 12 weeks. The most common symptoms were a feeling of not being able to draw in enough air, palpitations, muscle weakness and loss of smell and taste.

These individuals were compared with two other groups: healthy COVID-19 convalescents, and individuals who had not had COVID-19 when the samples were taken. The researchers measured the methylation pattern on 850,000 sites of the DNA and then used an algorithm that can find data similarities and differences. It turned out that the three groups differed from each other and had distinct methylation profiles. The researchers then identified the genes that differ in methylation patterns between the groups.

“We have found that, for example, signaling pathways that control taste and smell have been affected. This confirms that the epigenetic differences may in fact be associated with the set of symptoms and be physiologically relevant,” says Maria Lerm, Professor of Medical Microbiology at the Department of Biomedical and Clinical Sciences, BKV, at Linköping University.

A previous study conducted by the research group concerned individuals who had recently recovered from COVID-19 and who showed a similar epigenetic reprogramming of signaling pathways associated with taste and smell.

In their new study, the researchers also found epigenetic changes in what is known as the angiotensin-2 system in post-COVID sufferers. This could be biologically relevant as the coronavirus which causes COVID-19, i.e., the SARS-CoV-2 virus, uses the angiotensin-2 system to enter and infect cells.

One of several conditions similar to post-covid is chronic fatigue syndrome, CFS, which is also known as myalgic encephalomyelitis, ME.

“One important finding is that we can see that the cells’ energy factories, the mitochondria, are affected in the post-COVID group. Other studies have shown that the cells’ energy factories have also been affected in cases of chronic fatigue,” says Maria Lerm.

There is currently no test that doctors can use to decide whether a person has post-COVID syndrome. The researchers are hoping that their recent findings can contribute to the development of diagnostic tools for health care providers, tools that might perhaps even make it possible to distinguish post-COVID from similar conditions.

The study was financed with support from the Swedish Heart Lung Foundation and the Swedish Research Council. The methylation pattern of study participants’ DNA was analyzed at Clinical Genomics, a SciLifeLab platform at Linköping University and Region östergötland.

Source:

Linköping University

Journal reference:

Defining post-acute COVID-19 syndrome (PACS) by an epigenetic biosignature in peripheral blood mononuclear cells, Frida Nikesjö, Shumaila Sayyab, Lovisa Karlsson, Eirini Apostolou, Anders Rosén, Kristofer Hedman and Maria Lerm, (2022), Clinical Epigenetics 14:172, published online on 14 December 2022 https://doi.org/10.1186/s13148-022-01398-1

Microbiology

Altered gut microbiome plays a major role in the progression of endometriosis in animal model

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Reviewed by Emily Henderson, B.Sc.Jan 25 2023

About 196 million women worldwide suffer from endometriosis, a condition that typically causes pelvic pain and infertility. Endometriosis develops when lining inside the womb grows attached to surrounding tissues, such as the intestine or the membrane lining the abdominal cavity, causing bleeding, pain and other symptoms. Despite decades of research, little is known about the factors that contribute to the development of endometriosis.

Evidence suggests that the microbiome, a community of microorganisms living inside the body, is altered in women with endometriosis. In this study published in the journal Cell Death & Discovery, researchers at Baylor College of Medicine discovered that an altered gut microbiome plays a pivotal role in endometriosis disease progression in an animal model.

“To investigate the role of the microbiome in endometriosis we first implemented a novel mouse model of the condition in which we eliminated the microbiome using antibiotics,” said lead author Dr. Rama Kommagani, associate professor in the Departments of Pathology and Immunology and of Molecular Virology and Microbiology at Baylor.

The researchers found that mice lacking gut microbiome had smaller endometriotic lesions than mice with a microbiome. Furthermore, when gut microbiome-free mice received gut microbiota from mice with endometriosis, the lesions grew as large as those in mice retaining their microbiome. These findings suggest that altered gut bacteria drive disease progression. On the other hand, the uterine microbiome did not seem to affect disease progression.

The team also discovered a novel signature of microbiome-derived metabolites, products produced by the microbes, that were significantly altered in feces of mice with endometriosis. Supporting the role of microbiome metabolites in disease progression, Kommagani and his colleagues found that treatment of endometriotic cells and mice with the metabolite called quinic acid significantly enhanced the cellular proliferation and endometriotic lesion growth, respectively.

The findings suggest that certain microbiome communities and/or their metabolites can contribute to endometriosis progression and that modifying the composition of these communities could help control the condition in human patients. “We are currently investigating this possibility,” Kommagani said.

The findings also suggested that studying microbiome metabolites in human stool samples could be used as a diagnostic tool. “Endometriosis is typically diagnosed with ultrasound, and an invasive procedure is necessary to characterize the lesion well,” Kommagani said. “We are investigating whether microbiome metabolites in human stool samples could be a useful diagnostic tool and also whether some of these metabolites could be used as a treatment strategy.”

Women with endometriosis also tend to have bowel issues, such as colitis or inflammatory bowel syndrome.

We are interested in determining whether changes in the gut microbiome could affect bowel conditions and the possibility of controlling them by modifying the microbiome or with their metabolites.”

Dr. Rama Kommagani, Lead Author

Source:

Baylor College of Medicine

Journal reference:

Chadchan, S.B., et al. (2023) Gut microbiota and microbiota-derived metabolites promotes endometriosis. Cell Death Discovery. doi.org/10.1038/s41420-023-01309-0.

Microbiology

Maternal and perinatal outcomes of women infected with SARS-CoV-2 during the Omicron wave in Italy

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Bhavana KunkalikarBy Bhavana KunkalikarJan 25 2023Reviewed by Danielle Ellis, B.Sc.

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.

Study: Vaccination against SARS-CoV-2 in pregnancy during the Omicron wave: the prospective cohort study of the Italian obstetric surveillance system. Image Credit: GolF2532/Shutterstock
Study: Vaccination against SARS-CoV-2 in pregnancy during the Omicron wave: the prospective cohort study of the Italian obstetric surveillance system. Image Credit: GolF2532/Shutterstock

Background

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

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.

Journal reference:
Microbiology

New research evaluates clinical trials investigating post-acute COVID-19 syndrome treatment

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Neha MathurBy Neha MathurJan 23 2023Reviewed by Aimee Molineux

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.

Study: 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. Image Credit: GoodStudio/Shutterstock
Study: 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. Image Credit: GoodStudio/Shutterstock

Background

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.

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.2023.01.007 https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(23)00009-5/fulltext
Microbiology

Gut bacterial community found to be less diverse in people with irritable bowel syndrome

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Reviewed by Emily Henderson, B.Sc.Jan 19 2023

People with irritable bowel syndrome (IBS) have lower bacterial diversity in the intestine than do healthy people, according to a team of Korean investigators. The investigators believe that theirs is the first analysis to find a clear association between IBS and reduced diversity in the microbiota of the gut. The research appears in Microbiology Spectrum, an open-access journal of the American Society for Microbiology.

Normally, “More than 10,000 species of microorganism live in the human intestine,” said corresponding author Jung Ok Shim, M.D., Ph.D., professor of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Korea University College of Medicine, Seoul. Disruption of the microbiome of the human gastrointestinal tract can trigger IBS. Typically, IBS causes bloating, diarrhea, and stomach pain or cramps.

Previous studies of gut bacteria in patients with IBS have been controversial, with inconsistent results, due to small sample size and lack of consistent analytical methods used among these studies, said Shim. The investigators combined their own dataset with 9 published, shared datasets, encompassing 576 IBS patients and 487 healthy controls, analyzing them with a “unified data processing and analytical method.”

The researchers found that the gut bacterial community is less diverse in IBS patients than in healthy people, said Shim. Additionally, the abundance of 21 bacterial species differed between IBS patients and healthy controls. However, the findings were not statistically significant in the pediatric cohort due to small sample size.

The investigators proved that the disturbed gut bacterial community “is associated with IBS, though this does not mean that the relationship is causal,” said Shim. “Functional studies are needed to prove whether the change in gut micro-organisms contributes to development of IBS.”

Even though IBS is a common disorder, its pathogenesis remains unknown, and as yet there is no effective treatment strategy. “Based on the epidemiological studies of IBS patients, altered gut microbiota was proposed as one of the possible causes of IBS,” the researchers write. “Acute bacterial gastroenteritis can cause chronic, asymptomatic, low-grade intestinal wall inflammation sufficient to alter neuromuscular and epithelial cell function.”

Source:

American Society for Microbiology

Journal reference:

Kim, G-H., et al. (2023) Gut Bacterial Dysbiosis in Irritable Bowel Syndrome: a Case-Control Study and a Cross-Cohort Analysis Using Publicly Available Data Sets. Microbiology Spectrum. doi.org/10.1128/spectrum.02125-22.