18F-FDG brain PET hypometabolism in post-SARS-CoV-2 infection: substrate for persistent/delayed disorders?

PURPOSE: Several brain complications of SARS-CoV-2 infection have been reported. It has been moreover speculated that this neurotropism could potentially cause a delayed outbreak of neuropsychiatric and neurodegenerative diseases of neuroinflammatory origin. A propagation mechanism has been proposed across the cribriform plate of the ethmoid bone, from the nose to the olfactory epithelium, and possibly afterward to other limbic structures, and deeper parts of the brain including the brainstem. METHODS: Review of clinical examination, and whole-brain voxel-based analysis of 18F-FDG PET metabolism in comparison with healthy subjects (p voxel < 0.001, p-cluster < 0.05, uncorrected), of two patients with confirmed diagnosis of SARS-CoV-2 explored at the post-viral stage of the disease. RESULTS: Hypometabolism of the olfactory/rectus gyrus was found on the two patients, especially one with 4-week prolonged anosmia. Additional hypometabolisms were found within amygdala, hippocampus, parahippocampus, cingulate cortex, pre-/post-central gyrus, thalamus/hypothalamus, cerebellum, pons, and medulla in the other patient who complained of delayed onset of a painful syndrome. CONCLUSION: These preliminary findings reinforce the hypotheses of SARS-CoV-2 neurotropism through the olfactory bulb and the possible extension of this impairment to other brain structures. 18F-FDG PET hypometabolism could constitute a cerebral quantitative biomarker of this involvement. Post-viral cohort studies are required to specify the exact relationship between such hypometabolisms and the possible persistent disorders, especially involving cognitive or emotion disturbances, residual respiratory symptoms, or painful complaints.

18F-FDG brain PET hypometabolism in patients with long COVID.

PURPOSE: In the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as "long COVID." We here present a retrospective analysis of 18F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection. METHODS: PET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients' characteristics and functional complaints. RESULTS: In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p < 0.001). CONCLUSION: This study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients' symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.

Evaluating the serological status of COVID-19 patients using an indirect immunofluorescent assay, France.

An indirect in-house immunofluorescent assay was developed in order to assess the serological status of COVID-19 patients in Marseille, France. Performance of IFA was compared to a commercial ELISA IgG kit. We tested 888 RT-qPCR-confirmed COVID-19 patients (1302 serum samples) and 350 controls including 200 sera collected before the pandemic, 64 sera known to be associated with nonspecific serological interference, 36 sera from non-coronavirus pneumonia and 50 sera from patient with other common coronavirus to elicit false-positive serology. Incorporating an inactivated clinical SARS-CoV-2 isolate as the antigen, the specificity of the assay was measured as 100% for IgA titre ≥ 1:200, 98.6% for IgM titre ≥ 1:200 and 96.3% for IgG titre ≥ 1:100 after testing a series of negative controls. IFA presented substantial agreement (86%) with ELISA EUROIMMUN SARS-CoV-2 IgG kit (Cohen's Kappa = 0.61). The presence of antibodies was then measured at 3% before a 5-day evolution up to 47% after more than 15 days of evolution. We observed that the rates of seropositivity as well as the titre of specific antibodies were both significantly higher in patients with a poor clinical outcome than in patients with a favourable evolution. These data, which have to be integrated into the ongoing understanding of the immunological phase of the infection, suggest that detection anti-SARS-CoV-2 antibodies is useful as a marker associated with COVID-19 severity. The IFA assay reported here is useful for monitoring SARS-CoV-2 exposure at the individual and population levels.

Salt in stools is associated with obesity, gut halophilic microbiota and Akkermansia muciniphila depletion in humans.

BACKGROUND/OBJECTIVES: High salt intake has been linked to several diseases including obesity and an increased risk of death; however, fecal salinity and the ability of salt to alter the gut microbiota, which was recently identified as an instrumental factor for health and disease, remains poorly explored. METHODS/SUBJECTS: We analyzed the fecal samples of 1326 human individuals for salinity by refractometry, 572 for gut microbiota by culturomics, and 164 by 16S rRNA-targeted metagenomics. Geographical origin, age, gender, and obesity were tested as predictors of fecal salinity and halophilic diversity. All halophilic isolates were characterized by taxonogenomics and their genome sequenced. RESULTS: Fecal salinity was associated with obesity independently of geographical origin, gender, and age. The first 2 human-associated halophilic archaeal members were isolated along with 64 distinct halophilic species, including 21 new species and 41 known in the environment but not in humans. No halophiles grow in less than 1.5% salinity. Above this threshold, the richness of the halophilic microbiota was correlated with fecal salinity (r = 0.58, p < 0.0001). 16S metagenomics linked high fecal salinity to decreased diversity (linear regression, p < .035) and a depletion in anti-obesity Akkermansia muciniphila and Bifidobacterium, specifically B. longum and B. adolescentis. Genomics analysis suggested that halophilic microbes are not only transient passengers but may be residents of the human gut. CONCLUSIONS: High salt levels are associated with alteration of the gut microbial ecosystem and halophilic microbiota, as discovered during this study. Further studies should clarify if the gut microbiota alterations associated with high salt levels and the human halophilic microbiota could be causally related to human disease, such as obesity.

Antiphospholipid antibodies proposed in the diagnosis of infective endocarditis.

Antiphospholipid antibodies (aPL) may occur alone or associated with other diseases. To evaluate aPL, tested as anticardiolipin antibodies (IgG aCL) in infective endocarditis (IE) diagnosis, we investigated their prevalence in a cohort of 651 patients with IE suspicion. aPL was significantly associated with definite IE versus IE-rejected patients. Their mean levels were significantly higher in patients with definite IE versus possible IE. When applied as Duke minor criterion, they were significantly more often positive, and at higher levels, in patients with definite IE than in patients with possible or rejected IE. aPL could be helpful in difficult cases of IE diagnosis.

Dramatic reduction in Clostridium difficile ribotype 027-associated mortality with early fecal transplantation by the nasogastric route: a preliminary report.

Clostridium difficile ribotype 027 (CD027)-associated diarrhea preferentially affects elderly patients and causes a high mortality rate. Fecal microbiota transplantation has become an alternative treatment for recurrent C. difficile infections. An outbreak of CD027 infections has occurred in Marseille since March 2013. From March to November 2013, we treated patients using only antibiotics or fecal microbiota transplantation after at least three relapses. Beginning in November 2013, we performed early transplantation using a nasogastric tube during the first week of infection, in combination with antibiotic treatment. Sixty-one patients with a mean age of 84 years were hospitalized, including 42 patients treated only with antibiotics, three with tardive transplantation, and 16 with early transplantation. The patients were comparable in clinical involvement. The global mortality rate was 3/16 (18.75 %) among the patients treated by early transplantation and 29/45 (64.4 %) among the patients only treated by antibiotics or by tardive transplantation (p < 0.01). Among these 45 patients, 23 (51 %) died at day 31, including 17 who died at day 7. Early fecal transplantation was associated with a significantly reduced mortality rate, with only one patient dead at day 31 (6.25 %). In a Cox model, early transplantation was the only independent predictor of survival (hazard ratio 0.18, 95 % confidence interval 0.05-0.61, p = 0.006). Six of the 16 patients (37.5 %) needed a second transplantation before symptom resolution. Early fecal microbiota transplantation in combination with antibiotics should be the first-line treatment for CD027 infections.

Bone and joint infections due to anaerobic bacteria: an analysis of 61 cases and review of the literature.

The diagnosis of anaerobic bone and joint infections (BJI) were underestimated before the advent of molecular identification and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). We report 61 cases of anaerobic infections based on our 4-year experience with the management of BJI. A total of 75% of cases were post-surgical infections, associated with osteosynthesis devices (65%). Early infections occurred in 27% of cases, delayed infections in 17.5% of cases, and late infections in 55% of cases. We recorded 36 species of 93 anaerobic strains using MALDI-TOF MS (91) and molecular methods (2). We identified 20 strains of Propionibacterium acnes, 13 of Finegoldia magna, six of Peptoniphilus asaccharolyticus, and six of P. harei. Polymicrobial infections occurred in 50 cases. Surgical treatment was performed in 93.5% of cases. The antibiotic treatments included amoxicillin (30%), amoxicillin-clavulanic acid (16%), metronidazole (30%), and clindamycin (26%). Hyperbaric oxygen therapy was used in 17 cases (28%). The relapse rate (27%) was associated with lower limbs localization (p = 0.001). P. acnes BJI was associated with shoulder (p = 0.019), vertebra (p = 0.021), and head flap localization (p = 0.011), and none of these cases relapsed (p = 0.007). F. magna BJI was associated with ankle localization (p = 0.014). Anaerobic BJI is typically considered as a post-surgical polymicrobial infection, and the management of this infection combines surgical and medical treatments. MALDI-TOF MS and molecular identification have improved diagnosis. Thus, physicians should be aware of the polymicrobial nature of anaerobic BJI to establish immediate broad-spectrum antibiotic treatment during the post-surgical period until accurate microbiological results have been obtained.

Drug-resistant tuberculosis care and treatment outcomes over the last 15 years in Ethiopia: Results from a mixed-method review of trends.

BACKGROUND AND OBJECTIVES: Drug resistant tuberculosis (DR-TB) remains a global challenge with about a third of the cases are not detected. With the recent advances in the diagnosis and treatment follow-up of DR-TB, there have been improvements with treatment success rates. However, there is limited evidence on the successful models of care that have consistently registered good outcomes. Our aim was to assess Ethiopia's experience in scaling up an ambulatory, decentralized model of care while managing multiple regimen transition processes and external shocks. METHODS: This was a cross-sectional, mixed-method study. For the quantitative data, we reviewed routine surveillance data for the period 2009-2022 and collected additional data from publicly available reports. We then analyzed the data descriptively. Qualitative data were collected from program reports, quarterly presentations, minutes of technical working group meetings, and clinical review committee reports and analyzed thematically. RESULTS: The number of DR-TB treatment initiating centers increased from 1 to 67, and enrollment increased from 88 in 2010 to 741 in 2019, but declined to 518 in 2022. A treatment success rate (TSR) of over 70% was sustained. The decentralized and ambulatory service delivery remained the core service delivery model. The country successfully navigated multiple regimen transitions, including the recently introduced six-month short oral regimen. Several challenges remain, including the lack of strong and sustainable specimen transportation system, lack of established systems for timely tracing and linking of missed DR-TB cases, and data quality issues. CONCLUSIONS: Ethiopia scaled up a decentralized ambulatory model of care, kept up to date with recent developments in treatment regimens, and maintained a high TSR, despite the influence of multiple external challenges. The recent decline in case notification requires a deeper look into the underlying reasons. The feasibility of fully integrating DR-TB treatment and follow up at community level should be explored further.

Correlation between body mass index and gut concentrations of Lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli.

BACKGROUND: Genus and species level analysis is the best way to characterize alterations in the human gut microbiota that are associated with obesity, because the clustering of obese and lean microbiotas increases with the taxonomic depth of the analysis. Bifidobacterium genus members have been associated with a lean status, whereas different Lactobacillus species are associated both with a lean and an obese status. OBJECTIVES AND METHODS: We analyzed the fecal concentrations of Bacteroidetes, Firmicutes, Methanobrevibacter smithii, the genus Lactobacillus, five other Lactobacillus species previously linked with lean or obese populations, Escherichia coli and Bifidobacterium animalis in 263 individuals, including 134 obese, 38 overweight, 76 lean and 15 anorexic subjects to test for the correlation between bacterial concentration and body mass index (BMI). Of these subjects, 137 were used in our previous study. FINDINGS: Firmicutes were found in >98.5%, Bacteroidetes in 67%, M. smithii in 64%, E. coli in 51%, Lactobacillus species between 17 and 25% and B. animalis in 11% of individuals. The fecal concentration of Lactobacillus reuteri was positively correlated with BMI (coefficient=0.85; 95% confidence interval (CI) 0.12-0.58; P=0.02) in agreement with what was reported for Lactobacillus sakei. As reported, B. animalis (coefficient=-0.84; 95% CI -1.61 to -0.07; P=0.03) and M. smithii (coefficient=-0.43, 95% CI -0.90 to 0.05; P=0.08) were negatively associated with the BMI. Unexpectedly, E. coli was found here for the first time to negatively correlate with the BMI (coefficient=-1.05; 95% CI -1.60 to -0.50; P<0.001). CONCLUSION: Our findings confirm the specificity of the obese microbiota and emphasize the correlation between the concentration of certain Lactobacillus species and obesity.

Q fever and pregnancy: disease, prevention, and strain specificity.

The link between fetal morbidity and Q fever and the necessity of long-term antibiotics for Coxiella burnetii infection during pregnancy have been recently questioned in the Netherlands, where the clone responsible for the Q fever outbreak harbors the QpH1 plasmid. In this context, we assessed pregnancy outcomes according to antibiotic administration in a new series and compared the plasmid type between isolates associated with abortion and other clinical isolates to determine if there is a link between genotype and abortion in humans. All French patients who received a diagnosis of Q fever during pregnancy at the French National Referral Centre for Q Fever from 2006 through July 2011 were included. On the other hand, the plasmid types of 160 clinical isolates, including seven isolates from patients who experienced an abortion, were compared. The differences between the QpDV and QpH1 plasmid sequences were analyzed. Acute Q fever was a cause of fetal morbidity, and the absence of long-term cotrimoxazole therapy was associated with fetal death (p < 0.0001). Genotypic analysis showed that the QpDV plasmid was more frequent in isolates associated with abortion (p = 0.03). A comparison of the plasmid sequences revealed that four QpDV proteins had no direct counterparts in QpH1, with two whose functions were not present in QpH1. The different obstetrical morbidity of C. burnetii relative to different geographical areas could be related to strain specificity, possibly based on differences in plasmid sequences, or to a failure of public health authorities to detect early miscarriages.

Descriptors of multidrug-resistant TB deaths in Ethiopia.

Deaths related to multidrug-resistant TB among patients who had received a second-line anti-TB drugs in Ethiopia were analysed. Respectively 38/704 (5.4%) and 44/995 (4.4%) deaths were identified in two cohorts (2015 and 2022). In the 2015 cohort, severe malnutrition was less prevalent, previous treatment rates were three times higher, hypokalaemia was more frequent, and the use of the Xpert® MTB/RIF assay, respiratory failure and severe anaemia/pancytopenia were less common than in the 2022 cohort. We observed that there were variations in adverse events when different treatment regimens were used over different time periods. To ensure proper patient care, correct guidance must be consistently implemented.

Les décès liés à la TB multirésistante chez les patients ayant reçu des médicaments antituberculeux de seconde ligne en Éthiopie ont été analysés. Respectivement 38/704 (5,4%) et 44/995 (4,4%) décès ont été identifiés dans deux cohortes (2015 et 2022). Dans la cohorte 2015, la malnutrition sévère était moins fréquente, les taux de traitement antérieur étaient trois fois plus élevés, l'hypokaliémie était plus fréquente, et l'utilisation du test Xpert® MTB/RIF, l'insuffisance respiratoire et l'anémie/pancytopénie sévère étaient moins fréquentes que dans la cohorte 2022. Nous avons observé des variations dans les effets indésirables lorsque différents schémas thérapeutiques étaient utilisés sur différentes périodes. Pour garantir des soins adéquats aux patients, des consignes appropriées doivent être appliquées de manière régulière.

Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii.

BACKGROUND: Obesity is associated with increased health risk and has been associated with alterations in bacterial gut microbiota, with mainly a reduction in Bacteroidetes, but few data exist at the genus and species level. It has been reported that the Lactobacillus and Bifidobacterium genus representatives may have a critical role in weight regulation as an anti-obesity effect in experimental models and humans, or as a growth-promoter effect in agriculture depending on the strains. OBJECTIVES AND METHODS: To confirm reported gut alterations and test whether Lactobacillus or Bifidobacterium species found in the human gut are associated with obesity or lean status, we analyzed the stools of 68 obese and 47 controls targeting Firmicutes, Bacteroidetes, Methanobrevibacter smithii, Lactococcus lactis, Bifidobacterium animalis and seven species of Lactobacillus by quantitative PCR (qPCR) and culture on a Lactobacillus-selective medium. FINDINGS: In qPCR, B. animalis (odds ratio (OR)=0.63; 95% confidence interval (CI) 0.39-1.01; P=0.056) and M. smithii (OR=0.76; 95% CI 0.59-0.97; P=0.03) were associated with normal weight whereas Lactobacillus reuteri (OR=1.79; 95% CI 1.03-3.10; P=0.04) was associated with obesity. CONCLUSION: The gut microbiota associated with human obesity is depleted in M. smithii. Some Bifidobacterium or Lactobacillus species were associated with normal weight (B. animalis) while others (L. reuteri) were associated with obesity. Therefore, gut microbiota composition at the species level is related to body weight and obesity, which might be of relevance for further studies and the management of obesity. These results must be considered cautiously because it is the first study to date that links specific species of Lactobacillus with obesity in humans.

Lactobacillus rhamnosus bacteremia: an emerging clinical entity.

Lactobacillus spp. are ubiquitous commensals of the normal human flora that are only occasionally found in clinical infections. Their role in human disease is established for infectious endocarditis but is controversial for other infections. We sought to characterize clinically associated Lactobacillus spp. We conducted a retrospective study, which consisted of the screening of Lactobacillus isolates obtained in our laboratory from January 2004 to December 2009. The polymerase chain reaction (PCR) assay was selected as the gold standard method. The isolates were first identified using API Coryne strips, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and 16S rRNA gene sequencing. Lactobacillus tuf gene-based identification was used when the 16S rRNA results were inconclusive. Among the 60 strains of Lactobacillus spp. obtained in our laboratory, L. rhamnosus was the most commonly isolated species and was found in blood cultures from 16 patients. Combined with 45 patients reported in the literature, we found that patients presenting with L. rhamnosus bacteremia experienced nosocomial infections associated with both immunosuppression (66 %) and catheters (83 %).

Imported extensively drug-resistant Mycobacterium tuberculosis Beijing genotype, Marseilles, France, 2011.

Multidrug- (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are reported to gradually spread across European countries with low TB prevalence including France. Some isolates may even accumulate traits of resistance in addition to the XDR profile, as a result of therapeutic mismanagement. We report here the first case of XDR TB in Marseilles and discuss the potential effectiveness of sulfamide treatment in such cases.

Investigation of skin microbiota reveals Mycobacterium ulcerans-Aspergillus sp. trans-kingdom communication.

Mycobacterium ulcerans secrete a series of non-ribosomal-encoded toxins known as mycolactones that are responsible for causing a disabling ulceration of the skin and subcutaneous tissues named Buruli ulcer. The disease is the sole non-contagion among the three most common mycobacterial diseases in humans. Direct contact with contaminated wetlands is a risk factor for Buruli ulcer, responsible for M. ulcerans skin carriage before transcutaneous inoculation with this opportunistic pathogen. In this study, we analysed the bacterial and fungal skin microbiota in individuals exposed to M. ulcerans in Burkina Faso. We showed that M. ulcerans-specific DNA sequences were detected on the unbreached skin of 6/52 (11.5%) asymptomatic farmers living in Sindou versus 0/52 (0%) of those living in the non-endemic region of Tenkodogo. Then, we cultured the skin microbiota of asymptomatic M. ulcerans carriers and negative control individuals, all living in the region of Sindou. A total of 84 different bacterial and fungal species were isolated, 21 from M. ulcerans-negative skin samples, 31 from M. ulcerans-positive samples and 32 from both. More specifically, Actinobacteria, Aspergillus niger and Aspergillus flavus were significantly associated with M. ulcerans skin carriage. We further observed that in vitro, mycolactones induced spore germination of A. flavus, attracting the fungal network. These unprecedented observations suggest that interactions with fungi may modulate the outcome of M. ulcerans skin carriage, opening new venues to the understanding of Buruli ulcer pathology, prophylaxis and treatment of this still neglected tropical infection.

Taxonogenomics description of Bacillus marasmi sp. nov., a new species isolated from the stool sample.

Using the culturomics method, two strains were isolated, identified, and characterised following the taxonogenomics concept. Bacillus marasmi sp. nov. strain Marseille-P3556 (= CSURP3556) is isolated from a 13-month-old girl living in Niger. The phylogenetic tree, phenotypic criteria, and genomic analysis described here clearly show that this bacterium is different from previously known bacterial species withstanding in nomenclature and new members of Bacillus genus.