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.

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.

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.

Epidemiology of respiratory pathogen carriage in the homeless population within two shelters in Marseille, France, 2015-2017: cross sectional 1-day surveys.

OBJECTIVES: To assess risk factors for respiratory tract infection symptoms and signs in sheltered homeless people in Marseille during the winter season, including pathogen carriage. METHODS: Data on 479 male participants within two shelters who completed questionnaires and a total of 950 nasal and pharyngeal samples were collected during the winters of 2015-2017. Respiratory pathogen carriage including seven viruses and four bacteria was assessed by quantitative PCR. RESULTS: The homeless population was characterized by a majority of individuals of North African origin (300/479, 62.6%) with a relatively high prevalence of chronic homelessness (175/465, 37.6%). We found a high prevalence of respiratory symptoms and signs (168/476, 35.3%), a very high prevalence of bacterial carriage (313/477, 65.6%), especially Haemophilus influenzae (280/477, 58.7%), and a lower prevalence of virus carriage (51/473, 10.8%) with human rhinovirus being the most frequent (25/473, 5.3%). Differences were observed between the microbial communities of the nose and throat. Duration of homelessness (odds ratio (OR) 1.77, p 0.017), chronic respiratory diseases (OR 5.27, p <0.0001) and visiting countries of origin for migrants (OR 1.68, p 0.035) were identified as independent risk factors for respiratory symptoms and signs. A strong association between virus (OR 2.40, p 0.012) or Streptococcus pneumoniae (OR 2.32, p 0.014) carriage and respiratory symptoms and signs was also found. CONCLUSIONS: These findings allowed identification of the individuals at higher risk for contracting respiratory tract infections to better target preventive measures aimed at limiting the transmission of these diseases in this setting.

International experts' practice in the antibiotic therapy of infective endocarditis is not following the guidelines.

OBJECTIVE: The management of infective endocarditis (IE) may differ from international guidelines, even in reference centres. This is probably because most recommendations are not based on hard evidence, so the consensus obtained for the guidelines does not represent actual practices. For this reason, we aimed to evaluate this question in the particular field of antibiotic therapy. METHODS: Thirteen international centres specialized in the management of IE were selected, according to their reputation, clinical results, original research publications and quotations. They were asked to detail their actual practice in terms of IE antibiotic treatment in various bacteriological and clinical situations. They were also asked to declare their IE-related in-hospital mortality for the year 2015. RESULTS: The global compliance with guidelines concerning antibiotic therapy was 58%, revealing the differences between theoretical 'consensus', local recommendations and actual practice. Some conflicts of interest were also probably expressed. The adherence to guidelines was 100% when the protocol was simple, and decreased with the seriousness of the situation (Staphylococus spp. 54%-62%) or in blood-culture-negative endocarditis (0%-15%) that requires adaptation to clinical and epidemiological data. CONCLUSION: Worldwide experts in IE management, although the majority of them were involved and co-signed the guidelines, do not follow international consensus guidelines on the particular point of the use of antibiotics.

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.

[Climate, environment, and respiratory tract infections]. / Climat, environnement et infections respiratoires.

Climatic factors (temperature, wind, humidity) and their changes play a major role in the epidemiology of infectious diseases, mainly those vector borne or water-borne. In terms of respiratory tract infections, the role of cold remains controversial, although evident in popular belief: the winter peak is multifactorial, but exposure to cold causes a vasoconstriction of the nasal and upper respiratory tract mucosa, which decreases the local defense, and allows latent viral infections to become patent. The prevention of hand transmission remains essential. The role of wind in the transmission of pathogens able to survive outdoors was studied in the south of France for Coxiella burnetii. A correlation was found between the wind blowing across the Crau plain and cases of acute Q fever downwind, 2 months later.

Safety and efficacy of posaconazole in the long-term treatment of azole-refractory oropharyngeal and esophageal candidiasis in patients with HIV infection.

PURPOSE: To evaluate safety and efficacy of long-term posaconazole in HIV-infected patients with azole-refractory oropharyngeal candidiasis and/or esophageal candidiasis. METHOD: In this noncomparative, open-label study, participants received oral posaconazole 400 mg twice daily (bid) for 3 months. Enrolled patients (N = 100) included 60 from a previous 1-month acute study of posaconazole and 40 posaconazole-naïve participants. Participants with a clinical response could be followed untreated for up to 1 month afterwards. Participants who relapsed during follow-up, showed improvement at the end of 3 months of treatment (EOT), or were cured but likely to benefit from further therapy could continue on posaconazole 400 mg bid for up to 12 months. RESULTS: In the modified intent-to-treat population, clinical response (cure or improvement) occurred in 85.6% (77/90) at EOT. The results were similar in the previously treated participants and the posaconazole-naïve participants, 88.1% (52/59) and 80.6% (25/31), respectively. Posaconazole was well-tolerated, showing a similar safety profile during the 3-month study period and during suppressive therapy. The most frequently reported treatment-related adverse event was vomiting (4/100, 4%) during the early follow-up period (on or before day 105) and elevated hepatic enzymes (3/51, 6%) during the long-term follow-up (after day 105). CONCLUSION: Oral posaconazole 400 mg bid demonstrated long-term safety, tolerability, and efficacy, offering a long-term, suppressive treatment option for HIV-infected participants with azole-refractory mucosal candidiasis.

Treatment of imported malaria in adults: a multicentre study in France.

BACKGROUND: Data about anti-malarial drugs prescription practices in Europe and the safety of imported malaria treatments are scanty. In 1999, a French consensus development conference published guidelines for the prevention and treatment of imported P. falciparum malaria. The impact of these guidelines has not been evaluated. AIM: To investigate the impact of these guidelines on the prescription of anti-malarials, and to evaluate the incidence of acute drug events (ADEs) leading to discontinuation of treatment. DESIGN: Cross-sectional survey. METHODS: Members of the medical staff in 14 French infectious and tropical disease wards completed a standardized form for each patient treated for imported malaria in 2001. A propensity score matching technique was used to estimate the risk of ADEs leading to discontinuation of the regimen. RESULTS: In the 474 patients studied, quinine was the first-line anti-malarial most often prescribed. Only 3% of patients received halofantrine. Mefloquine was associated with a RR of 4.9 (95%CI 3.2-7.4, p < 0.00001) risk of discontinuation of treatment due to ADEs. DISCUSSION: The very limited use of halofantrine indicates that the main practice recommendations of the guidelines have been taken into account. Mefloquine was associated with a substantial risk of discontinuing the treatment because of ADEs. This is a serious limitation for the use of mefloquine in the treatment of out-patients with imported malaria.

Bartonella quintana and Mycobacterium tuberculosis coinfection in an HIV-infected patient with lymphadenitis.

Cat scratch disease (CSD) is usually associated with Bartonella henselae infection in patients with a history of cat exposure, but Bartonella quintana may also be a cause of chronic lympadenopathy in patients with cat or flea contact. The lymph node histopathology of CSD and tuberculosis may be indistinguishable. We report herein the first description of lymph node coinfection with B. quintana and M. tuberculosis in a 32-year HIV-infected woman. Culture of lymph node biopsy material on Columbia agar with sheep blood and on human endothelial cells in shell vial allowed us to isolate not only B. quintana, but also M. tuberculosis hominis.

Investigation of a slaughterhouse-related outbreak of Q fever in the French Alps.

The aim of the study presented here was to describe the different epidemiological methods used to investigate an outbreak of Q fever that occurred in the spring of 1996 among inhabitants of Briançon, a small town in the French Alps. Three approaches were used: (i) a comparison between a 2-month exhaustive serological survey among blood donors and a retrospective serological survey performed on frozen plasma collected by the transfusion centre in the spring of 1995; (ii) a serological survey performed in the general population by cluster sampling, using dried blood on blotting paper; and (iii) a case-control study. A total of 29 cases of acute Q fever were diagnosed by physicians during hospitalisations of the patients or ambulatory care. The case-con-trol study suggested that the outbreak resulted from airborne transmission of contaminated sheep waste, which had been left uncovered in the slaughterhouse area. Such transmission may have been facilitated by the nearby heliport. The comparison between the cumulative incidence of Q fever among blood donors during the spring seasons of 1995 and 1996 confirmed the outbreak (0.38% vs. 2.58%, respectively; P<0.0001). Health authorities promptly decided to close the slaughterhouse. The use of complementary epidemiological methods allows investigators to focus on major issues related to an outbreak: timely detection of cases, identification of the source, estimations of incidence, and public health intervention. Rapid recognition and management of outbreaks in the general population of a rural region need to be improved, particularly at a time when airborne agents could be used as biological weapons.

Thrombotic microangiopathy: a complication of Hodgkin's lymphoma in an HIV-infected patient.

We report a case of fulminant presentation of thrombotic microangiopathy associated with Hodgkin's lymphoma in an HIV-infected patient. After aggressive therapy with antiretroviral drugs, chemotherapy, and plasmatherapy, complete remission of thrombotic microangiopathy and Hodgkin's lymphoma was observed.

Seroprevalence of antibodies to Coxiella burnetti among pregnant women in South Eastern France.

OBJECTIVES: To estimate the seroprevalence of antibodies to Coxiella burnetii among pregnant women and to assess the effect of Q fever on pregnancy outcome. STUDY DESIGN: Anonymous seroprevalence survey between March and May 1996 in all gynecological and obstetrical medical departments of South Eastern France. Women were included irrespective of pregnancy outcome (N=12,716, response rate=96.1%). RESULTS: The seroprevalence rate was 0.15% with a global prevalence and a prevalence of recent or chronic infections, respectively, two and three times higher among women who had a spontaneous abortion than among those who delivered although the differences were not statistically significant. The highest proportion of preterm births (6.8%) was found in high prevalence areas (0.57%). CONCLUSION: The seroprevalence was higher than expected but data were not sufficient to confirm the suspected negative impact of Q fever on pregnancy outcome.

Highly active antiretroviral therapy (HAART) and circulating markers of immune activation: specific effect of HAART on neopterin.

The circulating levels of immune activation markers, including neopterin, tumor necrosis factor receptor type II, and interleukin-2 receptors, are increased in human immunodeficiency virus-infected patients. We show here that highly active antiretroviral therapy significantly decreased neopterin levels. This effect is reversible, since neopterin levels increased after the arrest of treatment. Their determination may be useful in the evaluation of the efficacy of antiretroviral therapy.

Rickettsia mongolotimonae: a rare pathogen in France.

We report a second case of laboratory-confirmed infection caused by Rickettsia mongolotimonae in Marseille, France. This rickettsiosis may represent a new clinical entity; moreover, its geographic distribution may be broader than previously documented. This pathogen should be systematically considered in the differential diagnosis of atypical rickettsioses, especially rashless fevers with lymphangitis and lymphadenopathy, in southern France and perhaps elsewhere.

Impact of highly active anti-retroviral therapy (HAART) on cytokine production and monocyte subsets in HIV-infected patients.

HIV infection is associated with cytokine production by monocytes and expansion of a monocyte subset that expresses high levels of CD16. Our study was designed to investigate the effects of anti-retroviral therapies on these immune parameters. Four groups of HIV+ patients were included in the study. The first group comprised drug-naive patients (n = 20); the second included patients who received two inhibitors of HIV reverse transcriptase (n = 45); the third group received a therapy combining these two inhibitors and one inhibitor of HIV protease (HAART) (n = 35); the fourth consisted of patients who had stopped their treatment (n = 20). The release of inflammatory cytokines (tumour necrosis factor, IL-1beta, IL-6) and immunoregulatory cytokines such as IL-10 by monocytes was determined by ELISA. The monocyte subsets expressing low or high levels of CD16 were studied by flow cytometry. Monocytes from patients naive of treatment released higher amounts of inflammatory cytokines and IL-10 than HIV- individuals. Each anti-retroviral therapy restored a normal pattern of cytokine secretion. Nevertheless, the release of cytokines increased again after the arrest of the treatment. The expansion of the monocyte subset that expresses high levels of CD16 was significantly decreased by HAART but not by the treatment including two inhibitors of reverse transcriptase. These results suggest that only HAART controls monocyte activation in the treatment of HIV infection.

Q fever 1985-1998. Clinical and epidemiologic features of 1,383 infections.

In order to describe the clinical features and the epidemiologic findings of 1,383 patients hospitalized in France for acute or chronic Q fever, we conducted a retrospective analysis based on 74,702 sera tested in our diagnostic center, National Reference Center and World Health Organization Collaborative Center for Rickettsial Diseases. The physicians in charge of all patients with evidence of acute Q fever (seroconversion and/or presence of IgM) or chronic Q fever (prolonged disease and/or IgG antibody titer to phase I of Coxiella burnetii > or = 800) were asked to complete a questionnaire, which was computerized. A total of 1,070 cases of acute Q fever was recorded. Males were more frequently diagnosed, and most cases were identified in the spring. Cases were observed more frequently in patients between the ages of 30 and 69 years. We classified patients according to the different clinical forms of acute Q fever, hepatitis (40%), pneumonia and hepatitis (20%), pneumonia (17%), isolated fever (17%), meningoencephalitis (1%), myocarditis (1%), pericarditis (1%), and meningitis (0.7%). We showed for the first time, to our knowledge, that different clinical forms of acute Q fever are associated with significantly different patient status. Hepatitis occurred in younger patients, pneumonia in older and more immunocompromised patients, and isolated fever was more common in female patients. Risk factors were not specifically associated with a clinical form except meningoencephalitis and contact with animals. The prognosis was usually good except for those with myocarditis or meningoencephalitis as 13 patients died who were significantly older than others. For chronic Q fever, antibody titers to C. burnetii phase I above 800 and IgA above 50 were predictive in 94% of cases. Among 313 patients with chronic Q fever, 259 had endocarditis, mainly patients with previous valvulopathy; 25 had an infection of vascular aneurysm or prosthesis. Patients with endocarditis or vascular infection were more frequently immunocompromised and older than those with acute Q fever. Fifteen women were infected during pregnancy; they were significantly more exposed to animals and gave birth to only 5 babies, only 2 with a normal birth weight. More rare manifestations observed were chronic hepatitis (8 cases), osteoarticular infection (7 cases), and chronic pericarditis (3 cases). Nineteen patients were observed who experienced first a documented acute infection, then, due to underlying conditions, a chronic infection. To our knowledge, we report the largest series of Q fever to date. Our results indicate that Q fever is a protean disease, grossly underestimated, with some of the clinical manifestations being only recently reported, such as Q fever during pregnancy, chronic vascular infection, osteomyelitis, pericarditis, and myocarditis. Our data confirm that chronic Q fever is mainly determined by host factors and demonstrate for the first time that host factors may also play a role in the clinical expression of acute Q fever.