COVID-19 early curative treatments in kidney transplant recipients: is it really reasonable at the Omicron era?

Objective: Data about efficacy and safety of the latest COVID-19 treatments as nirmatrelvir/ritonavir (n/r) or Sotrovimab is scarce in solid organ transplant recipients in the Omicron era. This study aims at describing the outcome of kidney transplant recipients (KTRs) presenting Omicron infection according to their management: n/r, sotrovimab or no specific treatment. Patients and methods: We conducted a monocentric, retrospective observational study, including KTRs diagnosed Omicron infection between January and May 1st 2022 and compared their outcome (primary outcome defined as hospital admission for COVID-19 within a month after symptoms onset) according to early COVID-19 management. Results: Forty-five patients were included: 22 treated (12 n/r, 10 sotrovimab) and 23 with no specific treatment. The groups were statistically comparable. Two patients were admitted for COVID-19: one in each group, resulting in a non-different probability of the primary outcome at on month (p=0.9). Three patients presented tacrolimus overdose including two with acute kidney injury. Conclusions: There was no difference in outcome according to early therapeutic management: n/r, sotrovimab or no specific treatment. Our study both underlines a decreased severity of Omicron COVID-19 in KTRs (probably related to vaccinal immunity and decreased virulence of Omicron) and a potential severe adverse effects with n/r.

Objectif: Les données sur l'efficacité et la sécurité des derniers traitements de la Covid-19 sont peu nombreuses à l'ère du variant Omicron. Cette étude avait pour objectif de décrire l'évolution des transplantés rénaux (TR) présentant une infection à Omicron selon le traitement précoce reçu : nirmatrelvir/ritonavir (n/r), sotrovimab, ou pas de traitement. Patients et méthodes: Il s'agissait d'une étude monocentrique rétrospective observationnelle incluant tous les TR présentant une infection confirmée à Omicron entre le 1er janvier 2022 et le 1er mai 2022 et comparant leur évolution (critère de jugement principal : admission hospitalière pour Covid-19 à un mois du début des symptômes) selon leur prise en charge. Résultats: Quarante-cinq patients ont été inclus : 22 traités (12 n/r et 10 sotrovimab) et 23 non traités. Les groupes étaient statistiquement comparables. Seulement deux patients ont présenté le critère de jugement principal : un n/r et un non traité, avec une probabilité à un mois non différente (p = 0,9). Trois patients sur 12 ont en revanche présenté des surdosages en tacrolimus dans le groupe n/r, dont deux avec une insuffisance rénale aiguë. Conclusions: Dans les limites d'un petit effectif, nous n'avons pas montré de bénéfice au traitement précoce par n/r ou sotrovimab. On peut évoquer un effet de l'immunité vaccinale et une baisse de virulence du SARS-CoV-2. En revanche, les effets secondaires du n/r ne sont pas anodins avec des surdosages sévères malgré des protocoles de service précis. La balance bénéfice-risque de ces traitements doit être rediscutée.

Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection.

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versus 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.

Sexually Transmitted Trichophyton mentagrophytes Genotype VII Infection among Men Who Have Sex with Men.

Transmission of dermatophytes, especially Trichophyton mentagrophytes genotype VII, during sexual intercourse has been recently reported. We report 13 such cases in France. All patients were male; 12 were men who have sex with men. Our findings suggest sexual transmission of this pathogen within a specific population, men who have sex with men.

Corrigendum to Persistent Aseptic Pyelonephritis After Acute Bacterial Pyelonephritis: Possible Role of Corticosteroids Kidney International Reports, Volume 7, Issue 8, August 2022, Pages 1897-1900.

[This corrects the article DOI: 10.1016/j.ekir.2022.05.025.].

Viral loads in clinical samples of men with monkeypox virus infection: a French case series.

BACKGROUND: Monkeypox virus (MPXV) is currently spreading among men who have sex with men, outside of sub-Saharan Africa, and close contact during sex seems to be one of the key pathways of viral transmission in the current outbreak. Our aim was to describe the distribution of MPXV in the human body, as it might play a role in its dissemination through sexual contact. METHODS: The study population in this case series consisted of patients with confirmed MPXV infection attending the Pitié-Salpêtrière Hospital (Paris, France), who had been sampled from multiple anatomical sites, including skin, anus, throat, blood, urine, and semen, at diagnosis and 2 weeks later. We compared the proportion of positive samples and MPXV viral loads (given as PCR cycle thresholds [Ct]) between anatomical sites, and between day 0 (D0) and D14. FINDINGS: Overall, 356 samples were collected between May 20 and June 13, 2022, from 50 men with a median age of 34 years (IQR 29-40). 22 (44%) of the 50 men were classified as HIV-negative on day (D)0, and 22 (44%) were living with HIV. At D0, MPXV detection was more frequent from skin (44 [88%] of 50), anus (30 [71%] of 42), and throat (36 [77%] of 47) than from blood (13 [29%] of 45), urine (nine [22%] of 41), or semen (13 [54%] of 24). Viral loads were significantly higher from skin lesions (Ct 19·8) and anal samples (Ct 20·9) than from throat (Ct 27·2), blood (Ct 32·8), urine (31·1), or semen samples (Ct 27·8). When analysing the 107 samples taken from 24 patients at D14, the proportion of positive samples strongly decreased between D0 and D14 at all sites: skin (four [22%] of 18), anus (two [9%] of 22), throat (none of 21), blood (one [5%] of 21), urine (none of 14), and semen (two [9%] of 11). INTERPRETATION: These data contribute to a better understanding of how the virus might spread between sexual partners over a relatively short period of time. High MPXV viral loads from skin and mucosa, including genital and anal sites, suggest that transmission most likely occurs through direct body contact rather than through the respiratory route or contact with body fluids, which should help to refine the prevention messages delivered to individuals most exposed to the virus. FUNDING: None.

Immunosuppressive therapy after solid organ transplantation and the gut microbiota: Bidirectional interactions with clinical consequences.

Our understanding of the involvement of the gut microbiota (GM) in human health has expanded exponentially over the last few decades, particularly in the fields of metabolism, inflammation, and immunology. Immunosuppressive treatment (IST) prescribed to solid organ transplant (SOT) recipients produces GM changes that affect these different processes. This review aims at describing the current knowledge of how IST changes the GM. Overall, SOT followed by IST results in persistent changes in the GM, with a consistent increase in proteobacteria including opportunistic pathobionts. In mice, Tacrolimus induces dysbiosis and metabolic disorders, and alters the intestinal barrier. The transfer of the GM from Tacrolimus-treated hosts confers immunosuppressive properties, suggesting a contributory role for the GM in this drug's efficacy. Steroids induce dysbiosis and intestinal barrier alterations, and also seem to depend partly on the GM for their immunosuppressive and metabolic effects. Mycophenolate Mofetil, frequently responsible for digestive side effects such as diarrhea and colitis, is associated with pro-inflammatory dysbiosis and increased endotoxemia. Alemtuzumab, m-TOR inhibitors, and belatacept have shown more marginal impact on the GM. Most of these observations are descriptive. Future studies should explore the underlying mechanism of IST-induced dysbiosis in order to better understand their efficacy and safety characteristics.

High Mortality and Graft Loss after Infective Endocarditis in Kidney Transplant Recipients: A Case-Controlled Study from Two Centers.

Kidney transplant recipients (KTRs) tend to develop infections with characteristic epidemiology, presentation, and outcome. While infective endocarditis (IE) is among such complications in KTRs, the literature is scarce. We describe the presentation, epidemiology, and factors associated with IE in KTRs. We performed a retrospective case/control study which included patients from two centers. First episodes of definite or possible IE (Duke criteria) in adult KTRs from January 2010 to December 2018 were included, as well as two controls per case, and followed until 31 December 2019. Clinical, biological, and microbiological data and the outcome were collected. Survival was studied using the Kaplan-Meier method. Finally, we searched for factors associated with the onset of IE in KTRs by the comparison of cases and controls. Seventeen cases and 34 controls were included. IE was diagnosed after a mean delay of 78 months after KT, mostly on native valves of the left heart only. Pathogens of digestive origin were most frequently involved (six Enterococcus spp, three Streptococcus gallolyticus, and one Escherichia coli), followed by Staphylococci (three cases of S. aureus and S. epidermidis each). Among the risk factors evaluated, age, vascular nephropathy, and elevated calcineurin inhibitor through levels were significantly associated with the occurrence of IE in our study. Patient and death-censored graft survival were greatly diminished five years after IE, compared to controls being 50.3% vs. 80.6% (p < 0.003) and 29.7% vs. 87.5% (p < 0.002), respectively. IE in KTRs is a disease that carries significant risks both for the survival of the patient and the transplant.

Cryptococcus neoformans meningitis in kidney transplant recipients: A diagnostic and therapeutic challenge.

Cryptococcosis is the third most common invasive fungal infection in solid organ transplant recipients. We describe three cases of neuro-meningeal cryptococcosis occurring among kidney transplant (KT) patients, and discuss the diagnostic and therapeutic challenges in this context. Median time from KT to infection was 6 months [range: 3-9]. The most common clinical manifestations at diagnosis were fever (2/3), headache (2/3), and confusion (2/3); none had extra-neurological involvement. CrAg was positive in all cases at diagnosis both in serum and cerebrospinal fluid (CSF). For two patients, analysis of previous samples showed that CrAg was detected in plasma up to 4 weeks before diagnosis. All patients received induction treatment with liposomal amphotericin-B (L-AmB) and flucytosine for a median duration of 10 days [range: 7-14], followed by fluconazole maintenance therapy. Acute kidney injury secondary to L-AmB therapy was observed in only one case, but all patients had a tacrolimus overdose following initiation of maintenance therapy due to drug-drug interactions between fluconazole and tacrolimus. Among KTR, early detection of Cryptococcus meningitis using serum CrAg is possible. Close monitoring of renal function during treatment is essential due to the nephrotoxicity of L-AmB, but also drug-drug interactions between fluconazole and calcineurin inhibitors.

Gut microbiota composition alterations are associated with the onset of diabetes in kidney transplant recipients.

METHODS: Patients transplanted at our institution provided fecal samples before, and 3-9 months after KT. Fecal bacterial DNA was extracted and 9 bacteria or bacterial groups were quantified by qPCR. RESULTS: 50 patients (19 controls without diabetes, 15 who developed New Onset Diabetes After Transplantation, NODAT, and 16 with type 2 diabetes before KT) were included. Before KT, Lactobacillus sp. tended to be less frequently detected in controls than in those who would become diabetic following KT (NODAT) and in initially diabetic patients (60%, 87.5%, and 100%, respectively, p = 0.08). The relative abundance of Faecalibacterium prausnitzii was 30 times lower in initially diabetic patients than in controls (p = 0.002). The relative abundance of F. prausnitzii of NODAT patients was statistically indistinguishable from controls and from diabetic patients. The relative abundance of Lactobacillus sp. increased following KT in NODAT and in initially diabetic patients (20-fold, p = 0.06, and 25-fold, p = 0.02, respectively). In contrast, the proportion of Akkermansia muciniphila decreased following KT in NODAT and in initially diabetic patients (2,500-fold, p = 0.04, and 50,000-fold, p<0.0001, respectively). The proportion of Lactobacillus and A. muciniphila did not change in controls between before and after the transplantation. Consequently, after KT the relative abundance of Lactobacillus sp. was 25 times higher (p = 0.07) and the relative abundance of A. muciniphila was 2,000 times lower (p = 0.002) in diabetics than in controls. CONCLUSION: An alteration of the gut microbiota composition involving Lactobacillus sp., A. muciniphila and F. prausnitzii is associated with the glycemic status in KT recipients, raising the question of their role in the genesis of NODAT.

Post-malaria neurological syndrome: four cases, review of the literature and clarification of the nosological framework.

BACKGROUND: Post-malaria neurological syndrome (PMNS) is a debated entity, defined by neurological complications following a post-malaria symptom-free period and a negative blood smear. Four cases of PMNS are hereby reported and a review the literature performed to clarify the nosological framework of this syndrome. METHODS: A French teaching hospital infectious diseases database was investigated for all PMNS cases occurring between 1999 and 2016 and the PubMed database for cases reported by other institutions after 1997. A case was defined by the de novo appearance of neurological signs following a post-malaria symptom-free period, a negative blood smear, and no bacterial or viral differential diagnoses. RESULTS: Four patients from the database and 48 from PubMed, including 4 following Plasmodium vivax infection were found matching the definition. In the institution, the estimated PMNS incidence rate was 1.7 per 1000 malaria cases overall. Of the 52 patients (mean age 33 years), 65% were men. Malaria was severe in 85% of cases, showed neurological involvement in 53%, and treated with quinine in 60%, mefloquine in 46%, artemisinin derivatives in 41%, antifolic drugs in 30%, doxycycline in 8% and other types in 8%. The mean symptom-free period was 15 days. PMNS signs were confusion (72%), fever (46%), seizures (35%), cerebellar impairment (28%), psychosis (26%), and motor disorders (13%). Cerebrospinal fluid analyses showed high protein levels in 77% (mean 1.88 g/L) and lymphocytic meningitis in 59.5% (mean 48 WBC/mm3) of cases. Electroencephalograms were pathological in 93% (14/15) of cases, and brain MRIs showed abnormalities in 43% (9/21) of cases with white matter involvement in 100%. Fourteen patients were treated with steroids. The 18 patients with follow-up data showed no sequelae. The mean time to recovery was 17.4 days. CONCLUSION: PMNS is a rare entity englobing neurological signs after severe or non-severe malaria. It appears after a symptom-free period. PMNS occurred following treatment of malaria with a wide range of anti-malarials. The disease is self-limiting and associated with good outcome. MRI patterns underline a possible link with acute disseminated encephalomyelitis (ADEM) or auto-immune encephalitis. Plasmodium falciparum and Plasmodium vivax should be added to the list of pathogens causing ADEM.

[Diagnostic procedure for acute kidney failure]. / Démarche diagnostique devant une insuffisance rénale aiguë.

A diagnostic procedure for acute kidney injury. The definition of acute kidney injury (AKI) is universal since 2011. It is simple, based on the increase in serum creatinine on a short time period. AKI may be life-threatening, which is why the priority is to rule out hyperkalemia, pulmonary edema, or severe acidosis. Then, a panel of clinical, biological and radiological analyses is required to establish the mechanism of AKI and treat it appropriately. Basically, a three steps process is suggested: an obstruction of the urinary cavities is looked for; circumstances of renal hypoperfusion are considered, and urinary electrolytes measured; by elimination, a diagnosis of parenchymal AKI is eventually made. In that case AKI is in most cases due to an acute tubular necrosis, which implies to collect positive and negative signs: a recent history of hypotension, intake of toxic drugs, etc.; proteinuria should be low, i.e. less than 1 g/L, and urinary cells in normal count. In the presence of extra-renal symptoms, and of urinary abnormalities such as abundant proteinuria and hematuria or leucocyturia, a specialized care is urgently needed and a renal biopsy often indicated.

Démarche diagnostique devant une insuffisance rénale aiguë. L'insuffisance rénale aiguë a aujourd'hui une définition simple et universelle, fondée sur l'élévation de la créatininémie sur un temps court. Elle peut représenter une menace vitale, et il est prioritaire de l'évaluer avant toute démarche étiologique. Cette dernière requiert une analyse clinique, biologique et radiologique, et elle est stéréotypée : on cherche dans un premier temps un obstacle sur les voies urinaires, puis une insuffisance rénale par défaut de perfusion efficace, et enfin, par élimination, on aboutit au diagnostic d'insuffisance rénale aiguë « organique ¼. Le cas échéant, la cause la plus fréquente, a fortiori en réanimation médicale, est la nécrose tubulaire aiguë ischémique qui est un diagnostic par défaut qui implique la présence d'un contexte évocateur, et de plusieurs signes négatifs : absence de signes extrarénaux, protéinurie faible et sédiment urinaire inactif. Dans tous les autres cas, un avis néphrologique est urgent, et la biopsie rénale est discutée.