Fanny Lanternier

SAVI is a rare STING1 gain-of-function disorder causing systemic inflammation, vasculopathy, and interstitial lung disease. JAK inhibitors are first-line therapy. We report a SAVI patient on prolonged JAK inhibitors who developed opportunistic infections, including fatal Aspergillus endocarditis, underscoring therapeutic challenges.

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23–dependent IFN-γ production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12Rβ1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-γ production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria.

Management of pulmonary mucormycosis includes intravenous liposomal amphotericin-B (L-AmB), followed by posaconazole or isavuconazole. We aimed to determine the optimal L-AmB duration before switching to triazole therapy. Using data from a retrospective study in France, we performed an emulated trial evaluating stopping L-AmB after 14 days (short treatment) versus continuing L-AmB (long treatment). The benefit of combination L-AmB therapy was also investigated. A cloning, censoring, and weighting approach was used to account for immortal time and indication biases. Ninety-four cases of pulmonary mucormycosis were included, of which 35% had dissemination. Eighty-nine patients received L-AmB first-line therapy for a median of 25 (IQR: 12–54) days, including 18 patients as combination therapy. L-AmB was discontinued for adverse events in 16/89 patients (18%). Treatment was switched to posaconazole ( n = 38) or isavuconazole ( n = 9) in 47 cases and was switched back to L-AmB due to disease progression in 11/47 (23%) cases. Overall, the 180-day mortality was 54%. Diagnosis in the ICU, dyspnea at diagnosis, disseminated disease, and ground-glass opacities on chest CT scan were associated with increased mortality. No difference in 180-day survival was found between patients receiving short or long L-AmB treatment (HR=0.80, 95% CI [0.29–1.99]) and between patients receiving L-AmB alone or in combination (HR=1.14, 95% CI [0.56–2.32]) in emulated trials, although confidence intervals were wide. Switching to triazole therapy after 14 days of L-AmB treatment was as effective as longer durations while reducing L-AmB side effects. Combination therapy did not improve prognosis. These results could inform randomized clinical trials assessing different first-line therapeutic strategies for pulmonary mucormycosis.

ECMM-Candida III was a pan-European, multicentre observational study of adult patients with blood culture-proven candidemia. Among a total of 632 patients with candidemia across 64 institutions in 20 European countries, a sub-analysis of 396 (63%) cases occurring outside the intensive care unit (ICU) was conducted. Compared with ICU-patients, non-ICU patients had a higher comorbidity burden (median Charlson Comorbidity Index [CCI] 6 vs. 5 in ICU patients, p=0.006). Hematologic and oncologic malignancies were more frequent among non-ICU cases (45.5%, vs 28.4%, pCandida scores were associated with lower mortality risk in the multivariable Cox regression models. In conclusion, despite higher co-morbidity rates, non-ICU patients with candidemia had higher survival rates.

Chronic granulomatous disease (CGD) is an inborn error of immunity leading to severe invasive mold infections (IMIs). Questions remain regarding the safety of hematopoietic stem cell transplantation (HSCT) in patients following IMI. We retrospectively collected data from CGD patients undergoing HSCT within 2 years after a diagnosis of probable or proven IMI in France. The primary endpoint was to describe 1-year overall survival (OS). 14 patients were included, with aspergillosis (n = 10), mucormycosis (N = 2), scedosporiosis, or lomentosporiosis (n = 1 each). IMI status at time of HCST included four in complete response, four in partial response (PR), one in stable response (SR), and five with disease progression (DP). 1-year OS was 86 % (12/14). Two patients with scedosporiosis and lomentosporiosis died before engraftment. The remaining patients all achieved engraftment followed by prolonged clinical response of IMI. HSCT appears safe in patients with complete response or PR of IMI and could be a promising curative option for progressive IMI, specifically in those with invasive aspergillosis.

Phaeohyphomycoses (PHM), infections caused by pigmented fungi, are increasingly reported in kidney transplant recipients (KTR), but data remains scarce. We retrospectively reviewed all episodes of PHM in KTR at the Guadeloupe University Hospital (French West Indies) from January 1st, 2012, to December 31st, 2022. Eighteen episodes of PHM occurred in 17 KTRs, corresponding to an incidence of 1.56 cases per 100 person-years. Median time from transplantation to PHM onset was 15 months (interquartile range: 9.0–23.5 months). Most episodes were localized cutaneous infections (n = 16/18). Twelve fungal species were identified; Paraconiothyrium cyclothyrioides was the most frequent (n = 6/18, 33%). This fungus it is not yet acknowledged as pathogenic in the current European guidelines. Surgery was performed in 41% of episodes with available data—some data are missing due to the loss of paper files. Eighty-two percent of patients received antifungal therapy (mainly azoles). Overall outcome was favorable in 82%. Three deaths occurred during follow-up; one was directly attributable to disseminated PHM. Diagnosing PHM is not that unusual in this caribbean transplant center, mainly presented as localized skin infections, with a distinctive species distribution characterized by predominance of P. cyclothyrioides and absence of Alternaria spp. With accurate diagnosis, combine surgical/medical therapy and control of transplant organ management, the vast majority of patients can be successfully managed.

Fungal pathogens and the infections they cause are notoriously understudied and underrepresented in public health surveillance programs. Recent initiatives, such as that of the Joint Programming Initiative on Anti-Microbial Resistance (JPIAMR), recognize these gaps and have supported the development of a fungal surveillance resistance network. The International Fungal Network for One-Health Resistance Surveillance: Antifungal Resistance (INFORM-AFR) network sought to enhance understanding of existing surveillance programs, with the ultimate goal of developing standardized fungal surveillance strategies that enable international comparisons. A survey was conducted involving mycology reference centers or public health institutes (n = 15) from 12 countries, each responsible for nationwide or regional surveillance programs on fungal infections or pathogens. The ongoing programs were heterogenous, not only in terms of the epidemiological focus of surveillance (pathogen vs disease based), but also in relation to the mycological procedures used (identification and antifungal susceptibility testing methods). Funding dedicated to surveillance was variable and often lacked long-term stability, resulting in suboptimal surveillance data in many centers and limiting the generation of accurate and consistent knowledge. With the expanding number of fungal disease cases and increasing reports of antifungal resistance, we strongly advocate for improved integration of fungal infections into nationwide health surveillance programs as well as international standardization.

Background: The increasing incidence of resistant invasive mold infections (IMIs) has highlighted the need for novel antifungal agents. Olorofim, a first-in-class orotomide, has shown promising efficacy in a recent phase II study, but clinical data remain limited. Methods: We conducted a retrospective multicenter cohort study in France, including all patients who received olorofim under compassionate use for proven or probable non-Mucorales IMIs. Eligible patients had IMIs refractory to or intolerance to standard antifungals or no effective treatment options. Efficacy was defined as mycological and clinical control of infection; safety was also assessed. Results: Between January 2020 and December 2023, 17 patients (median age, 39 years) received olorofim. Underlying conditions included primary immunodeficiency (n = 4) and lung transplantation (n = 5). Sites of infection included the lung (88.2%) and the central nervous system (23.5%), with 5 cases of disseminated disease. In total, 23 strains were identified, mostly Aspergillus fumigatus (34.8%) and Microascus spp (13%). The median duration of prior antifungal therapy was 9.1 months. Olorofim was used primarily for refractory IMIs (70.6%) and in combination with other antifungals in 82.4% of cases. Olorofim minimum inhibitory concentrations were ≤0.5 mg/L in the 8 available isolates. Among 15 evaluable patients, 5 (33.3%) achieved clinical and mycological success, 7 (46.7%) had partial responses, and 3 (20%) experienced treatment failure. The 3-month mortality rate was 29.4% (5 of 17). No severe adverse events were reported. Conclusions: Olorofim exhibited potential efficacy and good tolerability in patients with refractory IMIs. Further data from ongoing clinical trials are needed to confirm these findings.