Osteomyelitis due to Aspergillus spp. in patients with chronic granulomatous disease: comparison of Aspergillus nidulans and Aspergillus fumigatus

AbstractObjective: Chronic granulomatous disease (CGD) is a rare inherited disorder of NADPH oxidase in which phagocytes fail to generate reactive antimicrobial oxidants. Invasive fungal infections are an important cause of morbidity and mortality in CGD patients, with Aspergillus spp. being the most frequent fungal pathogens. We reviewed the reported cases of osteomyelitis in CGD patients due to Aspergillus nidulans and compared them with those due to Aspergillus fumigatus.Methods: Twenty-four cases of osteomyelitis due to Aspergillus spp. in 22 male CGD patients were found in MEDLINE.Results: Fourteen cases (58%) were due to Aspergillus nidulans and ten cases to Aspergillus fumigatus. No other aspergilli were reported as causes of osteomyelitis. Osteomyelitis due to Aspergillus nidulans was associated with pulmonary infection and involved ‘small bones’ more frequently than Aspergillus fumigatus osteomyelitis (p=0.032). Half of the CGD patients with Aspergillus nidulans osteomyelitis died compared with none of those with Aspergillus fumigatus osteomyelitis (p=0.019). In both Aspergillus nidulans and Aspergillus fumigatus cases, cure was achieved by prompt antifungal treatment combined with surgery and immunotherapy.Conclusion: Aspergillus nidulans causes osteomyelitis in CGD patients relatively frequently compared with Aspergillus fumigatus and may be accompanied by higher mortality. This contrasts with the low frequency with which Aspergillus nidulans causes osteomyelitis in patients with other types of immunodeficiency

Central nervous system aspergillosis in children: a systematic review of reported cases

SummaryObjectiveCentral nervous system (CNS) aspergillosis is a life-threatening disease that has had a published mortality of >80%. Little is known about this serious infection in the pediatric population. We conducted this study to analyze characteristics of CNS aspergillosis in infants and children.MethodsThe English literature was reviewed and all CNS aspergillosis cases in patients younger than 18 years of age were analyzed.ResultsNinety cases were recorded up to June 2005. The median age of the patients was 9 years, ranging from 18 days to 18 years (15.6% younger than 1 year). CNS aspergillosis most commonly presented as brain abscess(es), either single or multiple. While prematurity was the predominant underlying condition among infants, leukemia was the most frequent underlying disease in children. Aspergillus fumigatus was isolated from 75.5% of the cases. The overall mortality in published cases was 65.4%. In multivariate analysis, surgical treatment was independently associated with survival.ConclusionCNS aspergillosis in infants and children predominantly presents as brain abscess(es) and has significantly better outcome compared to published adult data. The findings of this systematic review could assist future investigations for improved outcome of this life-threatening infection in pediatric patients

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Human monocytes response to antifungal drugs and to combination of antifungal drugs with interferon-γ in vitro

Purpose: The purpose of this study was to investigate the effects of the 4 amphotericin B formulations [deoxycholate amphotericin B (DAMB) liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD)] on the antifungal activity of human monocytes and neutrophils against A. fumigatus and F. solani. In addition, we planned to investigate the effects of caspofungin with or without interferon-γ (IFN-γ) on the monocyte- and neutrophil- induced hyphal damage of A. fumigatus hyphae. Materials-Methods: Human monocytes and neutrophils were obtained from blood of healthy adult volunteers. Antifungal agents used were all four amphotericin B formulations in two different concentrations: DAMB (1 and 5 μg/ml), LAMB, ABLC and ABCD (5 and 25 μg/ml, for each lipid amphotericin B formulation) and the newest echinocandin, caspofungin. Strain of A. fumigatus and F. solani were used in this study. The mRNA levels and protein profiles of cytokines and chemokines expressed by human monocytes were comprehensively evaluated by semiquantitative reverse transcription-PCR and enzyme-linked immunosorbent assays (ELISA). Hyphal damage of A. fumigatus and F. solani was assessed by a modified method of XTT. Antifungal oxidative metabolism was assessed by the following methods: a) superoxide anion production (Ο2⁻) from human monocytes or neutrophils against hyphae of A. fumigatus and F. solani and b) hydrogen peroxide (H₂O₂) and secondary H₂O₂-dependent intracellular intermediates production from human monocytes against hyphae of A. fumigatus. Results: the mRNA levels of TNF-a were increased after incubation with DAMB and ABCD for 2h. ABLC was found to decrease the release of most cytokines and chemokines. DAMB and the rest of lipid amphotericin B formulations did not affect the superoxide anion production. Caspofungin increase hyphal damage induced by pretreated monocytes. Conclusions: deoxycholate amphotericin B and lipid amphotericin B formulations as well as caspofungin have certain immunomodulatory effects on human phagocytes. This means that antifungal agents have another mode of action except of the conventional antifungal action and also explain the role that they can play in the immune response of human body against invasive fungal infections.Σκοπός: Ο σκοπός της μελέτης αυτής ήταν να μελετηθεί η απάντηση των ανθρώπινων μονοκυττάρων και ουδετεροφίλων στη δράση των 4 ειδών αμφοτερικίνης Β [συμβατική δεοξυχολική αμφοτερικίνη Β (DAMB), λιποσωματική αμφοτερικίνη Β (LAMB), αμφοτερικίνη Β σε μορφή λιπιδικών συμπλεγμάτων (ABLC) και αμφοτερικίνη Β σε μορφή λιπιδικού κολλοειδούς (ABCD)] έναντι υφών A. fumigatus και F. solani. Επίσης, μελετήθηκε η επίδραση της κασποφουγκίνης με/ή χωρίς την προσθήκη ιντερφερόνης-γ (IFN-γ) στην καταστροφή των υφών A. fumigatus από μονοκύτταρα ή ουδετερόφιλα. Υλικό-Μέθοδοι. Ως υλικό χρησιμοποιήθηκαν ανθρώπινα μονοκύτταρα και ουδετερόφιλα που απομονώθηκαν από το περιφερικό αίμα φαινομενικά υγιών ενηλίκων αιμοδοτών. Τα αντιμυκητιακά που χρησιμοποιήθηκαν ήταν τα 4 είδη αμφοτερικίνης Β σε δύο διαφορετικές συγκεντρώσεις: DAMB (1 και 5 μg/ml), LAMB, ABLC και ABCD (5 και 25 μg/ml, αντίστοιχα για τα λιπιδικά είδη), καθώς και ένα νεότερο αντιμυκητιακό φάρμακο της κατηγορίας των εχονοκανδινών, η κασποφουγκίνη. Τα στελέχη των μηκήτων που μελετήθηκαν ήταν ο A. fumigatus και το F. solani. Ο προσδιορισμός του αγγελιοφόρου RNA των μονοκυττάρων έγινε με τη μεθοδολογία ανάστροφης μεταγραφής-αλυσιδωτής αντίδρασης πολυμεράσης. Ο προσδιορισμός της παραγωγής κυτταροκινών και χημειοκινών από μονοκύτταρα πραγματοποιήθηκε με την ανοσοενζυματική μέθοδο ELISA. Η καταστροφή των υφών A. fumigatus ή F. solani από μονοκύτταρα ή ουδετερόφιλα προσδιορίστηκε με την χρωματομετρική μέθοδο XTT. Ο αντιμυκητιακός οξειδωτικός μεταβολισμός προσδιορίστηκε: α) με την παραγωγή ανιόντος υπεροξειδίου (Ο2⁻) από μονοκύτταρα ή ουδετερόφιλα έναντι υφών A. fumigatus ή F. Solani, β) με την παραγωγή υπεροξειδίου του υδρογόνου (H₂O₂) και των H₂O₂-εξαρτωμένων ενδοκυττάριων παραπροϊόντων εναλλακτικών μεταβολικών οδών από μονοκύτταρα έναντι υφών A. fumigatus. Αποτελέσματα: Το mRNA του TNF-α αυξήθηκε στα μονοκύτταρα που επωάστηκαν με DAMB και ABCD για 2 ώρες. Η ABLC ελαττώνει την απελευθέρωση των περισσοτέρων κυτταροκινών και χημειοκινών. H DAMB και οι λοιπές λιπιδιακές μορφές αμφοτερικίνης Β δεν επηρέαζαν σημαντικά την παραγωγή υπεροξειδίου ανιόντος. Η κασποφουγκίνη αυξάνει τη μυκητοκτόνο δράση προεπωασμένων μονοκυττάρων. Συμπεράσματα: η δεοξυχολική και τα λιπιδιακά είδη αμφοτερικίνης Β καθώς και η κασποφουγκίνη έχουν ανοσομετατρεπτικές επιδράσεις πάνω στα φαγοκύτταρα. Το γεγονός αυτό έχει ιδιαίτερη σημασία γιατί υποδεικνύει έναν άλλο τρόπο δράσης των φαρμάκων αυτών πλην της αντιμυκητιακής τους δράσης και εξηγεί τη σημασία που μπορούν να έχουν στην άμυνα του οργανισμού, κατά σοβαρών και απειλητικών για τη ζωή συστηματικών μυκητιάσεων

Immunopathogenesis of central nervous system fungal infections

Fungal infections of the central nervous system (CNS) evoke humoral and cellular immune responses with the scope to enable the host to eliminate the pathogen. Immunopathogenesis of CNS fungal infections remains incompletely understood, with most of our understanding coming from studies on experimentally infected animals. However, activation of brain resident cells combined with relative expression of immunoenhancing and immunosuppressing cytokines and chemokines may play a determinant role and partially explain immunopathogenesis of CNS fungal infections

Immunologic Response to SARS-CoV-2 Vaccination in Pediatric Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

The pediatric population is at a lower risk of severe SARS-CoV-2 infection compared to adults. Nevertheless, immunosuppression in pediatric and adolescent kidney transplant recipients (KTRs) increases their hazard compared to the general population. This systematic review evaluates the efficacy of SARS-CoV-2 vaccines and determines the risk factors of no seroconversion in this population. PubMed-MEDLINE databases were searched for cohort studies. A meta-analysis was performed using fixed and random effect models. In total, seven studies including 254 patients were further analyzed. The random effect model demonstrated a 63% seroconversion rate (95% CI 0.5, 0.76) following a two-dose schedule, which increased to 85% (95% CI 0.76, 0.93) after the third dose administration. Seropositivity was lower in patients under mycophenolate mofetil compared to azathioprine (OR 0.09, 95% CI 0.02, 0.43). Rituximab administration decreased the seroconversion rate (OR 0.12, 95% CI 0.03, 0.43). The glomerular filtration rate (GFR) was 9.25 mL/min/1.73 m2 lower (95% CI 16.37, 2.13) in patients with no seroconversion. The seroconversion rate was lower in vaccinated compared to infected patients (OR 0.13, 95% CI 0.02, 0.72). In conclusion, vaccination against SARS-CoV-2 in pediatric and adolescent KTRs elicits a humoral response, and a third dose is advised. Previous rituximab administration, antimetabolite therapy with mycophenolate mofetil and lower GFR reduce the likelihood for seroconversion

Impact of Metabolomics Technologies on the Assessment of Peritoneal Membrane Profiles in Peritoneal Dialysis Patients: A Systematic Review

Peritoneal dialysis (PD) is an effective and frequent dialysis modality in adults, particularly preferred in infants and young children with end-stage renal disease (ESRD). Long-term exposure of the peritoneal membrane to dialysis solutions results in severe morphologic and functional alterations. Peritoneal dialysis effluent biomarkers are based on omics technologies, which could predict the onset or confirm the diagnosis of peritoneal membrane dysfunction, would allow the development of accurate early prognostic tools and, potentially, the identification of future therapeutic targets. The purpose of our study was to critically review the literature on the impact and the effectiveness of metabolomics technologies in peritoneal health. The main search was performed in electronic databases (PubMed/MEDLINE, Embase and Cochrane Central Register of Controlled Trials) from inception to December 2020, using various combinations of Medical Subject Headings (MeSH). The main search highlighted nine studies, of which seven were evaluated in detail. Metabolomics technologies may provide significant input in the recognition of peritoneal membrane dysfunction in PD patients and provide evidence of early intervention strategies that could protect peritoneum health and function