Report of the 25th Infectious Diseases Working Party Educational Course – 3-5 November 2022 – Florence

Summary written by Sílvia Policarpo – Infectious Diseases Department, Centro Hospitalar Universitário São João, Porto, Portugal

SESSION 1 | What’s new in ECIL 9 guidelines

Catherine Cordonnier (France) opened the session with a review on toxoplasmosis, a rare complication after HSCT, although with high mortality. Screening for seropositivity at an early stage, before immunosuppressive treatment is started, helps avoid false negative results. The difference between toxoplasmosis infection and toxoplasmosis disease was discussed. Toxoplasmosis PCR is nowadays essential for diagnosis. A new strategy of screening and preemptive treatment is recommended in the ECIL 9 guidelines.

Alessandro Busca (Italy) presented an update on the diagnosis of fungal infections except Candida and Cryptococcus. Different diagnostic tests and their performance were reviewed, as well as the ECIL 9 recommendations for the use of galactomannan, beta-D-glucan, specific fungal PCR, panfungal PCR and Aspergillus-specific lateral flow assays.

Per Ljungman (Sweden) focused on viral hepatitis. HEV is usually a foodborne infection but in hematologic patients the transfusion route is also to be considered; serology has no place in diagnosis, which is made through PCR, and ribavirin may be used for treatment. HBV reactivation remains a threat in patients with prior or active infection. Vaccination shroud be offered to non-immune patients. Periodic screening and antiviral prophylaxis were discussed, As well as the importance of monitorization after prophylaxis discontinuation. HCV treatment is recommended for all infected patients, and can be done simultaneously with chemotherapy if necessary.

SESSION 2 | Respiratory virus infection after SCT

José Luis Piñana (Spain) reviewed non-SARS-COV-2 viral respiratory infections, which hematologic patients are prone to have more often, with more prolonged courses and with higher contagiousness. These infections can also present more severely in this population, lead to secondary bacterial infection and increase the risk of invasive fungal infections. Treatment options for different virus were discussed, such as oseltamivir for Influenza and ribavirin for RSV, as well as the importance of vaccination.

Per Ljungman (Sweden) provided us with an update on the studies on COVID-19 that IDWP has been leading, enabled by the data that several centers in Europe have been collecting. COVID-19 mortality is higher in SCT patients, especially in those who acquire the infection in the first 30 days after transplant, those who are older, have poorer baseline performance status or are under ongoing immunosuppression. Survival is lower in patients seropositive for CMV, even after correction for different time periods and patient variables, although the cause for this association is as of yet not understood.

SESSION 3 | News in epidemiology and diagnosis of infections

Ilaria Cutini (Florence, Italy) reviewed the current evidence about infectious complications after CAR-T therapy, with an incidence of infectious complications grade III-IV around 12-32%. There are different risk factors for infections: host-related [disease (higher risk in ALL), recent infection, low IgG level (higher risk of viral infections)] and therapy-related [CRS, ICANS (use of corticosteroids), T-cells dose]. A new tool HEMATOTOX is an easy-to-apply score (variables: platelets, haemoglobin, neutrophils count, reactive C-protein, ferritin) that helps to identify patients at high risk for severe infections prior to lympho-depletion (Rejeski K. J Immunother Cancer. 2022;10(5).). Another issue is the difficulty in distinguishing between CRS and severe infections within 30-days after CAR-T reinfusion: one study identifies a double peak of IL-6 and a prediction model of three-cytokines (IL-8, IL-1β and interferon-γ) as predictive of severe infection (Luo H. J Immunother Cancer. 2019;7(1):271.). Comprehensive guidelines for management of antimicrobials prophylaxis were provided (Hayden, Ann Oncol 2022; 33: 259-275; Wudhikarn, Bone Marrow Transplant 2022; 57:1477-1488).

Livio Pagano (Rome, Italy) illustrated the management of infectious complication during target therapies in AML, as addressed in ECIL-9 (slides set on website). The main recommendations can be summarized as follow: 1] Gemtuzumab ozogamicin: standard infectious risk [same incidence of febrile neutropenia, ALFA-0701 trial (GO+SOC versus SOC for de novo AML) showed a slightly higher incidence of invasive aspergillosis with GO, although not significant (10% vs 7%)], standard of care prophylaxis when given in combination to SOC or high-dose GO, careful monitoring of hepatotoxicity; 2] Midostaurin: registration trials reported higher incidence of febrile neutropenia, no increase of fungal and viral infections (<10%), further studies are warranted to define the real-life incidence of invasive fungal diseases (Cattaneo C. J Fungi (Basel). 2022;8(6). standard of care prophylaxis when given in combination to SOC or as monotherapy, warning of midostaurin-triazole drug-drug interactions (do not co-administer); 3] Gilteritinib and Glasdegib: no specific warning; 4] Venetoclax: no specific warning, standard of care prophylaxis, drug-drug interactions with triazoles (75% dose reduction of VEN when co-administered with posaconazole), pay attention to simultaneous use of fluoroquinolones or macrolide (QT-c elongation); 5] Vyxeos: low risk of infections, same incidence of infectious complications, but lower infection-related mortality (lower gastro-intestinal mucosa toxicity?).

Gian Maria Rossolini (Florence, Italy) made an overview on advances in diagnostic of bacterial infections, focusing on new tests that shorten the time between blood culture positivity and availability of standard antimicrobials susceptibility test (AST) [phenotypic molecular MALDI (turn-around time 30 minutes), phenotypic cellular fast AST [turn-around time 2-9 hours (time lapse microscopy, metabolomics)], genotypic syndromic panels [turn-around time 5-6 hours (mNAAT)]. Detecting genes associated with resistance (KPC, CTX-M, OXA-48, VIM, NDM), these tests impact on appropriateness of empirical therapy and on antimicrobial stewardship of novel drugs (ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, aztreonam/avibactam, cefiderecol). Pay attention to: 1] Off-target pathogens and resistance mechanism [Acinetobacter baumanii OXA-23/40/58 carbapenemas, some ESBL (TEM, SHV)]; 2] Molecular antibiogram doesn’t replace phenotypic one; 3] Molecular antibiogram possible isogenotypic discrepancies [example: KPC-K. pneumoniae resistant to ceftazidime/avibactam (ompK35delta, ompK36 137DT, overexpressed KPC-3), potential role of phenotypic cellular fast AST].

SESSION 4 | How do I manage the prophylaxis in HCT patients

Diana Averbuch (Jerusalem, Israel) presented news regarding antibiotic prophylaxis in severe neutropenia. The main concern is the prevalence of resistance to fluoroquinolones that, nowadays, largely exceed 20-30%: recent observational studies showed prophylaxis to be preventive for blood-stream infections and febrile neutropenia, not for mortality (Mikulska M. J Infection 2018; 76(1):20-37; Zimmer AJ.  Open Forum Infect Dis. 2022;9(7):ofac240 ; Chumbita M. J Antimicrob Chemother. 2022;77(7):2017-23.). So, it is suggested to move from universal to target prophylaxis. Who can still benefit? 1] Children and adults during induction chemo and ASCT, not allo-HSCT; 2] neutropenic patients colonized by Enterobacteriaceae susceptible to FQ (Satlin MJ. Clin Infect Dis. 2021;73(7):1257-65.). Disadvantages of FQ-prophylaxis should be considered: it reduces gut microbiota diversity (Pergam, CID 2021), it correlates with MDR-P. aeruginosa bacteraemia (Gudiol C. Antimicrob Agents Chemother. 2020;64(4).;Hakki M. Clin Infect Dis. 2019;68(12):2045-52. ) and with worst survival of haematological patients admitted for community-acquired pneumonia [higher rates of inappropriate empirical antibiotic therapy (Certan M. Clin Infect Dis. 2022;75(6):1046-53.)].

Corrado Girmenia (Rome, Italy) reviewed the current indications to primary antifungal prophylaxis (PAP) in allo-HSCT recipients. Is PAP needed? Yes, invasive fungal infections (IFIs) must be prevented because they were associated to lower 1-year survival (Girmenia C. Biol Blood Marrow Transplant. 2014;20(6):872-80. ). Against what fungi? Mainly, aspergillosis and Candida. When? It is well-known that a-GVHD deserves mould-active prophylaxis (MAP) (posaconazole, AI); high-risk transplants (cord blood, MUD-MMRD, disease status not in complete remission, IFIs within 180-day before transplant) should receive posaconazole also in pre-engraftment phase (BII) [Maertens JA. J Antimicrob Chemother. 2018;73(12):3221-30. ]. How long? Not yet defined. Remember that there is no indication to PAP in c-GVHD not preceded by a-GVHD (low risk of IFIs). Are there candidates to allo-HSCT that deserve to start MAP before transplant? 1] AML unfit for chemo (AZA, DEC-VEN); 2] AML fit for chemo; 3] severe aplastic anaemia. Finally, it has been hypothesised a role of letermovir on the containment of IFIs that needs further investigations.

Rafael De La Camara (Madrid, Spain) reviewed viral complications after allogeneic HSCT, underlining the progress in transplant’s outcome achieved with better GVHD prevention (post-transplant cyclophosphamide in haploidentical setting) and better supportive care (for instance: letermovir). Patients receiving letermovir have reached the same mortality of CMV sero-negative recipients bridging the gap of survival related to CMV sero-status. It deserves to be investigated the possible benefit of letermovir in R-/D+ if high-risk transplant for clinically-significant CMV infections (cs-CMVi) and post-transplant Cy-based GVHD prophylaxis. Moving to varicella zoster, acyclovir prophylaxis is recommended until 1-year after transplant to be prolonged if GVHD and corticosteroids; breakthrough disseminated zoster could occur during prophylaxis. Recommendations on COVID vaccination are available on ECIL website (ECIL-9 revision). A remark on real-life data on Evusheld pre-exposure prophylaxis in immunocompromised hosts (ICHs) was presented: it works against Omicron and in ICHs reducing death and hospitalization, it seems to confer a benefit also in vaccinated IHCs.

Sanjeet Dadwal (California, USA) presented the state of art on the prevention of viral diseases after HSCT with cellular therapy. At least one viral infection occurs in >80% of allogeneic transplants within 100-day; even if letermovir is highly efficient, there are concerns about late cs-CMVi and delayed immune-reconstitution. Phase II open-label trial of multi-specific T-cell therapy for viral infections prevention was presented (allogeneic off-the-shelf T-cells targeting ADV, BKV, CMV, EBV, HHV6, JCV). Inclusion criteria: cord blood, haplo, MMRD or MMUD, T-cell depletion, MUD with persistent lymphopenia <180/mm³. Twenty-six patients enrolled, infusion every 14 days for 7 doses, then 12 weeks of follow-up: overall, 62% of patients on letermovir, 85% mis-matched donors, 23% a-GVHD grade II-IV. At week 14 (primary end-point): 2 cs-CMVi leading to PET, 1 end-organ disease (EBV PTLD). Between week 15 and 26: no end-organ diseases, some cs-CMVi. In conclusion, no safety warnings, initiation of phase III was endorsed without protocol modification.

SESSION 5 | Viral infections

Per Ljungman (Stockholm, Sweden) highlighted the epidemiology and therapy of CMV infection. It is well-known as transplants with unfavourable CMV sero-matching (R+/D-) retain decreased survival, delayed specific immune-reconstitution and higher probability of csCMVi compared to having a CMV D+. Nowadays, CMV management improved dramatically moving from pre-emptive therapy (PET) to universal prophylaxis with letermovir; however, CMV end-organ disease still retain significant morbidity and mortality (Erard V. Clinical Infectious Diseases. 2015;61(1):31-9. ): pneumonia has a poor outcome, gastro-intestinal disease frequently coexists with gut GVHD (crucial role of biopsy for diagnosis, plasmatic CMVDNA can be negative). The armamentarium of antivirals has two new compounds: letermovir for prophylaxis and maribavir for treatment of relapse/refractory infections (Avery, CID 2021). Some remarks: 1] in vitro antagonism between GCV and MBV; 2] low-level DNA blips are common under letermovir, usually indicative for abortive infection; earlier letermovir is started, less blips are observed 3] monitor CMVDNA once weekly, in case of blips don’t stop letermovir until viral load of 2000 U/L (lower threshold if cord blood or severe GVHD) (local practices at Huddinge University Hospital) ; 4] in case of PET, do not change antivirals too early (at least one week to decrease DNA levels); 5] in clinical practice, it is more frequent that clinical refractoriness than antiviral resistance (role of therapeutic drug monitoring); 6] in case of treatment failure, usually co-exists a T-cell response deficiency/absence.

Simone Cesaro (Verona, Italy) reviewed the epidemiology and therapy of adenovirus infections after allo-HSCT, that usually occur within 100-day. Adenovirus infections are more frequent in children and risk factors are: in vivo or ex vivo T-cell depletion, unrelated-donor, cord blood transplant, grade III-IV a-GVDH, low CD3 count <300. In adults the risk factors are quite the same (haploidentical or cord blood transplants, grade III-IV a-GVHD, alemtuzumab). The peak and the duration of viremia correlates with the risk of disseminated disease and mortality (Zecca M. Bone Marrow Transplant. 2019;54(10):1632-42. ). Weekly screening of plasmatic viremia is recommended until 120/180-day after transplant (in children screening also on stool): 1] pre-emptive therapy with weekly intravenous cidofovir if viremia ≥10³ (or ≥10⁶ on stool) and try to reduce immunosuppression; 2] consider adoptive immunotherapy in case of progression to end-organ disease.

Summary written by Marta Henriques, Clinical Haematology, Centro Hospitalar e Universitário São João, Porto, Portugal

SESSION 6 | Interventions to manage infections

Dionysos Neofytos (Geneve, Switzerland) focused on the optimal use of antifungals (AF) through careful selection, with the main goals being the optimization of patient’s clinical outcomes, the decrease of the resistance profiles and toxicities. There are limited drugs available, and the high rate of Azole-resistant Aspergillus in Europe should warn us to review our core elements of AF selection. Regarding toxicities, in  hematological patients with voriconazole prophylaxis, about 50% had to discontinue the AF due to hallucinations or hepatotoxicity. Do all AML patients need anti-mold prophylaxis? As it was shown first by Cordonnier's study – there is no inferiority of survival comparing preemptive use of AF drugs to empirical treatment in high risk, febrile, neutropenic patients. (Cordonnier C. Clin Infect Dis. 2009;48(10):1392-401. ). The PTX3-targeted AF prophylaxis is now one of the most promising markers for novel management strategies, especially in this population which may be particularly well suited for genetically-targeted antifungal prophylaxis (Brunel AS. Haematologica. 2018;103(11):e527-e30. ; ClinicalTrials.gov NCT03828773). The antifungal stewardship is essential for short- and long-term purposes, as well as the need to improve diagnostic approaches for fungal infections.

Riccardo Masetti (Bologna, Italy) explained how the microbiome is altered during hematopoietic stem cell transplant (HSCT). A higher diversity of intestinal microbiota at the time of engraftment is associated with lower mortality (Masetti R. Blood Adv. 2021;5(22):4619-29. ). Intestinal Blautia is associated with reduced death from graft-versus-host disease (GvHD) (Jenq RR. Biol Blood Marrow Transplant. 2015;21(8):1373-83.), while lactose drives Enterococcus expansion to promote GvHD (Stein-Thoeringer CK. Science. 2019;366(6469):1143-9.). Bile acids can influence immune response during acute GvHD (Michonneau D. Nat Commun. 2019;10(1):5695.). Enteral nutrition can prevent gut microbiota (GM) disruption, decrease both blood stream infections and incidence of acute GvHD, along with antibiotics sparing strategies and fecal microbiota transplantation. The study of the GM derived metabolites can be used as feasible markers to support the prediction of complications after HSCT and can provide information regarding possible therapeutic supplementations.

Lidia Gil (Poznan, Poland) stated that vaccination in HSCT setting is a life-saving procedure. However, the adherence to vaccination still remains an issue. After myeloablative conditioning, GvHD should not be a contraindication to vaccinate and postponing only in specific situations. Donor vaccination before donation is not recommended. A observational study with 96 patients conducted by Janssen et al. (Janssen MJM. Bone Marrow Transplant. 2021;56(12):2922-8. ) identified viral reactivation post-HSCT, B-cells <135/mm³ and NK-cells <170/mm³ as predictors for vaccine failure at one year post-alloHSCT, which happened in 27% of the patients. On the contrary, 40% responded adequately to all 6 vaccines. In 7%, the vaccination waspostponed . Age influences vaccine response and responses to childhood immunization vaccines post-HSCT are poor in comparison with healthy individuals (Janssen M. Cancers (Basel). 2021;13(23):6140.). Measure the vaccine response, immunological reconstitution and clinical analysis may allow the individualisation in  this field (Vaccination of Haemopoietic Stem Cell Transplant Recipients: Guidelines from ECIL 7, Cordonnier C. Lancet Infect Dis. 2019;19(6):e200-e12;Piekarska A. Acta Haematologica Polonica. 2017;48(1):1-9. ).

SESSION 7 | How do I…

Murat Akova (Istambul, Turkey) presented an update on how multidrug resistance is becoming an increasing concern among the immunosuppressed and how the local epidemiology should differ the choice of therapy for bacteraemia (European Guidelines for Empirical Antibacterial Therapy for Febrile Neutropenic patients in the era of growing resistance: Summary of  ECIL 4,Averbuch D. Haematologica. 2013;98(12):1826-35.). A study with 207 neutropenia episodes in 142 neutropenic cancer patients who all received levofloxacin prophylaxis (LP) showed that 42% with no E.Coli colonization at admission became colonized during LP and 12,5% developed a quinolone-resistant E.Coli bacteraemia (Etgül et al. Unpublished data 2022). The AMINOLACTAM study demonstrated that the addition of an aminoglycoside to the initial empirical therapy regimen for febrile neutropenic hematological patients should be considered (Albasanz-Puig A, Gudiol C. Antimicrob Agents Chemother. 2021;65(8):e00045-21. ). Lowest mortality with empirical beta-lactam plus other active antibiotic; 90% mortality when amikacin was the only active antibiotic and empirical gram-positive treatment had no effect on mortality were also key points (Chumbita M. Antimicrob Agents Chemother. 2022;66(2):e0174421. ).

Ana Alastruey (Madrid, Spain) highlighted the WHO 2022 fungal priority pathogens list that divided them in critical, high and medium group risk. A critical one, Aspergillus fumigatus, has been described as showing  significant rates of azole resistance, although is lower comparing to resistant cryptic species (Alastruey-Izquierdo A. Antimicrob Agents Chemother. 2018;62(9).). Antifungals (AF) resistance is arising: 1. secondary resistance development in C. glabrata [plastic genome with easily acquiring resistances with now lower susceptibility to fluconazole, fungemia should be treated with echinocandins] and in C. parapsilosis [susceptible to azole but some resistance to echinocandins]; 2. intrinsic resistance in cryptic species, A. lentulus and A. calidoustus [only susceptible to amphotericin B] and "emerging" species like C. auris [4% pan-resistant and 93% resistant to fluconazole], Mucorales [intrinsically resistant to voriconazole], Scedosporium-Lomentospora and Fusarium [resistant to azoles and sometimes amphotericin B]. The streamlined access to the panfungal marker β-glucan D and aspergillus galactomannan are crucial to appropriate diagnosis. Fortunately, new AF are coming.

Anne Bergeron (Geneve, Switzerland) update tuberculosis and non-tuberculous mycobacterial infections in HSCT and oncohematologic patients.  Patients to target for Tuberculosis (TB) Infection screening are only the high-risk subpopulation of haematological (HM) or HSCT patients. The i starting of preventive therapy for treatment of latent TB should not delay HM treatment/HSCT procedure. 20% of mycobacterium infections in HM patients are caused by non-tuberculous mycobacterial (NTM) infections – it’s necessary to distinguish between infection and colonization. Repeated clinical, microbiological and radiological evaluations should be considered for decision of treatment. A single positive respiratory sample for NTM with no clinical or lung CT scan abnormalities does not require a specific treatment pre-HSCT, with the main multidrug treatments reeling on the ATS/ERS/ESCMID/IDSA recommendations. There is no consensus for management of latent TB infection; active TB can be due to either reactivation or primary infection in case of exposure; a case-by-case discussion is pertinent due to the frequent drug interactions between antimycobacterial drugs and MH and immunosuppressive treatments (Mycobacterial infections in adults with Haematological malignancies and Haematopoietic stem cell transplants: Guidelines from ECIL 8,Bergeron A. Lancet Infect Dis. 2022. DOI: 10.1016/S1473-3099(22)00227-4 ).