Thursday, 7 November 2024
Summary written by Adrien Calame – Department of infectious disease, Hôpitaux Universitaires de Genève, Genève, Switzerland
Session I: ECIL/EBMT Update
Per Ljungman (Sweden) opened the meeting with the latest recommendations on infection definitions from the EBMT Practice Harmonization and Guidelines Committee. Primary and catheter-related bloodstream infections (BSIs) are now categorized as either probable or definite, based on pathogen type (commensal or non-commensal) and the number of positive blood cultures. Updates on community-acquired respiratory viruses (CARVs) included distinctions between upper and lower respiratory tract infections. Definitions for adenovirus infections were revised, including case definition, mortality rates, and treatment response criteria. Lastly, new definitions for pneumonia cases and guidelines for assessing treatment response were proposed.
Simone Cesaro (Italy) provided an update on the 2024 ECIL guidelines, focusing on SARS-CoV-2 infections. New recommendations regarding prevention and diagnostic measures were introduced, along with detailed guidelines for primary and booster vaccinations across different populations (HCT, CAR-T, and non-transplanted). Recommended vaccines for SARS-CoV-2 include Bimervax, Comirnaty, Spikevax, and Nuvaxovid. Updated indications for antivirals, immunomodulators, and monoclonal antibodies in COVID-19 treatment were also reviewed.
Session II: Case Presentations
The second session featured three case presentations.
Giulia Ferrando (Italy) presented two cases involving the use of dalbavancin as secondary prophylaxis against reactivation of deep-seated Staphylococcus aureus infections during pre-engraftment neutropenia in allogeneic HSCT patients. This second-generation, long-acting lipoglycopeptide successfully prevented reactivation of multiple methicillin-sensitive Staphylococcus aureus (MSSA) hepatic abscesses (Case 1) and methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis (Case 2).
Blanca Vegas (Spain) discussed a case of herpes-zoster meningoencephalitis and myelitis in a matched-unrelated donor HSCT recipient despite appropriate prophylaxis. The patient presented with fever and nystagmus without rash, which progressed to generalized seizures. Treatment involved high-dose corticosteroids, intravenous immunoglobulins, and six plasma exchange sessions, resulting in hospital discharge with residual neurological sequelae (paraplegia).
Sheila Torrado (Spain) concluded the session with a case of refractory invasive pulmonary aspergillosis in a 12-year-old with aplastic anemia. Despite treatment with micafungin, isavuconazole, and nebulized liposomal amphotericin B, the disease progressed, necessitating a rescue allo-HSCT. Eleven months post-transplant, the patient continues treatment with intravenous micafungin and compassionate olorofim.
Session III: Pre-Transplant questions
Stavroula Masouridi (Switzerland) commenced the third session with a presentation on the role of pre-HSCT consultations by transplant infectious disease (TID) specialists. Conducted 2–4 weeks before transplantation, pre-transplant evaluations provide structured, individualized assessments. TID consultations include comprehensive history-taking and routine screening for viral infections, MDR bacteria, tuberculosis, and parasites. A review of 292 TID consultations showed interventions in three key areas: HCT postponement (2.7%), recommendations for diagnostic or therapeutic procedures pre-HCT (6.2%), and reinterpretation of recipient CMV serostatus (20%), along with minor interventions such as adjustments in prophylaxis or empirical antibiotic recommendations. Overall, pre-transplant TID consultations enable systematic yet personalized assessment of infectious risk in recipients.
Dina Averbuch (Israel) presented on MDR screening prior to transplantation. Given the increasing prevalence of MDR bacteria and the associated risk of bacteremia in colonized individuals, regular screening for MDR pathogens allows for targeted empirical antibiotic therapy, which has been shown to improve survival. Most data support the use of ceftazidime-avibactam for KPC-producing Enterobacterales and ceftolozane-tazobactam for MDR Pseudomonas aeruginosa. Increased resistance rates to cefiderocol were also reported. The presentation underscored the importance of infection control protocols and explained the rationale for recommending against routine decolonization procedures, citing studies linking colonization with subsequent infection.
Malgorzata Mikulska (Italy) discussed the evidence regarding neutropenic diets. Multiple studies, including systematic reviews and meta-analyses, indicate no significant difference between neutropenic and regular hospital diets, with few cases of food-borne infections reported post-HSCT. Based on these findings, recommendations were made to replace strict neutropenic diets with food safety counseling for HSCT recipients.
Anat Stern (Israel) concluded the final session with a complex case involving concomitant GI GVHD, CMV colitis, and post-transplant lymphoproliferative disorder (PTLD) with bowel involvement. A 45-year-old female, following a second HSCT for relapsed AML, presented after nine months with abdominal pain and diarrhea. Diagnostic evaluation confirmed CMV colitis, which required dual therapy with ganciclovir and foscarnet. Despite this, she suffered bowel perforation, necessitating emergency laparotomy and bowel resection. Pathology revealed DLBCL, consistent with monomorphic B-cell PTLD. Her treatment included immunosuppression tapering and rituximab, with positive outcomes.
Friday, 8 November 2024
Summary written by Anat Stern – Infectious Diseases Department, Rambam Health Care Campus, Haifa, Israel
Session IV: Hosts and pathogens
Pierre-Yves Bochud (Switzerland) discussed genetic risks and infections following HCT. Polymorphism in pattern recognition receptors has been shown to impact the identification and neutralizing of different pathogens. Polymorphism in TLR4 was associated with an increased invasive pulmonary aspergillosis (IPA) risk following HCT. Yet, no clinical trials have been published so far that directly link the genetic profile to the actual infection phenotype. Multiple studies have shown the association of specific genes with CMV and IPA in transplant patients, however the clinical relevance and impact on management strategy are yet to be defined. In order to be useful as a tool for infection prediction, the specific genetic polymorphism has to be prevalent and with sufficient impact on phenotype. As an example for such a case, PTX3 was proposed. Polymorphism in PTX3 is relatively prevalent and has been linked to higher risk for Invasive mold infections (IMI) in HCT and solid organ transplant recipients. An ongoing study is assessing the implementation of PTX3 in the IMI risk assessment and antifungal prophylaxis selection.
Laurent Kaiser (Switzerland) introduced the innovative topic of the virome in HCT recipients. Metagenomics is used to identify viral genetic sequences within the human microbiome. It is important to recognize that not all detected sequences represent active viruses—some may have unknown significance or reflect viral contamination. Current databases hold vast amounts of viral genetic data, including 10^5 novel RNA viruses, but millions of DNA/RNA sequences remain unclassified. The virome of HCT recipients differs from that of healthy individuals, featuring a high prevalence of commensal viruses with unknown pathogenicity, varying dynamics based on immunosuppressive phases and antiviral treatments, and frequent viral co-detection. Reactivation and cumulative loads of multiple dsDNA viruses have been linked to complications and poorer outcomes following HCT. Examples of specific viruses that have been linked to patients outcomes following HCT include Human Pegivirus (may be associated with favorable outcome in HCT) and anellovirus (associated with late immune reconstitution and higher risk for infections). Other viruses (Astrovirus, Rubella) have been associated with higher risk of GVHD. In conclusion, virome analysis is an unbiased diagnostic tool, and its routine use in specific clinical situations is now warranted.
Louise Bondeelle (Switzerland) reviewed the association of respiratory viral infections (RVI) and chronic GVHD. According to current NIH guidelines, a lung biopsy confirming bronchiolitis obliterans (BOS) is diagnostic for chronic GVHD in the lungs, while a chest CT showing air trapping and bronchiectasis is suggestive. Up to 50% of HCT recipients develop RVI, which is marked by prolonged viral shedding and a higher risk of viral mutations. RVI may also trigger a decline in pulmonary function post-HCT, with about one-third of patients experiencing lung impairment. Chronic GVHD, lymphopenia, and myeloablative conditioning are predictors of this impairment. Lower respiratory tract infections (LRTI) such as parainfluenza and RSV within the first 100 days post-HCT, as well as pre-transplant rhinovirus in BAL, have been linked to lung impairment. BOS has also been associated with COVID-19 following HCT, possibly due to viral-induced T-Reg apoptosis and the activation of IFN-inducible genes and chemokines (CXCL9/CXCR3) linked to BOS. Risk factors for BOS after RVI include pre-transplant RVI, LRTI within the first 100 days post-HCT, and genetic factors. As there is no effective treatment for BOS and it is associated with higher mortality, prevention strategies, such as vaccines and post-exposure prophylaxis, are crucial.
Federico Simonetta’s (Switzerland) presentation focused on the T cell repertoire post-HCT and its association with infections. T cell counts are not sufficient to appreciate T cell reconstitution post HCT. Following HCT, T cells reconstitution consists of two parts, donor hematopoietic stem cells development to T cells in the thymus and peripheral T cell expansion. In adults peripheral T cell expansion is the main process responsible for TCR. This process is characterized by dominance of specific T cell clones (high clonality) and lower diversity relative to thymic T cell development. The low T cell diversity starts from D30 and lasts up to D180 from HCT and is associated with overall survival and relapse risk after HCT. TCR is associated with viral infections in a bi-directional way - viral infections may affect TCR, a phenomena most classically described with CMV, and TCR affects the outcomes of viral infections. Low TCR diversity has been associated with COVID19 outcomes following HCT as well as CMV and EBV.
Emanuele Pacini (Italy) presented a case of Aspergillus calidoustus and Talaromyces columbinus infections in a patient with chronic graft-versus-host disease. While on immunosuppressive therapy and posaconazole prophylaxis, the patient developed hemoptysis and worsening dyspnea, chest CT scan was suggestive for an invasive fungal infection and serum galactomannan index was elevated. In bronchoalveolar lavage both A. calidoustus and T. columbinus were isolated. Despite treatment with combination of anidulafungin and isavuconazole, the patient succumbed to his complications.
Session V: Post transplant questions
Anne Bergeron (Switzerland) addressed the important question of when is BAL necessary and safe. Respiratory events are common in patients with hematologic malignancies, with the highest rates in AML patients. Many different factors may result in pulmonary damage in this population including immune mechanisms, drug injury, infections, pulmonary edema, alveolar hemorrhage and others. While about 60% of patients develop post HCT pulmonary complications, there are currently no guidelines regarding bronchoalveolar lavage (BAL) performance. The diagnostic yield of BAL depends on the underlying hematological condition. When assessing the necessity of BAL in a specific patient, both diagnostic alternatives and safety of the procedure should be considered. The decision to perform BAL should be incorporated in a diagnostic strategy. In a metaanalysis assessing BAL yield, around 8% of patients had BAL associated complications, mainly hypoxemia and bleeding. Early BAL results in higher diagnostic yield while waiting may result in clinical worsening precluding later BAL performance. The best way to avoid complications is to optimize the pretest selection of patients.
Dionysios Neofytos (Switzerland) provided insights to the question of when to stop post-transplant prophylaxis. While current guidelines are helpful in defining which prophylaxis to administer and when to start prophylaxis, recommendations regarding when to stop prophylaxis are limited. Antibacterial prophylaxis in the pre-engraftment period is directed against gram negative bacilli and is stopped with engraftment. Post engraftment antibacterial prophylaxis is directed against encapsulated bacteria and according to guidelines should be given for at least a year post HCT providing no GVHD treatment. In many centers prophylaxis withdrawal is dependent on post vaccination serology. Over 30% of patients will reactivate VZV post-HCT without prophylaxis. Antiviral prophylaxis with acyclovir has shown significant benefit in the year following HCT. Longer acyclovir prophylaxis may have some extra benefit. A reasonable approach is to give at least one year or at least 6 months providing no immunosuppressive drugs. Letermovir prophylaxis should be given for longer than 100 days in patients with high risk for CMV reactivation. Future perspective would include adjusting prophylaxis duration based on CMV T-cell immunity. PCP prophylaxis is preferred with Co-trimoxazole and continued for at least 6 months and as long as immunosuppression is ongoing. Antifungal prophylaxis is generally continued for 75 days post HCT however the role of antifungal prophylaxis after neutrophil engraftment is not defined. Furthermore, there are no clear recommendations for the duration of prophylaxis in patients with GvHD.
Christiane Eberhardt (Switzerland) reviewed post-transplant vaccinations. Generally, HCT recipients lose vaccine-induced immunity as early as one month post-transplant. Vaccine efficacy is influenced by pre-transplant conditioning and the presence of GVHD. Compared to healthy individuals, HCT recipients show decreased vaccine response and increased antibody decay rate. The timing of vaccination must balance the need for early protection during high-risk periods with the risk of a suboptimal immune response if given too soon. Non-live vaccines should be delayed in cases of active GVHD, prednisone >0.3 mg/kg/day, recent IVIG substitution, or anti-CD20 treatment within the last 6 months. Live attenuated vaccines are avoided for at least 2 years post-transplant, with at least 12 months after stopping all immunosuppressive therapy and >5 months since the last IVIG dose. For pneumococcal vaccines, although there is no immunogenicity data for PCV20 in HCT patients, PCV13 has shown good responses. Studies show no significant difference in vaccine effectiveness between administration at 3 months versus 6 months post-transplant. For the recombinant zoster vaccine, no clinical data is available in allogeneic HCT, but a study in autologous HCT demonstrated 68% efficacy. Expert opinion suggests giving the first dose 6-12 months post-transplant, with prophylaxis continuing for at least one month after the second dose. It is still unknown if a booster dose is needed.
Nina Khanna (Switzerland) discussed T-cell therapy for viral infections, focusing on adoptive virus-specific T-cell therapy (VST). VST uses peripheral blood mononuclear cells (PBMCs) containing virus-reactive memory T cells that can expand in vivo to control infection. Mortality from dsDNA viruses after HCT is high, and with limited treatment options, VST offers a promising approach. Data from over 1500 patients, mostly using ex vivo expanded VST, show around 70% partial/complete response rates, with GVHD occurring in about 10% of cases, and no reports of cytokine release syndrome or transfusion reactions. However, practical and regulatory challenges exist due to the complexity and high cost of VST manufacturing, limiting its use to academic centers. ECIL guidelines recommend VST as first-line treatment for EBV-PTLD and as a consideration for refractory CMV post-HCT, with promising potential for HHV-6, AdV, and BKPyV. Common exclusions include active GVHD grade ≥2, corticosteroid use, and recent ATG or anti-CD52 antibody treatment. When donors are unavailable, third-party donors are a viable option, showing similar safety and efficacy, particularly in pediatric HCT recipients. Multi-virus VSTs are now available, offering broader treatment potential. However, competition between infused cells in low-immunogenic environments remains a concern. VST efficacy depends on factors like disease state, immunosuppression, and HLA compatibility. In terms of longevity, EBV-specific T cells were detectable for up to 9 years post-infusion and third-party T cells lasted up to 23.7 months.
Session VI: Diagnostics in HCT
Frederic Lamoth (Switzerland) discussed fungal PCR: help or confusion. The pros of fungal PCR include its high sensitivity, improved diagnostic accuracy (turning possible cases into probable invasive fungal infections, IFIs), the ability to optimize antifungal therapy, and early detection ahead of conventional methods. However, its cons involve a lack of specificity (especially for panfungal PCR), potential sample contamination, lack of standardization, limited availability, and delayed diagnoses due to the absence of commercial kits. The 2020 EORTC-MSG definitions incorporated Aspergillus PCR as a diagnostic criterion for invasive aspergillosis. For Mucorales PCR, a combination of three genus-specific real-time qPCR tests can detect Mucor/Rhizopus, Rhizomucor, and Lichtheimia with high sensitivity (80-90% in serum, 90-100% in BAL) and specificity over 95%. The commercial MucorGeniusTM PCR test also has strong sensitivity and specificity, particularly in BAL samples. Mucorales PCR outperforms culture in sensitivity and aids in anticipating diagnoses through histopathology or culture, with additional value in monitoring treatment response and prognosis. A suggested diagnostic algorithm involves performing A. fumigatus and Mucorales PCR in suspected invasive mold infections, followed by panfungal PCR if results are negative but suspicion remains high. If panfungal PCR is positive with a CT value <33.5, further sequencing may be performed.
Manuel Schibler (Switzerland) reviewed Semi-quantitative PCR in clinical virology: to “Ct” or not to “Ct”? In blood and other samples. The presentation discussed the use of semi-quantitative PCR in clinical virology, focusing on the interpretation of Ct values in blood and other samples. Unlike regular PCR, real-time PCR monitors the amplification process in real-time using fluorescent markers. The Ct value represents the number of cycles required for the fluorescent signal to cross a set threshold, with lower Ct values indicating higher target DNA amounts and higher Ct values suggesting lower DNA quantities. Semi-quantitative real-time PCR estimates relative DNA amounts between samples using Ct values, but does not provide exact copy numbers like quantitative PCR. Ct values are more accurate in blood specimens than in other types, such as nasal aspirates or stool. The COVID-19 pandemic popularized the use of Ct values. It is crucial to use the same assay for comparison and apply the "3 Ct value difference rule," which indicates a significant difference only when there is at least a 3-value variation between samples.
Chiara Garonzi (Italy) presented a case titled "The Insidious Power of Scedosporium." The patient was a 5-year-old boy with chronic granulomatous disease who underwent allogeneic HCT from an unrelated donor. He subsequently developed abscesses in the knee joint and parasternal region, with drainage fluid growing Scedosporium apiospermum. Treatment included voriconazole and polymorphonuclear leukocyte transfusions. After a second HCT from the same donor, the patient developed multiple bilateral cerebral abscesses, which were drained and grew the same pathogen. Unfortunately, despite ongoing antifungal treatment, the patient did not survive.
The last section for the day was a debate: are guidelines helpful or not.
Jan Styczynski (Poland) presented the case for the value of guidelines, highlighting the hierarchy of scientific evidence they are based on. The European Conference on Infections in Leukemia (ECIL) aims to develop European guidelines for the prevention and treatment of infectious complications in leukemic patients, assess current management practices across Europe, foster communication between groups, and identify new areas for clinical research. ECIL’s methods include addressing key questions set by the organizing committee, evaluating clinically significant endpoints, conducting thorough literature reviews, and grading the strength of evidence and recommendations using the CDC grading system. These guidelines aim to provide comprehensive coverage of a topic based on the latest knowledge, with particular emphasis on negative recommendations. Additionally, recommendations may evolve as new evidence emerges.
Christian van Delden (Switzerland) presented the arguments against the use of guidelines. Guidelines are often based on limited evidence due to a lack of well-designed studies and may be influenced by the personal opinions and clinical experiences of the guideline authors. Time and resource constraints can further impact their development, and patient needs may not always be the primary focus, as guidelines may prioritize cost control or specific interests. Additionally, they can be inconvenient, time-consuming, and potentially confusing, particularly when they conflict with guidelines from other professional bodies or become outdated. Guidelines may also oversimplify complex patient situations by offering binary recommendations (yes/no), and recommended drugs may not be available, appropriately approved, or affordable in certain countries. They also cannot fully account for local epidemiological factors or the specific needs of individual patients, such as variations in age, gender, organ function, or drug interactions. Consequently, guidelines should not be applied rigidly, and clinicians must critically assess their relevance to both local conditions and the unique circumstances of each patient.
Saturday, 9 November 2024
Summary written by Adrien Calame – Department of infectious disease, Hôpitaux Universitaires de Genève, Genève, Switzerland
Session VII: Future perspectives
Rafael de la Cámara (Spain) opened the session by identifying the top three unmet needs in the field of transplant infectious diseases (TID). The first was the inadequate evaluation of infectious complications in pivotal studies conducted for new therapy approvals. Examples of incomplete data on infectious complications were presented, supported by a consensus position statement from ECIL and EBMT emphasizing this gap. The second need was the discovery of new anti-infective agents, particularly for multidrug-resistant (MDR) pathogens. A review highlighted recent developments in anti-infective molecules targeting MDR bacteria and fungi, and several phase III studies on multivirus-specific T cells for treating double-stranded DNA viruses were presented—though all yielded negative results, marking another challenge in viral infection management for HSCT recipients. The third unmet need was the underrepresentation of oncohematology patients in phase III vaccine trials.
Per Ljungman (Sweden) shared his vision of an ideal study in TID, addressing key considerations like the rarity of infections, difficulties in achieving significant outcomes, and ethical concerns. He proposed two "dream studies" in the context of CMV infections: re-evaluating the use of IVIG or hyperimmune Ig for CMV pneumonia treatment, and assessing dual therapy with maribavir and letermovir for challenging CMV cases. Other examples included ribavirin for RSV infections, recombinant zoster vaccine in allo-HSCT recipients, and trials of new antiviral drugs like brincidofovir. Dr Ljungman’s “holy grail” study would involve randomizing patients to placebo or CMV vaccine after six months of letermovir prophylaxis to prevent late CMV reactivations post-HSCT.
A debate on “neutropenia and bacteremia: broad and long versus targeted and short” featured Malgorzata Mikulska (Italy) and Dina Averbuch (Israel). Dr. Mikulska advocated for targeted and short therapy, highlighting the lack of robust evidence supporting combination therapy for carbapenem-resistant Enterobacterales and the variability in approaches for difficult-to-treat resistant (DTR) Pseudomonas aeruginosa. Evidence was presented showing no inferiority of short-course (7–10 days) compared to long-course therapy for P. aeruginosa infections in immunocompromised patients.
Dr. Averbuch supported broad and long therapy, citing retrospective studies linking lower mortality to combination treatments (e.g., beta-lactams with aminoglycosides) for Gram-negative infections. While doubts persist for P. aeruginosa, ECIL and IDSA guidelines recommend combination therapy for infections with carbapenem-resistant Acinetobacter baumannii and Stenotrophomonas maltophilia. Additionally, longer treatments were associated with fewer recurrences of P. aeruginosa infections in one multicenter retrospective study (Olearo F, Open Forum Infect Dis, 2020).
Ana Belén Bocanegra (Spain) presented a challenging case of invasive Aspergillus terreus infection in a 43-year-old female with relapsed AML after HSCT. Despite extensive surgical (in collaboration with neurosurgeons and ENT surgeons) and medical interventions —including various antifungal agents such as voriconazole, anidulafungin, terbinafine, intrathecal caspofungin, and fosmanogepix— the patient succumbed to multi-organ failure.
Session VIII: Infection or not infection?
José Luís Piñana (Spain) discussed the complexities of correlating community-acquired respiratory virus (CARV) detection in the upper respiratory tract with lower respiratory tract infections (LRTIs) in HSCT recipients. Using a case of hPIV-3-related respiratory failure in a 57-year-old male, the discussion encompassed pulmonary syndromes (infectious and non-infectious), risk factors for LRTI progression, and associated complications like idiopathic pneumonia syndrome and bronchiolitis obliterans. Data highlighted MPV and RSV as posing the highest LRTI risk.
Simone Cesaro (Italy) reviewed hepatic complications post-HSCT, including infectious causes (e.g., hepatotropic viruses, Adenovirus) and non-infectious factors (e.g., drug-induced liver injury, iron overload). Hepatitis etiologies were categorized by timing (<3 or >3 months post-transplant) and liver enzyme profiles. Management strategies for conditions like sinusoidal occlusion syndrome (SOS) and drug-induced liver injury (DILI) were also discussed.
Lidia Gil (Poland) concluded with a presentation on infectious and non-infectious complications in CAR-T cell therapy recipients. Short-term complications primarily included cytokine release syndrome (CRS; ~80%) and immune effector cell-associated neurotoxicity syndrome (ICANS; ~40%). Bacterial infections were prevalent in the early phase, with an attributable mortality of 1.8% (Shahid Z, Transplant Cell Ther, 2024). Challenges in distinguishing CRS from bacterial infections were highlighted, along with emerging strategies involving biomarkers like CRP, PCT, IL-6, IFN-g and IL-1β. Viral reactivations and fungal infections in later phases of CAR-T therapy were also discussed, emphasizing the need for robust risk mitigation strategies.