Outcome of SARS-CoV2 infection in hematopoietic stem cell transplant recipients for autoimmune diseases.

Hematopoietic stem cell transplant (HSCT) recipients may be at high risk of mortality from coronavirus disease 2019 (COVID-19). However, specific data on COVID-19 after treatment with HSCT in patients affected by autoimmune diseases (ADs) are still lacking. In this multicenter observational study of the European Society for Blood and Marrow Transplantation (EBMT), clinical data on COVID-19 in 11 patients affected by severe ADs treated with HSCT (n = 3 allogeneic transplant; n = 8 autologous transplant) are reported. All patients were symptomatic during the initial phase of the SARS-CoV-2 infection. At screening, 5 patients reported upper respiratory symptoms, 3 patients had cough without oxygen requirement, and 6 patients exhibited extra-pulmonary symptoms. Four cases developed a lower respiratory tract disease (LRTD). Hospitalization was required in 6 cases, without necessity of intensive care unit (ICU) admission and/or ventilation/supplemental oxygen. Different interventions were adopted: remdesivir (n = 1), nirmatrelvir/ritonavir (n = 1), sotrovimab (n = 1), immunoglobulins (n = 1). At last follow-up, all patients are alive and had resolution of the infection. The current analysis describing the mild-moderate course of COVID-19 in transplant recipients affected by ADs, similar to the course observed in ADs under standard treatments, provides useful information to support the delivery of HSCT programs in this field. Vaccination and new treatments available for SARS-CoV-2 may be useful to further minimize the risk of infection.

Outcomes of keratolimbal allograft from ABO compatible donors for severe bilateral limbal stem cell deficiency.

PURPOSE: To report outcomes of keratolimbal allograft (KLAL) compatible for both human leukocyte (HLA) and/or blood type using oral prednisone, mycophenolate, and tacrolimus, with basiliximab if panel reactive antibodies (PRA) are present. Intravenous immunoglobulin (IVIG) was used post-operatively if donor-specific anti-HLA antibodies (DSA) were present. METHODS: Retrospective interventional series of consecutive patients with KLAL for limbal stem cell deficiency (LSCD) from HLA and/or blood type compatible deceased donors with a minimum follow-up time of 12 months. Main outcome measures were ocular surface stability, visual acuity and systemic immunosuppression (SI) adverse events. RESULTS: Eight eyes of eight patients with mean age of 48.6 ±â€¯10.1 years (range 34-65 years) were included. Mean follow-up time was 37.3 ±â€¯22.7 months (range 12-71 months) following KLAL; four (50%) had combined LR-CLAL surgery. The etiologies of LSCD were Stevens-Johnson Syndrome (n = 4/8), aniridia (n = 2/8), chemical injury (n = 1/8) and atopic eye disease (n = 1/8). All patients had PRA present and received basiliximab infusions. 5/8 patients received IVIG based on DSA identified pre-operatively. At last follow-up, 7 eyes (87.5%) had a stable ocular surface; 1 eye (12.5%) developed failure and had keratoprosthesis implantation. There was a significant improvement in visual acuity from 1.65 ±â€¯0.48 to 0.68 ±â€¯0.34 logMAR (p = 0.01). SI was tolerated well with minimal adverse events. CONCLUSIONS: Preliminary outcomes of KLAL with ABO compatible tissue using the Cincinnati protocol, preoperative basiliximab (when PRA present) and post-operative IVIG (when DSA present) are encouraging. This protocol may allow for utilization of deceased donor tissue with results approximating those of living donor tissue transplanted for severe bilateral LSCD.

Favorable outcomes of COVID-19 in vaccinated hematopoietic stem cell transplant recipients: A single-center experience.

INTRODUCTION: A high incidence of mortality and severe COVID-19 infection was reported in hematopoietic stem cell transplant (HSCT) recipients during the early phases of the COVID-19 pandemic; however, outcomes with subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, such as the omicron variant, have yet to be reported. Additionally, rollout of COVID-19 vaccinations in subsequent pandemic waves may modify COVID-19 disease severity and mortality in this immunocompromised population. We describe COVID-19 outcomes among a highly vaccinated population of HSCT recipients at a single center during successive waves of community transmission arising from the SARS-CoV-2 delta and omicron variants. METHODS: We retrospectively reviewed medical records of all HSCT recipients at our institution who tested positive for SARS-CoV-2 from May 2021 to May 2022. Descriptive statistics were reported; the chi-square test was utilized to identify factors associated with 90-day all-cause mortality and severity of COVID-19 infection. RESULTS: Over the 1-year study period, 77 HSCT recipients at our center contracted COVID-19 (43 allogenic; 34 autologous). Twenty-six (33.8%) patients were infected with the SARS-CoV-2 delta variant, while 51 (66.2%) had the SARS-CoV-2 omicron variant. Thirty-nine (50.6%) patients required hospitalization. More than 80% had received prior COVID-19 vaccination (57.1% with two doses, 27.3% with three doses). The majority (90.9%) had mild disease; only one (1.3%) patient required mechanical ventilation. Active hematological disease at time of COVID-19 infection was associated with increased odds of mortality [odds ratio (OR) = 6.90, 95% confidence interval (CI) = 1.20-40]. The 90-day all-cause mortality was 7.8% (six patients). Infection with the omicron variant (vs. delta) was associated with less severe illness (OR = 0.05, 95% CI = 0.01-0.47) and decreased odds of mortality (OR = 0.08, 95% CI = 0.01-0.76). Being on immunosuppression (OR = 5.10, 95% CI = 1.10-23.60) and being unvaccinated at disease onset (OR = 14.76, 95% CI = 2.89-75.4) were associated with greater severity of COVID-19 infection. CONCLUSION: We observed favorable outcomes with COVID-19 infection in a cohort of vaccinated HSCT patients. The SARS-CoV-2 omicron variant was associated with both less severe illness and decreased odds of mortality. As COVID-19 moves toward endemicity, early access to treatment and encouraging vaccination uptake is crucial in mitigating the challenge of COVID-19 management among HSCT recipients. Surveillance and assessment of clinical outcomes with new SARS-CoV-2 variants also remains important in this immunocompromised population.

Immunogenicity of SARS-CoV-2 vaccination in patients undergoing autologous stem cell transplantation. A multicentric experience.

COVID-19 disease has a strong impact on hematological patients; those receiving autologous hematopoietic stem cell transplantation (aHSCT) represent a particularly vulnerable group, in which the effectiveness of vaccination is very variable. Chiarucci et al. showed that patients affected by non-Hodgkin lymphoma (NHL) and treated with rituximab experienced a lower rate of immunization against SARS-CoV-2 (54%), as well as significantly lower IgG antibody titers. In our multicenter retrospective observational study, we included 82 patients who underwent aHSCT, divided into two groups: 58 patients vaccinated after aHSCT (group A) and 24 vaccinated before getting transplantation (group B). In group A, 39 (67%) patients had positive serology, and the rate of positivity increased with time after aHSCT. In the subgroup of patients with NHL, the administration of rituximab predicted negative serology, particularly when administered in the 6 months before vaccination (13% response rate). Patients affected by plasma cells had a higher rate of positivity (83% overall), independently of the time to aHSCT. In group B, no patient who initially showed positive serology became negative after transplantation, so the aHSCT did not affect the response to the vaccination. Our study confirmed the role of rituximab as a negative predictor of response to SARS-CoV-2 vaccination, whereas the conditioning and transplantation procedure itself seemed to be less important.

COVID-19 in the Immunocompromised Host, Including People with Human Immunodeficiency Virus.

This review describes the incidence, epidemiology, and risk factors for mortality of COVID-19 in immunocompromised patients, including persons with human immunodeficiency virus. It describes various preventive measures, including vaccines and their effectiveness and the role of monoclonal antibodies for pre-exposure prophylaxis. It also reviews the different treatment options for immunocompromised individuals, including antivirals, monoclonal antibodies, and immunomodulators. Lastly, it describes the impact of COVID-19 on transplantation and continuity care of this population.

Factors that predict severity of infection and seroconversion in immunocompromised children and adolescents with COVID-19 infection.

Objectives: We aimed to study the outcomes, severity, and seroconversion post SARS-CoV-2 infection in immunocompromised children and adolescents treated at our center. Method: For this observational study, all pediatric patients who had COVID-19 infection from Sep-22-2020 to Nov-10-2021were identified by reviewing our laboratory records. Their charts were reviewed to determine clinical severity and outcome. Blood samples were drawn for anti-SARS-CoV-2 antibody assay. Serious COVID-19 infection (SVI) was defined if the patient had moderate, severe, or critical illness. A cutoff of 100 U/mL anti-SARS-CoV-2 antibodies was used to categorize low and high titer seroconversion. Results: We identified 263 pediatric patients with COVID-19; most (68%) were symptomatic: 5% had severe or critical infection, 25% were hospitalized, 12 required respiratory support, 12 were admitted to the ICU, and five patients (2%) died. Multivariable analysis revealed several factors that predict SVI: Age above 12 years (p=0.035), body mass index above 95th percentile (p=0.034), comorbid conditions (p=0.025), absolute neutrophil count ≤500(p=0.014) and absolute lymphocyte count ≤300 (p=0.022). Levels of anti-SARS-CoV-2 spike antibodies were obtained for 173 patients at a median of 94 days (range, 14-300) after PCR diagnosis; of them 142 (82%) patients seroconverted; the lowest seroconversion rate was observed in patients with hematological malignancies (79%). Our univariable model showed that the following factors were predictive of low titer: lower ANC, p=0.01; hematologic malignancy, p=0.023; receiving steroids in the last 14 days, p=0.032; time since last chemotherapy or immunosuppressive therapy less than 30 days, p=0.002; and being on active chemotherapy in the last 3 months prior to infection, p<0.001. Conclusions: SARS-CoV-2 antibodies developed in most immunocompromised patients with COVID-19 infection in our study. Mortality was relatively low in our patients. Our univariable and multivariable models showed multiple variables that predict severity of infections and antibody response post COVID-19 infection. These observations may guide choice of active therapy during infection and the best timing of vaccination in this high-risk population.

Haploidentical CD3+ TCR αß/CD19+ depleted HSCT for MHC Class II deficiency and persistent SARS-CoV-2 pneumonitis.

Background & Objectives: SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterised by acute respiratory distress, needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against Covid-19 and have persistent disease. The authors describe a child with combined immunodeficiency, with favorable post-HSCT course following a haploidentical haematopoietic stem cell transplant in the presence of persistent SARS-CoV-2 infection. Methods & results: A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution post-HSCT, she underwent a maternal (with a recent history of Covid-19 infection) haploidentical haematopoietic stem cell transplant. The patient received Regdanvimab® (post stem cell infusion) and Remdesivir (pre and post stem cell infusion). We noted a gradual increase in the Ct (cycle threshold) values, implying reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical/radiological improvement. Conclusions: Combination of adoptive transfer of maternal CD45RO+ memory add-back T-lymphocytes after haploidentical HSCT, use of Regdanvimab® (SARS-CoV-2 neutralising monoclonal antibody) and Remdesivir may have led to the successful outcome in our patient with severe immunodeficiency, undergoing HSCT. Our case highlights the role of novel antiviral strategies (monoclonal antibodies and CD45RO+ memory T-lymphocytes) in contributing to viral clearance in a challenging clinical scenario.

COVID-19 and HSCT (Hematopoietic stem cell transplant).

HSCT recipients are at increased risk for COVID-19-associated morbidity and mortality. Early treatment of symptomatic SARS-CoV-2 infection is an important means to decreasing risk for severe disease and death. While some HSCT recipients, particularly those who are early post-transplant and severely immunosuppressed, may have diminished response to COVID-19 vaccines, the benefits of vaccination are uncontested. Public health, healthcare facility and individual level approaches are all necessary to mitigate risk for infection in this vulnerable population.

Infecciones respiratorias virales en episodios de fiebre en niños con trasplante de precursores hematopoyéticos

Abstract Background: Children undergoing hematopoietic stem cell transplant (HSCT) can develop respiratory viral infections (RVI) during fever episodes. There are few data about clinical outcomes in RVI and compared to bacterial infections (BI) in this population. Aim: To determine clinical outcome of RVI, compared to BI in children with HSCT. Methods: Prospective study, patients ≤ 18 years with cancer and HSCT admitted with fever at a National Bone Marrow Transplant Center (Hospital Calvo Mackenna), Chile, (April-2016 to May-2019). Clinical assessment, laboratory tests, blood cultures, nasopharyngeal sample for multiplex-PCR (Filmarray®), viral loads by PCR and cytokine panel (Luminex®, 38 cytokines) were performed. The following outcomes were evaluated: upper/lower respiratory tract disease (RTD), admission to ICU, mechanical ventilation, mortality and antimicrobial withdrawal. Results: Of 56 febrile episodes, 35 (63%) were RVI, 12 (21%) BI and 9 (16%) with unknown etiology (UE). Median of age was 8.5 years, 62% male gender. Rhinovirus (54%) and coronavirus (15%) were the more frequent detected viruses. No significant differences in cytokine levels were observed between RVI and BI. 94% of RVI patients had symptomatic RTD, versus 33% in BI and 33% in UE group (p < 0.001), with lower-RTD in 69% of RVI group (p < 0,001). Admission to ICU was 11% in RVI, 17% in BI and 11% in UE group (p = 0.88);only 2 patients required mechanical ventilation (p = 0.37) and no mortality was reported. After an RVI was detected by PCR, antimicrobials were withdrawal in 26% of patients with RVI (p: 0.04). Conclusion: RVI are frequent etiologic agents in febrile episodes of patients with HSCT. Viral detection might help to rationalize the use of antimicrobials in this population.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

Post-SARS-CoV-2 Atypical Inflammatory Syndrome in a Toddler with X-Linked Inhibitor of Apoptosis Deficiency After Stem Cell Transplant.

A 10-month-old boy was diagnosed with X-linked lymphoproliferative syndrome type 2 due to X-linked inhibitor of apoptosis deficiency after presenting with failure to thrive and refractory inflammatory bowel disease. He underwent a matched unrelated donor stem cell transplant with reduced intensity conditioning at 16 months. At 27 months, he presented with an atypical inflammatory syndrome in the setting of recent COVID-19 infection, Epstein-Barr viremia, and low chimerism (7.3%). He recovered after treatment with intravenous immunoglobulin and steroids.

Plasmablastic Lymphoma Presenting With Rectosigmoid Perforation in a Human Immunodeficiency Virus-Positive Patient.

Plasmablastic lymphoma (PBL) is a rare variant of diffuse large B-cell lymphoma (DLBCL) associated with human immunodeficiency virus (HIV)-positive patients. It accounts for only 2% of all acquired immune deficiency syndrome (AIDS)-related lymphomas (ARLs). We present the case of a 45-year-old male who presented to the emergency department (ED) with a three-month history of abdominal pain, diarrhea, and unintentional 50-lb weight loss. On an earlier presentation to the ED three months prior, the patient was diagnosed with norovirus and Helicobacter pylori infection and received outpatient treatment without resolution of his symptoms. This prompted further investigation with a CT of the abdomen and pelvis with IV contrast that revealed severe sigmoid colitis with pneumoperitoneum and a pericolonic air-containing fluid collection, consistent with a contained perforation with abscess formation. He was admitted, resuscitated, and initially treated with antibiotics and parenteral nutrition. The patient underwent a laparoscopic converted to open anterior resection with end colostomy. Pathology revealed HIV-related PBL. He was subsequently treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy regimen and an autologous stem cell transplant. Despite its rare association with HIV, PBL should be considered a differential diagnosis for HIV-positive patients who present with gastrointestinal (GI) pathology, and additional investigations should be conducted if symptoms do not resolve despite appropriate medical management at the time.

Impaired humoral and cellular response to primary COVID-19 vaccination in patients less than 2 years after allogeneic bone marrow transplant.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.

Prolonged Lenalidomide Induction Does Not Significantly Impair Stem Cell Collection in Multiple Myeloma Patients Mobilized With Cyclophosphamide or Plerixafor: A Report From The Covid Era.

INTRODUCTION: Induction therapy for multiple myeloma is traditionally capped at 6 cycles of lenalidomide due to concerns that longer treatment compromises the ability to collect sufficient stem cells for autologous stem cell transplantation (ASCT). However, during the COVID-19 pandemic, many of our patients received prolonged lenalidomide induction due to concerns about proceeding to ASCT. We investigated whether prolonged induction with lenalidomide affects the efficacy of stem cell collection among patients mobilized with cyclophosphamide and/or plerixafor. PATIENTS AND METHODS: This single center, retrospective study included patients who were treated with lenalidomide induction regimens, received mobilization with cyclophosphamide or plerixafor, and underwent apheresis in preparation for ASCT. 94 patients were included, 40 of whom received prolonged induction with >6 cycles of lenalidomide containing regimen. RESULTS: Patients who received prolonged induction were more likely to require >1 day of apheresis (38% vs. 15%; OR 3.45; P = .0154), and there was a significant correlation between the duration of lenalidomide treatment and the apheresis time required to collect sufficient cells for transplant (R2 = 0.06423, P = .0148). However, there was no significant difference between patients who received prolonged induction and those who did not with respect to CD34+ stem cell yields at completion of apheresis (9.99 vs. 10.46 cells/Kg, P = .5513) or on the first day of collection (8.29 vs. 9.59 cells/Kg, P = .1788). CONCLUSION: Among patients treated with >6 cycles of lenalidomide, mobilization augmented with cyclophosphamide and/or plerixafor will likely facilitate sufficient stem cell harvest to permit ASCT.

Case Report: Severe Acute Pulmonary COVID-19 in a Teenager Post Autologous Hematopoietic Stem Cell Transplant.

Pulmonary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally described as mild, and SARS-CoV-2 infection in immunocompromised children are observed as generally mild as well. A small proportion of pediatric patients will become critically ill due to (cardio)respiratory failure and require intensive care treatment. We report the case of a teenager with Hodgkin's lymphoma who acquired SARS-CoV-2 (detected by PCR) on the day of her autologous stem cell transplant and developed acute respiratory distress syndrome, successfully treated with a combination of antivirals, immunomodulation with steroids and biologicals, and ECMO.

Mesenchymal stem cell therapy in COVID-19 pneumonia: a prospective, randomized clinical research

Objective: Deficiencies in immune-regulatory mechanisms such as immune activation and T-regulatory cells are classically referred to as cytokine storms. Mesenchymal stem cells (MSCs) act as living anti-inflammatory cells that can rebalance cytokine/immune responses to restore balance in patients with coronavirus disease-2019 (COVID-19) acute respiratory distress syndrome by reducing the activation of T and B cells, and dendritic and natural killer cells. The aim of this study is to provide immune modulation with stem cell transplantation by reducing the damage caused and COVID-19 infection to tissues and organs. Material and Methods: In this prospective randomized single-center clinical trial, patients were divided into 3 groups: intubated without comorbidity (n = 7);intubated with comorbidity (n = 7);not intubated (n = 7). Dosage of MSCs transplantation for each group was 1 million cell/kg intravenous at days 0, 2, and 4. age, gender, APACHE II scores, procalcitonin, C-reactive protein (CRP) and leukocyte values, and cluster of difference 4 (CD4), CD8, interleukin 2 (IL-2), and IL-6 levels, morbidities, number of days in intensive care unit, mortality were recorded. Clinical results, changes in inflammatory and immune function levels, and side effects were evaluated. Each patient's improvement in oxygenation and symptoms were recorded in the days after MSC transplantation. After treatment, lymphocyte, CRP, tumor necrosis factor-a level, and IL-6 levels were recorded.

Allogeneic Hematopoietic Stem Cell Transplant for Acute Lymphoblastic Leukemia in a Pediatric Patient After COVID-19 Infection Complicated by MIS-C.

The COVID-19 pandemic has impacted the care of countless individuals, including pediatric oncology patients. The initial lack of knowledge about the disease course and implications of infection led to delays in treatment to minimize additional harm. In pediatric oncology, unnecessary delays in chemotherapy or hematopoietic stem cell transplantation may increase the risk of disease relapse. This case report describes one high-risk pediatric oncology patient's clinical course through hematopoietic stem cell transplantation immediately following COVID-19 infection complicated by multisystem inflammatory syndrome in children. The disease course, monitoring, long-term outcome, and recommendations for future research are reviewed.

The development of a home-based therapeutic platform for multiple myeloma.

BACKGROUND: Multiple Myeloma (MM) accounts for 1-2% of all malignancies but is the second most common hematological malignancy. It is characterized by a proliferation of malignant plasma cells. The treatment paradigm of MM in Australia is traditionally hospital-based, complex, and costly. While MM comprises 1-2% of cancer diagnoses, it appears in the top 10 cancer diagnoses requiring hospital admission. The cumulative time spent receiving treatment is a significant burden for patients. The ability to receive treatment at home and maximize time away from hospital-based settings is a key preference for patients receiving anticancer therapies over a prolonged period of time. METHODS: The Peter MacCallum Cancer Centre and Royal Melbourne Hospital's combined Clinical Hematology Unit has collaborated with their Hospital in the Home departments to develop several innovative programs to address this. RESULTS: We describe our current active programs and potential developments in home-based MM therapy. CONCLUSION: We have enabled large numbers of patients to receive complex therapies in their own home and the COVID-19 pandemic has increased the pace of the roll out without any compromise in safety. We anticipate that the next raft of immunotherapies will be able to transition into the @Home treatment setting in the coming years.