Critical care management of chimeric antigen receptor T-cell therapy recipients.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.

A diagnostic challenge-First case of chronic lymphatic leukemia-associated necrotizing sweet syndrome.

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is a rare disorder typically characterized by the clinical triad including a sudden onset of fever, painful skin lesions, and neutrophilia. The histopathological findings are a dense neutrophilic infiltrate and oedema of the dermis and epidermis without evidence of a vasculitis. Besides treatment of the underlying cause, sweet syndrome is typically treated with high-dose corticosteroids leading to a relapse-free response in 70% of patients. However, if left unrecognized or untreated, the condition may lead to serious complications. Here, we report on the case of a 38-year-old patient in whom, under the assumption of the presence of necrotizing fasciitis, exarticulation of the right arm was performed. In the absence of pathogen detection and insufficient response to anti-infective therapies, the diagnosis of a sweet syndrome was assumed and, later, confirmed by an excellent response to high-dose administration of systematic glucocorticoids. The case emphasizes the need to be aware of this rare syndrome, which can be easily misdiagnosed due to its close resemblance to infection and stresses the need of further research to define distinct diagnostic tools.

Marked hyperferritinemia in critically ill cancer patients.

OBJECTIVES: To investigate characteristics and outcomes of critically ill cancer patients with marked hyperferritinemia. METHODS: A single-center retrospective analysis comprising cancer patients with a ferritin level >10.000 µg/L treated in the intensive care unit (ICU) between 2012 and 2022 was conducted. RESULTS: A total of 117 patients were included in the analysis. The median age was 59 years (range: 15-86 years). Females accounted for 48% of cases. 90% of patients had a hematologic malignancy. The median maximum ferritin level was 27.349 µg/L (range: 10.300-426.073 µg/L). The diagnostic criteria of septic shock were fulfilled in 51% of cases; 31% of patients had hemophagocytic lymphohistiocytosis (HLH) according to the HLH-2004 criteria. Mechanical ventilation, renal replacement therapy and the use of vasopressors were necessary in 59%, 35% and 70% of cases, respectively. The ICU, hospital, 90-day and 1-year survival rates were 33.3%, 23.1%, 23.7% and 11.7%. Patients with septic shock had a worse survival than those without septic shock (p = .001); the survival of patients who fulfilled the HLH-2004 criteria did not differ from those who did not (p = .88). CONCLUSION: Critically ill cancer patients with marked hyperferritinemia have poor outcomes. The present data may help to make informed decisions for this patient group.

Characteristics and outcomes of patients undergoing high-dose chemotherapy and autologous stem cell transplantation admitted to the intensive care unit: a single-center retrospective analysis.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) can be associated with adverse events necessitating treatment on the intensive care unit (ICU). Data focusing on patients admitted to the ICU during hospitalization for high-dose chemotherapy and ASCT are scarce. We thus conducted a single-center retrospective analysis comprising 79 individuals who had high-dose chemotherapy and ASCT between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after ASCT. The median age was 57 years (range: 20-82 years); 38% of patients were female. B-cell non-Hodgkin lymphoma (34%) and plasma cell disorders (28%) were the most common indications for high-dose chemotherapy and ASCT. Sepsis represented the major cause for ICU admission (68%). Twenty-nine percent of patients required mechanical ventilation (MV), 5% had renal replacement therapy, and 44% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 77.2%, 77.2%, 72.2%, and 60.3%, respectively. Stable disease or disease progression prior to the initiation of high-dose chemotherapy (p = 0.0028) and MV (p < 0.0001) were associated with an impaired survival. A total of 36 patients died during observation. The most frequent causes of death were the underlying malignancy (44%) and sepsis (39%). Taken together, the present analysis indicates a favorable overall outcome for patients admitted to the ICU during hospitalization for high-dose chemotherapy and ASCT. Thus, this patient group should not be denied admission and treatment on the ICU.

Critical care of patients with cancer.

Answer questions and earn CME/CNE The increasing prevalence of patients living with cancer in conjunction with the rapid progress in cancer therapy will lead to a growing number of patients with cancer who will require intensive care treatment. Fortunately, the development of more effective oncologic therapies, advances in critical care, and improvements in patient selection have led to an increased survival of critically ill patients with cancer. As a consequence, critical care has become an important cornerstone in the continuum of modern cancer care. Although, in many aspects, critical care for patients with cancer does not differ from intensive care for other seriously ill patients, there are several challenging issues that are unique to this patient population and require special knowledge and skills. The optimal management of critically ill patients with cancer necessitates expertise in oncology, critical care, and palliative medicine. Cancer specialists therefore have to be familiar with key principles of intensive care for critically ill patients with cancer. This review provides an overview of the state-of-the-art in the individualized management of critically ill patients with cancer. CA Cancer J Clin 2016;66:496-517. © 2016 American Cancer Society.

Allogeneic stem cell transplant recipients admitted to the intensive care unit during the peri-transplant period have unfavorable outcomes-results of a retrospective analysis from a German university hospital.

The prognosis of allogeneic stem cell transplant recipients admitted to the intensive care unit (ICU) has improved over the last decades. However, data focusing on patients treated in the ICU during the peri-transplant period are scarce. We therefore conducted an analysis comprising 70 patients who had allogeneic stem cell transplantation at the University Hospital Cologne between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after transplantation. The median age was 59 years (range: 18 - 72 years). 50% of patients were female. Sepsis was the most common cause for ICU admission (49%). Mechanical ventilation (MV) was required in 56% of patients, 27% had renal replacement therapy (RRT), and 64% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 48.6%, 38.6%, 35.7%, and 16.2%, respectively. MV and/or RRT during the ICU stay were associated with an impaired survival (p < 0.0001). The same was true for the use of vasopressors (p < 0.0001). In contrast, baseline characteristics did not impact the outcome. Cardiopulmonary resuscitation (CPR) was performed in 17% of patients. None of the patients undergoing CPR was alive at 1 year. Among patients who died after discharge from the ICU (n = 23), sepsis and other infectious complications represented the major causes of death (48%). Taken together, the present analysis indicates unfavorable outcomes for allogeneic stem cell transplant recipients admitted to the ICU during the peri-transplant period. The data may help to make informed decisions with patients and their families.

Reactivation of EBV and CMV in Severe COVID-19-Epiphenomena or Trigger of Hyperinflammation in Need of Treatment? A Large Case Series of Critically ill Patients.

BACKGROUND: Reactivation of viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common in critically ill patients and have been described in patients with severe COVID-19. However, it is unclear whether these reactivations are associated with increased mortality and whether targeted treatments are beneficial. METHODS: In a retrospective single-center cohort study, patients with severe COVID-19 treated on our intensive care unit (ICU) were screened for EBV and CMV reactivation as detected by polymerase chain reaction. If present, patient characteristics, temporal connections to severe acute respiratory syndrome coronavirus 2 diagnosis and corticosteroid use, the use of targeted treatments as well as the course of disease and outcome were analyzed. As control group, non-COVID-19 patients with sepsis, treated within the same time period on our ICU, served as control group to compare incidences of viral reactivation. RESULTS: In 19 (16%) of 117 patients with severe COVID-19 treated on our ICU EBV reactivations were identified, comparable 18 (14%) of 126 in the non-COVID-19 control group (P = .672). Similarly, in 11 (9%) of 117 patients CMV reactivations were identified, comparable to the 16 (13%) of 126 in the non-COVID-19 sepsis patients (P = .296). The majority of EBV (58%) and CMV reactivations (55%) were detected in patients under systemic corticosteroid treatment. 7 (37%) of 19 patients with EBV reactivation survived the ICU stay, 2 (29%) of 7 patients with rituximab treatment and 5 (42%) of 12 patients without treatment (P = .568). Five (50%) of 10 patients with CMV reactivation survived the ICU stay, 5 (83%) of 6 patients with ganciclovir treatment and 0 of 4 patients without treatment (P = .048). Follow-up analysis in these patients showed that the initiation of treatment lead to decrease in viral load. CONCLUSION: Critically ill patients with COVID-19 are at a high risk for EBV and CMV reactivations. Whether these reactivations are a cause of hyperinflammation and require targeted treatment remains uncertain. However, in patients with clinical deterioration or signs of hyperinflammation targeted treatment might be beneficial and warrants further studying.

Critical Care Management of Chimeric Antigen Receptor T Cell-related Toxicity. Be Aware and Prepared.

CAR (chimeric antigen receptor) T cells (CARTs) are genetically engineered T cells that express CARs, with impressive clinical activity in relapsed and refractory hematologic malignancies, primarily acute lymphoblastic leukemia and diffuse large B-cell lymphoma. The most frequent life-threatening adverse events after CART infusion are cytokine release syndrome and CAR-related encephalopathy syndrome, which can occur within hours or days after administration. IL-6 released by macrophages and monocytes plays a major role in the pathogenesis of cytokine release syndrome and CAR-related encephalopathy syndrome, and IL-6 blockade and steroids contribute to fast resolution of symptoms. Critical care management plays an important role in patients receiving CARTs, as up to half of patients might need an admission to the ICU and lifesaving interventions. As new treatment indications and CART constructs enter the clinic, the number of patients requiring ICU admission will rapidly increase, with profound consequences for the use of ICU resources, training requirements, clinical expertise, multidisciplinary collaboration, and hospital organization. Research is also needed to validate at large scale biomarkers that allow doctors to risk-stratify patients for both their risk to develop severe toxicity and their likelihood to respond to therapy.

COVID-19 associated pulmonary aspergillosis.

OBJECTIVES: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany. METHODS: A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. RESULTS: COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. CONCLUSION: Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.

Fatal disseminated enterovirus infection in a patient with follicular lymphoma undergoing obinutuzumab maintenance therapy.

Follicular lymphoma is the most common subtype of the indolent non-Hodgkin lymphomas. Treatment usually consists of immuno-chemotherapy and results in long-lasting remissions in most cases. Progression-free survival with the second-generation anti-CD20 antibody obinutuzumab was shown to be better than with rituximab when given in combination with either bendamustine or anthracycline-based chemotherapy. Although treatment is generally well tolerated without an excessive rate of toxicities, there appear to be slightly more adverse events with obinutuzumab than with rituximab. Here, we report the case of a 45-year-old female patient that was diagnosed with a disseminated enterovirus infection while undergoing maintenance therapy with obinutuzumab after induction treatment with the combination of bendamustine and rituximab. Enterovirus RNA was detected in the blood, the cerebrospinal fluid, and the colon. A therapy with intravenous immunoglobulins was initiated since the patient presented with a severe treatment-related immunosuppression indicated by hypogammaglobulinemia. Nonetheless, she eventually died from the enterovirus infection without evidence of lymphoma progression. This case underscores that clinicians should be aware of rare but potentially fatal infectious complications related to treatment protocols containing anti-CD20 antibodies.

'Lost in Nasal Space': Staphylococcus aureus sepsis associated with Nasal Handkerchief Packing.

INTRODUCTION: Staphylococcus aureus frequently causes infections in outpatient and hospital settings and can present as a highly variable entity. Typical manifestations are endocarditis, osteoarticular infections or infection of implanted prostheses, intravascular devices or foreign bodies. A thorough diagnostic evaluation with early focus identification is mandatory to improve patient outcome. CASE REPORT: We report a case of a 68-year old patient with a history of double allogeneic stem cell transplant for acute myeloid leukemia who developed a S. aureus bacteremia with dissemination, severe sepsis and lethal outcome due to nasal handkerchief packing after nose bleeding. CONCLUSION: A thorough medical examination with further diagnostic work-up is most important in S. aureus blood stream infection to identify and eradicate the portal(s) of entry, to rule out endocarditis, to search for spinal abscesses, osteomyelitis or spondylodiscitis. Adherence to management guides for clinicians must be of major importance to achieve optimal quality of clinical care, and thus improve patient outcome.

B Cell-Based Cancer Immunotherapy.

B cells are not only producers of antibodies, but also contribute to immune regulation or act as potent antigen-presenting cells. The potential of B cells for cellular therapy is still largely underestimated, despite their multiple diverse effector functions. The CD40L/CD40 signaling pathway is the most potent activator of antigen presentation capacity in B lymphocytes. CD40-activated B cells are potent antigen-presenting cells that induce specific T-cell responses in vitro and in vivo. In preclinical cancer models in mice and dogs, CD40-activated B cell-based cancer immunotherapy was able to induce effective antitumor immunity. So far, there have been only few early-stage clinical studies involving B cell-based cancer vaccines. These trials indicate that B cell-based immunotherapy is generally safe and associated with little toxicity. Furthermore, these studies suggest that B-cell immunotherapy can elicit antitumor T-cell responses. Alongside the recent advances in cellular therapies in general, major obstacles for generation of good manufacturing practice-manufactured B-cell immunotherapies have been overcome. Thus, a first clinical trial involving CD40-activated B cells might be in reach.

Do Acute Exercise-Induced Activations of the Kynurenine Pathway Induce Regulatory T-Cells on the Long-Term? - A Theoretical Frame Work Supported by Pilot Data.

Regular physical activity and exercise interventions are suspected to have anti-inflammatory effects depending on exercise modality, thereby potentially reducing the risk and progress of several chronic diseases. Alterations in the kynurenine pathway may represent a link between inflammatory responses following acute exercise and chronic anti-inflammatory properties, such as increased levels of regulatory T-cells (Treg). Here, we hypothesize that acute exercise activates the kynurenine pathway and physical fitness is associated with proportions of circulating anti-inflammatory Treg in older healthy women. Nineteen older healthy female participants (55 years (SD: ± 5.6)) completed a cardiopulmonary incremental exercise test (CPET) with spirometry on a bicycle ergometer until exhaustion with maximum oxygen uptake (VO2max) as outcome. Blood samples were taken before (T0) and one minute after (T1) the CPET. Levels of tryptophan, serotonin and kynurenine were determined by enzyme-linked immunosorbent assays. Flow cytometry was used to identify proportions of T-cell subsets. Both, kynurenine (p = 0.003, d = 0.40) and the kynurenine/tryptophan ratio (p = 0.034, d = 0.48) increased significantly after acute exercise. Moreover, participants` VO2max was strongly correlated with Treg levels (p < 0.001, r = 0.689). This is the first study indicating a kynurenine pathway activation following acute exercise in older healthy women. The observed correlation between Treg levels and VO2max emphasizes a potential link between short-term upregulated kynurenine levels and longer-term anti-inflammatory properties of exercise. Future research is needed to clarify to what extend acute exercise-induced activations of the kynurenine pathway contribute to Treg differentiation.

Regulatory B10 cells display an altered homoeostasis in acute graft-versus-host disease.

OBJECTIVE: The role of B cells and the subgroup of IL-10 producing B cells, known to have a regulatory function, in patients following a haematopoietic stem cell transplant (alloSCT) has not been clearly understood to date. METHODS: We prospectively recruited 95 patients following an alloSCT and studied the B-cell reconstitution on days 30, 90 and 150. Regulatory B10 cells could be analysed in 22 consecutively recruited patients on day 30 post-transplant. RESULTS: The total B-cell percentages in transplant recipients (median 0.33; range 0.01-5.9) were significantly reduced than the controls (P = 0.0001) and constituted predominantly of transitional CD24high CD38high B cells. Regulatory B10 cells could be analysed in 22 consecutively recruited patients on day 30 post-transplant. The percentages of B10 cells (median 1.35; 0.0-4.5) were significantly reduced in the transplant recipients in comparison with the control cohort (P < 0.0001). Interestingly, the percentages of B10 cells in patients with acute GvHD (median 1.7; 0.33-4.5) were significantly higher than those without GvHD (median 0.7; 0-1.9) (P = 0.0003). CONCLUSION: This is the first report demonstrating B10 cells in stem cell transplant recipients in the early post-alloSCT (30 d) period. Our data suggest a possible role for B10 cells in the pathophysiology of acute GvHD. Further longitudinal studies are warranted to understand the implications of our findings.

Control measures following a case of imported Lassa fever from Togo, North Rhine Westphalia, Germany, 2016.

In a patient transferred from Togo to Cologne, Germany, Lassa fever was diagnosed 12 days post mortem. Sixty-two contacts in Cologne were categorised according to the level of exposure, and gradual infection control measures were applied. No clinical signs of Lassa virus infection or Lassa specific antibodies were observed in the 62 contacts. Thirty-three individuals had direct contact to blood, other body fluids or tissue of the patients. Notably, with standard precautions, no transmission occurred between the index patient and healthcare workers. However, one secondary infection occurred in an undertaker exposed to the corpse in Rhineland-Palatinate, who was treated on the isolation unit at the University Hospital of Frankfurt. After German authorities raised an alert regarding the imported Lassa fever case, an American healthcare worker who had cared for the index patient in Togo, and who presented with diarrhoea, vomiting and fever, was placed in isolation and medevacked to the United States. The event and the transmission of Lassa virus infection outside of Africa underlines the need for early diagnosis and use of adequate personal protection equipment (PPE), when highly contagious infections cannot be excluded. It also demonstrates that larger outbreaks can be prevented by infection control measures, including standard PPE.

Processing and MHC class II presentation of exogenous soluble antigen involving a proteasome-dependent cytosolic pathway in CD40-activated B cells.

Activated B cells have the capacity to present antigen and induce immune responses as potent antigen-presenting cells (APCs). As in other APCs, antigen presentation by B cells involves antigen internalization, antigen processing, and peptide loading onto MHC molecules. However, while the mechanism of antigen processing has been studied extensively in other APCs, this pathway remains elusive in B cells. The aim of this study was to investigate the MHC class II processing pathway in CD40-activated B cells (CD40Bs), as a model for activated, antigen-presenting B cells. Using CMV pp65 as a model antigen, we evaluated processing and presentation of the CD4 + T-cell epitope 509-523 (K509) by human CD40Bs in ELISPOT assays. As expected, stimulation of specific CD4 + T-cell clones was attenuated after pretreatment of CD40Bs with inhibitors of classic class II pathway components. However, proteasome inhibitors such as epoxomicin limited antigen presentation as well. This suggests that the antigen is processed in a non-classical, cytosolic MHC class II pathway. Further experiments with truncated protein variants revealed involvement of the proteasome in processing of the N and C extensions of the epitope. Access to the cytosol was shown to be size dependent. Epoxomicin sensitivity exclusively in CD40B cells, but not in dendritic cells, suggests a novel processing mechanism unique to this APC. Our data suggest that B cells process antigen using a distinct, non-classical class II pathway.

Immunological effects in patients with steroid-refractory graft-versus-host disease following treatment with basiliximab, a CD25 monoclonal antibody.

Steroid-refractory graft-versus-host disease (GvHD) is a complication following an allogeneic stem cell transplantation with limited therapeutic options. Studies have shown a response in up to 80% of patients with this condition after treatment with the CD25 monoclonal antibody, basiliximab. Despite the good responses to treatment, around 50% of the patients experience recurrence of their GvHD symptoms 4-6 wk following cessation of therapy. The in vivo changes in the following treatment with this antibody have not been elucidated so far. We treated 14 patients with severe steroid-refractory GvHD with basiliximab weekly for 4 wk and monitored the changes in the T-, B-, NK- and dendritic cell subsets over this time period. The overall response to treatment was 92% (13/14) with 50% (7/14) achieving a complete response. Fifty four percentage (7/13) of the patients who responded showed recurrence of their GvHD symptoms. Contrary to expectations, our observations showed a significant depletion of the regulatory T-cell subset following treatment. Our findings suggest that the undesirable depletion of the regulatory T cells along with the CD25(+) acute inflammatory cells might be responsible for the high incidence of GvHD recurrence in this cohort of patients.

Impact of a half marathon on cellular immune system, pro-inflammatory cytokine levels, and recovery behavior of breast cancer patients in the aftercare compared to healthy controls.

INTRODUCTION: Exercise has beneficial effects on cancer prevention as well as on prognosis of patients with cancer. To optimize the outcomes of exercise programs, more knowledge about the underlying mechanisms is needed. This study investigates the short-term effects of a half marathon on immune cell proportions, pro-inflammatory cytokine levels, and recovery behavior of patients with breast cancer in the aftercare compared to healthy controls. METHODS: Nine patients with breast cancer in the aftercare and 9 healthy age-matched controls participated in a half marathon. Blood samples were collected before, after, and 24 h after the run. Immune status was measured by flow cytometer analysis, while serum levels of the pro-inflammatory cytokines TNF-α, IL-6, and MIF were assessed using ELISA. Recovery behavior was determined using an ADL monitor. RESULTS: Both groups showed a similar recovery behavior and time courses in changes of granulocytes, monocytes, lymphocytes, and cytokine serum levels. Patients revealed increased proportions of cytotoxic and memory T cells, whereas helper and naïve T cells were decreased compared to healthy controls. Naïve and memory T-cell proportions were not affected by the intervention. CONCLUSIONS: Patients with breast cancer in the aftercare and healthy subjects show a similarly recovery behavior and immune response to the intervention. The detected differences in T-cell subsets need further investigation. Based on the results of the study, we hypothesize that immune cell subsets with known relevance in cancer were mobilized through the intervention. We confirm that the hypothesis of a midterm anti-inflammatory effect of exercise is also valid for patients with breast cancer in the aftercare.

FLAMSA reduced-intensity conditioning is equally effective in AML patients with primary induction failure as well as in first or second complete remission.

Reduced-intensity conditioning regimens have demonstrated lower toxicity but increased relapse rates in the context of allogeneic hematopoietic stem cell transplantation (aSCT) for patients with acute myelogenous leukemia (AML). The FLAMSA- reduced-intensity conditioning (RIC) regimen, combining a cytoreductive and a transplant-conditioning part, has been described to be efficacious in patients with refractory disease. We retrospectively analyzed clinical data of 130 patients with AML after aSCT following FLAMSA RIC at our center. The median follow-up was 37 (10-125) months. The 4-yr overall and disease-free survival rates of the whole cohort were 45% and 40%. Cumulative incidence of relapse was 29%, 35%, and 40% at 1, 2, and 4 yr. There were no significant differences regarding overall and disease-free survival for patients transplanted in CR1, CR2, or primary induction failure (PIF). Patients with refractory disease after salvage therapy had significantly lower disease-free and overall survival (OS). Disease-free and OS rates were also significantly decreased in patients with 10% or more BLASTS at transplant. non-relapse mortality was 15%, 19%, and 20% at 1, 2, and 4 yr and similar in all cohorts. These data underscore the potency of the FLAMSA RIC regimen for patients with AML especially with PIF. The decision for re-induction therapy prior to aSCT in relapsed patients has to be weighed against the potential toxicity of this approach and might be influenced by the amount of leukemic BLASTS present. Only randomised trials will answer this important question.