key: cord-017302-xez0zso3
authors: Stephens, R. Scott
title: ICU Complications of Hematopoietic Stem Cell Transplant, Including Graft vs Host Disease
date: 2019-07-24
journal: Evidence-Based Critical Care
DOI: 10.1007/978-3-030-26710-0_80
sha: 
doc_id: 17302
cord_uid: xez0zso3

Hematopoietic stem cell transplant (HSCT) is an essential treatment modality for many malignant and non-malignant hematologic diseases. Advances in HSCT techniques have dramatically decreased peri-transplant morbidity and mortality, but it remains a high-risk procedure, and a significant number of patients will require critical care during the transplant process. Complications of HSCT are both infectious and non-infectious, and the intensivist must be familiar with common infections, the management of neutropenic sepsis and septic shock, the management of respiratory failure in the immunocompromised host, and a plethora of HSCT-specific complications. Survival from critical illness after HSCT is improving, but the mortality rate remains unacceptably high. Continued research and optimization of critical care provision in this population should continue to improve outcomes.

non-infectious complications of HSCT. Respiratory failure is the most frequent cause of intensive care unit (ICU) admission after HSCT, most frequently from an infectious cause. The patient was placed on high-flow nasal cannula (HFNC) for oxygenation support and started on a norepinephrine infusion for hemodynamic support. Antibacterial coverage was changed to meropenem, levofloxacin, and vancomycin, and voriconazole was added for antifungal coverage. Her central line was removed. Her respiratory status continued to decline, and endotracheal intubation and mechanical ventilation were required 24 h after admission. She was placed on volume assist-control with a tidal volume of 6 mL/kg predicted body weight, and bronchoscopy with bronchoalveolar lavage (BAL) was performed. The BAL fluid was initially bloody, but cleared with sequential aliquots. Microbiologic studies of the BAL fluid were positive for respiratory syncytial virus and Pseudomonas aeruginosa. She was maintained on low tidal-volume ventilation and vasopressors were weaned off. Her white blood cell count slowly began to recover, and her respiratory status began to improve. She was extubated on hospital day 12 and was discharged from the ICU on hospital day 14.

Hematopoietic stem cell transplant (HSCT) has become an essential therapeutic modality in the treatment of malignant and non-malignant hematologic disease. In 2016, more than 23,000 HSCTs were performed in the United States, including approximately 15,000 autologous HSCTs and more than 8500 allogeneic transplants [1] . Allogeneic transplants are associated with more morbidity and mortality than autologous transplants, and are further categorized based on conditioning regimen (myeloablative [MA] vs non-myeloablative [NMA]), donor-recipient relation (related vs unrelated), HLA matching (full match vs haploidentical vs mismatched), and stem cell source (bone marrow, peripheral blood, umbilical cord blood). In general, NMA regimens are associated with less peri-transplant morbidity and mortality than fully ablative transplants. In both MA and NMA transplants, the cytotoxic conditioning regimen required in HSCT rapidly induces neutropenia by injuring hematopoietic precursor cells within the bone marrow [2, 3] . Neutropenia persists until donor cell engraftment or bone marrow recovery. The period of aplasia and neutropenia places the HSCT patient at high risk for infectious complications. In addition to the lack of immune cells, the mucosal barrier of the intestinal tract is disrupted by chemotherapy, creating portals through which enteric pathogens can enter the bloodstream [4] [5] [6] . The respiratory system is also more susceptible to infection, with qualitative and quantitative dysfunction of alveolar macrophages, lymphocytes, and neutrophils [7] [8] [9] . Even after the marrow and mucosal surfaces have recovered, the immunological consequences of HSCT can cause further complications requiring critical care. Refinement of transplant techniques over the last 2 decades has dramatically decreased transplant-related mortality, but approximately 15% of HSCT patients require critical care [10] and earlier ICU admission has been associated with improved survival rates [11, 12] . Still, ICU mortality in allogeneic HSCT patients remains approximately 50% [13] .

The early complications of HSCT (day 30-100) are predominantly infectious in nature, and patients typically present to the ICU with septic shock or respiratory failure. The latter is the most common reason for ICU admission after HSCT [10] . Non-infectious complications also occur, and can involve nearly any organ system.

Neutropenic fever, defined as any fever higher than 38.3 °C or a sustained fever greater than 38.0 °C for more than 1 h with an absolute neutrophil count (ANC) less than 1500 cells/ mm 3 , occurs in more than 80% of patients undergoing HSCT [14, 15] . No organism is identified in about 50% of neutropenic fevers [14, 15] . Bacteremia is documented in up to 25% of patients. Gram-positive bacteria are most commonly isolated [14, 16] (Table 80 .1), while Gram-negative infections confer a higher mortality risk [17] . Fungal infections, particularly Candida and Aspergillus species, are frequent, especially in prolonged or profound neutropenia [15] . Approximately 10% of allogeneic HSCT patients will develop severe sepsis during the engraftment period [18] , and mortality is approximately 50% in those who go on to develop septic shock [11, 19, 20] . Mortality predictors include concomitant graft-vshost disease (GVHD), respiratory failure, positive blood cultures, and multi-organ failure [18, 20] .

Neutropenic fever and sepsis are medical emergencies, and appropriate empiric antibiotics must be started without delay: ideally within 60 min of presentation [14, 15, 21] and potentially within 30 min [22] . Empiric antibiotics must cover common organisms and should be tailored to patientspecific culture data and institutional epidemiology [14, 15] . Appropriate empiric antibiotics include an anti-pseudomonal penicillin or cephalosporin (e.g. piperacillin/tazobactam or cefepime, respectively), or a carbapenem [14, 15] . Vancomycin is not routinely indicated but should be added in the presence of a suspected catheter-related infection, soft tissue infection, oral mucositis, pneumonia, known colonization with resistant gram-positive organisms, or hemodynamic instability [14, 15, 21] . Aminoglycosides should not be added to an anti-pseudomonal beta-lactam unless required by allergies, resistant organisms, or refractory hemodynamic instability [14, 21, [23] [24] [25] . Fluoroquinolones, which are frequently used as prophylaxis in HSCT patients, should not be used as empiric monotherapy due to the likelihood of resistance.

In hemodynamically unstable patients, anti-pseudomonal beta-lactams should be escalated to a carbapenem and consideration should be given to the addition of an aminoglycoside or aztreonam [14, 15, 21, 23] . Vancomycin should be added if not already part of the regimen, and anti-fungals with activity against yeasts and molds (e.g. liposomal amphotericin, caspofungin, or voriconazole) should be strongly considered in all unstable patients [14, 15, 26, 27] .

Identification of infectious organisms and control of infectious sources are essential to optimize outcomes but the infectious workup should not delay antibiotic administration. Blood cultures and respiratory cultures should be obtained and sinus, head, chest, and abdominal imaging performed as indicated [14, 15] . Abdominal pain or diarrhea associated with fever suggests neutropenic enterocolitis (typhlitis) which can lead to intestinal necrosis [28, 29] . In the hemodynamically unstable patient with a central venous catheter, early catheter removal is associated with improved survival [19] ; infected or potentially infected catheters should be removed without delay.

Acute respiratory failure and acute respiratory distress syndrome (ARDS) are major problems after HSCT [30, 31] . Data from the 1990s indicated that 40-60% of patients undergoing HSCT experience a respiratory complication [32] . More recent data suggest that more than 15% of patients undergoing allogeneic transplant develop ARDS with a mortality rate of 50-70% [33, 34] . Most cases of respiratory failure and ARDS after HSCT are related to infection, either a primary pulmonary infection or sepsis [35] . Common pulmonary infections and associated risk factors are shown in Table 80 .

HSCT [36, 37] , and is associated with significant mortality, especially with progression to lower respiratory tract infection [38] [39] [40] . In some cases, antiviral therapy with agents such as oseltamivir (influenza) or ribavirin (respiratory syncytial virus) is indicated [41] . Bacterial pneumonias are also common and may occur as a co-infection or secondary infection with a respiratory virus. Fungal and other opportunistic infections such as Pneumocystis jirovecii must also be considered [42] . As in immunocompetent patients, treatment of ARDS centers on treatment of the underlying cause while providing supportive care with low tidal volume mechanical ventilation. Neuromuscular blockade and prone positioning should be considered in patients with an arterial PO 2 : FiO 2 ≤ 150 mmHg [43] [44] [45] .

Non-invasive ventilation (NIV) is frequently used as firstline respiratory support in HSCT patients [46] . However, early studies which showed a mortality benefit in immunosuppressed patients with using NIV compared to invasive mechanical ventilation were limited by relatively few numbers of HSCT patients and extremely high mortality in the control groups [47, 48] . It is nearly impossible to control delivered tidal volume with NIV and high delivered noninvasive tidal volumes are linked to higher rates of NIV failure [49] . More recent data suggest that NIV may not be beneficial in HSCT patients and heated humidified high-flow oxygen may be a better option [30, [49] [50] [51] [52] [53] .

Chest computed tomography (CT) scanning should be performed in all patients with respiratory symptoms [15] . The presence of respiratory failure, respiratory symptoms, or abnormalities on chest imaging should prompt evaluation for a respiratory infection. In many cases a non-invasive evaluation is appropriate, but bronchoscopy may be indicated in some patients [48, 54, 55] , and bronchoscopic findings that lead to a change in management are associated with improved outcomes [55] .

Two specific forms of respiratory failure after HSCT warrant special mention: diffuse alveolar hemorrhage and idiopathic pneumonia syndrome. Diffuse alveolar hemorrhage (DAH) occurs in up to 12% of patients and is associate with poor outcomes [56, 57] . Diagnosis is most commonly made by observation of progressively bloody aliquots of bronchoalveolar lavage. Steroids are the mainstay of treatment of DAH, with some evidence that efficacy is greatest at doses <250 mg/day of methylprednisolone equivalent [57] . Idiopathic pneumonia syndrome (IPS) is a form of noninfectious lung injury after HSCT and is clinically defined by diffuse alveolar injury when infection, cardiac dysfunction, renal failure, and volume overload have been excluded [58] . IPS can have many manifestations, including ARDS, pulmonary capillary leak, DAH, or cryptogenic organizing pneumonia. IPS is thought to affect up to 15% of patients after myeloablative allogeneic HSCT, and only ~ 2% of patients after non-myeloablative HSCT. Median time of onset of IPS [35, 42] is 19 days after HSCT and mortality ranges from 60-80% in all patients, with nearly 100% mortality if mechanical ventilation is required [58] . Though the pathophysiology of IPS is incompletely understood, research indicating a pathogenic role for TNF-α has led to the use of the anti-TNF-α antibody etanercept to treat IPS, with mixed clinical results [59] [60] [61] [62] .

The single randomized placebo-controlled trial in adults included only 34 patients and showed no benefit to etanercept when added to steroids (methylprednisolone 2 mg/kg/ day) [63] .

Neurologic complications are frequently encountered after HSCT [64] . Intracerebral hemorrhages are a constant threat in thrombocytopenic patients. Infections of the central nervous system (CNS), including viral, bacterial, and fungal, can occur, and may require modification of antibiotic regimens to ensure CNS penetration. Seizures and generalized encephalopathy can occur, often with cryptic causes. Posterior reversible encephalopathy syndrome (PRES) is increasingly recognized, especially in patients receiving tacrolimus-based GVHD prophylaxis. Any of these complications may be life-threatening, and close collaboration with neurology and neurocritical care specialists may be required.

Acute kidney injury (AKI) is common after HSCT and affects up to 40% of patients, with higher incidence after allogeneic transplant than autologous transplant [65, 66] . In addition to the usual ICU causes of AKI such as septic shock, there are many specific contributors to the risk of AKI in HSCT, including preparative chemotherapeutic regimens, nephrotoxins (e.g. tacrolimus, cyclosporine, antimicrobials), elevated cytokine levels, GVHD, and hepatic sinusoidal obstruction [65] . Hemorrhagic cystitis arising from chemotherapy toxicity or viral infection can cause significant blood loss and obstructive nephropathy due to blood clots. Management of AKI primarily consists of limiting exposure to nephrotoxins (if able) and maintaining adequate hemodynamics. If hemorrhagic cystitis is present, continuous bladder irrigation with a three-way catheter should be considered. The requirement for renal replacement therapy is ominous and portends a high mortality rate [65] .

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, primarily occurs after myeloablative HSCT, but can occur after a non-myeloablative transplant [67] . VOD is thought to be caused by damage to the hepatic endothelium and leads to obliteration of hepatic sinusoids and hepatocyte necrosis. Incidence of VOD is thought to be approximately 14%, though estimates vary. Diagnosis is based on clinical findings (table) including hepatomegaly, elevated bilirubin ascites, and weight gain [68] . There are limited therapeutic options for VOD, and the prognosis is poor.

A major complication of allogeneic HSCT is graft-versushost disease (GVHD), which is divided into acute and chronic forms. Acute GVHD is a major contributor to peritransplant morbidity and mortality, and is caused by donororigin T-cells recognizing recipient tissues as foreign and instigating an immune response against the transplant recipient [69] . Acute GVHD generally occurs within the first 100 days after transplant and can affect the skin, mucosa, intestinal tract, and liver. Grading is based on severity of clinical manifestations, which include skin erythema or maculopapular rash; nausea, emesis, or diarrhea, and elevated bilirubin levels ( Fig. 80.1 , Table 80 .3) [69] [70] [71] [72] . Acute GVHD can progress to frank epidermal desquamation, massive diarrhea and hematochezia, and fulminant liver failure, respectively. Severe skin acute GVHD behaves much like a burn injury, and the expertise of a burn center may be required.

Corticosteroids are the mainstay of treatment for acute GVHD, and the prognosis of steroid-refractory disease is poor [69, 73] . Prophylaxis against GVHD is an essential part of allogeneic transplant regimens and includes a variety of modalities, including calcinuerin inhibitors, anti-metabolites, and post-transplant cyclophosphamide [74] . As GVHD prophylaxis has improved, more patients are presenting with Grade II or Grade III acute GVHD (and fewer are presenting with Grade IV acute GVHD), the incidence of hepatic acute GVHD is decreasing, and overall mortality from acute GVHD is decreasing in patients treated with tacrolimusbased GVHD prophylaxis [73] .

Chronic GVHD is the major cause of non-relapse-related mortality after HSCT [75] . Despite its name, chronic GVHD is defined clinically, rather than by time after transplant, and can present at any time during the transplant course. By 2 years after transplant, up to 30-70% of patients will have some manifestation of chronic GVHD [76] [77] [78] . Though the biology of chronic GVHD is complex and incompletely understood, clinically it mimics autoimmune disease [75] . While diagnostic criteria include effects on the skin, oral mucosa, eyes, liver, GI tract, joints, genitals, and lungs, chronic GVHD can affect almost any organ system and is staged according to severity of organ involvement [78] . Selected manifestations and diagnostic criteria are in Table 80 .4. Of the manifestations of chronic GVHD, the most relevant to the ICU physician is pulmonary chronic GVHD.

The only recognized manifestation of chronic pulmonary GVHD is bronchiolitis obliterans syndrome (BOS), which is diagnosed by documentation of the new onset of an obstructive ventilator defect (FEV 1 : FVC < 0.7 and FEV 1 < 75% predicted) and air trapping (documented by expiratory CT scan or pulmonary function tests) in the absence of an explanatory pulmonary infection [78] . BOS results from a b c d peribronchiolar fibrosis and obliteration of small airways resulting in the characteristic obstructive physiology [75] . Interstitial and subpleural fibrosis may also occur, resulting in concomitant restrictive physiology. BOS occurs in approximately 3-5% of all patients after allogeneic HSCT, and 14% of those with chronic GVHD, but is likely underdiagnosed [76, 79, 80] . Inhaled corticosteroids appear efficacious in improving FEV 1 in established BOS [81] . Systemic steroids are also commonly used to treat BOS and most patients are maintained on anti-GVHD immunosuppression with tacrolimus, sirolimus, or a calcineurin inhibitor [76] . The combination of inhaled fluticasone, azithromycin, and montelukast (FAM) appears to slow the decline in lung function with BOS [82] but has not yet been proven in a randomized controlled trial. While FAM is standard therapy for established BOS, recent data argue strongly against using azithromycin as prophylaxis against BOS due to decreased survival due to a higher rate of hematologic relapse [83] . Though FAM has been shown to decrease the progression of BOS, mortality due to progressive lung disease remains high, and patients typically present to the ICU with respiratory failure. Unfortunately, with end-stage BOS, there are no effective therapeutic options. A select few patients may be eligible for consideration for lung transplantation, but this is unusual, 

HSCT is increasing in volume and importance as a therapeutic modality, and the volumes of HSCT patients requiring critical care is accordingly continuing to increase. There is good reason to think that the pathogenesis of critical illness is substantially different in the immunosuppressed HSCT patient. Yet our understanding of critical illness in this population is limited, and many practices are extrapolated from the general critical care population without direct evidence in the HSCT population. In response to this, research agendas for critically ill hematology and oncology patients have been proposed [48] .

Neutropenic sepsis is typically thought of as an uncontrolled variant of non-neutropenic sepsis. However, the real picture is likely much more complicated, and neutropenic sepsis and respiratory failure may be very different from their nonneutropenic counterparts. Even the phrase "neutropenic sepsis" is a misnomer, as the HSCT myelopreparative regimens also result in pancytopenia. Leukopenia, including neutropenia, lymphopenia, and monocytopenia, dramatically changes not only the acute response to infection, but the regulation of the adaptive immune response and the resolution and repair of injury [3, 7, 8, [84] [85] [86] [87] [88] [89] [90] . Platelets are increasingly recognized to play a vital role in the defense against bacterial, viral, and fungal infections, and like leukocytes, are integral to the development and resolution of organ failure [91] [92] [93] [94] [95] .

Not surprisingly, thrombocytopenia is associated with poor outcomes in critical illness [96] . Taken together, these data strongly support the notion that common critical care conditions, such as sepsis and respiratory failure, may differ dramatically in HSCT patients compared to "normal" patients. Encouragingly, survival in neutropenic sepsis appears to be improving, but still lags that of non-neutropenic patients [12, 19, 48] , and more research is needed.

Drug-resistant and multi-drug resistant (MDR) organisms are an increasing problem in HSCT patients, and the situation shows no sign of improving [16, 97, 98] . Vancomycinresistant enterococcus (VRE) bacteremia affects up to 35% of patients after HSCT and is associated with poor outcomes [99] [100] [101] . Similarly, MDR gram negative infections, particularly carbapenem-resistant Enterobacteriaceae (CRE), are associated with high mortality rates in allogeneic HSCT patients [102] . Successful treatment CRE infections is challenging, and requires early use of multi-drug antibiotic regimens, typically including aminoglycosides, carbepenems, and polymyxins. However, none of the available regimens are particularly effective, and new antimicrobials are desperately needed.

An increasingly recognized complication of HSCT is HSCTassociated thrombotic microangiopathy (HSCT-TMA) [103] , which has some features in common with betterknown microangiopathic processes such as thrombotic Patients can present to the ICU with acute kidney injury and neurologic changes in addition to hemolytic anemia and thrombocytopenia [65, 104] . Management is predominantly supportive, with blood pressure control, cessation of any possible pharmacologic instigators (tacrolimus or cyclosporine), and renal replacement therapy playing major roles. Recent case reports have suggested a possible role in some patients for the anti-CD20 antibody rituximab or the anti-complement antibody eculizumab, though neither of these agents has been definitively proven effective [104] .

As noted above, advances in transplant techniques have allowed the increased use of alternative donors, including related haploidentical donors [105] [106] [107] . Similarly, peripheral blood stem cells (PBSC) are increasingly used for transplant instead of bone marrow stem cells [108] . However, the use of peripheral blood results in a larger number of donor T-cells included in the transplanted stem cells. This higher T-cell dose can result in a profound syndrome of fevers, vascular permeability, hemodynamic instability, acute kidney injury, and respiratory failure. This constellation of findings is associated with elevated levels of inflammatory cytokines and has accordingly been labeled as cytokine release syndrome (CRS). While most associated with chimeric antigen receptor (CAR) T-cell therapy [109] , CRS is increasing recognized after PBSC transplant and is associated with poor outcomes [110] . Emerging data suggest that anti-IL-6 therapy with tocilizumab may improve outcomes, but more research is needed [110] .

HSCT continues to grow as a therapeutic modality and the pool of both potential donors and recipients continues to increase. As HSCT volumes increase and the complexity and potential toxicity of HSCT regimens expands, the number of critically ill HSCT patients will increase [48] . In response to this growing ICU volume, some centers continue to admit HSCT patients to general ICUs, but many high-volume transplant centers have developed specialty HSCT ICUs. While specialty HSCT ICUs have a number of potential benefits, there are few data to support (or dissuade) their development. Development of best practices for the provision of critical care to HSCT patients, including the optimum ICU organization is an important area for study [48] . Great progress in the critical care of HSCT patients has been made, but with continued basic and clinical research and further development of the sub-specialty of oncologic critical care, outcomes for critically ill HSCT patients should continue to improve.

Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides

Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy

The significance and regulatory mechanisms of innate immune cells in the development of sepsis

Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview

Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients

Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis

Deactivation of alveolar macrophages in septic neutropenic ARDS

Monocyte deactivation in neutropenic acute respiratory distress syndrome patients treated with granulocyte colonystimulating factor

Bronchoalveolar lavage during neutropenic episodes: diagnostic yield and cellular pattern

Critical care of the hematopoietic stem cell transplant recipient

Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium--a groupe de recherche respiratoire en reanimation oncohematologique study

Managing critically Ill hematology patients: Time to think differently

Critically ill allogenic HSCT patients in the intensive care unit: a systematic review and meta-analysis of prognostic factors of mortality

Clinical practice guideline for the use of antimicrobial R. S. Stephens agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

Recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance

Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey

Severe sepsis in hematopoietic stem cell transplant recipients *

Survival in neutropenic patients with severe sepsis or septic shock

Prognosis of neutropenic patients admitted to the intensive care unit

Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO)

Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

Beta-lactam versus beta-lactamaminoglycoside combination therapy in cancer patients with neutropenia

Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis

Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group

Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia

Neutropenic enterocolitis: new insights into a deadly entity

The prognostic impact of abdominal surgery in cancer patients with neutropenic enterocolitis: a systematic review and meta-analysis, on behalf the Groupe de Recherche en Reanimation Respiratoire du patient d'Onco-Hematologie (GRRR-OH)

Acute respiratory distress syndrome in patients with malignancies

Acute respiratory distress syndrome during neutropenia recovery

Pulmonary complications of bone marrow transplantation

Outcomes of stem cell transplant patients with acute respiratory failure requiring mechanical ventilation in the United States

Epidemiology of acute respiratory distress syndrome following hematopoietic stem cell transplantation

Pulmonary infections complicating hematological disorders

Febrile neutropenia: significance of elaborated screening for respiratory viruses, and the comparison of different sampling methods, in neutropenic patients with hematological malignancies

Viral pneumonia in patients with hematologic malignancy or hematopoietic stem cell transplantation

Mortality rates of human metapneumovirus and respiratory syncytial virus lower respiratory tract infections in hematopoietic cell transplantation recipients

BCSH/BSBMT/UK clinical virology network guideline: diagnosis and management of common respiratory viral infections in patients undergoing treatment for haematological malignancies or stem cell transplantation

Management of RSV infections in adult recipients of hematopoietic stem cell transplantation

Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies

Fungal pneumonia in patients with hematologic malignancy and hematopoietic stem cell transplantation

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome

Neuromuscular blockers in early acute respiratory distress syndrome

Prone positioning in severe acute respiratory distress syndrome

Immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the LUNG SAFE database

Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure

The Intensive Care Medicine research agenda on critically ill oncology and hematology patients

Failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume

Noninvasive ventilation during acute respiratory distress syndrome in patients with cancer: trends in use and outcome

Effect of noninvasive ventilation vs oxygen therapy on mortality among immunocompromised patients with acute respiratory failure: a randomized clinical trial

Acute respiratory failure in patients with hematological malignancies: outcomes according to initial ventilation strategy. A groupe de recherche respiratoire en reanimation onco-hematologique (Grrr-OH) study

High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure

Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial

Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data

Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients

Low-, medium-and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage

An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome

Etanercept and corticosteroid therapy for the treatment of late-onset idiopathic pneumonia syndrome

High-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allo-SCT

TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521)

The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation

Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol

Risk factors for ICU admission and ICU survival after allogeneic hematopoietic SCT

Mini-review of kidney disease following hematopoietic stem cell transplant

A multicenter, retrospective study of acute kidney injury in adult patients with nonmyeloablative hematopoietic SCT

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment

Venoocclusive disease of the liver following bone marrow transplantation

Acute graft-versus-host disease -biologic process, prevention, and therapy

Graft-versus-host disease

International, multicenter standardization of acute graftversus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium

Atlas of graft-versus-host disease: approaches to diagnosis and treatment

Improved survival after acute graft-versus-host disease diagnosis in the modern era

High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease

The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation

Pathophysiology of chronic graftversus-host disease and therapeutic targets

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report

Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease

Bronchiolitis obliterans syndrome epidemiology after allogeneic hematopoietic cell transplantation

Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation

Fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation

Effect of azithromycin on airflow decline-free survival after allogeneic hematopoietic stem cell transplant: the ALLOZITHRO randomized clinical trial

Neutrophils in critical illness

Neutrophil recruitment and function in health and inflammation

Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9

The role of neutrophils in immune dysfunction during severe inflammation

Neutrophil-mediated suppression of influenza-induced pathology requires CD11b/CD18 (MAC-1)

Role of circulating lymphocytes in patients with sepsis

Neutropenic sepsis is associated with distinct clinical and biological characteristics: a cohort study of severe sepsis

Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood

Blood platelets and sepsis pathophysiology: a new therapeutic prospect in critical ill patients? Ann Intensive Care

Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice

Platelets in pulmonary immune responses and inflammatory lung diseases

Small but mighty: Platelets as central effectors of host defense

Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients

Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america

Clinical impact of pretransplant multidrug-resistant gramnegative colonization in autologous and allogeneic hematopoietic stem cell transplantation

Impact of vancomycin-resistant enterococcal bacteremia on outcome during acute myeloid leukemia induction therapy

Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant

Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course

The global challenge of carbapenem-resistant Enterobacteriaceae in transplant recipients and patients with hematologic malignancies

Emerging concepts in hematopoietic stem cell transplantation-associated renal thrombotic microangiopathy and prospects for new treatments

Hematopoietic stem cell transplant-associated thrombotic microangiopathy

Outcomes of related donor HLA-identical or HLA-haploidentical allogeneic blood or marrow transplantation for peripheral T cell lymphoma

Outcomes of nonmyeloablative HLAhaploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults

HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide

Peripheral-blood stem cells versus bone marrow from unrelated donors

Management of the critically ill adult chimeric antigen Receptor-T cell therapy patient: a critical care perspective

Severe cytokine-release syndrome after T cell-replete peripheral blood haploidentical donor transplantation is associated with poor survival and Anti-IL-6 therapy is safe and well tolerated