key: cord-0720513-8zwjuur1
authors: Azoulay, Elie; Mokart, Djamel; Kouatchet, Achille; Demoule, Alexandre; Lemiale, Virginie
title: Acute respiratory failure in immunocompromised adults
date: 2019-02-28
journal: The Lancet Respiratory Medicine
DOI: 10.1016/s2213-2600(18)30345-x
sha: 280ba6db75a0b1d4c2189558f0bd11e379660954
doc_id: 720513
cord_uid: 8zwjuur1

Summary Acute respiratory failure occurs in up to half of patients with haematological malignancies and 15% of those with solid tumours or solid organ transplantation. Mortality remains high. Factors associated with mortality include a need for invasive mechanical ventilation, organ dysfunction, older age, frailty or poor performance status, delayed intensive care unit admission, and acute respiratory failure due to an invasive fungal infection or unknown cause. In addition to appropriate antibacterial therapy, initial clinical management aims to restore oxygenation and predict the most probable cause based on variables related to the underlying disease, acute respiratory failure characteristics, and radiographic findings. The cause of acute respiratory failure must then be confirmed using the most efficient, least invasive, and safest diagnostic tests. In patients with acute respiratory failure of undetermined cause, a standardised diagnostic investigation should be done immediately at admission before deciding whether to perform more invasive diagnostic procedures or to start empirical treatments. Collaborative and multidisciplinary clinical and research networks are crucial to improve our understanding of disease pathogenesis and causation and to develop less invasive diagnostic strategies and more targeted treatment options.

A growing number of adults have immune dysfunction. 1 Up to 5% of the general population are cancer survivors, 2 transplantation is on the rise, 3 and immunosuppressant drugs are being used for more indications. 4 Moreover, intensive treatments now improve disease-free survival, 2 but also increase the risk of life-threatening events, many of which affect the lungs. [5] [6] [7] [8] Acute respiratory failure can be defined as a triad of clinical signs, radiographic findings, and gas exchange alterations. Most patients present with newly developing or worsening respiratory symptoms over a period of 7 days. Severe acute respiratory failure manifests as respiratory distress with severe tachypnoea, laboured breathing, and recruitment of accessory respiratory muscles. Various patterns of pulmonary infiltrates might be seen, the most common of which are diffuse bilateral infiltrates. 9 Patients with acute respiratory failure require oxygen therapy and most studies of acute respiratory failure included patients receiving ≥6 L/min of standard oxygen. However, depending on the country and number of available hospital beds, patients with acute respiratory failure can be managed on wards, in intermediate care units, or in intensive care units (ICUs). Overall, the need for ICU admission, need for invasive mechanical ventilation (IMV), or mortality increase with the required oxygen flow. 10 Thus, for patients that require 6 L/min of standard oxygen or more, need for intubation throughout the ICU stay and mortality before hospital discharge are up to 40%. 9-16 Delayed ICU admission has been associated with increased mortality. 13, 14, 17 Immunocompromised patients with acute respiratory failure can be encountered by all clinicians in their daily practice. In this Review, we look at the epidemiology, outcomes, and diagnostic investigations in immunocompromised patients with acute respiratory failure, with emphasis on the broad range of causes that must be considered. We discuss the role for invasive and non-invasive tests in identification of the cause of acute respiratory failure, although the huge diversity of tests available for each cause, coupled with the scarcity of randomised controlled trials, creates major challenges. We also suggest an approach to the management of hypoxaemia based on the latest literature.

The incidence of respiratory events varies across different groups of immunocompromised patients (table 1) . Few studies have followed cohorts of patients with the main objective of collecting information about the incidence of pulmonary infiltrates or respiratory complications. Observational studies have shown that among haematological malignancies, lymphoproliferative dis orders (acute lymphoblastic leukaemia and lymph oma) were associated with a moderate incidence of respiratory events (8-18%) 18 compared with acute myeloid leukaemia and myelodysplastic syn dromes (22- 84%; table 1) . 19, 20, 38 Review Key messages

• Acute respiratory failure occurs in up to 50% of haematology patients (primarily patients with acute myeloid leukaemia or allogeneic haemopoietic stem cell transplantation) and in up to 15% of patients with solid tumours (chiefly lung cancer) or solid organ transplants (chiefly of the heart or lung). • Mortality is high and is associated with invasive mechanical ventilation and organ dysfunction; older age; frailty or poor performance status; delayed intensive care unit admission; and acute respiratory failure due to an invasive fungal infection or unknown cause. • In addition to appropriate antibacterial therapy, initial management aims to restore oxygenation and predict the most probable cause on the basis of variables related to the underlying disease, the characteristics of acute respiratory failure, and the radiographic findings. The cause of acute respiratory failure must then be confirmed using the most efficient, least invasive, and safest diagnostic tests. • In patients with acute respiratory failure of undetermined cause, a standardised diagnostic investigation should be done immediately at admission before deciding whether to perform more invasive diagnostic procedures or to start empirical treatments. • Collaborative and multidisciplinary clinical and research networks are crucial both to improve our understanding of disease pathogenesis and causation and to develop less invasive diagnostic strategies and more targeted treatment options.

More over, patients with prolonged neutropenia 6 and autologous or allogeneic stem cell transplant recipients [24] [25] [26] [27] have higher incidences of respiratory events compared with other haematology patients. Solid tumours are associated with a lower incidence of respiratory events than haematological malignancies, with lung cancer having the highest rates (up to 50%), because endobronchial obstruction and atelectasis are risk factors for pneu monia. 30 However, in patients with breast cancer treated with radiation and paclitaxel, the crude rate of pneumonitis was 14·6% (95% CI 5·6-29·2). 31 Of note, in patients with cancer receiving immunotherapy (mostly with program med death 1 and programmed death ligand 1 inhibitors), the incidence of pneumonitis can reach 4%. 32, 39 Acute respiratory failure occurs in about 5% of kidney transplant recipients and 12-14% of heart or lung transplant recipients. 34, 36 Overall, mortality among patients with acute respiratory failure is about 50%, depending on the underlying condition, nature, severity, and course of the respiratory failure, need for IMV, and associated organ dysfunctions. 13

Several studies have assessed risk factors for mortality in immunocompromised patients with acute respiratory failure. These factors can be grouped into five categories:

(1) factors reflecting the severity of the acute respiratory failure and associated organ dysfunctions, (2) factors related to delayed ICU admission, (3) factors related to the underlying disease and comorbid conditions, (4) factors related to the initial oxygenation and ventilation strategy, and (5) factors related to the cause of acute respiratory failure.

Hypoxaemia is the hallmark of respiratory failure. The clinical signs and tolerance of hypoxaemia are usually a function of respiratory symptom duration. For instance, an acute hypoxaemic episode can lead to respiratory distress within a few hours, whereas a subacute or non-acute lung insult of similar magnitude can result in deep hypoxaemia without signs of respiratory distress. Overall, degree of hypoxaemia reflects the extent of lung involvement. Hypoxaemia, measured directly as the PaO 2 on room air or assessed on the basis of the oxygen flow needed to achieve an peripheral capillary oxygen saturation (SpO 2 ) of 95% or the estimated or calculated ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO 2 /FiO 2 ratio), has been used for many years to risk-stratify patients and guide ICU admission decisions. Increased oxygen flow has been associated with the need for ICU admission, 10 need for IMV, 10,16 and hospital mortality. 17 Similarly, lower PaO 2 /FiO 2 has been associated with mortality in patients with acute respiratory distress syndrome, 40 the need for non-invasive ventilation (NIV), 41 or failure of high-flow nasal oxygen therapy (HFNO). 42 Persistent tachypnoea has also been associated with failure of standard oxygen, 42 NIV, 41 or highflow nasal cannula, requiring the imple mentation of another strategy (eg, intubation). 43 No study has evaluated the impact of hyperoxygenation in this setting. 44 Associated organ dysfunctions are best depicted by the Sequential Organ Failure Assessment (SOFA) score, which has consistently been identified as a determinant of mortality, with higher scores associated with increased mortality. 5, 13, 45 Delayed ICU admission has been associated with increased mortality in immuno comprom ised patients, 14 particularly in those with acute respiratory failure. 10,13,17 Benefits from earlier ICU admission might be the result of the careful clinical assessment, optimal oxygenation strategy, avoidance of potentially harmful investigations, and selection of the least invasive diag nostic tests in ICUs. The characteristics of the underlying immuno suppressive condition are not usually associated with hospital mortality following ICU admission, 46 although variations occur depending on ICU admission policies. A higher proportion of patients admitted to ICU with do-not-resuscitate or do-not-intubate status results in stronger associations between variables reflecting characteristics of disease status and mortality. 47, 48 Performance status and comorbidities have been associated with increased mortality. 13, 14, 49, 50 The effects of initial oxygen ation and ventilation strategy on mortality are discussed later in this Review. Furthermore, as previously mentioned, several studies have assessed the association between the cause of acute respiratory failure and mortality. Mortality is lowest in patients with cardiac pulmonary oedema and highest in those with invasive fungal infections or no identified cause of acute respiratory failure.

Early assessment of pre-test probability of acute respiratory failure cause One of the first and key steps in the early management of immunocompromised patients with acute respiratory fail ure is to establish the probable cause of acute respiratory failure, at the bedside, based on clinical examination before undertaking tests. No standard combination therapy is suitable for all patients with acute respiratory failure; each patient must be considered individually. Clinicians should make every effort to identify the cause of acute respiratory failure in patients at high risk of intubation and mortality (eg, those with a higher SOFA score or more hypoxaemic). Bacterial infection is the main cause of acute respiratory failure, and up to 90% of patients receive antibacterial drugs soon after admission. 9 Cardiogenic pulmonary oedema must be considered in every patient. However, other diagnoses should be considered on a case-by-case basis. Thus, the basic diagnostic investigation is the same for all patients (panel 1). It includes tests for cardiogenic pulmonary oedema, sputum examination, and blood cultures to detect bacterial or fungal infections, induced sputum exam ination for Pneumocystis, viral multiplex PCR on nasopharyngeal aspirates or swabs, viral PCR on plasma or blood, an assessment of the likelihood that the underlying condition and its treatments will affect the lungs, and an analysis of the imaging data. When performing the first clinical examination, the mnemonic DIRECT can be used to assess the cause of acute respiratory failure at the bedside. 51,52 D refers to respiratory symptom duration in days, I to the type of immunosuppression, R to the chest X-ray pattern, E to the clinician's experience of similar cases, C to the clinical findings, and T to high-resolution CT. In patients with myeloproliferative diseases such as acute myeloid leukaemia, myelodysplastic syndrome, or chronic myeloid leukaemia, most cases of acute respir atory failure that occur early after disease onset are related to leukaemic infiltrates (figure 1), although some patients might present with pneumonia or cardiogenic pulmonary oedema. 20, 53, 54 Acute respiratory failure of infectious origin is, however, more common at the earliest phase of lympho proliferative disorders (figure 1), such as acute lymphoblastic leukaemia or lymphoma. 21, 55 In patients with T-cell proliferations, opportunistic infections have been reported before cancer treatment initiation, ex emplifying the role played by disease-related immuno suppression. 56 Later, during follow-up, infection is the main cause (figure 1), although treatment-related toxicities and disease relapse can also lead to acute respiratory failure. Clinicians can struggle with non-infectious causes whose diagnosis is believed to rely solely on biopsies, which are difficult to obtain in hypoxaemic patients with thrombocytopenia and haemostatic disorders, or on bronchoscopy and bronchoalveolar lavage, and have been reported as possibly deteriorating the respiratory status and increasing IMV needs. However, a multidisciplinary and collaborative approach allows earlier recognition of typical patterns of clinical and laboratory findings, for which no addition al diagnostic procedures are needed (lung infiltration by the underlying condition, leukaemic infiltrates in patients with acute myeloid leukaemia, diffuse alveolar haemorrhage, cytarabine-related pul monary toxicity, immuno therapy-related pneu monitis, etc). Patients with these patterns are often considered to have no known cause of acute respiratory failure until a multidisciplinary team makes the appropriate diagnosis. Similarly, conditions such as neutro penia or allogeneic haemopoietic stem cell trans plantation are associated with both a high risk of respiratory events and specific acute respiratory failure causes such as exacerbation of previous lung injury during neutropenia recovery, 57 or non-infectious interstitial lung diseases following haemo poietic stem cell transplantation. 26, 58 Acute respiratory failure in the first few days after solid organ transplantation is probably related to either a Biopsy or puncture of extra-pulmonary involvement (skin, joints, peripheral lymph nodes, sternal puncture, buccal smear, etc) Imaging data, including chest X-ray, lung and pleural echography, and high-resolution CT scan (without first-line contrast media unless there is a clinical suspicion of pulmonary vascular disease) Review surgical complication or to decompensation of a chronic respiratory or cardiac comorbid condition. 34, 36, 59, 60 Invasive candidiasis might occur quite early after transplantation. 37 However, most opportunistic infections are reported more than 3 months after transplantation and depend heavily on adherence to prophylactic regimens by the patient. 35, 37, [61] [62] [63] [64] [65] [66] Of note, with the use of intensive immuno suppression in patients experiencing acute humoral or interstitial rejection 67 and with the use of immuno suppressant drug combinations to ensure graft tolerance, clinicians must carefully assess the individual risk for each possible cause and perform a complete diagnostic investigation. 68 In each individual case, the type of immune deficiency must be assessed to allow appropriate adjustment of the initial anti-infectious treatment (figure 2) and to avoid treatment delays. Imaging studies, particularly highresolution CT, are another important bedside tool for determining the cause of acute respiratory failure. 69 This Review does not detail the radiological findings in immunocompromised patients with acute respiratory failure. Patterns of lung involvement are an important piece of the puzzle but are not predictive of a specific cause. 69 However, a combination of positive and negative high-resolution CT findings suggest specific causes of lung infiltrates. 70 Different components of the DIRECT mnemonic contribute to determining the pre-test clinical probability for each individual diagnosis (figure 3). A given clinical situation can be related to different causes of acute respiratory failure, because contextual elements and clinical findings vary across patients. However, the administration of antifungal drugs or anti-Pneumocystis therapy should not be delayed if the pre-test probability of the disease is substantial.

Non-invasive diagnostic tests offer an alternative to bronchoscopy and bronchoalveolar lavage, which carry a risk of respiratory deterioration requiring IMV. 51 However, bronchoalveolar lavage might be required when non-invasive respiratory samples are either not feasible or of poor quality. Performing bronchoalveolar lavage with the support of NIV or high-flow nasal cannula can help patients tolerate the procedure. Also, first-line bronchoalveolar lavage must be considered in situations in which patients have a possible diagnosis of diffuse alveolar haemorrhage, Pneumocystis jirovecii pneumonia, or drugrelated pul monary toxicity, or when lung infiltrates might be involved in the underlying disease (vasculitis, lymphoma, etc). The diagnostic yield of non-invasive tests has, however, increased since the introduction of more sensitive diagnostic tests, such as PCR. However, these tests are more sensitive than specific, and the clinical relevance of a positive PCR is sometimes uncertain. In patients with cancer, the standard diagnostic investigation done immediately at ICU admission includes a physical examination, a pre-test probability assessment using DIRECT, sputum (if possible) and induced sputum examinations, nasopharyngeal aspirates or swabs, blood cultures, serum and urine antigen assays, imaging studies, and biomarker assays. These non-invasive tests perform as well as bronchoscopy and bronchoalveolar lavage. 9, 71 In solid organ transplant recipients, however, bronchoalveolar lavage has a higher diagnostic yield, 36 although the riskbenefit ratio has not been assessed in this population. Moreover, with the advent of omics to assist in the diagnosis of infections, 72 as well as sophisticated immunology and molecular biology methods and advances in imaging techniques to establish the diagnosis of non-infectious conditions, a reappraisal of the diagnostic yield of non-invasive tests in immunocompromised patients is warranted. Nevertheless, despite an optimal early diagnostic investigation, the cause remains undetermined in 10-15% 4; table 2 ). Failure to identify the cause of acute respiratory failure was independently associated with mortality in several studies. 5, 13, 76, 84 In some patients, the cause of acute respiratory failure is identified late, and the impact of a late diagnoses and correspondingly late treatment has not been assessed. The association between absence of a documented cause and mortality raises several questions (table 3) . The association might be related in part to patients who die within a few hours with intractable hypoxaemia and multiple organ dysfunction before diagnostic tests can be performed. When providing expert opinion, careful attention should be directed to the clinical situation, underlying disease, comorbid conditions, and ongoing long-term treatments, as well as to the response to treatments given for the current acute respiratory failure episode. Figure 5 shows first-line diagnostic strategy according to clinical and radiographic presentation. The expert will also have the (sometimes difficult) task of determining which tests are actually performed, obtaining their exact results (as opposed to a classification as positive or negative), and potentially obtaining results that might not yet have been made available to the bedside physicians.

We are aware that lung biopsy is often not feasible, due to haemodynamic instability, deep hypoxaemia, or Review with acute respiratory failure who were receiving IMV at the time of biopsy than in non-intubated patients. In a cohort of 63 haematology patients, the diagnostic yield of lung biopsy was 62% and the therapeutic yield 57%. 73 The diagnostic yield was lower in patients on IMV and in those with neutropenia, but was higher in patients with focal infiltrates. Invasive aspergillosis was also a common biopsy finding in this study. Complications occurred in 13% of patients. 73 The 15% prevalence of invasive aspergillosis is in line with data on acute respiratory distress syndrome in patients with cancer 40 and with autopsy findings in patients with acute respiratory distress syndrome. 90 In 21 haematology patients, including 10 in whom the lung biopsies were obtained post-mortem, inflammatory and malignant infiltrates were the most common diagnoses. 85 A retro spective autopsy study of 7 haemopoietic stem cell transplant recipients showed that fungal infections, potentially steroid-responsive lung involve ment, and malignant infiltrates were underdiagnosed. 96 Compli cations associ ated with lung biopsies occurred in about 10% of patients who were highly selected based on platelet count, performance status, and goals of care. Given the lower diagnostic yield of lung biopsy in ICU patients, the risk-benefit ratio is not favourable; therefore, lung biopsy is rarely performed in critically ill immuno compromised patients with acute respiratory failure and lung infiltrates of unknown cause. However, minimally invasive CT-guided lung biopsies and transbronchial cryobiopsies are increasingly done. 88, 89, 92, 93, 97, 98 Studies to assess the timing of these minimally invasive diagnostic techniques in this setting are warranted. The diagnostic yield should be better defined as the identification of a new diagnosis that was not detected by any other less invasive technique and that resulted in a change in treatment. Moreover, the risk-benefit ratio needs to be re-assessed. If these minimally invasive biopsy techniques are evaluated in a randomised controlled trial, control patients should receive empirical treatment for the most common lung biopsy diagnoses, namely, invasive fungal infection or steroid-responsive lung disease (panel 2).

The initial oxygenation and ventilation strategy aims to restore safe oxygenation, reduce the respiratory rate, alleviate the dyspnoea and respiratory distress, and improve patient comfort. 99 Over the past two decades, studies have consistently shown higher mortality in immunocompromised patients who required IMV. Priority has, therefore, been given to avoidance of IMV by use of non-invasive oxygenation or ventilation devices ( figure 6 ). However, failure of NIV 13,41,100 or HFNO 13 was associated with higher mortality, 13 and two older studies even suggested that early IMV was associated with improved survival. 101, 102 Furthermore, because respiratory disease severity or associated organ dysfunctions are usually worse in intubated patients, determining whether the excess mortality in patients on IMV is due to the IMV itself or to the greater severity of the acute illness is difficult. In other words, a focus on avoiding intubation might not be effective, because the need for IMV might identify a group of patients with high disease severity. Overall, five initial oxygenation methods are available for patients with hypoxaemic acute respiratory failure (figure 6). Guidelines from the European Respiratory Society and American Thoracic Society advocate the use of NIV. 101 This recommendation is based mainly on a 2001 single-centre trial in 52 patients, 75 in which mortality was 81% in the group assigned to standard oxygen, the highest ever reported in this setting ( 11 This trial showed neither benefits nor harms from NIV, in sharp contrast with a post-hoc analysis of the trial by Frat and colleagues, 12 which compared outcomes in 82 immunocompromised patients treated with HFNO, NIV, or standard oxygen. In this trial, the IMV and mortality rates were higher in the NIV group compared with the HFNO and standard oxygen groups. These results are consistent with studies reporting an increased risk of failure and mortality in patients receiving NIV for severe acute respiratory distress syndrome. 41, 75, 79 Thus, these data raise concerns about the use of NIV in immunocompromised patients with hypoxaemic acute respiratory failure. When first introduced, HFNO seemed a promising alternative to NIV. HFNO is easy to use and delivers humidified warmed oxygen, thereby allowing high flows by improving tolerability and comfort. 104 HFNO improves oxygenation, lowers the respiratory rate, inspiratory effort, 105 HFNO also increases end-expiratory lung volume and dynamic lung compliance. 105 These physiological effects are even more pronounced when increasing flow rates are delivered. 106 However, in a randomised controlled trial in 310 unselected patients with hypoxaemic acute respiratory failure and a PaO 2 /FiO 2 ratio ≤300 mm Hg, 107 the number of patients requiring intubation was not significantly reduced with HFNO compared with NIV or standard oxygen. However, the number of ventilator-free days on day 28 was significantly higher with HFNO, and the hazard ratio for day-90 mortality was lower with HFNO. Five studies evaluated the feasibility and safety of HFNO in immunocompromised patients with acute respiratory failure. In a retrospective single-centre study of 45 patients with haematological malignancies (half were bone marrow transplant recipients, 108 half had recently received systemic chemotherapy, and 42% were neutropenic), HFNO allowed recovery without intubation Figure 6 : Nine oxygenation and ventilation methods Standard oxygen can be administered through a wide array of devices. Low-flow oxygen systems comprise a nasal cannula (or nasal catheters; A) providing supplemental oxygen at flows below the total minute ventilation, leading to oxygen dilution with ambient air and lowering the inspired oxygen concentration. A standard nasal cannula delivers an inspiratory FiO 2 of 0·24-0·44 at supply flows 1-8 L/min, depending on respiratory rate and tidal volume. A humidification device is recommended for flows >4 L/min. Reservoir masks (B) can deliver FiO 2 values of 0·40-0·60 at 5-10 L/min. The reservoir system (~100-300 cm³) stores oxygen. A flow rate >5 L/min must be set to ensure the washout of exhaled gas and avoid CO 2 retention. The non-rebreathing facemask (C) may deliver up to 0·90 FiO 2 at flow settings >10 L/min. It should be used only for short periods, as humidification is difficult and there is also a risk of CO 2 retention if the mask's reservoir bag is allowed to collapse on inspiration. Lastly, the Venturi system (D) mixes oxygen with room air (humidification is not necessary) and provides an accurate and constant FiO 2 despite variations in respiratory rate and tidal volume. It is employed when concern arises about CO 2 retention or when the respiratory drive is inconsistent. High-flow oxygen therapy through nasal prongs or cannulas (high-flow nasal oxygen therapy; E) supplies an exact FiO 2 (up to 1) at a flow equal to or greater than the patient's inspiratory flow demand. Nasal oxygen is administered at a flow rate of up to 60 L/min. It is warmed to body temperature and saturated to full humidity by molecular humidification. Non-invasive positive-pressure ventilation provides ventilator support without an endotracheal tube, using an oronasal (F) or total face (G) mask or a helmet (H). The main non-invasive ventilation mode used in hypoxaemic acute respiratory failure is pressure support; continuous positive airway pressure and bi-level positive airway pressure are used less often. Finally, invasive mechanical ventilation (I) uses a tracheal tube inserted into the trachea under general anaesthesia and a neuromuscular-blocking drug. The tube is then secured to the face or neck and connected to a ventilator. In patients with hypoxaemic acute respiratory failure, intubation and invasive mechanical ventilation are used after failure of standard oxygen and, in some cases, of the aforementioned non-invasive options. FiO 2 = fraction of inspired oxygen. 

in one-third of the patients. The hospital mortality rate was 13·3% when HFNO was successful and 86·7% when HFNO failed. The HFNO failure rate was only 15% in a single-centre study of 183 patients with solid tumours, 109 but was 80% in a study of 56 haematology patients. 110 A phase 2 trial in 30 patients with advanced cancer and persistent dyspnoea compared HFNO with biphasic positive airway pressure. 111 Oxygen saturation improved only with HFNO, whereas both treatments provided similar improvements in dyspnoea and respiratory rate. In 37 lung transplant recipients with acute respiratory failure, HFNO proved feasible and safe and decreased the absolute risk of intubation by 29•8%, with a numberneeded-to-treat to avoid one intubation of 3. 34 Although no results from trials specifically assessing HFNO in immunocompromised patients with hypoxaemic acute respiratory failure are available, six studies compared HFNO with other oxygenation or ventilation strategies in this setting (table 2). In a retrospective cohort of 178 patients with cancer and acute respiratory failure, 112 76 (43%) patients received NIV plus HFNO, 74 (42%) NIV plus standard oxygen, 20 (11%) HFNO alone, and 8 (4%) standard oxygen alone. The combination of NIV and HFNO was associated with lower mortality rates (37% vs 52% in the other patients, p=0·04) and was independently associated with higher day-28 survival. In a post-hoc analysis of data from the iNVIctus randomised controlled trial of early NIV in immunocompromised patients with acute respiratory failure, 11 neither the intubation rate nor day-28 mortality differed significantly between the HFNO arm and the standard oxygen arm. 113 In the post-hoc analysis of the trial by Frat and colleagues, 12 outcomes were compared across standard oxygen, NIV, and HFNO. Although NIV was associated with increased need for intubation and higher mortality, neither parameter differed significantly between the 30 patients assigned to standard oxygen and the 26 patients assigned to HFNO. In a retrospective study of 115 immuno compromised patients with acute respir atory failure, 81 the proportion of patients that required intubation (55% vs 35%) and mortality (40% vs 20%) were higher with NIV than with HFNO. In the Efraim multicentre, multinational, prospective cohort study of 1611 immunocompromised patients, 13 915 patients were not intubated on ICU admission and received standard oxygen, HFNO, NIV, or NIV plus HFNO. Hospital mortality was not affected by the initial oxygenation or ventilation management. There was a non-significant trend towards reduced intubation in patients given HFNO. In a retrospective study of 38 kidney recipients, 80 the number of ventilator-free days on day 28 was significantly higher in the HFNO group than in the NIV group. The results of two trials of HFNO focusing specifically on immuno compromised adults with acute respiratory failure (NCT02739451 and NCT02978300) are expected to be available in a few months. 82 HFNO has not yet been properly evaluated regarding its ability to assist diagnostic procedures such as bronchoscopy with bronchoalveolar lavage and bronchial or transbronchial biopsies.

Changes in the initial oxygenation and NIV strategy are unlikely to translate into improved survival. The response of patients to standard oxygen, HFNO, or NIV should be carefully assessed. If the initial strategy of standard oxygen, NIV, or HFNO lowers the respiratory rate and minute ventilation then it should be continued and continuously revaluated. If the tachypnoea and high respiratory drive persist, the risk of intubation is very high and it is reasonable to evaluate the potential benefits of avoiding delayed intubation and adding self-inflicted lung injury to the initial pulmonary insult. 83 Early intubation has been associated with improved survival in haematology patients. 101, 102 Studies of early intubation in patients with a persistently high respiratory drive despite the initial oxygenation strategy are warranted.

In summary, acute respiratory failure is a common and often fatal event in immunocompromised patients that raises major diagnostic and therapeutic challenges. In the near future, with the use of more intensive therapeutic regimens designed to cure cancer, induce transplant tolerance, or control autoimmune and inflammatory diseases in ever older and frailer patients, the incidence of acute respiratory failure against a background of immunodeficiency can be expected to increase. Moreover, the expanding use of targeted therapies and immuno therapies will lead to a growing burden of toxicity and infection during the increasing life spans of these populations. Our knowledge of the effects of acute respiratory failure needs to be improved by longer-term follow-up studies. Multinational registries must be developed to analyse the effect of new drugs and update clinicians on future trends in the incidence of acute respiratory failure and in the use of intensive care for patients with acute respiratory failure. Targets for improving survival, such as early ICU admission and the early identification or treatment of the cause of acute respiratory failure, require evaluation in large random ised controlled trials. Patients with substantial life expectancy and who agree to undergo ICU manage ment should be offered unrestricted access to diagnostic and therapeutic strategies. The greatest challenges are the identification of patients at high risk for specific diagnoses, earlier treatment of acute respiratory failure causes, and selection of the least invasive diagnostic tests. The non-invasive approach is promising but still needs to be refined and updated. Combining clinical algorithms and sophisticated tests, such as genomics, metagenomics, proteomics, or transcriptomics, on noninvasive samples to document or rule out infections will be a major advance only if the results include survival benefits, shorter ICU and hospital stay lengths, reduced costs, and improved patient-reported outcomes. Given that the initial oxygenation and NIV strategy is unlikely to be associated with survival, assessing the patient's

We searched Medline and PubMed for reviews and original articles on pulmonary involvement in immunocompromised adults published in English between Jan 1, 1998 and April 30, 2018, using the terms ("respiration disorders"[Mesh]) AND "immunocompromised host"[Mesh]), ("pneumonia"[Mesh]) AND ("immunocompromised host"[Mesh]), and ("respiratory insufficiency"[Mesh]) AND "immunocompromised host"[Mesh]). We also searched using individual terms such as "leukaemia", "lymphoma", "solid tumours", "cancer", "haematology", "malignancies", "transplantation", "immunosuppressant drugs", "systemic vasculitis", "connective tissue diseases", and "primary immunodeficiency". Although most of the studies we retrieved were published within the specified period, we did not exclude earlier reports. Furthermore, we searched the reference lists of the articles identified by this search strategy and our own personal files. We used original reports when available. Patients with HIV infection are not in the scope of this Review.

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

Effect of non-invasive oxygenation strategies in immunocompromised patients with severe acute respiratory failure: a post-hoc analysis of a randomised trial

Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study

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

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

Identifying cancer subjects with acute respiratory failure at high risk for intubation and mechanical ventilation

Delayed intensive care unit admission is associated with increased mortality in patients with cancer with acute respiratory failure

Pneumonia during remission induction chemotherapy in patients with acute leukemia

Incidence and prognostic value of respiratory events in acute leukemia

Respiratory events at the earliest phase of acute myeloid leukemia

Acute monocytic leukemia presenting as acute respiratory failure

Pneumonia in acute leukemia patients during induction therapy: experience in a single institution

Incidence and outcome of pneumonia in patients with acute leukemia receiving first induction therapy with anthracycline-containing regimens

Characteristics of and risk factors for pneumonia in patients with hematological malignancies developing fever after autologous blood stem cell transplantation

Risk factors and outcome of pulmonary complications after autologous hematopoietic stem cell transplant

Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation

Prognostic factors for early severe pulmonary complications after hematopoietic stem cell transplantation

Risk factor analysis of blood stream infection and pneumonia in neutropenic patients after peripheral blood stem-cell transplantation

Post-obstructive pneumonia in patients with cancer: a review

Analysis of factors associated with in-hospital mortality in lung cancer chemotherapy patients with neutropenia

Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel

Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials

Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients

Humidified high flow nasal cannula supportive therapy improves outcomes in lung transplant recipients readmitted to the intensive care unit because of acute respiratory failure

Acute respiratory failure in cardiac transplant recipients

Acute respiratory failure in kidney transplant recipients: a multicenter study

Acute respiratory failure in renal transplant recipients: a single intensive care unit experience

Prognosis of patients with acute myeloid leukaemia admitted to intensive care

Diagnosis and management of pulmonary toxicity associated with cancer immunotherapy

Acute respiratory distress syndrome in patients with malignancies

Predictors of noninvasive ventilation failure in patients with hematologic malignancy and acute respiratory failure

Predictors of intubation in patients with acute hypoxemic respiratory failure treated with a noninvasive oxygenation strategy

High-flow nasal oxygen vs. standard oxygen therapy in immunocompromised patients with acute respiratory failure: study protocol for a randomized controlled trial

Mechanical ventilation to minimize progression of lung injury in acute respiratory failure

Predicting success of high-flow nasal cannula in pneumonia patients with hypoxemic respiratory failure: the utility of the ROX index

Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis

Noninvasive versus invasive ventilation for acute respiratory failure in patients with hematologic malignancies: a 5-year multicenter observational survey

Managing critically ill hematology patients: time to think differently

Intensive care in patients with lung cancer: a multinational study

Clinical characteristics and outcomes of cancer patients requiring intensive care unit admission: a prospective study

Survival in solid cancer patients following intensive care unit admission

The effects of performance status one week before hospital admission on the outcomes of critically ill patients

Diagnostic strategy in cancer patients with acute respiratory failure

Clinical assessment for identifying causes of acute respiratory failure in cancer patients

Dexamethasone in patients with acute lung injury from acute monocytic leukaemia

Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience

Outcomes after intensive care unit admission of patients with newly diagnosed lymphoma

Quantification of the effect of chemotherapy and steroids on risk of Pneumocystis jiroveci among hospitalized patients with adult T-cell leukaemia

Deterioration of previous acute lung injury during neutropenia recovery

Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies

The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET)

Outcome and treatment of nocardiosis after solid organ transplantation: new insights from a European study

Recurrence of CMV infection and the effect of prolonged antivirals in organ transplant recipients

Bloodstream infections after solid-organ transplantation

A retrospective study to describe the epidemiology and outcomes of opportunistic infections after abdominal organ transplantation

A 10-year experience of tuberculosis in solid-organ transplant recipients

Pneumonia after kidney transplant: incidence, risk factors, and mortality

Early-and late-onset severe pneumonia after renal transplantation

Combined use of rituximab and plasmapheresis pre-transplant increases post-transplant infections in renal transplant recipients with basiliximab induction therapy

Immune monitoring of infectious complications in transplant patients: an important step towards improved clinical management

Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography

Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients (allogeneic SCT excluded): updated guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

Utility of fiberoptic bronchoscopy in neutropenic patients admitted to the intensive care unit with pulmonary infiltrates

Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures

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

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

Intensive care in hematologic and oncologic patients (iCHOP); caring for critically ill immunocompromised patients multinational network (NINE-I)

Six-month outcome of immunocompromised severe acute respiratory distress syndrome patients rescued by extracorporeal membrane oxygenation. An international multicenter retrospective study

Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial

High-flow nasal cannula oxygenation in immunocompromised patients with acute hypoxemic respiratory failure: a groupe de recherche respiratoire en réanimation onco-hématologique study

High-flow oxygen therapy in cancer patients with acute respiratory failure

High-flow nasal cannula oxygen therapy versus noninvasive ventilation in immunocompromised patients with acute respiratory failure: an observational cohort study

High-flow nasal cannula versus noninvasive ventilation for treatment of acute hypoxemic respiratory failure in renal transplant recipients

Metagenomic sequencing complements routine diagnostics in identifying viral pathogens in lung transplant recipients with unknown etiology of respiratory infection

The utility of open lung biopsy in patients with hematologic malignancies

Thoracoscopy or CT-guided biopsy for residual intrathoracic masses after treatment of lymphoma

Impact of open lung biopsy for undiagnosed pulmonary infiltrates in patients with hematological malignancies

Importance of open lung biopsy in the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies

Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings

Surgical lung biopsy in patients with hematological malignancy or hematopoietic stem cell transplantation and unexplained pulmonary infiltrates: improved outcome with specific diagnosis

CT-guided percutaneous lung biopsies in patients with haematologic malignancies and undiagnosed pulmonary lesions

Feasibility and outcome of CT-guided lung biopsy in patients with hematological diseases and suspected fungal pneumonia

Diagnostic contribution from pulmonary biopsies in hematology patients with acute respiratory failure from undetermined etiology

Biopsy-verified bronchiolitis obliterans and other noninfectious lung pathologies after allogeneic hematopoietic stem cell transplantation

Increased mortality in hematological malignancy patients with acute respiratory failure from undetermined etiology: a groupe de recherche en réanimation respiratoire en onco-hématologique (Grrr-OH) study

ARDS: a clinicopathological confrontation

CT-guided biopsies in lung infections in patients with haematological malignancies

Utility of percutaneous lung biopsy for diagnosing filamentous fungal infections in hematologic malignancies

Transbronchial cryobiopsy in immunocompromised patients with pulmonary infiltrates: a pilot study

Diagnostic yield and safety of cryoprobe transbronchial lung biopsy in diffuse parenchymal lung diseases: systematic review and meta-analysis

Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure

End of life care in Italian intensive care units: where are we now?

Outcome in noninvasively and invasively ventilated hematologic patients with acute respiratory failure

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

Noninvasive ventilation of patients with acute respiratory distress syndrome. Insights from the LUNG SAFE study

Use of high-flow nasal cannula oxygenation in ICU adults: a narrative review

Physiologic effects of high-flow nasal cannula in acute hypoxemic respiratory failure

Optimum support by high-flow nasal cannula in acute hypoxemic respiratory failure: effects of increasing flow rates

High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure

Feasibility of high-flow nasal cannula oxygen therapy for acute respiratory failure in patients with hematologic malignancies: a retrospective single-center study

Humidified high-flow nasal oxygen utilization in patients with cancer at Memorial Sloan-Kettering Cancer Center

Clinical utility of high-flow nasal cannula oxygen therapy for acute respiratory failure in patients with hematological disease

High-flow oxygen and bilevel positive airway pressure for persistent dyspnea in patients with advanced cancer: a phase II randomized trial