Cystic fibrosis: Management of advanced lung disease

INTRODUCTION — 

Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic mutations of the CFTR (CF transmembrane conductance regulator) gene [1-3]. Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF. When CF lung disease becomes severe, additional evaluations and treatments need to be overlaid onto the standard therapies that are applicable to all patients with CF lung disease. This expanded management approach has been published as guidelines by the CF Foundation and European CF Society [4,5].

Management of advanced lung disease in CF is discussed below. Other aspects of CF-associated lung disease are discussed in the following topic reviews:

●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●(See "Cystic fibrosis: Overview of the treatment of lung disease".)

●(See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

●(See "Cystic fibrosis: Management of pulmonary exacerbations".)

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●(See "Cystic fibrosis: Treatment with CFTR modulators".)

The diagnosis and pathophysiology of CF and its manifestations in other organ systems are also discussed separately:

●(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●(See "Cystic fibrosis: Genetics and pathogenesis".)

●(See "Cystic fibrosis-related diabetes mellitus".)

●(See "Cystic fibrosis: Overview of gastrointestinal disease".)

●(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

●(See "Cystic fibrosis: Nutritional issues".)

●(See "Cystic fibrosis: Hepatobiliary disease".)

DEFINITION OF ADVANCED CYSTIC FIBROSIS LUNG DISEASE — 

It is appropriate to use a relatively broad definition to avoid excluding any patient who might benefit from the treatments that are recommended for severely affected patients. Based on a systematic review of the literature, the CF Foundation guidelines committee defined advanced CF lung disease as [4]:

●Forced expiratory volume in one second (FEV₁) <40% predicted when stable, or

●Referred for lung transplantation evaluation, or

●One or more of the following clinical characteristics:

•Previous intensive care unit (ICU) admission for respiratory failure

•Hypercarbia (arterial partial pressure of carbon dioxide [PaCO₂] >50 mmHg or tension of carbon dioxide in peripheral venous blood [PvCO₂] >56 mmHg)

•Daytime resting oxygen requirement

•Pulmonary hypertension (on echocardiogram)

•Severe functional impairment from respiratory disease (New York Heart Association class IV)

•Six-minute walk test distance <400 meters

In addition, it was recognized that some patients who do not meet the above definition have clinical characteristics that predict accelerated deterioration and who might benefit from early application of the expanded treatments. These conditions include frequent pulmonary exacerbations, rapid rate of FEV₁ decline, supplemental oxygen for exercise or sleep, worsening malnutrition, infection with difficult-to-manage organisms, CF-related diabetes, pneumothorax, and massive hemoptysis requiring ICU or bronchial artery embolization. Children with moderately severe lung disease should also be considered for early implementation because their rate of deterioration must have been relatively rapid for them to have reached severe lung disease at a young age.

ADVANCED CARE DIRECTIVES — 

When patients progress to having advanced lung disease, discussions should be held regarding prognosis and care options [4,6]. Family members and friends should be included, if requested by the patient. The clinician should guide the discussion to include:

●Detailed information about lung transplantation

●End-of-life options, with recording of the patient's preferences in a manner consistent with local laws

●Decisions about who will serve as the patient's health care proxy/durable power of attorney

CHRONIC INTERVENTIONS TO SUPPORT HEALTH — 

As a patient's lung disease progresses, the CF clinician should review the treatment program to ensure that all standard evaluations and therapies are being implemented. For patients with advanced lung disease, the following areas should be given special attention:

Key therapies

●CF transmembrane conductance regulator (CFTR) modulators – The introduction of highly effective CFTR modulator therapy (HEMT) has led to substantial improvements in the well-being of people with advanced CF lung disease (see "Cystic fibrosis: Treatment with CFTR modulators"). We recommend modulator therapy for all those with advanced CF lung disease who are eligible based on CFTR genotype and age (algorithm 1). Although patients with advanced lung disease were poorly represented in the early clinical trials of CFTR modulators [7], subsequent studies have provided considerable evidence supporting their use in these patients [8]. The largest study prospectively followed 434 people in France with advanced CF lung disease treated with elexacaftor-tezacaftor-ivacaftor (ETI) [9]. The mean increase in absolute percent predicted forced expiratory volume in one second (FEV₁) was 14 points one month after starting treatment and was maintained during follow-up of a median of 1.6 years. The need for lung transplantation decreased markedly following introduction of HEMT (see 'Lung transplantation' below). The treatment was well tolerated, with only three participants discontinuing modulator therapy for reasons other than lung transplantation. Additional information regarding CFTR modulator therapy in patients with advanced lung disease is available in a separate topic review. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'People with advanced lung disease' and "Cystic fibrosis: Treatment with CFTR modulators", section on 'Pulmonary outcomes'.)

After lung transplantation, CFTR modulators have no direct benefits on the transplanted lungs but are increasingly prescribed because of beneficial effects on other organs. If the decision is made to treat with CFTR modulators, some drugs may require dosing adjustments because of common drug-drug interactions. These considerations are discussed in more detail separately. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Post-transplant'.)

●Pulmonary rehabilitation – All patients with CF who have limited functional activity due to pulmonary disease should have a prescribed pulmonary exercise/rehabilitation program. This is particularly important for those with advanced lung disease whose activities of daily living are becoming impaired and in preparation for lung transplantation. (See "Pulmonary rehabilitation".)

●Nutritional status – As lung disease progresses, many patients with CF develop nutritional failure. Because of the tight link between pulmonary and nutritional status, treating advanced lung disease requires attention to nutrition. Enteral tube feeding is recommended when oral intake is insufficient to achieve adequate weight. The CF Foundation's enteral feeding guidelines state that low FEV₁ is not an absolute contraindication for percutaneous insertion of a feeding tube, but the risk of tube insertion needs to be considered [10]. (See "Cystic fibrosis: Nutritional issues".)

●Sinonasal disease – Virtually all patients with advanced CF lung disease have chronic sinusitis. A retrospective study of patients with advanced CF lung disease reported that sinonasal symptom scores improved markedly following initiation of ETI [11]. Although endoscopic sinus surgery improves symptoms in those who are refractory to medical therapy, surgery does not appear to alter the pattern of pulmonary function decline and is not recommended except for symptom control [12-14]. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Sinus and nasopharyngeal disease'.)

●CF-related diabetes – Patients should be rigorously screened for CF-related diabetes, which is common in CF and is associated with worse lung function, poorer nutritional status, and more chest infections. For patients with CF-related diabetes, insulin therapy has beneficial effects on nutrition and probably improves pulmonary function and survival. (See "Cystic fibrosis-related diabetes mellitus".)

●Inhaled antibiotics – For patients with chronic Pseudomonas aeruginosa infection and advanced lung disease, the CF Foundation and European CF Society recommend continuous alternating inhaled antibiotics [4,5]. This practice is based primarily on clinical experience and observational evidence. A randomized clinical trial to evaluate the benefits of this approach failed to enroll the targeted number of patients due in part to the widespread adoption of continuous altering antibiotics in clinical practice for patients with frequent pulmonary exacerbations [15]. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Inhaled antibiotics'.)

Psychosocial support

●Adherence – People with advanced CF lung disease often have problems adhering to their complex and time-consuming medical regimens. The exception is ETI therapy, where median adherence rates are reported to be over 90 percent [1]. The general problem of low adherence to other treatments is compounded in patients with advanced lung disease who have difficulties performing their activities of daily living. Consistently obtaining medications and equipment is made more difficult by shifting insurance coverage and prior approval rules, changes in preferred formularies, and the need to use multiple pharmacies [16]. Special efforts need to be made to assist patients in navigating these challenges. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Chronic measures to promote lung health' and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●Palliative care – The high symptom burden caused by advanced CF lung disease should be addressed by early inclusion of palliative care approaches by the patient's management team [6,17,18]. Introduction of palliative care does not preclude continuing aggressive pulmonary care, including intensive care unit (ICU) admission, mechanical ventilation in the event of respiratory failure, or movement toward lung transplantation. A randomized study is underway to determine the effect of providing longitudinal palliative care delivered by a palliative care expert [19]. Consensus guidelines from the CF Foundation and European CF Society encourage providing palliative care services to patients with CF and provide models for their implementation [6,18]. (See "Benefits, services, and models of subspecialty palliative care" and "Pediatric palliative care".)

●Psychosocial support – Deteriorating pulmonary status generates increasing levels of depression and anxiety, and these may be exacerbated by financial challenges due to threats to employment and medical costs [20]. When the severity of a patient's pulmonary disease becomes advanced, mental health should be assessed more frequently using tools such as PHQ-9 and GAD-7 and by interview during clinic visits. Mental health counseling should be offered early in the course of disease, with addition of psychotherapeutic medications if needed. The CF care team should assess the patient's financial status regularly, including access to adequate food, with referrals to support programs when needed.

LUNG TRANSPLANTATION — 

Lung transplantation provides a viable option for patients with end-stage CF lung disease [21,22] (see "Lung transplantation: An overview"). A registry compiled by the International Society for Heart and Lung Transplantation (ISHLT) reported that, between January 1992 and June 2017, 1220 lung transplants for CF were performed in children [23] and 9428 in adults [24]. However, notably, with the approval of elexacaftor-tezacaftor-ivacaftor (ETI), the number of lung transplants for both adults and children has decreased markedly (figure 1) [25-29] (see "Cystic fibrosis: Treatment with CFTR modulators", section on 'Pulmonary outcomes'). For example, the CF Foundation Patient Registry reported a decrease from 259 transplants performed in 2018, the last year prior to ETI approval, to 61 in 2023 [30]. However, unfortunately, premature death from respiratory failure still occurs in people with CF, particularly in those who are ineligible for modulators or are unable to acquire or tolerate them, so lung transplantation continues to be an important treatment option.

Virtually all lung transplants for patients with CF require replacing both lungs because leaving a native lung in place would present a huge source of infected secretions that would threaten the transplanted lung.

Indications for referral to a lung transplant center — Referral guidelines were published in 2019 and updated in 2021 by a consensus committee of the CF Foundation and endorsed by the Society for Heart and Lung Transplantation [31,32]. The guidelines emphasize the importance of beginning the referral process well before the patient reaches end-stage lung disease. Of note, these guidelines were written prior to the widespread use of highly effective CFTR modulator therapy (HEMT). Because HEMT leads to substantial improvement in the majority of patients with advanced CF lung disease, it is recommended that patients who are eligible to take HEMT should be evaluated for transplant listing only after their responses to HEMT are known [6] (see "Cystic fibrosis: Treatment with CFTR modulators"). However, despite the benefits from HEMT, the recommendation for early referral to a transplant center remains valid because a transplant center may be able to identify and address modifiable factors that could delay or prevent future transplant listing or adversely affect outcome.

The guidelines recommend that the CF care team engage the patient and family in routine periodic discussion of the disease trajectory and treatment options including lung transplantation as a therapeutic option when the patient's forced expiratory volume in one second (FEV₁) falls to <50 percent predicted. Meanwhile, modifiable barriers to lung transplantation should be addressed to optimize candidacy, including nutritional status, optimal management of CF-related diabetes, physical deconditioning, adherence to the medical regimen, and any psychosocial or mental health challenges. However, prophylactic sinus surgery to reduce bacterial burden is not recommended by guidelines unless done to relieve symptoms unresponsive to medical therapy [13,14,33].

The CF Foundation has published a series of indications for referral to a lung transplant center, as listed in the table (table 1) [31]. Key indications for referral are a FEV₁ <50 percent predicted for those with a rapidly declining FEV₁ (>20 percent relative decline in the previous year), FEV₁ <40 percent predicted with markers of shortened survival, and FEV₁ <30 percent predicted for all others. Adolescent patients are generally referred at higher FEV₁ values than adults because reaching advanced lung disease at an early age implies more aggressive lung disease with shortened survival compared with adults with the same FEV₁ percent predicted.

Patients with FEV₁ <40 percent predicted should undergo an annual six-minute walk test, assessment of need for supplemental oxygen, and venous blood gas to screen for markers of severe lung disease that may warrant transplant referral. To screen for pulmonary hypertension, a baseline echocardiogram should be performed for adult patients with FEV₁ <40 percent predicted or for younger patients with FEV₁ <50 percent predicted.

If possible, patients in the United States should be referred to a transplant center that is associated with an accredited Cystic Fibrosis Foundation Care Center [CFFCC]. These centers are expert in providing specialized management for CF-related problems that can complicate lung transplantation including malnutrition, distal intestinal obstruction syndrome, sinus disease, bone disease, CF-related diabetes, and infections common in post-transplant CF patients. In a study of more than 2500 patients, those who were transplanted at a hospital with a CFFCC had a 33 percent reduction in risk of death or re-transplantation compared with those undergoing transplantation at a hospital not affiliated with a CF center [34]. Most (50 of 68) of the lung transplant centers involved in this study did have an affiliated CFFCC. To guide post-transplant management, the CF Foundation has published a consensus statement containing 32 recommendations covering a broad range of post-transplant topics [33].

Pediatric patients with CF require a somewhat more individualized approach [35]. Importantly, there are few pediatric lung transplant centers, so distance and relocation burdens for families of children and adolescents with CF may be more imposing. Furthermore, there is evidence that outcomes after referral of children and adolescents to adult lung transplant programs have been suboptimal [36]. The reasons are multiple but include the drop in adherence to medication that has been described in adolescents receiving solid organ transplants [33].

Lung allocation and wait list — Since March 2023, in the United States, the position of each lung transplant candidate on the priority list for transplant is determined by a lung composite allocation score (CAS) formulated by the United Network for Organ Sharing (UNOS). The CAS is calculated using estimates of one-year survival without transplant and five-year survival with transplant. It also compensates for delays due to difficulty with identifying a suitable donor, the historically low access to transplant of those less than age 18 years, and logistical issues regarding transferring the donor lung to the recipient site. Details about the scoring system and an approximate lung CAS calculator are available from the Organ Procurement and Transplantation Network [37].

There are wide variations in the length of waiting lists among transplant centers, and individual patients may be served by exploring a number of different lung transplant centers. Noninvasive positive-pressure ventilation (NIPPV), endotracheal intubation, and extracorporeal membrane oxygenation (ECMO) have been used to bridge patients to transplantation [38]. (See 'Respiratory support' below.)

Contraindications — Each transplant center has its own list of relative and absolute contraindications for lung transplantation. Because some of these contradictions are relatively subjective, a patient who is denied listing at one transplant center should be considered for referral to another. Some of the criteria that are more subjective and open to interpretation include those involving psychosocial situations, nonadherence to medical treatment, and substance use disorders [32].

In addition to the general contraindications for lung transplantation applicable for all disease indications, there are several CF-specific considerations. Chronic infection with Burkholderia cenocepacia connotes a worse prognosis following transplantation [39-44]. Most, but not all, transplant centers consider infection with this organism to be a contraindication to the procedure [5,32,43]. Other species of Burkholderia do not appear to have the same adverse effects, with the possible exception of Burkholderia gladioli [39-42,44]. Patients infected with multidrug-resistant P. aeruginosa have a minor, if any, survival disadvantage following lung transplant [45,46]. Those infected with Mycobacterium abscessus frequently develop post-transplant complications and should be evaluated by centers with experience managing this infection [47]. Similarly, there is increased risk of dissemination of the fungi Scedosporium apiospermum and Lomentospora prolificans post-transplant and patients with these infections should be assessed at transplant centers experienced with their management [32].

Respiratory colonization with Aspergillus is not a contraindication for transplantation but is associated with a substantially increased risk for post-transplant invasive aspergillosis [48]. As a result, many centers employ antifungal prophylaxis after lung transplantation. (See 'Outcomes' below and "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Disease-based choice of procedure".)

Most lung transplant centers in the United States will not accept referral of intubated patients in acute respiratory failure from another institution for lung transplant evaluation. Admittedly, the survival of these patients without transplantation is very poor, but prolonged intensive care unit (ICU) stays are associated with progressive deconditioning, which is a strong contraindication to transplantation at many centers. In addition, the patient's poor clinical status truncates the usual evaluation for suitability of lung transplantation and prevents the necessary education to obtain a truly informed consent.

Symptomatic osteoporosis is a relative contraindication for lung transplantation in general, but it takes on special significance for patients with CF. The frequency of osteopenia, osteoporosis, or bone fractures in CF increases with age and affects approximately 20 percent of individuals at age 25 years, increasing to 40 percent at age 55 years [49]. Thus, presymptomatic diagnosis and treatment of osteopenia/osteoporosis is important to avoid exclusion of a patient from consideration for transplantation.

A consensus document from the ISHLT addressing transplantation for all causes reported that a body mass index (BMI) <17 kg/m² is a risk factor for an unfavorable outcome [32]. This was confirmed in a CF population in a retrospective study of 2195 transplant recipients, in which the median survival was lower for those with a BMI <17 kg/m² compared with those with BMI above this threshold (7.0 versus 8.2 years, respectively) [50]. However, it was noted that the low-BMI cohort still had favorable outcomes compared with all patients transplanted for chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis. Therefore, a low BMI alone should not be considered a contraindication for referral to a transplant center [51]. The ISHLT consensus document also noted that a BMI >35 kg/m² is correlated with worse outcome [32]. This observation is becoming more pertinent to CF as the prevalence of obesity in people with CF increases, likely due to improved nutrient absorption and utilization associated with the use of HEMT (see "Cystic fibrosis: Treatment with CFTR modulators"). For children, nutrition status is monitored by BMI Z-scores (or percentiles) because normal values for BMI vary during childhood. (See "Cystic fibrosis: Nutritional issues", section on 'Growth'.)

Outcomes — Among adult patients with CF who underwent lung transplantation between 1992 and 2017, the median (50 percent) survival was 9.9 years [24], which is significantly better than the survival for patients who are transplanted for other disease indications (figure 2) (see "Lung transplantation: An overview"). Reports of survival data from single centers restricting the analysis to more recent experience suggest that survival is improving [43,52,53]. Analysis using UNOS registry data of the 1567 patients with CF listed for lung transplant between 2005 and 2011 found a clear survival advantage for those who underwent transplantation [54].

Factors that predict post-transplant outcomes include:

●Health system and other social drivers of health – Post-transplant outcomes for CF lung transplant in Canada are better than those in the United States due to more United States patients dying while on the waiting list as well as better post-transplant survival in Canada [55]. In particular, patients in the United States on Medicare/Medicaid or of non-White race had worse outcomes than those in Canada [56].

●Age – In one study using UNOS data, the median survival of those age >30 years was better than those age 18 to 29 years (9.5 and 5.2 years, respectively) [57]. Pediatric patients receiving lung transplants for CF between 1992 and 2017 had a 50 percent survival of 5.6 years, which is similar to the 5.4-year median survival for pediatric patients who were transplanted for other indications [23]. Data from two single-center reports provide a mixed picture of how much of the decreased pediatric survival was attributable to children under age 12 years; adolescents had survival rates similar to adults [43,58].

●Repeat transplant – Outcomes following re-transplantation are significantly worse, with a five-year median survival of 40 to 50 percent compared with approximately 60 percent for those undergoing their first transplant [59,60].

Limitations of transplantation — Many problems remain after lung transplantation for CF. The procedure does not address the nonpulmonary problems associated with CF. Chronic sinusitis, cirrhosis, cholelithiasis, pancreatic insufficiency, CF-associated diabetes mellitus, osteoporosis, and distal intestinal obstruction syndrome remain causes of morbidity and, occasionally, of mortality, but CFTR modulator therapy may ameliorate these problems in those who are eligible and tolerate them.

Medication management after transplantation also can be challenging. Pancreatic insufficiency and abnormalities in bowel motility can make cyclosporine absorption and dosing difficult; tacrolimus itself is diabetogenic. Glucocorticoid treatment to suppress graft rejection complicates diabetic management and accelerates osteoporosis. If CFTR modulator therapy is used, some drugs may require dosing adjustments because of common drug-drug interactions. These considerations are discussed in more detail separately. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Post-transplant'.)

Studies examining quality of life after lung transplantation for CF generally show improvement [61-63]. Most children return to school, and many adults return to work.

RESPIRATORY SUPPORT

Long-term supplemental oxygen — For CF patients with chronic hypoxemia, we recommend supplemental oxygen for at least 15 hours/day, consistent with guidelines from the CF Foundation, European CF Society, and American Thoracic Society [4,6,64,65]. This approach is extrapolated from the management of patients with chronic obstructive pulmonary disease (COPD) and other non-CF lung diseases. Randomized trials involving patients with chronic hypoxemia due to COPD have shown that long-term oxygen therapy for at least 15 hours/day improves survival and quality of life [66]. These data are discussed separately. (See "Stable COPD: Overview of management", section on 'Supplemental oxygen'.)

Given the paucity of data on long-term oxygen use in patients with CF, we follow the same recommendations for use as in patients with COPD and other forms of chronic lung disease, as summarized in the table (table 2) and discussed in detail separately. (see "Long-term supplemental oxygen therapy", section on 'Indications'). Additional details about prescribing long-term oxygen therapy are provided elsewhere. (See "Long-term supplemental oxygen therapy", section on 'Prescribing oxygen'.)

While there is extensive clinical experience using long-term oxygen therapy in people with advanced CF, published data in this population are limited. A 2013 systematic review did not identify any high-quality studies that examined this question [67,68]. Studies that focused on short-term physiologic responses to short-term administration of supplemental oxygen during exercise testing or polysomnography in individuals with advanced CF demonstrated improved oxygenation accompanied by modest hypercapnia that was likely not clinically significant [67].

Noninvasive positive-pressure ventilation — Guidelines from the United States CF Foundation and European CF Society recommend consideration for the use of noninvasive positive-pressure ventilation (NIPPV) for those with chronic respiratory failure [4,6]. We generally offer nocturnal NIPPV to patients whose arterial carbon dioxide level remains elevated (eg, ≥55 mmHg, or ≥50 mmHg with nocturnal desaturation) despite maximizing other treatments. (See "Nocturnal ventilatory support in COPD".)

This approach is supported by a systematic review in which NIPPV for patients with advanced CF lung disease and hypercapnia improved gas exchange during sleep [69]. One of the included trials involved eight adults with daytime hypercapnia and compared nocturnal use of BPAP to supplemental oxygen or placebo (air) [70]. Six weeks of BPAP improved self-reported chest symptoms, exertional dyspnea and exercise capacity, nocturnal hypoventilation, and peak exercise capacity, without measurable improvement in lung function, and was tolerated by 90 percent of patients. In another study, 29 patients with nocturnal oxygen desaturations who were randomized to NIPPV had improved event-free survival at 3 and 12 months compared to those receiving supplemental oxygen alone. Events were defined as an arterial partial pressure of carbon dioxide (PaCO₂) >60 mmHg or a partial pressure of carbon dioxide (PCO₂) increase of >10 mmHg measured by arterial blood gas or by transcutaneous CO₂ monitor [71]. Several case series also reported successful long-term use of NIPPV as a bridge to transplant; the intervention was associated with improved hypercarbia, weight gain, and/or improvement in the trajectory for forced expiratory volume in one second (FEV₁) [72-75]. In a study of 56 patients with advanced lung disease started on NIPPV, those who were able to continue treatment for longer than six months had a slower rate of decline of their FEV₁ compared with their previous trajectory, although the rates of pulmonary exacerbation and need for intravenous antibiotics did not change [76]. However, of note, a small crossover trial in adults with advanced CF lung disease reported that NIPPV and high-flow oxygen therapy resulted in similar improvements in levels of oxygenation and work of breathing [77]. This result suggests the possibility of doing a trial of high-flow oxygen therapy before positive-pressure ventilation because it is easier to administer and potentially more comfortable for the patient.

Intensive care unit treatment — Advanced CF lung disease should not be considered a contraindication to intensive care unit (ICU) care and mechanical ventilation, regardless of the patient's lung transplant status [4]. The prognosis following an episode of mechanical ventilation due to acute respiratory failure in advanced CF lung disease has been improving, with 36 to 56 percent surviving until hospital discharge [4,78,79].

Outcomes for children and adolescents with CF who are admitted to intensive care may be somewhat better than for adults. In a large study from a registry of pediatric intensive care units (ICUs; primarily in North America), mortality during the ICU admission was 6.9 percent overall and 19.1 percent for patients who were intubated [80]. However, it is unclear what proportion of this cohort was admitted to the ICU with respiratory failure. A single-center study of 29 pediatric patients reported that five died while in the ICU, 14 received lung transplantation while in the ICU, and 10 were discharged alive without lung transplant [81].

Interventions may include:

●Noninvasive respiratory support – Heated high-flow oxygen by nasal cannula or NIPPV. In particular, the CF Foundation recommends a trial of high-flow oxygen by nasal cannula for patients in respiratory failure [4]. (See 'Respiratory support' above and "Cystic fibrosis: Management of pulmonary exacerbations", section on 'Respiratory support'.)

●Endotracheal intubation – Endotracheal intubation with mechanical ventilation is not contraindicated in advanced CF lung disease. It is particularly beneficial when the acute decompensation is caused by pneumothorax or hemoptysis but should be considered for all causes of respiratory failure. If endotracheal intubation is required for more than five to seven days, early tracheostomy should be considered to promote physical mobilization to avoid deconditioning and reduce the need for sedation [4]. (See "Cystic fibrosis: Management of pulmonary exacerbations", section on 'Respiratory support'.)

●Extracorporeal membrane oxygenation support (ECMO) – Venovenous ECMO is sometimes employed as a bridge to lung transplant in CF patients who are approved for transplantation [4,82-84]. In addition, in highly selected patients, ECMO may be considered as a bridge to recovery, based on anecdotal reports as outlined in the CF Foundation guideline [4]. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

Decisions about ICU admission and each of the above interventions must be individualized, depending on the patient's prognosis for recovery or lung transplantation and on their desires and preferences, as expressed in advanced care directives. (See 'Advanced care directives' above.)

In the past, outcomes for CF patients requiring treatment in an ICU were uniformly poor [85] but have since fortunately improved [84]. There are probably multiple reasons for the improved outcomes, including the use of NIPPV to sustain the patient until other measures to reverse the respiratory failure take effect [86,87]. In modern series, survival was dependent upon the severity of respiratory failure, with the best outcomes for those who could be managed by NIPPV and the worst for those requiring endotracheal intubation/ventilation [78,79,87-90]. Patients requiring ICU treatment admission for pneumothorax or hemoptysis had a better prognosis as compared with CF patients admitted to the ICU for other indications [90,91]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Spontaneous pneumothorax' and 'Hemoptysis' below.)

Hemoptysis — Blood streaking in sputum is a common occurrence in patients with CF and is often accompanied by other signs of a pulmonary exacerbation. (See "Cystic fibrosis: Management of pulmonary exacerbations".)

Massive hemoptysis is defined in the CF population as acute bleeding of more than 240 mL within 24 hours or recurrent bleeding of more than 100 mL daily for several days [92]. It is more common in patients with advanced lung disease (approximately 2 percent of these patients per year), but can also occur in other patients who have regions of the lung with advanced bronchiectasis [93-95]. Massive hemoptysis increases the risk of progression to lung transplant and death without lung transplant [31,93]. In patients with severe lung disease, massive hemoptysis is an indication for lung transplant referral [31].

Evaluation and management of hemoptysis in people with CF is discussed separately. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Hemoptysis'.)

Emergency management of unstable patients with massive hemoptysis (hemodynamic instability or impending respiratory failure) is discussed separately. (See "Evaluation and management of life-threatening hemoptysis" and "Hemoptysis in children", section on 'Control of life-threatening hemoptysis'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cystic fibrosis (The Basics)" and "Patient education: Bronchiectasis in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Cystic fibrosis (CF)-related lung disease is considered advanced if the forced expiratory volume in one second (FEV₁) is <40 percent predicted or the patient is referred for lung transplantation evaluation, or if the patient has one of several clinical characteristics that are associated with worse pulmonary status, such as chronic hypercarbia. (See 'Definition of advanced cystic fibrosis lung disease' above.)

●Key interventions for all patients – When CF-related lung disease progresses to an advanced stage, special attention should be given to optimizing key therapies:

•CF transmembrane conductance regulator (CFTR) modulators – Therapy with a CFTR modulator therapy is recommended for most patients with advanced lung disease, as for other patients with CF. Recommendations for CFTR therapy are summarized in the algorithm (algorithm 1) and discussed separately. (See 'Key therapies' above and "Cystic fibrosis: Treatment with CFTR modulators", section on 'People with advanced lung disease'.)

•Other key therapies – Other key therapies that should be optimized for this group of patients are pulmonary rehabilitation, nutritional support, screening and management of CF-related diabetes, and continuous alternating inhaled antibiotics (for those with Pseudomonas aeruginosa infection). (See 'Key therapies' above.)

•Psychosocial support – The patient's care program should place increased emphasis on maintaining mental health. Levels of anxiety and depression should be measured and treated with counseling and medication, when needed. Discussion of advanced care directives and palliative care strategies should be introduced early and do not preclude aggressive pulmonary care and consideration for lung transplantation. (See 'Advanced care directives' above and 'Psychosocial support' above.)

●Additional interventions for selected patients – Decisions about advanced care must be individualized, depending on the patient's desires and preferences as expressed in advanced care directives, as well as their prognosis for recovery or lung transplantation. Strategies may include:

•Lung transplantation – Severe CF lung disease is a common indication for lung transplantation, and outcomes are better than those of patients undergoing lung transplantation for other indications. Guidelines emphasize beginning the process of lung transplant referral well before a patient with advanced lung disease reaches end-stage and suggest clinical indications for referral, as outlined in the table (table 1). Chronic infection with Burkholderia cenocepacia connotes a worse prognosis following transplantation and is often considered a contraindication to the procedure. (See 'Lung transplantation' above.)

•Palliative care – As symptom burden increases and quality of life deteriorates, palliative care strategies should be introduced without precluding continuation of other therapies or eligibility for lung transplantation.

•Supplemental oxygen – For patients with chronic hypoxemia due to advanced CF lung disease, we recommend long-term supplemental oxygen therapy (Grade 1B), using the same indications as for patients with chronic obstructive pulmonary disease (COPD) and other forms of chronic lung disease (table 2). There are limited published data on the benefits and safety of long-term oxygen therapy in patients with advanced CF. This practice is largely extrapolated from studies in patients with COPD, for whom long-term oxygen therapy has been shown to improve survival and quality of life. (See 'Long-term supplemental oxygen' above and "Stable COPD: Overview of management", section on 'Supplemental oxygen'.)

•Nocturnal noninvasive positive-pressure ventilation (NIPPV) – For patients with persistent hypercarbia (arterial carbon dioxide level ≥55 mmHg, or ≥50 mmHg with nocturnal desaturation) despite maximizing other treatments, we suggest nocturnal NIPPV (Grade 2B). NIPPV is tolerated by most patients and improves self-reported chest symptoms, exertional dyspnea and exercise capacity, nocturnal hypoventilation, and peak exercise capacity. (See 'Noninvasive positive-pressure ventilation' above.)

•Intensive care – Improved outcomes support use of intensive care unit (ICU) care for CF patients with respiratory failure. Interventions may include heated high-flow oxygen and NIPPV. Similarly, having advanced CF should not preclude endotracheal intubation with mechanical ventilation, tracheostomy, and extracorporeal membrane oxygenation (ECMO) for select patients. (See 'Intensive care unit treatment' above.)