Cystic fibrosis: Management of pulmonary exacerbations

INTRODUCTION — 

Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic variants in the CFTR gene (CF transmembrane conductance regulator) [1-3]. (See "Cystic fibrosis: Genetics and pathogenesis".)

Pulmonary disease remains the leading cause of morbidity and mortality in people with CF [4], and pulmonary exacerbations are associated with accelerated loss of lung function, decreased quality of life, and increased mortality [5-11]. The causes of pulmonary exacerbations are multifactorial, with infection playing an important but somewhat ill-defined role [12]. The development of treatments that reduce the frequency and severity of pulmonary exacerbations is an important contributor to the marked improvements in survival of people with CF (figure 1).

Considerable variation exists in how patients with CF are treated for pulmonary exacerbations [13-16], despite the availability of clinical guidelines [17-20]. The recommendations in this topic review generally adhere to published guidelines and/or conform to common clinical practices.

Treatment of pulmonary exacerbations in CF is multifaceted, involving antibiotics, chest physiotherapy, inhaled medications to promote secretion clearance, and, sometimes, antiinflammatory agents. An overview of these interventions will be reviewed here. Selection of antibiotics for pulmonary exacerbations is discussed in a separate topic review. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

Other aspects of pulmonary disease in CF are discussed in separate topic reviews:

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

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

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

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

●(See "Cystic fibrosis: Management of advanced lung disease".)

PULMONARY EXACERBATIONS IN CYSTIC FIBROSIS

Definition — The clinical course of most patients with CF is punctuated by acute episodes of worsening pulmonary status that are referred to as "pulmonary exacerbations" [8,9]. The CF field has not reached a consensus definition of pulmonary exacerbation for the purposes of patient care or clinical research [21,22]. In many clinical trials, exacerbations were defined solely on the criterion that a participant's CF clinician initiated antibiotic treatment for an acute worsening of clinical status [14,23]. Other trials have defined exacerbations based on specific symptoms and signs, but these criteria do not perform well at identifying those patients whose CF clinicians choose to treat with antibiotics [21,22]. Part of the difficulty may be that pulmonary exacerbations are not a single entity but have differing etiologies, inflammatory profiles, and clinical outcomes [24,25].

Diagnosis — In clinical practice, a pulmonary exacerbation is diagnosed based on changes from an individual patient's recent baseline health status [26], typically including several of the following symptoms and signs:

●Symptoms:

•New or increased cough

•New or increased sputum production or chest congestion

•Decreased exercise tolerance or new or increased dyspnea with exertion or at rest

•Increased fatigue

•Decreased appetite and possible weight loss

•Increased respiratory rate at rest

•Change in sputum appearance

•Hemoptysis

•Fever (present in a minority of patients)

•Increased nasal congestion or drainage

In infants and young children, the most frequent symptom of a pulmonary exacerbation is cough that is either wet or occurs at night [27].

●Pulmonary function tests – Reductions in pulmonary function as measured by forced expiratory volume in one second (FEV₁) are often present during pulmonary exacerbations but are not required for its diagnosis, although large decrements in FEV₁ (eg, more than a 10 percent decline from baseline) are more likely to cause clinicians to initiate treatment in patients presenting with typical signs and symptoms of an exacerbation [28]. Change in lung clearance index is likely more sensitive than FEV₁ for detecting a pulmonary exacerbation, particularly in those having milder disease [29]. The test is not readily available for clinical care but is used primarily in clinical trials of investigational drugs. Although it was hypothesized that routine monitoring by home spirometry would promote earlier detection of pulmonary exacerbations and therefore better outcomes, a randomized 52-week study in which people with CF were monitored twice weekly with home spirometry failed to detect long-term benefit relative to usual management, as measured by rate of decline of FEV₁ [30]. Contrasting results were reported from another CF center that instituted a protocol that triggered treatment for a pulmonary exacerbation whenever percent predicted FEV₁ decreased ≥5 points from baseline. The best percent predicted FEV₁ improved from 87.4 recorded during the 12 months prior to starting the protocol to 98.4 at two years afterward.

●Other – Chest radiographs may not show significant changes over baseline and are not routinely obtained for people with mild symptoms. A decrease in arterial hemoglobin oxygen saturation may occur but is not required to diagnose an exacerbation.

There are no absolute thresholds that determine a pulmonary exacerbation. For example, an individual who is asymptomatic at baseline is typically considered to have a pulmonary exacerbation if there is a new cough with sputum production, fatigue, and decreased appetite, even though FEV₁ may remain in normal range [31].

Severity grading — CF clinicians routinely distinguish mild from severe exacerbations when planning treatment [13,32], although there are no protocols for severity grading [33]. A common approach is to consider the degree of worsening from baseline of each of the patient's signs and symptoms and arrive at a global assessment of the extent of decline. As examples:

●In an individual with mild pulmonary disease at baseline, an exacerbation is considered severe if the acute illness is characterized by the onset of a productive cough and a large decline in FEV₁ (eg, greater than 10 percent).

●In an individual with severe pulmonary disease at baseline, an exacerbation is considered mild if the cough, sputum production, exercise tolerance, and FEV₁ worsened minimally but perceptibly from prior baseline status.

Incidence — In 2022, the Cystic Fibrosis Foundation Patient Registry reported that 10 percent of children and 15 percent of adults had at least one pulmonary exacerbation severe enough to be treated with intravenous antibiotics, down from 23 percent of children and 43 percent of adults in 2018 [4]. A major driver of the decreased incidence is the availability of the highly effective CF transmembrane conductance regulator (CFTR) modulator elexacaftor-tezacaftor-ivacaftor, which brings treatment to approximately 94 percent of patients ≥6 years of age. (See "Cystic fibrosis: Treatment with CFTR modulators".)

The risk of pulmonary exacerbation increases with age, female sex, declining lung function, CF-related diabetes (CFRD), and cirrhosis [34]. A strong predictor of developing a pulmonary exacerbation is having had one or more exacerbations during the previous year. Other risk factors include nonadherence to chronic CF treatments and depression [35,36].

PATHOGENESIS

Viruses — Viruses are detected in respiratory secretions during pulmonary exacerbations in many people with CF, and there is evidence that they are important contributors to declining pulmonary function [37]. Among children with a pulmonary exacerbation during the winter months, viruses were detected by a molecular method in 34 to 60 percent [38,39]. The pathogens were coxsackie/echovirus, rhinovirus/enterovirus, respiratory syncytial virus, parainfluenza, adenovirus, and influenza. Among adults with pulmonary exacerbations, viruses were detected in 10 to 40 percent, including rhinovirus/enterovirus, respiratory syncytial virus, parainfluenza virus, coronaviruses, and influenza [40-43]. In a large study of adults with pulmonary exacerbations, 39 percent were positive for a respiratory virus, with human rhinovirus/enterovirus accounting for 68.6 percent [44].

Bacteria — Most people with CF have chronic bacterial infection of the airways, as demonstrated by sputum cultures; the prevalence of each bacterial type varies with the age of the patient (figure 2). (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pathogens'.)

Important pathogens include (table 1):

●Pseudomonas aeruginosa

●Staphylococcus aureus (methicillin-sensitive or methicillin-resistant species)

●Burkholderia cepacia complex

●Nontypeable Haemophilus influenzae

●Stenotrophomonas maltophilia

●Achromobacter species

●Nontuberculous mycobacteria

Anaerobic bacteria are frequently identified, but their role in pulmonary exacerbations is uncertain [45-47]. Nonculture-based assays to identify bacteria have shown that the number of species present in respiratory secretions from CF patients is often considerably higher than what is revealed by culture-based methods, with substantial variation among patients [48].

Although bacteria are clearly involved in the pathophysiology of pulmonary exacerbations in CF, the mechanisms are uncertain [12,49]. Most exacerbations are not associated with the appearance of new bacterial species or strains [50]. Furthermore, there is no consistent pattern of change in bacterial communities leading up to pulmonary exacerbations [48].

Inflammation — The CF airway is characterized by chronic neutrophil-rich inflammation (see "Cystic fibrosis: Clinical manifestations of pulmonary disease"). Inflammatory markers in serum and airway secretions increase during pulmonary exacerbations [24,51,52] and decrease with treatment [53]. Although pulmonary infection is a major contributor to the airway inflammation, there is some evidence that CF transmembrane conductance regulator (CFTR) deficiency itself can cause inflammation in the absence of infection [54]. During an exacerbation, bacterial or viral infection induces further inflammation, which contributes to the lung damage. As a result, some antiinflammatory strategies are effective at limiting lung damage. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Antiinflammatory therapy'.)

SITE OF CARE — 

Depending, in part, on the severity of a pulmonary exacerbation, treatment may be administered in hospital, at home, or both.

Triage by severity

●Mild exacerbations – Most mild exacerbations are routinely managed in an outpatient setting with intensified airway clearance therapies and oral and/or inhaled antibiotics. However, a pilot study in children has suggested that immediately starting oral antibiotics at the first sign of a mild pulmonary exacerbation may not be necessary in many cases [55]. More definitive studies are needed to determine if this is true (see "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Severity of the exacerbation'). Clinical care should include counseling to encourage close adherence to the regimen and close follow-up to monitor progress. Some patients with mild exacerbations will still require hospitalization and/or intravenous antibiotics, particularly if they show inadequate improvement or if they have failed outpatient oral/inhaled regimens during prior episodes. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Severity of the exacerbation'.)

●Moderate exacerbations – Moderate pulmonary exacerbations are often managed in an inpatient setting. However, home management may be appropriate for select patients with nonsevere exacerbations and sufficient support to ensure optimal treatment. When considering home therapy for a pulmonary exacerbation, resources must be available at home to replicate the hospital program, including the prescribed antibiotics and close adherence to airway clearance therapies (inhaled agents and chest physiotherapy), with provisions for rest and good nutrition [17]. Children require greater assistance than adults to accomplish these goals, and adult supervision is needed even for teenagers. In considering home treatment for children, one must consider the impact of lost work hours, the number of other children in the household, the number and competence of available adult caregivers, and family stress before deciding whether home treatment is preferable to hospitalization.

●Severe exacerbations – Severe pulmonary exacerbations usually require hospitalization to adequately manage the complex regimen; closely monitor symptoms and laboratory test results; and ensure intensive airway clearance therapy, nutrition, and rest.

Comparison of outcomes for home versus hospital care — Concern over hospital costs as well as the preference of many patients have encouraged home treatment with intravenous antibiotics for pulmonary exacerbations in CF. Although it has not been feasible to perform randomized trials comparing outcomes of home versus hospital care, there are large observational studies that address the question [56-59]. The most recent studies suggest that in-hospital treatment is more effective at recovering the forced expiratory volume in one second (FEV₁) that was lost during the exacerbation. As an example, in a large prospective study of standardized care for pulmonary exacerbations (STOP2 study [23]), in which 33 percent of participants received treatment exclusively in hospital, 21 percent exclusively at home, and 46 percent initiated in hospital and completed at home [56]. The mean increase in percent predicted FEV₁ of those treated only in hospital (8.0, 95% CI 6.7-9.4) was significantly better than those treated only at home (5.0, 95% CI 3.5-6.5) or at both locations (7.0, 95% CI 5.9-8.1). Because the participants were not randomly assigned to treatment location, sophisticated statistical analyses were used to adjust for assignment bias in these studies, but residual bias cannot be excluded. Similar conclusions were reached in another registry-based study of 4497 pulmonary exacerbations, which found that recovery of FEV₁ to ≥90 percent of baseline level was 9.1 percent more likely when all treatment was delivered in-hospital compared with treatment delivered entirely at home [57]. In a separate study, treatment at home was also associated with a shorter time to the next pulmonary exacerbation requiring treatment [59]. By contrast, an earlier retrospective observational study of 1535 participants detected no significant differences in outcomes for patients treated with intravenous antibiotics at home [58].

Factors other than the medical features of the exacerbation heavily influence the decision to treat at home verses in hospital [60]. Linked data from the STOP2 clinical trial and the CF Foundation Patient Registry showed that the major drivers that led to hospitalization were having Medicaid insurance, living farther distance from the CF clinic, and having been treated in hospital for the prior exacerbation. Older patients and those with intravenous access ports were more likely to be treated at home. The baseline FEV₁ and the magnitude of the FEV₁ drop preceding the exacerbation were not significantly different between the groups treated at home versus hospital.

Intensive care unit treatment — Indications for intensive care unit (ICU) care include:

●Respiratory insufficiency requiring respiratory support (see 'Respiratory support' below)

●Pneumothorax (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Spontaneous pneumothorax')

●Severe hemoptysis (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Hemoptysis')

Outcomes for adults and children with CF who require ICU care were previously reported to be uniformly poor [61] but have fortunately improved [62,63]. Advanced CF lung disease should not be considered a contraindication to mechanical ventilation or ICU care in general, regardless of the patient's lung transplant status [64]. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Intensive care unit treatment'.)

An episode of respiratory failure should prompt discussion of end-of-life care, quality of life, and possible indications for lung transplantation. Ideally, these discussions should occur when a patient's clinical trajectory suggests increasing risk for respiratory failure but well before ICU care is needed. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Lung transplantation'.)

TREATMENT — 

The goals of treatment are to return the patient's symptoms to baseline and recover any lost forced expiratory volume in one second (FEV₁), which are not always possible. (See 'Prognosis' below.)

Antibiotics — Treatment of exacerbations with systemic antibiotics is a mainstay of CF care and is recommended in virtually all consensus guidelines. Selection and dosing of antibiotics are summarized in the table (table 2) and discussed separately. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

Periodic elective hospitalization for preventive therapy (referred to as "clean outs") is not recommended, as reviewed separately. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Periodic hospitalizations'.)

Continuation of the chronic treatment regimen — The patient's chronic treatment regimen should be continued or intensified during an acute exacerbation, as recommended by virtually all guidelines, although high-quality studies are generally lacking to assess this strategy [17]. The role for inhaled antibiotics during pulmonary exacerbations is uncertain. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Managing the chronically prescribed antibiotics'.)

Key components include:

●CF transmembrane conductance regulator (CFTR) modulators. (See "Cystic fibrosis: Treatment with CFTR modulators".)

●Airway clearance therapy, with inhaled agents (eg, inhaled dornase alfa or hypertonic saline) and chest physiotherapy. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Airway clearance therapies'.)

●Antiinflammatory medications (eg, azithromycin, ibuprofen) in selected patients. Decisions about continuing or suspending azithromycin during a pulmonary exacerbation are discussed separately. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Managing the chronically prescribed antibiotics' and "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Antiinflammatory therapy'.)

●Optimization of nutritional status. (See "Cystic fibrosis: Nutritional issues", section on 'Nutrition support'.)

●Ensuring glucose control for those with CF-related diabetes (CFRD). (See "Cystic fibrosis-related diabetes mellitus", section on 'Treatment'.)

●Exercise, as tolerated. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Chest physiotherapy'.)

Many patients have poor adherence to these treatments when they are at their baseline status and require encouragement to increase their use during exacerbations [35]. If possible, the frequency of airway clearance treatments should be increased during exacerbations beyond what is prescribed as part of the chronic therapy regimen (eg, increasing to four times per day), as recommended by Cystic Fibrosis Foundation guidelines [17].

Other medications (for selected patients)

Bronchodilators — During pulmonary exacerbations, our practice is to administer short-acting bronchodilator medications:

●Prior to airway clearance therapy and exercise

●Prior to other inhaled medications for those who develop bronchial constriction in response to them

●As a rescue medication for those with airway hyperreactivity

We use these same indications for bronchodilators during baseline health. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Bronchodilators'.)

Evidence supporting routine use of bronchodilators during pulmonary exacerbations is limited. Poor responsiveness to bronchodilators was reported in a retrospective study in which the median bronchodilator-induced increase in FEV₁ was only 4.3 percent and only 9 percent of the participants met standard criteria for being responsive to bronchodilator treatment [65]. Somewhat better bronchodilator responsiveness was shown in a randomized crossover study that compared the effects of albuterol with placebo (normal saline) in 24 hospitalized patients who were evaluated after they had been on antibiotic therapy for at least six days [66]. A significant increase in FEV₁ was seen 45 minutes following albuterol administration but not following normal saline (mean FEV₁ increase 14.8 versus 1 percent). However, by the following morning, there was no between-group difference in FEV₁. No studies have evaluated more prolonged effects of bronchodilators on pulmonary exacerbations, eg, duration of antibiotic treatment, recovery to baseline FEV₁, or improvement in symptoms.

Glucocorticoids — There is considerable variation in practice regarding use of glucocorticoids for pulmonary exacerbations, and evidence is limited [15,23,67,68].

●Patients with typical features of acute asthma – For the small subset of CF patients whose exacerbations have characteristics of an acute asthmatic episode (eg, chest tightness, wheezing, acute symptomatic response to inhaled beta-adrenergic agonists), we administer a course of prednisone (2 mg/kg/day [maximum 60 mg daily] for five days). We use this strategy because glucocorticoids are beneficial for asthmatic symptoms in patients without CF. (See "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Systemic glucocorticoids' and "Acute exacerbations of asthma in adults: Home and office management", section on 'Initiation of oral glucocorticoids'.)

●Other patients – For patients without features typical of an acute asthma exacerbation, we do not routinely administer systemic glucocorticoids. However, other clinicians use glucocorticoids for most patients with exacerbations, based largely on the assumption that acute exacerbations in CF are similar to acute exacerbations of chronic obstructive pulmonary disease (COPD) in adults, for which glucocorticoids are routinely used. (See "COPD exacerbations: Management".)

●Evidence – Our selective approach to systemic glucocorticoids is consistent with 2009 clinical care guidelines from the CF Foundation, which stated that there was insufficient evidence to recommend use of glucocorticoids for routine treatment of pulmonary exacerbations [17]. Subsequently, two studies using retrospective data could find no benefit from glucocorticoids [68,69]. In particular, an analysis of linked data from the CF Foundation Patient Registry and the Pediatric Health Information System found that glucocorticoids, which were administered in 15 percent of pulmonary exacerbations, did not improve recovery of FEV₁ [68]. Similarly, a secondary analysis of data from the STOP2 study [23] found that the 168 patients who received glucocorticoids had no greater improvement in symptoms or FEV₁ when compared with those of a propensity-matched control group [69].

The only two placebo-controlled trials of systemic glucocorticoids for CF pulmonary exacerbations did not find benefit. The first trial involved 24 participants who were starting antibiotics and did not detect an effect of adjunctive glucocorticoids on change in FEV₁ [70]. The second trial involved 76 participants with suboptimal response to a course of antibiotics and also failed to detect a benefit of adjunctive glucocorticoids on recovery of FEV₁ [71]. However, neither trial was sufficiently powered to exclude clinically significant treatment effects, as indicated by the wide confidence intervals.

Antiviral agents

●Influenza – Antiviral treatment is indicated for people with CF with known or suspected influenza because they are at high risk for severe or complicated disease. Antiviral treatment should be initiated regardless of the duration of symptoms or severity of initial illness, although it is likely to have the greatest benefit if it is initiated within 48 hours after symptom onset. Indications and regimens are discussed separately. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy' and "Seasonal influenza in nonpregnant adults: Treatment".)

Annual vaccination against viral influenza is recommended for all CF patients older than six months of age, using an inactivated vaccine delivered by injection. Vaccination is highly preferred over the use of pre- or postexposure chemoprophylaxis [72]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Prevention of infection'.)

●COVID-19 – CF is a condition associated with a higher risk of developing severe COVID-19 disease, according to the United States Centers for Disease Control and Prevention (CDC). Patients with CF should follow CDC recommendations for higher-risk individuals regarding vaccination and treatment of infection (see "COVID-19: Vaccines" and "COVID-19: Management in children" and "COVID-19: Evaluation and management of adults with acute infection in the outpatient setting"). Of note, nirmatrelvir-ritonavir, which is used to treat mild to moderate COVID-19 disease in adults, is a strong cytochrome P450 3A4 (CYP3A) inhibitor and will reduce the clearance of CFTR modulators. Administration of nirmatrelvir-ritonavir requires large reductions in modulator doses [73]; consultation with a pharmacist is advisable.

Hyperglycemia management — Elevated blood glucose levels occur frequently during pulmonary exacerbations in people with CF, with or without preexisting CFRD [74,75]. Accordingly, routine testing of fasting and postprandial blood glucose concentrations is recommended for the first 48 hours of treatment in patients requiring intravenous antibiotics and/or systemic glucocorticoids [76]. (See "Cystic fibrosis-related diabetes mellitus", section on 'When to test'.)

Management depends on the degree of hyperglycemia and history of CFRD:

●People without CFRD – For those without CFRD but with blood glucose concentrations in the diabetic range after the first 48 hours of antibiotic treatment, insulin therapy should be initiated [77]. The approach to initiating insulin is similar to that used to start insulin during a clinically stable period. (See "Cystic fibrosis-related diabetes mellitus", section on 'Insulin therapy'.)

People with hyperglycemia during the pulmonary exacerbation should have follow-up diagnostic testing after they have fully recovered to determine if they have CFRD and if chronic insulin therapy is warranted. (See "Cystic fibrosis-related diabetes mellitus", section on 'Diagnosis'.)

●People with CFRD – For those who are already diagnosed with CFRD and are on insulin therapy, treatment during hospitalization should follow guidelines for hospitalized patients with non-CFRD (see "Management of diabetes mellitus in hospitalized patients"). However, of note, relatively high insulin doses many be required early in the course of a pulmonary exacerbation due to the increased insulin resistance induced by infection, inflammation, and/or glucocorticoid use. During recovery, close monitoring of blood glucose and deescalation of insulin dose are needed to avoid hypoglycemia as insulin resistance wanes.

Respiratory support — During a pulmonary exacerbation, escalating interventions may be used for respiratory support. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Intensive care unit treatment'.)

●Supplemental oxygen – We administer supplemental oxygen during pulmonary exacerbations by nasal cannula, targeting an oxygen hemoglobin saturation by pulse oximetry of 88 to 92 percent or an arterial blood oxygen tension of 60 to 70 mmHg. This approach is based mainly on extrapolation from the management of patients with acute exacerbations of COPD and is consistent with CF guidelines [64,78] (see "COPD exacerbations: Management"). Despite the high prevalence of nasal and sinus symptoms in people with CF, supplemental oxygen by nasal cannula or heated high-flow nasal cannula is well tolerated [79,80]. After initiation of supplemental oxygen, patients should be monitored for deterioration in mental status due to hypercapnia, although the incidence of this complication is low.

For those with impending respiratory failure, oxygen therapy may be escalated to heated high-flow oxygen by nasal cannula or noninvasive positive pressure ventilation, as recommended in CF guidelines [64,78].

●Noninvasive ventilation – We offer noninvasive positive pressure ventilation to patients who develop acute respiratory failure (eg, acute elevation of arterial carbon dioxide tension to >45 mmHg or hypercapnic acidosis) and who have none of the contraindications (eg, severely impaired consciousness, inability to cooperate, or inability to protect their airway) [64] (see "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications"). The noninvasive ventilation regimen must accommodate intermittent treatments for assisting airway secretion clearance (inhaled airway clearance medications and chest physiotherapy). The approach is consistent with guidelines for people with COPD who develop acute ventilatory failure during exacerbations. However, the long-term benefits of noninvasive ventilation during CF exacerbations are unclear [81].

A secondary benefit of noninvasive ventilation is that it might enhance airway clearance therapy. This was evaluated in a randomized study of 38 participants admitted for treatment of a pulmonary exacerbation [82]. There was no significant increased rate of improvement in FEV₁ or symptom scores in the noninvasive ventilation group. However, another trial found that adding noninvasive ventilation to airway clearance treatments mildly improved oxygen saturation and reduced dyspnea [83]. Since the observed benefits were relatively minor yet the cost is high, we do not recommend noninvasive ventilation for the purpose of enhancing airway clearance therapy.

●Invasive ventilation – CF patients with acute respiratory failure are candidates for endotracheal intubation and mechanical ventilation, if noninvasive ventilation fails and if the intervention is congruent with the patient's goals of care. The decisions are consistent with guidelines used for people with COPD and acute respiratory failure. (See "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease".)

Input from the appropriate transplant center should be sought to determine how intubation with mechanical ventilation will affect the patient's listing for transplantation. (See "Cystic fibrosis: Management of advanced lung disease".)

●Extracorporeal membrane oxygenation support (ECMO) – When adequate ventilation and/or oxygenation cannot be supported by assisted ventilation, ECMO has been used to successfully bridge CF patients to lung transplantation [84,85]. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Intensive care unit treatment'.)

Individuals who require invasive ventilation should also be considered for early institution of ECMO, if this is congruent with the patient's goals of care and with input from the pertinent transplant center, as outlined in Cystic Fibrosis Foundation guidelines for advanced CF lung disease [64]. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

PROGNOSIS — 

Following a pulmonary exacerbation, recovery of the forced expiratory volume in one second (FEV₁) decrement is often incomplete. With each exacerbation, between 12 and 35 percent of patients fail to recover to at least 90 percent of their baseline FEV₁ [14,86,87]. Quality of life also declines with increasing numbers of pulmonary exacerbations [6]. Following treatment of a pulmonary exacerbation, symptomatic improvements are not well correlated with FEV₁ recovery [88]. As an example, in a prospective study of 58 adults with CF, 23 percent of pulmonary exacerbations were associated with ongoing symptoms after 14 days of antibiotics, with further symptomatic improvement when treatment was extended to 21 days [89]. However, continuation of antibiotic treatment was not associated with further improvement in FEV₁ or body mass index. These observations are relevant to decisions about duration of treatment. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Duration of treatment'.)

Given the adverse consequences of exacerbations, reducing exacerbation frequency is an important rationale for many of the chronic treatments for CF pulmonary disease. (See "Cystic fibrosis: Overview of the treatment of lung disease" and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection" and "Cystic fibrosis: Treatment with CFTR modulators".)

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".)

SUMMARY AND RECOMMENDATIONS

●Definition – In clinical practice, a pulmonary exacerbation is diagnosed based on a clinician's global assessment of changes from the patient's recent baseline health status, including changes in symptoms (cough, sputum production, exercise tolerance) with or without changes in pulmonary function tests. (See 'Diagnosis' above.)

●Pathogenesis – The clinical course of cystic fibrosis (CF) is frequently complicated by acute pulmonary exacerbations, superimposed on a gradual decline in pulmonary function. Mechanisms include:

•Bacteria – Bacteria play an important but somewhat ill-defined role in the pathophysiology of pulmonary exacerbations. Key bacterial pathogens are discussed separately (table 1). (See 'Bacteria' above and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pathogens'.)

•Viruses – Viral pathogens frequently play a role in initiating exacerbations and may be important contributors to declining pulmonary function. Influenza is an important vaccine-preventable pathogen. (See 'Viruses' above.)

●Treatment

•Antibiotics – Treatment of exacerbations with systemic antibiotics is a mainstay of CF care. Selection and dosing of antibiotics are summarized in the table (table 2) and discussed separately. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

•Continuation of the chronic treatment regimen – The patient's chronic treatment regimen should be continued or intensified during an acute exacerbation, including CF transmembrane modulator (CFTR) therapy, airway clearance therapies, optimization of nutrition, and management of CF-related diabetes (if present). (See 'Continuation of the chronic treatment regimen' above.)

The role for inhaled antibiotics during pulmonary exacerbations is uncertain. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Managing the chronically prescribed antibiotics'.)

•Antiviral agents – Antiviral treatment is indicated for people with CF with known or suspected influenza because they are at high risk for severe or complicated disease. Indications and regimens are discussed separately. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy' and "Seasonal influenza in nonpregnant adults: Treatment".)

•Other medications – We use bronchodilators as pretreatment for airway clearance therapies and to treat asthma-like symptoms. We use glucocorticoids only for the small subset of patients with asthma-like symptoms, although practice varies. (See 'Bronchodilators' above and 'Glucocorticoids' above.)

●Respiratory support – People with respiratory failure or complications (hemoptysis, pneumothorax) are candidates for respiratory support during a pulmonary exacerbation, including supplemental oxygen, noninvasive ventilation, invasive ventilation, or extracorporeal membrane oxygenation support (ECMO). (See 'Respiratory support' above.)

An episode of respiratory failure should prompt discussion of end-of-life care, quality of life, and possible indications for lung transplantation. Advanced CF lung disease is not a contraindication to intensive care unit (ICU) admission or mechanical ventilation, regardless of the patient's lung transplant status. (See 'Intensive care unit treatment' above.)

●Prognosis – Following a pulmonary exacerbation, the recovery of lost forced expiratory volume in one second (FEV₁) is often incomplete. Pulmonary exacerbations are associated with accelerated loss of lung function, decreased quality of life, and increased mortality. Thus, reducing the frequency and optimizing treatment of exacerbations is an important goal of CF care. (See 'Prognosis' above.)