Abstract
Cystic fibrosis (CF) is the most common, life-shortening inherited disease of Caucasians. Much of its morbidity and mortality is related to progressive airway involvement, the consequence of defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) and associated apical ion channels that lead to impaired mucociliary clearance and innate defenses. The lungs of a person with CF are susceptible to chronic infection that induces an intense inflammatory response, causing airway obstruction, bronchiectasis, and ultimately respiratory failure. Current management of CF incorporates antibiotics, inhaled mucolytics, airway clearance techniques, antiinflammatory agents, and, increasingly, small molecule potentiators and correctors that target specific CFTR mutations. Indeed, treatment for CF lung disease has evolved over the past 5 years, and newer therapies have begun to radically change clinical outcomes. In this chapter, we will review the pathophysiology of CF lung disease and describe current and emerging therapies for this progressive lung disease.
Keywords
cystic fibrosis, bronchiectasis, airway, infection, inflammation
Epidemiology
While present in all races and ethnicities, cystic fibrosis (CF) is the most common, life-shortening inherited disease of Caucasians. An autosomal recessive defect, occurring in approximately 1 in 3500 live births based on data from neonatal screening, the life expectancy of a child born with CF has gradually improved and now exceeds 40 years in the United States. The predominant morbidity and mortality from CF continues to result from progressive pulmonary involvement. The CF lung is susceptible to infection; endobronchial infection induces an intense inflammatory response that leads to bronchiectasis and eventually respiratory failure, thus shortening the life of the patient. In this chapter, we will build on earlier sections and relate the pulmonary manifestations and complications of CF lung disease to its pathophysiology, and describe current and emerging therapies to address this progressive lung disease.
Etiology and Pathogenesis
CF is caused by defects in the CF transmembrane conductance regulator (CFTR), a cyclic adenosine monophosphate (cAMP)-regulated chloride channel expressed on the surface of airway epithelial cells and the serous cells of the submucosal glands (discussed in more detail in Chapter 49 ). CFTR is functionally linked to other apical chloride channels, such as the calcium-dependent chloride channels (ClCa), and the epithelial sodium channel (ENaC), which reabsorbs sodium in the airways ( Fig. 51.1 ). Aberrant expression or function of CFTR in the airway leads not only to reduced chloride conductance but also upregulation of ENaC activity. Failure of chloride secretion and sodium hyperabsorption result in dehydration of the airway surface. The reduced airway surface liquid and desiccated secretions obstruct the airways and reduce mucociliary clearance, permitting bacterial infection to become established and allowing the inflammatory response to be amplified. The mucus secreted by submucosal glands in the CF airway is also abnormal, possibly related to altered CFTR anion transport, and hinders bacterial clearance. Gaps in innate airway defenses contribute to bacterial persistence and chronic infection in the CF airway. Altered bicarbonate secretion in the CF airway impairs the activity of airway epithelial antimicrobial proteins and thus interferes with innate airway defenses resulting in chronic infection ( Fig. 51.2 ).
Respiratory infections are not a consequence of altered or abnormal pulmonary development. The lungs of neonates with CF appear histologically normal with the exception of plugging and distension of submucosal gland ducts. Bacterial cultures of respiratory secretions from infants often fail to yield a specific pathogen. Early in life, the airways are not chronically infected, although various bacteria may be found intermittently. As intrabronchial mucus stasis evolves, the respiratory tract becomes persistently infected with common patterns of bacterial species ( Fig. 51.3 ). Bacterial infection is highly localized to the airway.
Initially, Staphylococcus aureus and Haemophilus influenzae are isolated from patients with CF. S. aureus is often found in the respiratory tract of infants and young children with CF and the prevalence of methicillin-resistant S. aureus strains has greatly increased. There is mounting evidence that methicillin-resistant S. aureus contributes to pulmonary deterioration and poorer survival. The significance of H. influenzae in the progression of CF lung disease is uncertain, although it is a recognized and often treated pathogen in other forms of bronchiectasis.
Pseudomonas aeruginosa emerges as the predominant organism over time but the percentage of children with chronic lung infection with P. aeruginosa has declined, with less than 50% of patients transitioning to adult care centers testing positive for P. aeruginosa. Early P. aeruginosa isolates have planktonic, motile, nonmucoid phenotypes. Most patients eventually become chronically infected with mucoid P. aeruginosa that survives in the lung as biofilms, and these anaerobic, sessile communities of bacteria contribute to antibacterial resistance in the CF airway. Approximately 70% of CF adults in the United States are chronically infected with mucoid P. aeruginosa and the isolation of mucoid strains from the lungs of a patient is characteristic but not pathognomonic for CF. Isolation of mucoid strains of P. aeruginosa from the lungs of a patient is associated with a poorer prognosis. Encouragingly, studies have reported that persistent infection with P. aeruginosa can be delayed or avoided with antibiotic treatment, which may lead to slower decline in pulmonary function.
Antibiotic-resistant strains of P. aeruginosa are found increasingly in CF respiratory secretions. Other resistant, gram-negative bacteria, Stenotrophomonas maltophilia and Achromobacter xylosoxidans, are opportunistic organisms that may appear later in life; recent cohort data suggest some impact on disease progression with Stenotrophomonas, but further analysis is warranted. Alternatively, Burkholderia cepacia complex can have profound effects on the clinical course of the disease and be associated with rapidly progressive necrotizing pneumonia and greater mortality. The prevalence of B. cepacia complex varies markedly between care centers with a nationwide prevalence of about 2%. Most B. cepacia complex infections are caused by genomovar II (B. multivorans) and genomovar III (B. cenocepacia). These organisms are transmissible, and infection control policies are critical to limiting exposure and spread. Epidemic infections have been linked to B. cenocepacia, but other genomovars have been associated with severe disease. To prevent bacterial transmission between CF patients, infection control guidelines have been developed and applied to patients in both clinical settings and during social activities.
Invasive fungal infections are rare. Nontuberculous mycobacteria, typically M. avium-intracellulare complex or M. abscessus, can infect the CF lung. About 13% of patients in the United States harbor nontuberculous mycobacteria in their lungs. Therefore CF patients should be screened at least annually for mycobacterial colonization.
In patients with respiratory symptoms refractory to antibiotic therapy, viral infections should be considered. Indeed, there is evidence indicating that viruses play a significant role in the pathogenesis of pulmonary exacerbations and are associated with progressive clinical deterioration. Respiratory viruses have the potential for injuring or altering the airway and can induce secretion of inflammatory mediators from respiratory epithelium. Moreover, viral infections result in a damaged epithelial barrier, leading to acquired ciliary dyskinesis, disruption of cell-cell connections, and cell death. A breach in the airway epithelium potentially allows pathogens to reach the basolateral surface, provoking a greater inflammatory response. Viral infections can affect airway surface fluid levels in CF epithelial cell cultures, which could further impair mucociliary clearance. In particular, influenza can complicate CF disease, but immunization and chemoprophylaxis have lessened its clinical impact.
Although pulmonary infection contributes to the morbidity of patients with CF, an intense host inflammatory response hastens the progressive, suppurative pulmonary disease. Inflammation in the CF lung is primarily contained in the airway lumen, while the alveolar space is relatively spared ( Fig. 51.4 ). The airway is filled with mucopurulent secretions. Large numbers of neutrophils are found in the airway, even in children with mild disease. Bronchoalveolar lavage (BAL) fluid from CF patients has remarkably high concentrations of proinflammatory mediators. Infection and local mediators stimulate epithelial cell secretion of IL-8, a potent neutrophil chemoattractant and activator that perpetuates airway inflammation. Complement-derived chemoattractants and leukotriene B 4 also contribute to neutrophil influx. Both IL-1β and TNF-α are macrophage-derived cytokines that contribute to the local inflammatory response in the CF airway by mediating neutrophil chemoattraction and degranulation. IL-17 pathways have also been identified to contribute to the proinflammatory gene expression in the airway and are especially involved in established CF lung disease.
Inflammation in the CF lung is primarily driven by local stimuli, mediators, and chemoattractants and is not a local effect of a systemic inflammatory reaction. Systemic indicators of inflammation are often normal or only modestly increased, even during acute illnesses. Several lines of evidence suggest that airway inflammation in CF may be excessive to the threat posed by bacteria, possibly mediated through dysregulation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) or other signal transduction molecules. Although not a universal finding, infants and children with CF have high levels of proinflammatory cytokines and neutrophils in BAL fluid, even in the absence of detectable infection. It is possible that inflammation may occur independent of infection or that a relatively minor infection may induce a robust inflammatory reaction in the CF lung that does not subside. However, not all experimental models and clinical studies have demonstrated an exaggerated inflammatory response in the CF airway, and this phenomenon may be related to reduced apical surface fluid volume.
The inflammatory response in the CF airways is characterized by a massive influx of neutrophils across the respiratory epithelium, even in individuals with mild pulmonary involvement. The phagocytic system affords protection against bacterial invasion, and neutrophil-derived proteases, such as neutrophil elastase, are released during phagocytosis and neutrophil death. These proteases participate in the intralysosomal degradation of engulfed bacteria and with disease progression the protease burden in the CF airway overwhelms existing antiprotease defenses. Neutrophil elastase plays several roles in the pathogenesis of CF lung disease. It digests diverse substrates, including structural proteins, which weakens the airway and results in bronchiectasis and bronchomalacia. Uninhibited neutrophil elastase can enhance the inflammatory response in the bronchi and, paradoxically, interfere with nonspecific airway defenses.
As disease progresses, the airway lumen is filled with neutrophil exudates, acute and chronic inflammation, and bacteria. Mononuclear cell infiltration of the submucosa, goblet cell hyperplasia, and submucosal gland dilatation are also features of the CF airway. Respiratory cilia are normal or have nonspecific changes secondary to epithelial injury. Bronchiectasis is the predominant pathological feature, more severe in the upper lobes. Despite high bacterial concentrations in the CF lung, bacteremia and sepsis are rare. Tissue invasion is uncommon, and usually associated with particular organisms, such as B. cepacia complex. Segmental hyperinflation or atelectasis results from airway obstruction. Lung overinflation, postinflammatory blebs, and bronchiectatic cystic lesions increase susceptibility to pneumothorax. Over time, bronchial arteries become hypertrophied and can cause pulmonary hemorrhage. Chronic alveolar hypoxia and inflammatory changes contribute to pulmonary hypertension and cor pulmonale.
Clinical Features
Symptoms and Physical Findings
The onset and progression of clinical manifestations of CF lung disease is highly variable and detecting the presence of disease in infants and children can be challenging. Although it is unusual for neonates to manifest respiratory symptoms, the work of the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has shown that relatively well children have evidence of CF lung disease during the first few months of life. Viral illnesses in older infants can precipitate tachypnea, wheezing, and cough, but early colonization with lower airway pathogens, specifically S. aureus and P. aeruginosa, may be associated with pulmonary inflammation, early-onset bronchiectasis, and an associated decline in lung function.
Most children will present with cough as their primary symptom, which becomes increasingly productive. Mucociliary clearance is impaired throughout the conducting airways, and the CF patient depends on cough to mobilize purulent endobronchial secretions and reduce bacterial burden. As the lung disease progresses, CF patients can experience exercise intolerance, dyspnea, and shortness of breath. Typically, bronchiectasis begins in the upper lobes in CF patients and then progresses to involve the whole lung ( Fig. 51.5 ). The treatment of bronchiectasis is the treatment for the CF lung disease. Lobar resection is seldom indicated but may be considered in instances of severe hemoptysis or bronchiectasis that are not responsive to conservative management.
Atelectasis often coexists with bronchiectasis because of the accumulation of purulent secretions and airway obstruction. Atelectasis also generates negative intrapleural pressure and dilates the associated bronchus that has been already weakened by the lytic enzymes released from neutrophils in the purulent material in the airway. Typically, treatment for atelectasis involves airway clearance techniques, inhaled recombinant DNAse (dornase alfa), or other mucolytic agents, plus antimicrobials.
Altered balance between airway pathogens and local host defenses leads to acute changes in respiratory signs and symptoms; this phenomenon is termed a pulmonary exacerbation . Clinically, a pulmonary exacerbation is manifested as increased respiratory symptoms such as cough, dyspnea, and sputum production, often accompanied by systemic symptoms such as fatigue, anorexia, and weight loss. Pulmonary function values usually decrease during exacerbations, and a therapeutic goal is to restore the best baseline of pulmonary function, regardless of the patient’s symptoms. Exacerbations are treated with aggressive airway clearance techniques and antibiotic therapy based on bacterial isolates from sputum or oropharyngeal cultures.
CF patients have chronic upper respiratory tract involvement, clinically manifested as nasal congestion and rhinorrhea. Pansinusitis is almost universally present in affected individuals. If upper airway symptoms worsen, systemic antibiotic therapy may be indicated. The percentage of CF patients who have features consistent with clinical sinusitis varies widely. Bacteria isolated from the paranasal sinuses parallel those found in the lower respiratory tract, although distinct strains may colonize different anatomic sites in the CF airway. Occurring in 7%–56% of CF patients, nasal polyposis is a common complication leading to nasal obstruction and congestion, which can require surgical intervention. Surgical management usually results in symptomatic improvement, but sinusitis and polyps often recur.
Digital clubbing is a sign of long-standing pulmonary involvement and eventually develops in virtually all CF patients. Hypertrophic pulmonary osteoarthropathy, a syndrome characterized with clubbing, long bone periostitis, and synovitis that usually flares during acute pulmonary exacerbations, has been described infrequently in CF patients and is usually associated with more advanced lung disease.
As airway disease progresses, there is an increased likelihood of respiratory complications, including hemoptysis and pneumothorax. Pneumothorax is a late and worrisome complication of CF lung disease resulting from severe obstructive airways disease and/or the rupture of overexpanded apical blebs. Approximately 3% of CF patients will experience pneumothorax during their lifetime, and the average annual incidence of pneumothorax is 0.6%. Pneumothoraces are usually associated with more severe disease (75% occur in patients with a forced expiratory volume in one second [FEV 1 ] of less than 40%) and can be associated with fatalities. Although small pneumothoraces can be treated conservatively, evacuation of intrapleural air is often necessary to reexpand the lung. With recurrence rates ranging 50%–90%, chemical or mechanical pleurodesis may be indicated, depending on the clinical scenario; even with pleurodesis, the risk for recurrent pneumothorax remains high. Whereas pleurodesis was previously considered an absolute contraindication for lung transplant referral, that is no longer universally applied.
Hemoptysis is common in older CF patients, particularly during pulmonary exacerbations, and is usually treated with antibiotics and, depending on the volume, withholding airway clearance. As CF lung disease progresses, bronchial arteries or collateral vessels enlarge and may rupture into an inflamed airway, producing massive hemoptysis, defined as more than 240 mL in 24 hours. This is a medical emergency, and roughly 4% of all patients with CF will suffer massive hemoptysis in their life. These episodes can be fatal. Although many episodes spontaneously remit, hemoptysis can be worsened by coagulopathy secondary to hypovitaminosis K or underlying CF liver disease. Although patients can be stabilized with intravenous vasopressin, selective bronchial artery embolization is the definitive treatment. Recurrent hemoptysis does occur, and repeated embolization may be indicated.
Airway hyperreactivity is often diagnosed in patients with CF, as evidenced by routine treatment with inhaled albuterol and corticosteroids. Roughly half of CF children and adults have a bronchodilator response, even if they do not have asthmalike symptoms, and the degree of airway hyperresponsiveness may change over time. In different studies, airway hyperresponsiveness to exercise, histamine, or methacholine were found in 22%–54% of CF children.
The defect in airway clearance associated with CF may also allow for endobronchial fungal growth and the development of allergic bronchopulmonary aspergillosis (ABPA). ABPA is an inflammatory complication, clinically manifested by wheezing and cough refractory to standard therapies. Bronchiectasis with mucus impaction and atelectasis should also prompt consideration of ABPA. ABPA is an intense immunologic response to surface colonization with the fungus Aspergillus fumigatus, which is characterized by (1) clinical deterioration that is not explained by other etiologies, (2) elevated serum quantitative immunoglobulin (Ig) E concentrations (>500 IU/mL), (3) positive skin prick test to Aspergillus fumigatus or elevated in vitro Aspergillus -specific IgE levels, and (4) Aspergillus -specific IgG levels or precipitins. Fulfilling these diagnostic criteria complicates the diagnosis and results in varying prevalence rates. Features that should raise concerns for the diagnosis include high-resolution computed tomography (HRCT) findings of mucus impaction, central bronchiectasis, tree-in-bud opacities, and centrilobular nodules. Serum quantitative IgE concentrations should be measured annually to monitor for this complication. Once the diagnosis is made, patients are treated with extended courses of high-dose corticosteroids. Antifungal therapy is a therapeutic option to reduce the antigen burden in the lung, but few studies have shown that this strategy reduces the duration of corticosteroid treatment or improves outcome.
Cor pulmonale is a complication of hypoxemia that is most commonly seen in older patients with advanced disease. Aggressive treatment of the underlying lung disease is indicated in early pulmonary hypertension, combined with oxygen supplementation. With disease progression and volume overload, diuretics are indicated to treat the right-sided heart failure. With more advanced disease, the presence of pulmonary hypertension significantly reduces life expectancy.
Imaging and Laboratory Studies
The United States Cystic Fibrosis Foundation (CFF) has established Clinical Practice Guidelines that outline standards for routine monitoring and intervention to slow progression of lung disease. Evaluations include regular radiologic examinations, pulmonary function testing, and microbiologic cultures of airway secretions. Clinical evaluations are also essential and include monitoring for weight loss, anorexia, exercise tolerance, and school attendance, which are indirect measures of pulmonary morbidity. Indeed, the child’s nutritional health is relevant to pulmonary outcomes. Younger children who have maintained their body weight had better pulmonary function at age 6 years, showing the relationship between nutrition and lung disease.
Monitoring Lung Disease
Chest imaging studies are useful tools to assess disease progression. Standard chest radiographs are often normal early in life, but as lung disease evolves, hyperinflation, peribronchial thickening, mucus plugging, and atelectasis develop. The progressive bronchiectasis, characteristic of CF lung disease, is usually a later finding on plain chest films. HRCT of the chest is more sensitive and provides greater anatomic detail, showing abnormalities well before detection on plain radiographs or changes in pulmonary function. HRCT can be performed on infants and small children, and it may reveal unsuspected airway wall thickening, segmental overinflation, and early bronchiectasis. Although scoring systems to measure the extent and progression of CF lung disease have been developed, there are still no consensus guidelines regarding the use of computerized tomography, and the long-term consequences of radiation exposure remain concerns.
Pulmonary function testing is routinely used to assess lung disease in children and adolescents with CF. Spirometric measurements permit assessment of progression of airway disease and are routinely used to diagnose pulmonary exacerbations and response to antibiotic therapy. Most CF children are able to perform reproducible spirometric maneuvers by age 6 years. The FEV 1 , or more accurately, the rate of FEV 1 decline, is a useful index of disease severity. Deteriorating FEV 1 is a key marker for disease progression. Pulmonary function decline varies greatly between patients, but in this decade, the average annual reduction in FEV 1 is approximately 2% per year in the United States. Although first described more than 25 years ago, CF patients with a baseline FEV 1 30% of predicted for age, still have a 2-year mortality rate of 50%. Blood gas measurements are remarkably normal until late in the course of disease, but may reveal gas exchange abnormalities related to worsening ventilation-perfusion inequalities in patients with more advanced lung disease or clinical deterioration. Finally, infant pulmonary function testing can be a useful tool to assess infants and young children, but its value is limited by its ability to predict later disease severity. Recent testing in preschool children, including the multiple breath washout test or lung clearance index (LCI), has promise as an objective outcome measure in CF.
Since progression of CF lung disease is inextricably linked to airway infection, regular comprehensive microbiological assessments of specimens from the lower respiratory tract, for example, sputum, are important. Younger patients may not be able to expectorate, and in those cases, respiratory secretions can be collected using posttussive oropharyngeal swabs or BAL. Investigations have shown that negative oropharyngeal cultures may exclude lower airway infections, but a positive culture is not reliable to make the diagnosis of P. aeruginosa endobronchitis. It is essential that respiratory cultures are processed and performed in laboratories with expertise in the handling of CF specimens and that recognize the difficulties in speciation of infecting pathogens. The CFF has established guidelines for handling and processing of respiratory tract specimens and supports reference laboratories for confirmatory identification of certain organisms such as B. cepacia complex.
Hypertonic saline has been used to induce sputum for lower airway sampling for both microbiological and inflammatory markers in older pediatric patients. Cytokines, chemokines, oxidation species, and neutrophil products are elevated in the CF lung and may also be increased in the sputum and BAL fluid during exacerbations. However, such measures can have significant interpatient and intrapatient variability, even in those with seemingly stable lung disease. It is unclear whether these markers reflect disease progression, although the presence of detectable neutrophil elastase in lavage fluid early in life predicts development of bronchiectasis. Inflammatory markers in the blood, such as peripheral leukocyte counts and C-reactive protein levels, have not been useful in the assessment of lung disease.
Management and Treatment
Treatment for CF lung disease is evolving, incorporating the newer therapies developed over the last two decades. Current management of CF incorporates antibiotics, inhaled mucolytics, vigorous airway clearance, nutritional support, antiinflammatory agents, and, increasingly, small molecule potentiators and correctors in an attempt to forestall progression ( Fig. 51.6 ). Indeed, early intervention and primary prevention of CF lung disease may be possible.
Airway Clearance
Effective airway clearance is a critical component of CF therapy. To maintain lung health, physical removal of airway secretions is needed to not only relieve airway obstruction but also to reduce infection and airway inflammation. Numerous airway clearance therapies (ACT) have been utilized and remain one of the most fundamental therapies for individuals with CF. Additionally, novel agents aimed at restoring airway surface liquid and changing mucus viscosity have provided new opportunities to clear mucus and sustain normal lung function.
There are many passive and active methods of ACT used in CF care. Active ACT includes positive expiratory pressure, active-cycle-of-breathing technique, and autogenic drainage. No specific ACT has been definitively shown to be superior in changing long-term clinical outcomes, although this may be attributable to the challenges of performing randomized controlled trials in this area and the resultant paucity of data. An individual’s choice should be based on age, experience, apparent effectiveness, and adherence.
As an adjunct to airway clearance techniques, one must consider the benefit offered by aerobic exercise to mobilize secretions. In a systematic review of exercise for children with CF, both improved pulmonary function and aerobic fitness were demonstrated. In addition to increased aerobic fitness, exercise programs may confer both short and long-term protection against pulmonary function decline.
Any discussion of ACT would be incomplete without discussing the advances in agents aimed at rehydrating secretions. Reduced mucus viscosity and increased mucociliary clearance is achieved by improved airway surface hydration offered by these agents. Hypertonic saline acts directly as an osmotic agent and may increase airway surface liquid volume. In older CF patients, hypertonic saline resulted in reduced frequency of pulmonary exacerbations and enhanced airway clearance. A similar beneficial effect was not seen in children between 4 and 60 months of age. However, in a small, pilot, single-center sub-study of young children, the lung clearance index (LCI) was significantly decreased in the group that received hypertonic saline. As a result, a larger, multicenter investigation is ongoing. Working as a surface-acting osmotic agent, inhaled mannitol has been shown to improve lung function over 52 weeks in a placebo-controlled trial. In addition, trials are underway to study the effect of ENaC inhibitors to rehydrate the CF airway. Finally, inhaled bronchodilators are often used before ACT to maintain airway patency and facilitate mucus removal.
Inhaled Mucolytics
Aerosolized mucolytics facilitate airway secretion clearance. The inspissated secretions in CF are predominately composed of pus with high concentrations of DNA from degraded neutrophils. Inhaled recombinant DNAse treats CF lung disease by reducing sputum viscosity and increasing mucus clearance. Regular administration leads to improvement in lung function in some individuals with CF and is widely used. N -acetyl- l -cysteine is an alternative mucolytic agent, as it hydrolyzes disulfide bonds in mucins, and it has a long history of use in CF ; however, few data support its effectiveness other than as an airway irritant that induces cough. Other mucolytics remain under investigation as potential therapeutic agents.
Antibiotic Therapy
During the past two decades, antibiotic use in CF care has evolved in both indications for usage and modes of delivery. Antibiotics continue to be utilized in the setting of acute infections and pulmonary exacerbations, but they are now also routinely used to eradicate organisms in otherwise asymptomatic young children or to reduce the bacterial burden in chronically infected patients.
CF patients acquire bacterial pathogens in an age-dependent manner that will chronically colonize their airways over time. Chronic infection with P. aeruginosa portends a poorer prognosis and, once established, is virtually impossible to eradicate. However, studies treating initial acquisition of P. aeruginosa have shown that the organism can be eradicated with aggressive antibiotic therapy. Although patients reacquired the organism later, the realization that early P. aeruginosa infection can be effectively eradicated led to a change in how antibiotics are prescribed in CF. No longer are antibiotics solely used to treat symptomatic disease; now they are used to treat early positive P. aeruginosa cultures, even in the absence of symptoms. Although effective in reducing reacquisition of P. aeruginosa, the impact of early eradication on later lung function remains obscure. Potential confounders include the frequent use of antibiotics for pulmonary exacerbations and the need for longer follow-up of the two groups (those who achieved eradication and those who did not). In addition, there is insufficient evidence to support whether one antibiotic regimen is superior to another in achieving eradication.
Although there is no consensus as to what defines a pulmonary exacerbation, most clinicians would agree that increase in cough, increase in sputum production, decline in lung function, shortness of breath, weight loss, and new adventitious sounds on auscultation warrant further investigation or therapy. Antibiotic treatment during an exacerbation, depending on the circumstance, may be delivered intravenously, orally, or by nebulization. The severity of the symptoms and the patient’s available resources will assist the clinician in determining the appropriate course of therapy. Antibiotic therapy is typically guided by the findings of previous sputum or deep oropharyngeal culture and the susceptibility testing of the identified organisms. These cultures typically reflect the airway flora in older children and adolescents, but that may not be the case in infants. BAL fluid cultures may be necessary to more accurately direct therapy. Antibiotics may be changed during the course of treatment based on more recent culture and susceptibility results or the patient’s clinical response. It is important to note, however, that susceptibility testing in vitro does not necessarily correlate with clinical response.
Infections caused by P. aeruginosa in patients with CF are usually treated with two antibiotics of different classes in an attempt to prevent the emergence of resistance and in the hopes of achieving synergy. However, using the results from testing for susceptibility to multiple drug combinations does not confer any advantage to clinician-selected combinations of antibiotics, and multiple drug combination synergy testing is no longer routinely recommended. The most common combination of intravenous therapy for P. aeruginosa involves the use of an aminoglycoside with a β-lactam antibiotic. Higher doses of systemic aminoglycosides are required in patients with CF because of increased clearance and altered pharmacokinetics so drug concentrations must be monitored and maintained in the therapeutic window. For CF patients with multidrug-resistant P. aeruginosa, colistin may be used intravenously, but its use requires close monitoring for neurological symptoms and renal toxicity. Concurrent intravenous aminoglycoside therapy should be avoided with intravenous colistin. Oral fluoroquinolones are frequently used, but P. aeruginosa can develop resistance rapidly. Inhaled antibiotics can be used in conjunction with either intravenous or oral therapy depending on antibiotic sensitivities.
Length of antibiotic therapy is determined by resolution of symptoms and return of lung function to its previous baseline or to a new plateau. Concern for emergence of resistant organisms limits extending courses beyond these endpoints. Complete eradication of organisms in the chronically infected patient is not achievable in most patients. Typically, return of lung function to baseline and resolution of symptoms can be achieved with 10–21 days of therapy with the majority of patients receiving 2 weeks of antibiotics, although little data is available that precisely defines adequate length of therapy.
Suppressive or maintenance therapy with inhaled antibiotics is appropriate for the majority of patients who are chronically infected with P. aeruginosa. Inhaled tobramycin administered on an alternate month basis led to a significant improvement in lung function. Additionally, emergence of tobramycin resistance is low when employing this strategy. Similar improvement in FEV 1 was described with inhaled aztreonam. Aerosolized colistin has been used and this route minimizes the risk of systemic toxicity.
Infection with nontuberculous mycobacteria is a growing concern. Finding “atypical” mycobacteria presents a perplexing problem for the CF clinician trying to determine whether this organism is colonizing the airway or is acting as a pathogen; many of the presenting symptoms and radiographic findings can be explained by the more commonly isolated bacteria. In addition, therapy for nontuberculous mycobacteria involves prolonged treatment with multiple antibiotics, each of which has associated toxicities and variable tolerability. The recommended approach is to first treat the other organisms found on culture and closely monitor the patient’s response to this therapy. When nontuberculous mycobacteria are cultured from a patient with CF, it is recommended that routine macrolide therapy be discontinued to prevent the emergence of resistance. The long-term implication of the presence of nontuberculous mycobacteria in the CF airway is unclear.
Cystic Fibrosis Transmembrane Conductance Regulator Modulators
Treatment of CF is increasingly based on the specific CFTR defect, which is defined by the mutation class ( Fig. 51.7 ). Ivacaftor, the first US Food and Drug Administration (FDA)-approved therapy to address the basic defect in CF, is a small molecule potentiator. In patients with the G551D mutation, a class III gating mutation, it decreased sweat chloride concentrations by 48 mmol/L and improved percent predicted FEV 1 by 10.6 percentage points compared to placebo. In addition, there was a 55% decrease in pulmonary exacerbations as well as significant changes in weight gain and Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain scores. Similar improvements were documented in a subsequent trial of patients with most other class III mutations. However, when studied in patients with the R117H mutation, a class IV mutation, the results were mixed. Improvement was documented in both sweat chloride concentrations and CFQ-R scores, while FEV 1 percent predicted improved significantly only in subjects older than 18 years of age, but not in children.
