Frontiers in Research on the Respiratory System

Type and consequences

Examples of mutations

Potential therapies

1. No CFTR synthesis

G542X, W1282X, R553X, 3950delT


2. Abnormal CFTR retained in the endoplasmic reticulum and damaged





3. CFTR reaches the cell membrane but does not open correctly

G551D, 9 other known gating mutations


4. CFTR reaches the cell membrane but the channel properties are abnormal

R1117H, R334W


5. Decreased CFTR synthesis



6. Unstable CFTR in the cell membrane (rapid replacement)

N287Y, 120del23, 4326delTC, 4279insA


The most dramatic molecular success has been observed with VX-770 (ivacaftor; Kalydeco) for class 3 mutations. It was approved initially for the mutation G551D, and its approval was then broadened to include eight of another nine known class 3 mutations. A large-scale, double-blind, randomized, placebo-controlled trial was conducted in children aged over 12 years and adults with at least one G551D mutation. The study showed an improvement of absolute FEV1 of 12% with concomitant improvements in weight and quality of life associated with cystic fibrosis, as well as in the timing of the first pulmonary exacerbation. Surprisingly, the chloride level in sweat fell by close to 50% toward the doubtful diagnostic range (60–80 mEq/l). Other studies have subsequently shown similar benefits in children 6–11 years old and in children with a normal FEV1 (≥90% of the predicted value). There is currently a tendency to broaden the use of VX-770 to prevent pathological complications in very small children. Other proposed indications include the class 4 mutation R117H, the channel conductance of which decreases by 20%, with a 75% reduction in the probability of channel opening. The high cost of this medication is questionable, given the slight mutation, never mind the fact that patients effectively lose a significant level of pulmonary function in adult life. Theoretically, VX-770 can also be used to strengthen class 5 mutations and to “rescue” DF508, which has a residual gate defect.

VX-809 (lumacaftor) has been studied in class 2 mutations—in particular, DF508. These studies have shown small improvements in chloride levels in sweat, but when lumacaftor is combined with ivacaftor, the changes are less notable than those seen with VX-770, and it is improbable that VX-809, used by itself or in association with VX-770, serves to undo the dysfunction of the residual damper of “recovered” CFTR DF508 and is sufficient to provide real clinical benefit. This is because CFTR folding has multiple phases. Formation of functional CFTR requires contact between the domains and cotranslational and post-translational folding. Consequently, it is likely that more than one compound is required to correct class 2 mutations. Small-molecule therapy for DF508 is currently being developed.

Introduction to Complex Mutations

The problem of correcting class 3 mutations has been resolved easily, but a more sophisticated strategy could be required for other more complex anomalies. One model is that CFTR function can be described as an equation: CTFR function = (quantity of CFTR) × (probability of opening) × (protein conductance). Hypothetically, independently of the mutation, VX-770 can be used to improve the probability of opening and possibly conductance, while specific strategies are required to raise the quantities of CFTR in the epithelium. A new era of specific and multiple molecular manipulations has begun. The effects of VX-770 on sweat chloride are notable, although it is not clear if this finding is significant. There is only a weak correlation between sweat chloride and change in pulmonary function. We know that the sweat test provides one of the best diagnoses in medicine, but this does not mean that chloride transport is related to chronic lung disease. In fact, there are reasons to suppose that it is not.

A major challenge for the community with cystic fibrosis is control of the costs of these new molecules. VX-770 currently costs US$330,000 per patient per year. It is not clear how it has become so expensive. It is calculated that use of VX-770 raises the cost of treating cystic fibrosis in the UK by 50%, driven by the 5% of the population with this disease. If patients need to take two or more newly discovered molecules, the cost can be frightening. There are no easy answers. Without public and private investment, these medications would not have been discovered, no country anywhere in the world—whatever its political system is—has unlimited resources for health care.

The Challenge: How Can We Know It Works?

In the past, mortality was an inevitable outcome of cystic fibrosis. Subsequently, improvements in the FEV1 were accepted as a reasonable substitute for mortality, although the relationship between the FEV1 and mortality is increasingly uncertain. However, the FEV1 is currently so good and the decline curves are so flat that measurement is becoming less useful as a variable for clinical assessment. The US CF Gene Therapy Consortium has used an innovative strategy to address this problem on the basis of the observation that substitute markers improved during an intervention with demonstrated efficacy (intravenous antibiotics) for pulmonary exacerbations in 44 cystic fibrosis patients. The improvements were evidenced by symptoms, the FEV1, the LCI, HRCT (showing thickening of the airway wall, air entrapment, and large mucosal buffers) and markers of inflammation in serum (interleukin (IL)-6, C-reactive protein (CRP), and calprotectin). However, what can be considered more direct measures of airway inflammation (sputum and mucus rheology, exhalation condensate) have not changed. The study would have been more important if it had been considered ethical to recruit a control group to establish the natural variability among the events in these measurements.

The Problem: Delicate Secondary Effects Associated with Longevity

Historically, cystic fibrosis was a childhood disease, with patients rarely surviving into adulthood. Consequently, the long-term toxicity of medications did not need to be balanced against their short-term benefits. However, patients now have life expectancies of several decades, and so it is necessary to consider the question of long-term accumulation of toxicity.

Selection of Resistant Organisms

The use of antibiotics has provided major benefits for cystic fibrosis patients, but there has been a cost in terms of selecting new organisms and selecting for antibiotic resistance in organisms that are known and common in this disease. A study compared a historical cohort of 520 patients with a comparable contemporary cohort and found an increase in P. aeruginosa resistant to tobramycin, amikacin, and other drugs, and a higher percentage of isolation of methicillin-resistant Staphylococcus aureus (MRSA) , Stenotrophomonas maltophilia, and Achromobacter. It is evident that we cannot stop using antibiotics, but this information emphasizes the need for responsible antibiotic management and use.

Allergies to Antibiotics

It is inevitable that the more antibiotics are used, the more allergy to antibiotics becomes a factor. Allergy to antibiotics is common with cystic fibrosis and although desensitization is possible, it must be repeated with each application, which is time consuming and poses potential risks. This is not an argument against the use of antibiotics; rather, it is a reminder that they need to be used responsibly.

Chronic Renal Insufficiency

Chronic renal insufficiency (CRI) has been well described and is usually the consequence of treatment with aminoglycosides indicated at the same time as other nephrotoxic drugs—in particular, nonsteroidal anti-inflammatory drugs—and dehydration owing to excessive sweating or gastroenteritis. Nevertheless, CRI is a growing problem. The cause is controversial. One study has pointed to the glomerular filtration rate (GFR) with respect to the number of intravenous antibiotic treatments received (in some cases, >100). Another study identified nebulized aminoglycosides, and a third study found that the GFR is higher in persons who require insulin. Whatever the explanation is, it is clear that a medication that is administered for many decades needs to be carefully monitored.

Cystic fibrosis has set the pattern in this changing paradigm, but other diseases will certainly follow. For example, it is probable that primary ciliary dyskinesia (PCD) is on the cusp of similar advances, considering the rapid expansion of knowledge of multiple genetic mutations that cause diseases and their consequences, for example, such as nonsense mutations that can be sensitive to PTC124. It is clear that we need to expand our therapeutic horizons in the coming years. The challenge is to overlook therapies without losing the benefits of the aggressive regimens that have accomplished so much to improve the prognosis of cystic fibrosis in the past. There is a real danger of complacency; in the case of children who have been diagnosed but have never been sick, it can be difficult to get them to adhere to treatment, which could be especially important if unexpected complications emerge. We need to maintain clarity between the double risk of imposing a large therapeutic load on persons who are asymptomatic but have this disease and thinking that the problem of cystic fibrosis is resolved.

Chronic Lung Disease Crises or Attacks: Lessons for a Long-Term Response

“Exacerbation” is a not-very-convincing term that describes acute deterioration in the symptoms of a chronic lung disease. The definition is often circular: “I know this is an exacerbation because I have received treatment (prednisone for asthma, intravenous antibiotics for cystic fibrosis), and I have received this treatment because it is an exacerbation.” The term “exacerbation” implies something relatively benign—a minor inconvenience that is completely reversible. The purpose of the following section is to suggest that this is an error and that the term “pulmonary attack” is preferable. A pulmonary attack is an emergency that could lead to irreparable harm and must therefore be addressed, necessitating a response focused on determination of the cause and measures to prevent it from occurring again.

Pulmonary Attacks in Cystic Fibrosis

These are common (so-called pulmonary exacerbations—a term that will not be employed here) and have been used increasingly in randomized, controlled therapeutic trials. In fact, in a study of airway clearance in cystic fibrosis, positive pressure techniques were superior to external oscillation of the thoracic wall in decreasing pulmonary attacks, but there was no change in spirometry findings. Pulmonary attacks in the context of cystic fibrosis are far from benign.

Several studies have concluded that these patients cannot recover a basal spirometry level after completing adequate treatment in response to a pulmonary attack. Another study showed that at 3 months after treatment, 24 of 104 cystic fibrosis patients (23.1%) had not recovered even 95% of their maximum FEV1 from 6 months earlier. Pulmonary attacks in cystic fibrosis are associated with a more rapid rate of FEV1 reduction. A study of 8490 patients from the Cystic Fibrosis Foundation Patient Registry reported that 60% had no exacerbations, 23% had one per year, 10% had two per year, and 7% had at least three per year. Even one exacerbation per year in children is associated with accelerated rates of FEV1 decline, while in adults, accelerated decline is observed only in those with at least three exacerbations per year.

Pulmonary attacks with cystic fibrosis are associated with a higher rate of mortality. In a three-year prospective cohort study involving 446 adult patients, 140 subjects had one exacerbation per year at most, 160 had one or two exacerbations per year, and 146 had more than two exacerbations per year. In this work, the exacerbations were defined as an indication for oral or intravenous antibiotics. There was a higher probability of more frequent exacerbations in women, individuals with low pulmonary function, and diabetics. Individuals with more than two exacerbations per year had a higher probability of having a reduction of more than 5% per year in the FEV1 and a higher probability of death or of receiving a transplant.

Not surprisingly, those with a high risk of not achieving a complete recovery had a more pronounced decline in the FEV1, with respect to the baseline value, during the exacerbation, which provides more evidence of inflammation (a higher CRP level at the time of hospitalization and a higher white blood cell count at the end of treatment). However, the absence of these risk factors should not be considered satisfactory. Given the evidence above, are we making optimal use of conventional treatments? For example, would use of more antibiotics be more helpful than intensive use of anti-inflammatories? In terms of the duration of treatment with antibiotics, there is no evidence to guide the doctor. However, in a study that was an extension of work on antibiotics, which analyzed the evolution of spirometry in 95 cystic fibrosis patients who had received antibiotics intravenously for at least 4 days (mean 12.6 days, median 13, standard deviation 3.2), the average time to reach the maximum FEV1 was 8.7 days and, in practice, everyone reached a FEV1 peak within 13 days of treatment. These data indicate that 2 weeks of treatment with intravenous antibiotics does not result in an improved response to pulmonary attacks in cystic fibrosis.

There have been several studies on the use of anti-inflammatory medication for short-term treatment of pulmonary attacks in cystic fibrosis. Studies of steroids (prednisolone 2 mg/kg up to a maximum of 60 mg for 5 days and methylprednisolone in pulses) indicate that the benefits do not exceed the potential secondary effects. An initial trial of DNase (which has certain putative anti-inflammatory effects) showed no benefits of application during exacerbation.

There is a tacit supposition that pulmonary attacks in cystic fibrosis involve a general change rather than a focused change. This notion has been challenged by a recent report featuring fluorodeoxyglucose–positron emission tomography (FDG-PET), which detected inflammation and infection, and HRCT in 20 cystic fibrosis patients 14–54 years of age. FDG-PET showed active focal spots, which were more pronounced during pulmonary attacks in cystic fibrosis and, in contrast to the HRCT findings, the changes were sensitive to intravenous antibiotics, at least in this study. We may need biomarkers of local signals of the disease. Unfortunately, the level of exposure to radiation with the current technique is prohibitively high.

Pulmonary Attacks in Asthma

There is less evidence of long-term effects of pulmonary attacks in children with asthma. Asthma attacks are significant causes of morbidity and a reduction in the quality of life. Observational studies suggest that exacerbations are associated at some level with a more rapid decline in spirometry readings, but it is not clear if this is related to low adherence associated with exacerbations independent of the accelerated decline in lung function, due possibly to nonuse of medications. In an original study based on a controlled trial, 7165 adults and children with asthma were randomly assigned to receive either a low dose of budesonide or a placebo by inhalation. Despite the large size of the study, only a minority of patients experienced exacerbations (190 in the placebo group and 115 in the budesonide group). There was an accelerated decline in spirometry values among both children and adults who were taking the placebo and experienced an exacerbation, but not in the group that received budesonide (−2.43% in placebo recipients without exacerbations versus −6.44% in placebo recipients with exacerbations, p < 0.001; and −1.72% in budesonide recipients without exacerbations versus −2.48% in budesonide recipients with exacerbations, p value not significant). This study did not establish whether the exacerbations caused the decline in spirometry values or whether the accelerated decline and the exacerbations were part of an underlying phenotype, but subsequent analysis of the data suggested that budesonide lessened the effects of the exacerbations. Inhaled steroids can have more long-term benefits than has been thought.

It is important to understand that pulmonary attacks in asthma and control of asthma at the basal level should not be treated in a similar manner, even though they can coexist in the same subject; in fact, poor control of asthma is an important risk factor for the development of acute attacks. The new antibiotics appear to be good, particularly for reducing acute infectious attacks, but they have a much smaller effect on basal control of asthma. This might be surprising, considering that acute attacks are almost invariably due to viral infection. Although there are certainly interactions between viral infection and inflammation of the airway by eosinophils, controlling basal eosinophilic inflammation reduces exacerbations, as can be clearly seen with the use of omalizumab to prevent seasonal outbreaks of acute asthma among children returning to school.

Like a heart attack, a pulmonary attack requires a focused response and a detailed assessment to prevent a reoccurrence. Protocols have been recommended for asthma and cystic fibrosis. The general theme in the context of asthma has been To achieve what it is suggested by the guidelines. We use a detailed protocol with a nursing guide indicating that in at least half of the patients with severe asthma, we need to consider adherence to medication (including use of the appropriate drug and correct use of the device employed), the environment (allergens and exposure to cigarette smoke), and educational as well as psychological problems. We need to understand that pulmonary attacks are not benign, and we also need to focus on other diseases (PCD and bronchiectasis) and work to prevent their recurrence. An important scientific focus is the mechanisms of pulmonary attacks in the different diseases and factors for prediction and optimal management.

Genetically Associated Diseases and Their Close Systemic Relationship: Ciliopathy

Until now, ciliary bronchopulmonary disease has been limited to PCD. It is now clear that aspects of ciliary function extend to the systems of practically all organs, and pediatric bronchopulmonary specialists need to be familiar with these manifestations. There are three types of cilia (Table 7.2): primary (which, disconcertingly, are not really abnormal in PCD), nodal, and mobile. The cilium structure is very complex, with at least 1000 polypeptides. The process of elaboration and assembly is also complex and involves multiple stages coded by genes that do not by themselves have a role in ciliary structure. Functional genomic detection using RNA interference recently found 36 positive cilium assembly modulators and 13 negative ones. Consequently, the genetics of ciliopathy is clearly complex, which should be registered during assessment of diagnostic paths in PCD. It can be argued that there is at least one additional level of complexity. The cilia function not in isolation but, rather, in a complex extracellular environment of periciliary mucus and fluid. At least in theory, a PCD phenotype should be produced, even if the cilia are completely normal in cases where the genes that regulate the extraciliary environment mutate.

Table 7.2

Different types of cilia




They have a 9+0 axoneme structure (generally with no pair of central microtubule singlets)

There is a primary cilium in every tubular epithelial cell and in many others

They participate in numerous chemosensory and mechanosensory functions, linking with key metabolic pathways such as Hippo, Sonic Hedgehog, canonical and noncanonical wnt, pdgf, and mtor

The structure varies along the axoneme (they may have regions with central singles)

They play an important role in reabsorption of water in the kidney


They are structurally of the primary type and are the only known primary mobile cilia


They have the classic 9+2 axoneme structure (9 outer doublets, 2 central microtubule singlets)

They move mucus along epithelial surfaces or drive unicellular organisms through liquids

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Nov 7, 2020 | Posted by in Uncategorized | Comments Off on Frontiers in Research on the Respiratory System
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