Download Pulmonary Disease BoarD review manual management of

Pulmonary Disease Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Pulmonary Disease Board
Review Manual is a peer-reviewed study guide
for fellows and practicing physicians preparing
for board examinations in pulmonary disease.
Each manual reviews a topic essential to current
practice in the subspecialty of pulmonary disease.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
Senior EDITOR
Robert Litchkofski
Management of Pulmonary
Exacerbations and
Complications in Adults
with Cystic Fibrosis
Contributors:
Rolando Sanchez, MD
Senior Fellow in Pulmonary and Critical Care Medicine,
Medical University of South Carolina, Charleston, SC
Antine E. Stenbit, MD, PhD
Assistant Professor of Medicine, Division of Pulmonary
and Critical Care Medicine, Medical University of South
Carolina, Charleston, SC
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Table of Contents
NOTE FROM THE PUBLISHER:
This publication has been developed without involvement of or review by the Amer­
ican Board of Internal Medicine.
www.turner-white.com
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Pathophysiology of Exacerbation. . . . . . . . . . . . . 3
Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Other Pulmonary Complications. . . . . . . . . . . . . 9
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Board Review Questions. . . . . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Pulmonary Disease Volume 14, Part 6 1
Pulmonary Exacerbations and Complications in Cystic Fibrosis
Pulmonary Disease Board Review Manual
Management of Pulmonary Exacerbations and
Complications in Adults with Cystic Fibrosis
Rolando Sanchez, MD, and Antine E. Stenbit, MD, PhD
Introduction
Cystic fibrosis (CF) is the most common lifeshortening autosomal recessive disease among
Caucasian populations, with an incidence of 1 in
2000 to 3000 live births and a median survival of
36.8 years (95% confidence interval [CI], 34.7–40.3)
in the United States, according to the Cystic Fibrosis
Foundation 2011 Registry Report.1 Lung disease
remains the most common cause of morbidity and
mortality in CF patients, resulting from the progressive loss of lung function due to chronic infection
and recurrent exacerbations. Therefore, prevention
and appropriate treatment of pulmonary exacerbations are mainstays in the management of patients
with CF to prevent morbidity and mortality.2–6
BACKGROUND
Definition of Exacerbation
Although pulmonary exacerbation is a common
complication in CF patients, a standard definition
of what an exacerbation entails has not been established within the CF community. There is significant variation in the diagnosis and management of
exacerbations between CF centers in the United
States, and even between physicians from the
same center. Furthermore, a single physician can
demonstrate significant inconsistency in treatment
strategies and diagnosis over time.7,8 The European Consensus Group for Cystic Fibrosis defines
CF exacerbation as the need to provide additional
antibiotic therapy due to a recent change in at
least 2 of the following clinical parameters: change
in sputum volume or color; increased cough; increased dyspnea; increased malaise, fatigue, or
lethargy; anorexia or weight loss; decrease in pulmonary function by at least 10% or radiographic
changes.9 This definition is well accepted and is
often used in clinical trials. However, it fails to address the degree of symptom severity, which may
influence the patient’s perceptions of the event and
the type of prescribed therapy as well as the duration and route of administration of therapy.6,10,11
A continually growing area of interest and research in CF is the use of biomarkers of inflammaton to define and monitor CF exacerbations. A great
variety of biomarkers in the serum, sputum, urine,
and breath condensate have been described, but
their routine clinical use is still limited.6,8,12–17
Copyright 2014, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying,
recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White
Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content.
The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of
Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors
of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment.
2 Hospital Physician Board Review Manual
www.turner-white.com
Pulmonary Exacerbations and Complications in Cystic Fibrosis
Impact of exacerbations
Pulmonary exacerbations are associated with
decreased survival, lung function deterioration,
impaired quality of life (poor sleep, missed work/
school, family dislocation, impaired neurobehavioral functioning), and increased health care cost.8,18–26
A recent study suggested that 50% of lung function decline in CF patients can be attributed to
pulmonary exacerbations.27 Moreover, up to 25%
of patients with CF exacerbation do not recover
their lung function to baseline levels after 3 months
of therapy.25–28
While the frequency of exacerbations contributes directly to declining lung function, it may also
be an indicator of an underlying CF genotype and
immune dysregulation that predispose patients to
persistent infection, lung inflammation, and more
rapid decline in lung function compared to other
patients. This has been suggested by studies
showing that in some patients lung function continues to deteriorate even after the pathogen causing
the exacerbation has been eradicated.29 Studies
looking at the characteristics of Pseudomonas
aeruginosa isolates failed to show any difference
between the isolates from patients who were successfully treated with eradication therapy versus
those in whom eradication therapy failed. This suggests that the interaction between host immune
response and the pathogen may play a major role
in the propensity of some CF patients for persistent
and recurrent infections.30
Pathophysiology of exacerbation
The pathogenesis of CF exacerbation has not
been completely elucidated. A widely accepted theory hypothesized that exacerbations are
caused by the clonal expansion of a single dominant pathogen causing an increase in the load or
www.turner-white.com
change in the phenotype of the bacteria colonizing
the airways.31–35 This theory has been questioned
by recent studies showing discordance between
the microbiological susceptibility and the clinical
and bacteriological response to antibiotic therapy
in CF patients with exacerbations.36,37 Furthermore,
there is no significant change in the bacterial load
in the sputum prior to and during an exacerbation
in some CF patients.37,38 The polymicrobial nature of the airways of patients with CF as well as
dynamic interactions within the airways suggests
a more complex model is needed to explain the
mechanism behind the CF exacerbation.39 The
bacterial community colonizing the CF airways, or
microbiome, is unique to each patient and can vary
spatially and temporally.40–42 A misbalance in the
airway microbiome has been hypothesized recently to play a major role in the pathogenesis of CF
exacerbations and worsening of the disease.6,8,43–45
However, the relationship between microbiome diversity and lung function is still poorly understood
and currently an active area of investigation.
There is growing evidence of dynamic synergy
between different pathogens (virus, bacteria, fungi)
of the CF airways microbiome. The interaction
between these pathogens is influenced by the CF
genotype, patient immunity, and environmental
factors. Animal models have shown that when
bacteria not pathogenic by themselves (commensal microbiota) are cultured in the presence
of Pseudomonas aeruginosa, they act synergistically by increasing inflammation and worsening
disease severity without a change in the bacterial
load of the pathogenic species.46,47 In addition, the
majority of pathogens present in the CF airway
microbiome are not readily cultured by standard
techniques,43,48 suggesting that we usually underestimate the co-colonization of other important
bacteria species.43 These findings would explain
Pulmonary Disease Volume 14, Part 6 3
Pulmonary Exacerbations and Complications in Cystic Fibrosis
why some CF patients improve with antibiotics in
spite of the presence of resistant pathogens in the
sputum. Perhaps in these patients the antibiotics
exert their action by eradicating unrecognized synergistic bacteria of the microbiome.49,50
MANAGEMENT
PREVENTION OF EXACERBATION
Antibiotic Therapy
The initial Pseudomonas aeruginosa colonization/infection of the airways of CF patients eventually results in persistent chronic colonization and
infection, which is associated with significant increased risk of exacerbations, more severe lung inflammation, and lung function decline.2,51 Antibiotic
eradication therapy (AET) and suppression therapy
with inhaled antibiotics are relatively new interventions that have become the standard of care in
the management of the CF patients.2,52 Evidence
suggests that both AET and suppression therapy
decrease the risk of CF exacerbations and delay
the decline of lung function.29,53–57 AET consists
of treating CF patients with antibiotics for approximately 28 days as soon as they become colonized
with Pseudomonas aeruginosa in the hope of complete eradication. Several antibiotic regimens have
been studied, including inhaled, oral, and intravenous therapy, with similar efficacy (average rate of
success of 81.2%).2,58–62 The success rate of AET
may decrease if the Pseudomonas aeruginosa infection is left untreated for more than 12 weeks.63,64
Once AET fails and chronic Pseudomonas aeruginosa infection develops, the risk for pulmonary
exacerbations increases and the strategy shifts to
suppressive therapies. For those patients in whom
AET fails and who develop chronic Pseudomonas
aeruginosa infection, the CF pulmonary guidelines
recommend chronic suppressive antibiotic therapy
4 Hospital Physician Board Review Manual
with inhaled tobramycin or aztreonam (both with
formulations that are approved by the US Food and
Drug Administration and have more evidence supporting their use).2,52,55–57,65–67 The best schedule
for administering this therapy remains unclear: one
month-on one month-off schedule versus continuous therapy with one drug or alternating agents.
Chronic therapy with azithromycin in CF patients
aged 6 years and older with chronic Pseudomonas
aeruginosa infection has been shown to be associated with a 50% decrease in the rate of exacerbations.68,69 Due to concerns about an increased rate
of nontuberculous mycobacteria (NTM) infection
resistance, it is recommended that patients should
be screened for NTM before initiating azithromycin
therapy, and reassessed at 6- to 12-month intervals. In addition, this monotherapy should be withheld in those infected with NTM.52
Airway Clearance
Airway clearance is an integral component of
the long-term management of CF patients with or
without chronic Pseudomonas aeruginosa infection
to improve lung function and prevent exacerbations.
A variety of pharmacologic and nonpharmacologic
methods are available for airway clearance. The
CF pulmonary guidelines recommend the longterm use of dornase alfa and inhaled hypertonic
saline to improve lung function, improve the quality
of life, and reduce exacerbations in CF patients.52
Among the nonpharmacologic methods for promoting airway clearance, some require mechanical
devices, while others utilize physical manipulation
of the chest (eg, physiotherapy). Conventional chest
physiotherapy through the assistance of a caregiver
is the current standard of care for achieving airway
clearance, particularly in young patients. As patients
with CF live longer, there is a need for patients to
be able to perform airway clearance independently.
www.turner-white.com
Pulmonary Exacerbations and Complications in Cystic Fibrosis
There are at least 3 classes of independent airway
clearance devices: positive expiratory pressure devices, airway oscillating devices (either handheld or
stationary), and high-frequency chest compression/
mechanical percussion devices. Until recently, there
was insufficient evidence to suggest superiority between any of the airway clearance techniques.70–73
However, a recent prospective multicenter randomized controlled study in Canada showed that positive expiratory pressure may prevent more exacerbations than high-frequency chest wall oscillation
via a vest in CF patients ages 6 years and older.74
Exercise
Exercise has become an important component in
the chronic management of CF patients. Exercise
intolerance is well established in this population. It is
mainly related to impaired lung function (especially
those with severe disease)75–78 as well as poor nutritional status and low muscle mass,75–79 although
other factors such as muscle dysfunction,80–83 CF
genotype,84 and physical activity (which is influenced
by a variety of psychosocial factors, such as gender
and parental involvement)85–90 may also influence
exercise capacity in CF patients. Exercise intolerance is dependent on the progression of the disease
and may have a significant role as a prognostic indicator of lung function decline, quality of life, and survival in CF patients.91,92 Exercise training programs
may be a useful therapeutic strategy to improve not
only physical fitness and exercise capacity in CF
patients,93 but also to improve airway clearance,94–96
quality of life,97,98 and lung function preservation93,97,98
and decrease the rate of hospitalization.98 Exercise
training is thought to have a positive impact on nonpulmonary complications from CF, such as bone
mineral density99,100 and CF-related diabetes.101
Despite the evidence suggesting that exercise
may be beneficial in CF patients, there are no studwww.turner-white.com
ies showing that exercise training prolongs survival
in this population. There is also no consensus about
the best exercise training modality: aerobic versus
anaerobic or a combination thereof. Unfortunately,
there have not been any successful strategies to increase participation of CF patients in exercise training and maintain their adherence to it (the adherence rate of CF patients to exercise training ranges
between 24% and 57%).91,92 The recommendations
for exercise training in CF patients at this time are
based on extrapolations from small studies as well
as an understanding of the physiological mechanism
of exercise and clinical reasoning.91,92 The incorporation of exercising training as part of the chronic
management of CF patients should be individualized and take into consideration the patient’s age,
physical fitness, nutritional status, disease severity,
and potential barriers to adherence such as burden
of therapy, lack of information about the benefits of
exercise, and lack of parental involvement.
Treatment of exacerbation
The management of CF exacerbations should
include the participation of the CF multidisciplinary
team including physicians, nurses, respiratory therapists, social workers, pharmacists, and dietitians.
In addition to appropriate antibiotic therapy, the
therapeutic strategy should focus on airway clearance, nutrition support, drug monitoring, physical
therapy, and detection and management of other
complications such as CF-related diabetes.
The Cystic Fibrosis Foundation recommends
that CF patients receiving chronic treatment with
dornase alfa and hypertonic saline, macrolide
therapy, and bronchodilators should continue and
intensify these therapies during the course of an
exacerbation.6,10 With regard to the chronic inhaled
antibiotic therapy, there is no evidence that continuing inhaled antibiotics in addition to systemic
Pulmonary Disease Volume 14, Part 6 5
Pulmonary Exacerbations and Complications in Cystic Fibrosis
antibiotic therapy offers any benefit during CF exacerbations.102 Despite the lack of evidence, physicians usually prescribe and continue inhaled antibiotics in up to 25% of CF exacerbations, often to
maintain the therapeutic routine for the patient.2,103
Nevertheless, caution must be taken with this
strategy since some inhaled antibiotics can be absorbed systemically, leading to an increase in the
levels of the systemically administered drugs. This
increase in drug levels can result in an increased
risk of drug toxicity and affects the interpretation of
the serum drug monitoring levels. This is particularly relevant with aminoglycosides, as described
by Stenbit and colleagues,104 where up to 45% of
trough tobramycin concentrations were significantly influenced by the timing of administration of the
inhaled dose, leading to either the under dosing of
the systemically administered drug or changing the
administration interval.
Setting: Inpatient or Outpatient?
Once the diagnosis of CF exacerbation is established, the next step in the management of
these patients is to select the setting in which the
treatment will be administered. Studies addressing
clinical and quality of life outcomes based on the
setting of treatment have shown conflicting results,
with some favoring in-hospital therapy versus
home therapy,105–109 while others showed no difference between settings.110 The decision should be
individualized, and it should take into consideration
the severity of the exacerbation, the need for intravenous therapy, the patient’s adherence, need for
drug monitoring and diabetes control, as well as
the social and logistical support of the patient at
home. The Cystic Fibrosis Foundation guidelines
recommend against the nonhospital setting unless
the resources and support at home are equivalent
to those in the hospital setting.6,10
6 Hospital Physician Board Review Manual
Route of Antibiotics: Inhaled versus Systemic
(Oral and Intravenous)
During an exacerbation, there is increased inflammation along with increased vascular permeability
and production of mucus plugs, often causing obstruction of the small airways. Because of this airway
obstruction, inhaled antibiotic therapy would only be
delivered to the large airways without reaching the
distal portions of the bronchial tree. Based on this
rationale, systemic administration (either oral or parenteral) is preferred. The use of inhaled antibiotics
as adjuvant to systemic therapy is still controversial
since it has not been shown to improve outcomes.102
Oral therapy for CF exacerbations can avoid hospitalization and cost less than intravenous therapy,
and may cause less impairment of the patient’s
quality of life. Some studies suggest that CF patients with mild exacerbations caused by methicillinresistant Staphylococcus aureus (MRSA),111–113
Pseudomonas,114,115 and other bacteria like Haemophilus influenzae116–119 can be successfully treated with oral regimens, avoiding the need for intravenous antibiotics in up to 73.8% of patients.120
However, the evidence supporting the use of oral
antibiotics in mild CF exacerbations is still scarce.121
Unfortunately, the difference between mild and
severe exacerbation has yet to be clearly defined.
Thus, the decision to use oral antibiotics should be
individualized on a case-by-case basis and take into
consideration the severity of the exacerbation, the
underlying lung function, microbiological susceptibility patterns, nutritional status and oral tolerance,
patient’s adherence, and the logistical support at
home to provide the other essential components
of the CF exacerbation management (eg, airways
clearance, diabetes control).6 If symptoms worsen
or new symptoms develop while undergoing oral
therapy, intravenous antibiotic administration should
be promptly considered.
www.turner-white.com
Pulmonary Exacerbations and Complications in Cystic Fibrosis
Choice of Antibiotic: Microbiology and Role of
Antibiotic Susceptibility Testing
For many years a group of bacteria including
Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenza, Burkholderia species
like B. cenocepacia, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans were thought
to be the main etiologic pathogens causing CF
exacerbations. As our understanding of the pathogenesis of CF exacerbation and airway microbiome continues to improve, we have learned that
CF exacerbations can also be caused by other
pathogens such as virus (eg, influenza A and
B, rhinovirus, respiratory syncytial virus), NTM,
fungus (mainly Aspergillus), and bacteria other
than the organisms described above, including
the normal oral flora. Also, rather than one predominant pathogen causing the exacerbation, it
seems that the complex interaction between the
host immunity, environmental factors, and multiple
organisms acting synergistically cause a misbalance of the CF airway microbiome, resulting in a CF
exacerbation.43
Traditionally, the selection of antibiotic therapy
for CF exacerbations was based on the results of
antibiotic susceptibility testing from the CF airway
microbiome. However, there are 2 caveats to this
approach. First, several studies have shown poor
correlation between in vitro susceptibility data and
clinical outcome after systemic antibiotic therapy
for CF exacerbation.122,123 Parkins and colleagues
described a rate of success of 57% in treating CF
exacerbations, even when the Pseudomonas aeruginosa from the airway cultures were resistant
to the antibiotic administered.124 Second, most of
the standard culture methods utilized in hospitals are unable to cultivate a significant number
of pathogens present in the CF airway microbiome.43,48 These findings have challenged the
www.turner-white.com
previous practice of selecting antibiotics based on
the results from in vitro microbiological susceptibility. The Cystic Fibrosis Foundation guidelines
recommend selecting antibiotics based on previously successful response to antibiotics during
CF exacerbations. It is still reasonable to perform an airway culture to select the spectrum of
bacteria to be covered. Microbiological antibiotic
susceptibility testing is still advised when patients
fail to improve while on antibiotic therapy and a
change in the antibiotic regimen is required.6,10
For the treatment of P. aeruginosa, the Cystic Fibrosis Foundation guidelines recommend double
therapy, since there is not sufficient evidence
showing that monotherapy is equivalent to dual
therapy for this pathogen. If aminoglycosides are
chosen, once-daily dosing is preferable to 3-times
daily dosing.10 In general, the first line of treatment
is a beta-lactam antibiotic in addition to an aminoglycoside. Often when this combination is no
longer effective a carbapenem can be substituted
for the beta-lactam, or alternatively an extendedspectrum penicillin such as piperacillin/tazobactam
can be used.
The Cystic Fibrosis Foundation guidelines recommend against synergy testing as part of the routine evaluation of patients with CF exacerbation.10
Duration of Antibiotic Therapy
There are no clear guidelines on the optimum
duration of antibiotic therapy for CF exacerbations.
The average duration of therapy in CF exacerbation is 10 to 14 days. Although shorter duration of
therapy would improve quality of life and compliance as well as reduce the incidence of side effects
and the cost, it may also be insufficient to clear the
infection and may cause early recurrences.125 The
CF pulmonary guidelines recommend that the duration of therapy should be decided based on cliniPulmonary Disease Volume 14, Part 6 7
Pulmonary Exacerbations and Complications in Cystic Fibrosis
cal response rather than microbiology data. Ideally,
therapy should be continued until patients achieve
resolution of symptoms and restoration of lung
function, but therapy should not exceed 3 weeks.2,10
Collaco and colleagues demonstrated that the improvement of forced expiratory volume in 1 second
(FEV1) in patients with CF exacerbations usually
plateaus after 6 to 10 days of therapy,110 although
often patients, their parents, and treating physicians feel that a third week of therapy would be
beneficial.126
Approximately 25% of patients do not improve in
spite of adequate antibiotic therapy. In these cases,
multidrug-resistant Pseudomonas and MRSA,112
NTM, and allergic bronchopulmonary aspergillosis
should be suspected and aggressively treated if
confirmed. These patients usually need longer
periods of antibiotic therapy. Other factors associated with treatment failure include very advance
airway disease, the use of enteric feed, presence
of CF-related diabetes and liver disease, low socioeconomic status, and elevated markers of inflammation.120,124
Nutrition and Glucose Control
CF patients with a pulmonary exacerbation
have an increase in energy expenditure and consequently increased nutritional need.127 The lack
of appetite due to worsening dyspnea and other
symptoms like nausea, vomiting, and abdominal
discomfort can further complicate the ability of
patients to meet their nutritional requirements. In
addition, patients with CF-related diabetes have
an increase in insulin demand during an exacerbation,128 and even those with normoglycemia
showed impaired glucose tolerance during exacerbations.129 Nutritional support and good blood
glucose management are essential components in
the treatment of a CF exacerbation.
8 Hospital Physician Board Review Manual
Oxygen Therapy and Noninvasive Ventilation
There are no well-designed studies to guide the
prescription of chronic oxygen supplementation
in CF patients with advanced lung disease. According to a recent systematic review, short-term
oxygen therapy during sleep and exercise improve
oxygenation, although it may be associated with
mild hypercapnia. Short-term oxygen improves
exercise duration, time to fall asleep, and regular
attendance at school or work. However, it remains
unclear what the best schedule for oxygen supplementation therapy is: continuous versus during
exercise or sleep or both.130
Another modality that is used in advanced lung
disease is noninvasive ventilation. The impact of
noninvasive ventilation on pulmonary exacerbations and disease progression has not been clearly
defined. Noninvasive ventilation may be a useful
adjunct to other airway clearance techniques, particularly in CF patients who have difficulty expectorating sputum. When used in addition to oxygen,
noninvasive ventilation may improve gas exchange
during sleep to a greater extent than oxygen therapy alone in CF patients with moderate to severe
disease.131
Exercise and Physical Therapy
Even though exercise has become an essential
component of the chronic management of CF patients, little is known about exercise as part of the
therapy in acute exacerbations. In a randomized
controlled study involving children admitted to the
hospital due to a pulmonary exacerbation, children
who underwent in-hospital aerobic and anaerobic
exercise training had significantly better aerobic
capacity, activity levels, quality of life, weight gain,
lung function, and muscle strength than children in
the placebo control group at the time of discharge
and for at least 1 month after discharge.132 Physiwww.turner-white.com
Pulmonary Exacerbations and Complications in Cystic Fibrosis
cians should be aware that CF patients have much
higher energy expenditure and nutritional requirement at rest and during exercise compared to
normal patients. Moreover, due to the high sodium
and chloride concentration in the sweat and abnormal thirst stimulus, CF patients are more prone to
dehydration during exercise and heat stress. Thus,
adequate nutrition and fluid electrolyte replacement should be guaranteed for CF patients undergoing exercise training programs, especially during
acute exacerbations.
Other pulmonary complications
Pneumothorax
Spontaneous pneumothorax is a pulmonary
complication in the CF population, with up to 3.4%
of CF patients experiencing an episode of spontaneous pneumothorax during their lifetime. The incidence of spontaneous pneumothorax increases as
lung function declines, with 75% of events occurring in patients with FEV1 less than 40% predicted.133 After an episode of pneumothorax, the risk
of a subsequent unilateral and contralateral pneumothorax is approximately 50% to 90% and 46%,
respectively. Given the correlation of spontaneous
pneumothorax with poor lung function, it is not surprising that 72.4% of spontaneous pneumothorax
cases occur in adult patients. The occurrence of
spontaneous pneumothorax remains a prognostic
factor of poor outcome, with a 2-year mortality rate
of 48.6%.133
The most likely mechanism underlying the pathogenesis of spontaneous pneumothorax appears to
be air trapping within alveoli due to mucus plugging in the airways. When the alveolar pressure
exceeds the interstitial pressure, air moves into the
interstitium, traveling to the hilum (pneumomediastinum), and eventually rupturing into the mediastinal
www.turner-white.com
pleura.133 Spontaneous pneumothorax arising from
the rupture of blebs in the visceral pleural are a less
common mechanism of pneumothorax, evidenced
by the poor correlation between blebs or cysts and
the incidence of spontaneous pneumothorax in CF
patients.134
In addition to poor lung function, other factors
associated with an increased risk of the development of a spontaneous pneumothorax are airway
infection by Pseudomonas (odds ratio [OR], 2.27;
95% CI, 2.07–2.49) and Burkholderia (OR, 1.78;
95% CI, 1.52–2.10); allergic bronchopulmonary aspergillosis (OR, 1.48; 95% CI, 1.20–1.81); chronic
therapy with dornase alfa (OR, 2.05; 95% CI,
1.48–2.85) and inhaled tobramycin (OR, 1.60; 95%
CI, 1.20–2.14); pancreatic insufficiency (OR, 1.39;
95% CI, 1.17–1.65); and tube feeds (OR, 1.68; 95%
CI, 1.49–1.90).133
The clinical presentation and diagnosis of spontaneous pneumothorax are similar in CF patients and in non-CF patients. However, physicians
should be aware that in some CF patients the chest
radiograph fails to provide the diagnosis of spontaneous pneumothorax because of the presence
of pleural adhesions, which prevents collapse
of the lung. In these cases, chest computed tomography will demonstrate a loculated pneumothorax.133
In 2010, the Cystic Fibrosis Foundation published
guidelines for the management of CF patients with
spontaneous pneumothorax.135 It is recommended
that patients with a small pneumothorax (<5 cm)
and without significant clinical compromise can
be managed by outpatient observation or small
catheter aspiration. Therapy with dornase alfa and
inhaled tobramycin, as well as airway clearance
techniques, should not be discontinued, with the
exception of positive pressure ventilation and intrapulmonary percussive ventilation. CF patients with
Pulmonary Disease Volume 14, Part 6 9
Pulmonary Exacerbations and Complications in Cystic Fibrosis
a large pneumothorax (>5 cm) or significant clinical
compromise should be hospitalized and managed
with chest tube placement. The guidelines do not
recommend withholding dornase alfa and inhaled
tobramycin in these patients, but recommend discontinuing airway clearance therapy. Pleurodesis
should be reserved for patients who fail to improve with chest tube placement (around 37%) or
those with recurrent large pneumothorax. Surgical
pleurodesis is preferred over chemical medical, unless the patient is unable to tolerate surgery.
Hemoptysis
The expectoration of blood is a common pulmonary complication in CF patients. Most patients
will have a scant (<5 mL) or mild episode (≥5 mL),
but up to 4.1% of CF patients will have an episode
of massive hemoptysis (≥500 mL of expectorated
blood over a 24-hour period or bleeding at a rate
≥100 mL/hour) during their lifetime.6 The 2010 Cystic
Fibrosis Foundation guidelines also included recommendations for the management of CF patients
with hemoptysis.135 The guidelines recommend
that CF patients should contact their health care
provider even with scant episodes of hemoptysis.
Those with massive hemoptysis should always
be hospitalized as this complication could be
life-threatening. Because hemoptysis should be
considered a result of infection and a manifestation of pulmonary exacerbation, the guidelines
recommend that CF patients with at least mild hemoptysis should receive antibiotics. For episodes
of scant hemoptysis, there is no consensus about
the need to start antibiotic therapy.
Because of the concern that airway clearance
therapy can impair the ability to stabilize clot formation, the guidelines recommend withholding these
techniques during massive hemoptysis. They can
be continued in patients with scant hemoptysis,
10 Hospital Physician Board Review Manual
however. For those with mild hemoptysis, there
is no consensus for an official recommendation.
The guideline recommends withholding the use of
hypertonic saline in cases of massive hemoptysis.
There was no consensus to make an official recommendation in relation to the therapy with dornase alfa and inhaled antibiotics in these patients,
nor about the need to withhold inhaled therapy in
patients with mild to moderate hemoptysis. For
those with scant hemoptysis, the guideline recommends continuing inhaled therapy.
While most episodes of hemoptysis in CF patients will stop spontaneously, some patients will
have persistent bleeding. These patients should
be evaluated for bronchial artery embolization
therapy. Bronchoscopy is not mandatory prior to
this therapy.
Conclusion
Pulmonary exacerbations are common events
during the course of CF, and they are associated
with progressive lung function decline, poor nutritional status, impaired quality of life, and increased
health care cost. However, there is a lack of consensus in how to define a CF exacerbation and
determine its severity. The pathogenesis of CF
exacerbation is also still poorly understood. The
management of CF exacerbations should include
the participation of the CF multidisciplinary team.
The therapeutic strategy should take into consideration the severity of the exacerbation, the need
for intravenous therapy, patient’s adherence, drug
monitoring, diabetes control, as well as the social
and logistical support of patients at home. Specific
recommendations have been published by the Cystic Fibrosis Foundation about the management of
other pulmonary complications in CF patients, such
as spontaneous pneumothorax and hemoptysis.135
www.turner-white.com
Pulmonary Exacerbations and Complications in Cystic Fibrosis
BOARD REVIEW QUESTIONS
Test your knowledge of this topic.
Go to www.turner-white.com and select Pulmonary Disease
from the drop-down menu of specialties.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Cystic Fibrosis Foundation patient registry: annual data report 2011. Cystic Fibrosis Foundation. 2012. http://www.cff.
org/UploadedFiles/research/ClinicalResearch/2011-PatientRegistry.pdf. Accessed March 26, 2014.
Doring G, Flume P, Heijerman H, et al. Treatment of lung
infection in patients with cystic fibrosis: current and future
strategies. J Cyst Fibros 2012;11:461–79.
Rosenfeld M, Gibson RL, McNamara S, et al. Early pulmonary infection, inflammation, and clinical outcomes
in infants with cystic fibrosis. Pediatr Pulmonol 2001;32:
356–66.
Emerson J, Rosenfeld M, McNamara S, et al. Pseudomonas aeruginosa and other predictors of mortality and
morbidity in young children with cystic fibrosis. Pediatr
Pulmonol 2002;34:91–100.
Sagel SD, Gibson RL, Emerson J, et al. Impact of Pseudomonas and Staphylococcus infection on inflammation
and clinical status in young children with cystic fibrosis. J
Pediatr 2009;154:183–8.
Stenbit AE, Flume PA. Pulmonary exacerbations in cystic
fibrosis. Curr Opin Pulm Med 2011;17:442–7.
Kraynack NC, Gothard MD, Falletta LM, McBride JT. Approach to treating cystic fibrosis pulmonary exacerbations
varies widely across US CF care centers. Pediatr Pulmonol 2011;6:870–81.
Bhatt JM. Treatment of pulmonary exacerbations in cystic
fibrosis. Eur Respir Rev 2013;22:205–16.
Bilton D, Canny G, Conway S, et al., Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome
parameters in clinical trials. J Cyst Fibros 2011;10 Suppl
2:S79–81.
Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic
fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009;180:802–8.
Abbott J, Holt A, Hart A, et al. What defines a pulmonary
exacerbation? The perceptions of adults with cystic fibrosis. J Cyst Fibros 2009;8:356–9.
Roderfeld M, Rath T, Schulz R, et al. Serum matrix metalloproteinases in adult CF patients: Relation to pulmonary
exacerbation. J Cyst Fibros 2009;8:338–47.
Reid DW, Misso N, Aggarwal S, et al. Oxidative stress and
www.turner-white.com
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
lipid-derived inflammatory mediators during acute exacerbations of cystic fibrosis. Respirology 2007;12:63–9.
Robroeks CM, Rosias PP, van Vliet D, et al. Biomarkers in
exhaled breath condensate indicate presence and severity of cystic fibrosis in children. Pediatr Allergy Immunol
2008;19:652–9.
Laguna TA, Wagner BD, Starcher B, et al. Urinary desmosine: a biomarker of structural lung injury during CF pulmonary exacerbation. Pediatr Pulmonol 2012;47:856–63.
Harris WT, Muhlebach MS, Oster RA, et al. Plasma TGFbeta(1) in pediatric cystic fibrosis: potential biomarker of
lung disease and response to therapy. Pediatr Pulmonol
2011;46:688–95.
Gray RD, et al. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J Cyst Fibros
2010;9:193–8.
Liou TG, Adler FR, Fitzsimmons SC, et al. Predictive
5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001;153:345–52.
Simmonds NJ, D’Souza L, Roughton M, et al. Cystic fibrosis and survival to 40 years: a case-control study. Eur
Respir J 2010;36:1277–83.
Britto MT, Kotagal UR, Hornung RW, et al. Impact of recent
pulmonary exacerbations on quality of life in patients with
cystic fibrosis. Chest 2002;121:64–72.
Dobbin CJ, Bartlett D, Melehan K, et al. The effect of infective exacerbations on sleep and neurobehavioral function
in cystic fibrosis. Am J Respir Crit Care Med 2005;172:
99–104.
Lieu TA, Ray GT, Farmer G, Shay GF. The cost of medical
care for patients with cystic fibrosis in a health maintenance organization. Pediatrics 1999;103:e72.
Ouyang L, Grosse SD, Amendah DD, Schechter MS.
Healthcare expenditures for privately insured people with
cystic fibrosis. Pediatr Pulmonol 2009;44:989–96.
Konstan MW, Wagener JS, Vandevanter DR, et al. Risk
factors for rate of decline in forced expiratory volume in one
second in children and adolescents with cystic fibrosis. J
Pediatr 2007;151:134–9, 139 e1.
Sanders DB, Bittner RC, Rosenfeld M, et al. Pulmonary
exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr
Pulmonol 2011;46:393–400.
Amadori A, Antonell A, Balteri I, et al. Recurrent exacerbations affect FEV(1) decline in adult patients with cystic
fibrosis. Respir Med 2009;103:407–13.
Waters V, Stanojevic S, Atenafu EG, et al. Effect of pulmonary exacerbations on long-term lung function decline in
cystic fibrosis. Eur Respir J 2012;40:61–6.
Sanders DB, Bittner RC, Rosenfeld M, et al. Failure to
recover to baseline pulmonary function after cystic fibroPulmonary Disease Volume 14, Part 6 11
Pulmonary Exacerbations and Complications in Cystic Fibrosis
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
sis pulmonary exacerbation. Am J Respir Crit Care Med
2010;182:627–32.
Kozlowska WJ, Bush A, Wade A, et al. Lung function from
infancy to the preschool years after clinical diagnosis of
cystic fibrosis. Am J Respir Crit Care Med 2008;178:42–9.
Tramper-Stranders GA, van der Ent CK, Molin S, et al.
Initial Pseudomonas aeruginosa infection in patients with
cystic fibrosis: characteristics of eradicated and persistent
isolates. Clin Microbiol Infect 2012;18:567–74.
VanDevanter DR, Van Dalfsen JM. How much do Pseudomonas biofilms contribute to symptoms of pulmonary exacerbation in cystic fibrosis? Pediatr Pulmonol
2005;39:504–6.
Fothergill JL, Mowat E, Ledson MJ, et al. Fluctuations in
phenotypes and genotypes within populations of Pseudomonas aeruginosa in the cystic fibrosis lung during
pulmonary exacerbations. J Med Microbiol 2010;59(Pt
4):472–81.
Aaron SD, Ramotar K, Ferris W, et al. Adult cystic fibrosis
exacerbations and new strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med 2004;169:811–5.
Smith AL, Redding G, Doershuk C, et al. Sputum changes
associated with therapy for endobronchial exacerbation in
cystic fibrosis. J Pediatr 1988;112:547–54.
Regelmann WE, Elliott GR, Warwick WJ, Clawson CC.
Reduction of sputum Pseudomonas aeruginosa density
by antibiotics improves lung function in cystic fibrosis more
than do bronchodilators and chest physiotherapy alone.
Am Rev Respir Dis 1990;141(4 Pt 1):914–21.
Hurley MN, Ariff AH, Bertenshaw C, et al. Results of antibiotic susceptibility testing do not influence clinical outcome
in children with cystic fibrosis. J Cyst Fibros 2012;11:288–
92.
Fodor AA, Klem ER, Gilpin DF, et al. The adult cystic fibrosis airway microbiota is stable over time and infection type,
and highly resilient to antibiotic treatment of exacerbations.
PLoS One 2012;7:e45001.
Stressmann FA, Rogers GB, Marsh P, et al. Does bacterial
density in cystic fibrosis sputum increase prior to pulmonary exacerbation? J Cyst Fibros 2011;10:357–65.
Delhaes L, Monchy S, Fréalle E, et al. The airway microbiota in cystic fibrosis: a complex fungal and bacterial community--implications for therapeutic management.
PLoS One 2012;7:e36313.
Sibley CD, Surette MG. The polymicrobial nature of airway
infections in cystic fibrosis: Cangene Gold Medal Lecture.
Can J Microbiol 2011;57:69–77.
Willner D, Haynes MR, Furlan M, et al. Spatial distribution
of microbial communities in the cystic fibrosis lung. ISME J
2012;6:471–4.
Zhao J, Schloss PD, Kalikin LM, et al. Decade-long bacte-
12 Hospital Physician Board Review Manual
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
rial community dynamics in cystic fibrosis airways. Proc
Natl Acad Sci U S A 2012;109:5809–14.
Rabin HR, Surette MG. The cystic fibrosis airway microbiome. Curr Opin Pulm Med 2012;18:622–7.
Tunney MM, Klem ER, Fodor AA, et al. Use of culture
and molecular analysis to determine the effect of antibiotic treatment on microbial community diversity and abundance during exacerbation in patients with cystic fibrosis.
Thorax 2011;66:579–84.
Zemanick ET, Harris JK, Wagner BD, et al. Inflammation
and airway microbiota during cystic fibrosis pulmonary
exacerbations. PLoS One 2013;8:e62917.
Sibley CD, Duan K, Fischer C, et al. Discerning the complexity of community interactions using a Drosophila model
of polymicrobial infections. PLoS Pathog 2008;4:e1000184.
Duan K, Dammel C, Stein J, et al. Modulation of Pseudomonas aeruginosa gene expression by host microflora through interspecies communication. Mol Microbiol
2003;50:1477–91.
Sibley CD, et al. Culture enriched molecular profiling
of the cystic fibrosis airway microbiome. PLoS One
2011;6:e22702.
Sibley CD, Grinwis ME, Field TR, et al. The relevance of
the polymicrobial nature of airway infection in the acute
and chronic management of patients with cystic fibrosis.
Curr Opin Investig Drug 2009;10:787–94.
Sibley CD, Parkins MD, Rabin HR, et al. A polymicrobial
perspective of pulmonary infections exposes an enigmatic
pathogen in cystic fibrosis patients. Proc Natl Acad Sci U
S A 2008;105:15070–5.
Mayer-Hamblett N, Kronmal RA, Gibson RL, et al. Initial
Pseudomonas aeruginosa treatment failure is associated
with exacerbations in cystic fibrosis. Pediatr Pulmonol
2012;47:125–34.
Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic
fibrosis pulmonary guidelines. Chronic medications for
maintenance of lung health. Am J Respir Crit Care Med
2013;187:680–9.
Taccetti G, Campana S, Festini F, et al. Early eradication
therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J 2005;26:458–61.
Amin R, Lam M, Dupuis A, Ratjen F. The effect of early
Pseudomonas aeruginosa treatment on lung function in
pediatric cystic fibrosis. Pediatr Pulmonol 2011;46:554–8.
Ryan G, Singh M, Dwan K. Inhaled antibiotics for longterm therapy in cystic fibrosis. Cochrane Database Syst
Rev 2011(3):CD001021.
McCoy KS, Quittner AL, Oermann CM, et al. Inhaled
aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med
2008;178:921–8.
www.turner-white.com
Pulmonary Exacerbations and Complications in Cystic Fibrosis
57. Assael BM, Pressler T, Bilton D, et al. Inhaled aztreonam
lysine vs. inhaled tobramycin in cystic fibrosis: A comparative efficacy trial. J Cyst Fibros 2012 Sep 14.pii: S15691993(12)00136-1.
58. Ratjen F, et al. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE
trial. Thorax 2010;65:286–91.
59. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, et al.
Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in
children with cystic fibrosis. Arch Pediatr Adolesc Med
2011;165:847–56.
60. Langton Hewer SC, Smyth AR. Antibiotic strategies for
eradicating Pseudomonas aeruginosa in people with cystic
fibrosis. Cochrane Database Syst Rev 2009(4):CD004197.
61. Taccetti G, Bianchini E, Cariani L, et al. Early antibiotic
treatment for Pseudomonas aeruginosa eradication in patients with cystic fibrosis: a randomised multicentre study
comparing two different protocols. Thorax 2012;67:853–9.
62. Noah TL, Ivins SS, Abode KA, et al. Inhaled versus
systemic antibiotics and airway inflammation in children
with cystic fibrosis and Pseudomonas. Pediatr Pulmonol
2010;45:281–90.
63. Hansen CR, Pressler T, Hoiby N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa
airway colonization in cystic fibrosis patients: 15 years
experience. J Cyst Fibros 2008;7:523–30.
64. Treggiari MM, Rosenfeld M, Retsch-Bogart G, et al. Approach to eradication of initial Pseudomonas aeruginosa
infection in children with cystic fibrosis. Pediatr Pulmonol
2007;42:751–6.
65. Chuchalin A, Csiszer E, Gyurkovics K, et al. A formulation
of aerosolized tobramycin (Bramitob) in the treatment of
patients with cystic fibrosis and Pseudomonas aeruginosa
infection: a double-blind, placebo-controlled, multicenter
study. Paediatr Drugs 2007;9 Suppl 1:21–31.
66. Konstan MW, Flume PA, Kappler M, et al. Safety, efficacy and convenience of tobramycin inhalation powder
in cystic fibrosis patients: The EAGER trial. J Cyst Fibros
2011;10:54–61.
67. Konstan MW, Geller DE, Minić P, et al. Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis:
The EVOLVE trial. Pediatr Pulmonol 2011;46:230–8.
68. Saiman L, Anstead M, Mayer-Hamblett N, et al. Effect of
azithromycin on pulmonary function in patients with cystic
fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010;303:1707–15.
69. Southern KW, arker PM, Solis-Moya A, Patel L. Macrolide
antibiotics for cystic fibrosis. Cochrane Database Syst Rev
2012; 11:CD002203.
70. McKoy NA, Saldanha IJ, Odelola OA, Robinson KA. Active
www.turner-white.com
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
cycle of breathing technique for cystic fibrosis. Cochrane
Database Syst Rev 2012;12:CD007862.
Morrison L, Agnew J. Oscillating devices for airway clearance in people with cystic fibrosis. Cochrane Database
Syst Rev 2009(1):CD006842.
Elkins MR, Jones A, van der Schans C. Positive expiratory pressure physiotherapy for airway clearance in
people with cystic fibrosis. Cochrane Database Syst Rev
2006(2):CD003147.
Health Quality Ontario. Airway clearance devices for cystic
fibrosis: an evidence-based analysis. Ont Health Technol
Assess Ser 2009;9:1–50.
McIlwaine MP, Alarie N, Davidson GF, et al. Long-term
multicentre randomised controlled study of high frequency
chest wall oscillation versus positive expiratory pressure
mask in cystic fibrosis. Thorax 2013;68:746–51.
Klijn PH, van der Net J, Kimpen JL, et al. Longitudinal
determinants of peak aerobic performance in children with
cystic fibrosis. Chest 2003;124:2215–9.
Pianosi P, LeBlanc J, Almudevar A. Relationship between
FEV1 and peak oxygen uptake in children with cystic fibrosis. Pediatr Pulmonol 2005;40:324–9.
Javadpour SM, Selvadurai H, Wilkes DL, et al. Does
carbon dioxide retention during exercise predict a more
rapid decline in FEV1 in cystic fibrosis? Arch Dis Child
2005;90:792–5.
Dodd JD, Barry SC, Gallagher CG. Respiratory factors do
not limit maximal symptom-limited exercise in patients with
mild cystic fibrosis lung disease. Respir Physiol Neurobiol
2006;152:176–85.
Coates AL, Boyce P, Muller D, et al. The role of nutritional
status, airway obstruction, hypoxia, and abnormalities
in serum lipid composition in limiting exercise tolerance
in children with cystic fibrosis. Acta Paediatr Scand
1980;69:353–8.
Wells GD, Wilkes DL, Schneiderman JE, et al. Skeletal
muscle metabolism in cystic fibrosis and primary ciliary
dyskinesia. Pediatr Res 2011;69:40–5.
Selvadurai HC, Allen J, Sachinwalla T, et al. Muscle function and resting energy expenditure in female athletes with
cystic fibrosis. Am J Respir Crit Care Med 2003;168:1476–
80.
Sahlberg ME, Svantesson U, Thomas EM, Strandvik B.
Muscular strength and function in patients with cystic fibrosis. Chest 2005;127:1587–92.
Troosters T, Langer D, Vrijsen B, et al. Skeletal muscle
weakness, exercise tolerance and physical activity in
adults with cystic fibrosis. Eur Respir J 2009;331:9–106.
Selvadurai HC, McKay KO, Blimkie CJ, et al. The relationship between genotype and exercise tolerance in
children with cystic fibrosis. Am J Respir Crit Care Med
Pulmonary Disease Volume 14, Part 6 13
Pulmonary Exacerbations and Complications in Cystic Fibrosis
2002;165:762–5.
85. Nixon PA, Orenstein DM, Kelsey SF. Habitual physical activity in children and adolescents with cystic fibrosis. Med
Sci Sports Exerc 2001;33:30–5.
86. Selvadurai HC, Blimkie CJ, Cooper PJ, et al. Gender differences in habitual activity in children with cystic fibrosis.
Arch Dis Child 2004;89:928–33.
87. Gruber W, Orenstein DM, Braumann KM, et al. Effects of
an exercise program in children with cystic fibrosis: are
there differences between females and males? J Pediatr
2011;158:71–6.
88. Prasad SA, Cerny FJ. Factors that influence adherence to
exercise and their effectiveness: application to cystic fibrosis. Pediatr Pulmonol 2002;34:66–72.
89. Craig S, Goldberg J, Dietz WH. Psychosocial correlates of
physical activity among fifth and eighth graders. Prev Med,
1996. 25(5): p. 506-13.
90. Trost SG, Pate RR, Saunders R, et al. A prospective study
of the determinants of physical activity in rural fifth-grade
children. Prev Med 1997;26:257–63.
91. Dwyer TJ, Elkins MR, Bye PT. The role of exercise in
maintaining health in cystic fibrosis. Curr Opin Pulm Med
2011;17:455–60.
92. Rand S, Prasad SA. Exercise as part of a cystic fibrosis
therapeutic routine. Expert Rev Respir Med 2012;6:341–
51.
93. Bradley J, Moran F. Physical training for cystic fibrosis.
Cochrane Database Syst Rev 2008(1):CD002768.
94. Dwyer T, Zainuldin M. Effects of exercise and PEP on mucociliary clearance in adults with cystic fibrosis. 9th Australian Cystic Fibrosis Conference; Melbourne, Australia,
2011.
95. Schmitt L, Wiebel M, Frese F, et al. Exercise reduces airway sodium ion reabsorption in cystic fibrosis but not in
exercise asthma. Eur Respir J 2011;37:342–8.
96. Hebestreit A, Kersting U, Basler B, et al. Exercise inhibits
epithelial sodium channels in patients with cystic fibrosis.
Am J Respir Crit Care Med 2001;164:443–6.
97. Hebestreit A, Kieser S, Junge S, et al. Long-term effects
of a partially supervised conditioning programme in cystic
fibrosis. Eur Respir J 2010;35:578–83.
98. Dwyer T, McKeough ZJ. Differences in quality of life, lung
function and hospitalization rates for adults with cystic
fibrosis, according to exercise participation. J Cyst Fibros
2010;9(S1): S69.
99. Tejero Garcia S, Giráldez Sánchez MA, Cejudo P, et al.
Bone health, daily physical activity, and exercise tolerance
in patients with cystic fibrosis. Chest 2011;140:475–81.
100. Dwyer TJ, Alison JA, McKeough ZJ, et al. Evaluation of
the SenseWear activity monitor during exercise in cystic
fibrosis and in health. Respir Med 2009;103:1511–7.
14 Hospital Physician Board Review Manual
101. Moran A, Brunzell C, Cohen RC, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical
practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care
2010;33:2697–708.
102. Ryan G, Jahnke N, Remmington T. Inhaled antibiotics for
pulmonary exacerbations in cystic fibrosis. Cochrane Database Syst Rev 2012;12:CD008319.
103. Moskowitz SM, Silva SJ, Mayer-Hamblett N, et al. Shifting
patterns of inhaled antibiotic use in cystic fibrosis. Pediatr
Pulmonol 2008;43:874–81.
104.Stenbit AE, Bullington WM, Heh JL, Flume PA. Timing
of inhaled tobramycin affects assessment of intravenous
tobramycin pharmacokinetic monitoring. J Cyst Fibros
2013;124:403–6.
105. Bosworth DG, Nielson DW. Effectiveness of home versus
hospital care in the routine treatment of cystic fibrosis. Pediatr Pulmonol 1997;24:42–7.
106. Nazer D, Abdulhamid I, Thomas R, Pendleton S. Home
versus hospital intravenous antibiotic therapy for acute
pulmonary exacerbations in children with cystic fibrosis.
Pediatr Pulmonol 2006;41:744–9.
107.Termoz A, Touzet S, Bourdy S, et al. Effectiveness of
home treatment for patients with cystic fibrosis: the intravenous administration of antibiotics to treat respiratory
infections. Pediatr Pulmonol 2008;43:908–15.
108.Thornton J, Elliott R, Tully MP, et al. Long term clinical
outcome of home and hospital intravenous antibiotic treatment in adults with cystic fibrosis. Thorax 2004;59:242–6.
109.Esmond G, Butler M, McCormack AM. Comparison of
hospital and home intravenous antibiotic therapy in adults
with cystic fibrosis. J Clin Nurs 2006;15:52–60.
110. Collaco JM, Green DM, Cutting GR, et al. Location and
duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med
2010;182:1137–43.
111. Miall LS, McGinley NT, Brownlee KG, Conway SP. Methicillin resistant Staphylococcus aureus (MRSA) infection in
cystic fibrosis. Arch Dis Child 2001;84:160–2.
112.Ren CL, Morgan WJ, Konstan MW, et al. Presence of
methicillin resistant Staphylococcus aureus in respiratory
cultures from cystic fibrosis patients is associated with
lower lung function. Pediatr Pulmonol 2007;42:513–8.
113. Szaff M, Hoiby N. Antibiotic treatment of Staphylococcus
aureus infection in cystic fibrosis. Acta Paediatr Scand
1982;71:821–6.
114.Trust CF. Antibiotic treatment for cystic fibrosis. Report
of the UK Cystic Fibrosis Trust Antibiotic Working Group
2009. 3rd ed. London.
115.Richard DA, Nousia-Arvanitakis S, Solich V, et al. Oral
www.turner-white.com
Pulmonary Exacerbations and Complications in Cystic Fibrosis
ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of
antipseudomonas efficacy and assessment of safety
with ultrasonography and magnetic resonance imaging.
Cystic Fibrosis Study Group. Pediatr Infect Dis J 1997;16:
572–8.
116.Cardines R, Giufrè M, Pompilio A, et al. Haemophilus
influenzae in children with cystic fibrosis: antimicrobial susceptibility, molecular epidemiology, distribution of adhesins
and biofilm formation. Int J Med Microbiol 2012;302:45–52.
117. Moller LV, Regelink AG, Grasslier H, et al. Antimicrobial
susceptibility of Haemophilus influenzae in the respiratory
tracts of patients with cystic fibrosis. Antimicrob Agents
Chemother 1998;42:319–24.
118. Rayner RJ, Hiller EJ, Ispahani P, Baker M. Haemophilus
infection in cystic fibrosis. Arch Dis Child 1990;65:255–8.
119. Pressler T, Szaff M, Hoiby N. Antibiotic treatment of Haemophilus influenzae and Haemophilus parainfluenzae
infections in patients with cystic fibrosis. Acta Paediatr
Scand 1984;73:541–7.
120. Briggs EC, Nguyen T, Wall MA, MacDonald KD. Oral antimicrobial use in outpatient cystic fibrosis pulmonary exacerbation management: a single-center experience. Clin
Respir J 2012;6:56–64.
121. Remmington T, Jahnke N, Harkensee C. Oral anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database
Syst Rev 2007(3):CD005405.
122. Smith AL, Fiel SB, Mayer-Hamblett N, et al. Susceptibility
testing of Pseudomonas aeruginosa isolates and clinical
response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest 2003;123:1495–502.
123. Aaron SD, Vandemheen KL, Ferris W, et al. Combination
antibiotic susceptibility testing to treat exacerbations of
cystic fibrosis associated with multiresistant bacteria: a
randomised, double-blind, controlled clinical trial. Lancet
2005;366(9484):463–71.
124.Parkins MD, Rendall JC, Elborn JS. Incidence and risk
factors for pulmonary exacerbation treatment failures in
patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. Chest 2012;141:485–93.
125. Plummer A, Wildman M. Duration of intravenous antibiotic
therapy in people with cystic fibrosis. Cochrane Database
Syst Rev 2013;5:CD006682.
126. Brown SM, Balfour-Lynn IM. Duration of intravenous antibiotic treatment for respiratory exacerbations in children with
cystic fibrosis. Arch Dis Child 2010;95:568.
127. Bell SC, Bowerman AM, Nixon LE, et al. Metabolic and inflammatory responses to pulmonary exacerbation in adults
with cystic fibrosis. Eur J Clin Invest 2000;30:553–9.
128. Moran A, Hardin D, Rodman D, et al. Diagnosis, screening
and management of cystic fibrosis related diabetes mellitus: a consensus conference report. Diabetes Res Clin
Pract 1999;45:61–73.
129. Sc NN, Shoseyov D, Kerem E, et al. Patients with cystic fibrosis and normoglycemia exhibit diabetic glucose
tolerance during pulmonary exacerbation. J Cyst Fibros
2010;9:199–204.
130. Elphick HE, Mallory G. Oxygen therapy for cystic fibrosis.
Cochrane Database Syst Rev 2013;7:CD003884.
131.Moran F, Bradley JM, Piper AJ. Non-invasive ventilation for cystic fibrosis. Cochrane Database Syst Rev
2013;4:CD002769.
132.Selvadurai HC, Blimkie CJ, Meyers N, et al. Randomized controlled study of in-hospital exercise training programs in children with cystic fibrosis. Pediatr Pulmonol
2002;33:194–200.
133. Flume PA. Pneumothorax in cystic fibrosis. Curr Opin Pulm
Med 2011;17:220–5.
134. Tomashefski JF Jr, Bruce M, Stern RC, et al. Pulmonary
air cysts in cystic fibrosis: relation of pathologic features
to radiologic findings and history of pneumothorax. Hum
Pathol 1985;16:253–61.
135.Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic
fibrosis pulmonary guidelines: pulmonary complications:
hemoptysis and pneumothorax. Am J Respir Crit Care
Med 2010;182:298–306.
Copyright 2014 by Turner White Communications Inc., Wayne, PA. All rights reserved.
www.turner-white.com
Pulmonary Disease Volume 14, Part 6 15