Authors: Frank Edenborough, Shammi L Ramlakhan / Editor: Jason M Kendall / Codes: CAP6, HAP6 / Published: 22/10/2013 / Review Date: 22/10/2017
Cystic fibrosis (CF) is the most common lethal genetic disease in white populations . There are over 8500 patients with the disease in the UK, of which more than half are adults over the age of 16 .
Improvements in the care of patients with CF over the past 30 years means that most now survive well into adulthood, with the current median age at death approaching 27 years and with a predicted survival of almost 39 years . It is estimated that a child born today with CF will typically live to be 50 or more .
In addition, older patients are being diagnosed with CF more frequently, with over 5% of new diagnoses being made in patients over the age of 16 .As a group, adults with CF have more severe pulmonary disease and are at higher risk of serious complications .
Although care is generally delivered in specialist units across the UK, emergency department (ED) clinicians are more likely than in the past to see CF patients and will therefore have to manage their acute complications.
Patients with CF are surviving longer and are more likely to present to the ED with a complication of their disease
Basic science and pathophysiology
Cystic Fibrosis is caused by a mutation in a gene that encodes cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is expressed in many epithelial and blood cells. The primary function of the CFTR protein is as an ion channel that regulates liquid volume on epithelial surfaces through chloride secretion and inhibition of sodium absorption .It is also involved in bicarbonate-chloride exchange. A deficiency of bicarbonate secretions leads to poor solubility and aggregation of luminal mucins .
Decreased hydration of mucus makes it stickier to bacteria, resulting in infection and inflammation as well as obstruction of glandular ducts. It also results in viscid secretions in the respiratory and Gastrointestinal (GI) tract, pancreas, sweat glands and other exocrine tissues. The increased viscosity of these secretions makes them difficult to clear.
Approximately 2 million people in the UK carry the defective gene; however the disease is inherited as an autosomal recessive disorder with a rate of 1 in 2500-3500 births.
(i) The Respiratory system
Viscous secretions and poor clearance leads to colonization with pathogenic bacteria. The hallmark of CF and the cause of death in more than 90% of patients is chronic pulmonary infection [7,8]. Persistent colonization and infection leads to an increase in inflammatory response which promotes tissue destruction. This results in bronchiectasis, abnormal lung function and respiratory failure.
The most common infecting bacteria are:
- Pseudomonas aeruginosa
- Staphylococcus aureus
- Haemophilus influenza
- Stenotrophomonas maltophilia
- Burkholderia cepacia complex organisms
- A typical mycobacteria
Between 16 and 20% of adults with CF over 18 will develop a pneumothorax . The pathogenesis is likely to be similar to secondary spontaneous pneumothorax.
Almost 1 in 5 adults with CF will suffer a secondary spontaneous pneumothorax. The cause of death in 90% of patients with CF is respiratory infection and the most common colonising bacteria are P aeruginosa and S aureus
(ii) The Gastrointestinal (GI) system
Abdominal pain is a frequent complaint in CF and the second most common reason for admission. Of all the causes only distal intestinal obstruction syndrome (DIOS) is unique to CF. GORD, biliary disease and constipation are more common in patients with CF due to abnormal motility. The risk of appendicitis is unchanged, however many infants would have had an appendicectomy at the same time as other lower GI surgery. Thickened GI secretions, malabsorbtion and decreased gut motility can lead to distal intestinal obstruction or chronic constipation .
Ninety percent of CF patients have pancreatic insufficiency. Abnormal CFTR function in the pancreatic ducts causes loss of enzyme rich digestive secretions and bicarbonate. Ductal obstruction and proximal inflammation contributes to destruction and fibrosis of pancreatic tissue. Consequently, absorption of lipids and fat-soluble vitamins (A, D, E, and K) is reduced, which can lead to steatorrhoea, malabsorbtion and malnutrition.
This pancreatic destruction leads to a loss of secretory cells, including insulin-producing cells in the Islets of Langerhans. The resulting CF-related diabetes (CFRD) is also aggravated by peripheral insulin resistance.
Clogging of the biliary ducts may lead to liver involvement and biliary cirrhosis, however only about 5% of CF patients develop clinical cirrhosis. Hepatic steatosis may result from malnutrition, and congestion of the liver may result from hypoxia-induced cor pulmonale. Liver failure is the second most common cause of death in adult CF patients.
Faecal loss of bile acids is increased in CF, leading to a reduction in the bile-salt pool. About 30% of adult CF patients have a small, poorly functioning gallbladder and may develop gallstones .
(iii) The musculoskeletal system
Poor nutrition and vitamin D deficiency, chronic inflammation, reduced weight bearing exercise and steroid use results in osteoporosis. Adults with CF have twice the risk of fractures .
Adults with CF have twice the risk of fractures compared with the normal population
(iv) Conditions specific to CF
Pulmonary Exacerbations are characterised by intermittent episodes of acute worsening of symptoms on a background of chronic disease which usually warrants a change in treatment. Symptoms defining an exacerbation may include change in sputum volume or colour, increased dyspnoea, cough, malaise, fatigue, anorexia or radiological changes.
Distal Intestinal Obstruction Syndrome is defined as a short history (days) of abdominal pain and/or distension with a faecal mass in the ileo-caecum, but without signs of complete obstruction.
The widespread presence of CFTR protein throughout the body (and its absence in CF) explains why CF is a multisystem condition affecting many organs. The two major systems affected, however, are the respiratory and gastrointestinal systems.
Table 1 summarises the main clinical manifestations of CF in adults.
|Organ System||Clinical Manifestation|
|Respiratory||Pulmonary exacerbationPulmonary infectionBronchiectasisRespiratory Failure |
Allergic Bronchopulmonary Aspergillosis (ABPA)
Sinusitis, nasal polyposis
|Gastrointestinal||ConstipationDistal Intestinal Obstruction Syndrome (DIOS)IntussusceptionPancreatitis (in pancreatic sufficient patients) |
Gastro Oesophageal Reflux Disease (GORD)
Gastritis, peptic ulcer disease
Biliary fibrosis, cirrhosis
Portal Hypertension, variceal bleeding
Colonic strictures, fibrosing colonopathy
Clostridium difficile colitis
|Other||Renal calculi, renal failureCF Related Diabetes (CFRD)Port (Totally Implantable Venous Access Device) problems98% Male infertility, reduced female fertility|
(i) The respiratory system
Pulmonary exacerbations of CF are manifested by an increase in respiratory symptoms:
- increased cough or change in character of cough
- increase in sputum or change in quality of sputum
- reduced exercise tolerance
These respiratory symptoms are associated with systemic symptoms such as malaise, anorexia and weight loss [1,13,14]. Examination may reveal new crackles or wheeze. Rarely do patients have the fever and/or leucocytosis  classically associated with pneumonia.
Pulmonary exacerbations may present without pyrexia, new x-ray changes or leucocytosis
Haemoptysis is a relatively common symptom in CF, and clinical assessment must identify whether it is scant (< 5 ml), mild-to-moderate (5240 ml) or massive (>240 ml in a 24 hour period or >100 ml/day over several days). Minor haemoptysis can be the result of infection or a manifestation of a pulmonary exacerbation of CF .
Occasionally, bronchial artery involvement from destructive bronchiectasis may result in life threatening bleeding through airway compromise and/or hypovolaemia; these patients will require prompt assessment and resuscitation.
Pneumothorax may present with dyspnoea and chest pain, although these symptoms, along with the typical examination findings of reduced lung expansion, hyper-resonance and diminished breath sounds on the side of the pneumothorax may be inconsistent or subtle. A high index of suspicion is therefore required.
A high index of suspicion will be required to identify pneumothorax in patients with CF in whom this condition is common and the presentation may be atypical
(ii) The gastrointestinal system
Abdominal pain is a frequent complaint in CF and the second most common reason for admission. Of all the causes only distal intestinal obstruction syndrome (DIOS) and fibrosing colonopathy are unique to CF. Fibrosing colonopathy is found mostly in the paediatric age group although it has been described in adults taking pancreatic supplements. All other causes of abdominal pain in the general population also present in patients with CF and with the same signs and symptoms . The location of pain may give some indication as to the differential diagnosis.
DIOS and fibrosing colonopathy are unique to CF all other causes of abdominal pain in the general population also present in patients with CF and with the same signs and symptoms
Epigastric pain with dyspepsia or heartburn suggests gastro-oesophageal reflux disease (GORD). Pancreatitis (in pancreatic sufficient patients), symptomatic cholelithiasis and gastritis/peptic ulcer disease may also present with epigastric pain and vomiting.
Periumbilical pain is most often caused by DIOS. Intussusception has also been associated with similar symptoms. Appendicitis, with classical periumbilical pain which then migrates to the right iliac fossa occurs no more frequently in adults with CF, although the symptoms are sometimes mistakenly attributed to DIOS. It should be noted that some patients will have had an appendectomy in infancy or childhood at the time as other surgery. Constipation can also present with colicky periumbilical pain.
Hypogastric pain and bloating are common complaints in CF. The most frequent cause is malabsorbtion, which also results in steatorrhoea. DIOS is likely if there is also distension and intermittent constipation. Rarely, Clostridium difficile colitis can also cause hypogastric pain, and a history of recent antibiotics, fever and bloody stools support the diagnosis.
DIOS presents with recurrent colicky periumbilical or right lower quadrant pain, bloating, nausea/vomiting and anorexia. In addition, signs of partial or complete small bowel obstruction, with a tender mass in the right iliac fossa are also typical .
Haematemesis can result from gastritis/peptic ulcer disease, GORD, or from oesophageal variceal bleeding secondary to portal hypertension associated with cirrhosis.
(iii) The musculoskeletal system
CF associated arthralgia (and rarely arthritis) is the commonest form of joint pain in CF and mostly affects the large joints (knee, ankle, wrist, elbow and shoulder). Episodes usually last less than a week but can be quite disabling. Rarely the attacks are associated with high swinging fevers, skin rashes, nodules and purpura .
Hypertrophic pulmonary osteoarthropathy (HPOA) has an insidious onset of pain, which is generally mild at the beginning. Clinically, findings range from a minimally swollen joint to tender, warm and swollen joints resembling those seen in rheumatoid arthritis. Symptoms are often worse in cold weather. It should be noted that HPOA also occurs in a variety of other lung diseases .
Both these forms of arthropathy can be associated with acute respiratory exacerbations.
Osteoporosis is twice as common in patients with CF and may present with sudden onset of severe back pain from vertebral collapse. A full neurological examination is necessary to exclude any resulting nerve compression. Patients may also present with cough fractures of their ribs. Osteoporotic fractures of other areas are also likely with lesser degrees of trauma, and a high index of suspicion should be maintained when evaluating a seemingly innocuous mechanism of injury.
Patients with CF are also susceptible to joint disease unrelated to their underlying illness, and a careful history and examination is required to differentiate these.
Have a high index of suspicion for fractures in patients with CF presenting with seemingly innocuous mechanisms of injury
(iv) Port problems
Totally Implantable Vascular Access Devices (TIVADs) are a safe and effective method of providing long term intravenous therapy for patients with CF and can usually be left in situ for up to 2 years. Special needles are used to access ports and this should only be done by trained staff with strict asepsis.
Overall complication rates of 12-20% have been reported: the most common complications are infection manifesting as pain, pyrexia or sepsis (11%), catheter blockage (7%), leakage (5%), vascular thrombosis (4%), detached and migrating catheter (4%), malposition (2%), pneumothorax (1%) and fractured line (<1%) .
(v) Adult Diagnosis
The first-time diagnosis of CF in adults is being made with increasing frequency. Patients often present with chronic respiratory problems, but also with chronic/recurrent pancreatitis, chronic sinusitis or male infertility due to congenital bilateral absence of vas deferens (CBAVD).
Overall, patients diagnosed with CF as adults have milder lung disease, less pseudomonal infection and are more likely to be pancreatic sufficient than patients diagnosed in childhood .
The diagnosis is, however, confirmed in the same way as in children (see European CF Diagnostic working group and US CF Foundation for algorithms).
Just because a young adult is not known to have CF, doesnt mean that they cannot have CF: primary diagnosis in adulthood is becoming more frequent.
(i) The respiratory system
Pulse oximetry (SpO2) gives a rapid, non-invasive estimate of oxygenation. This serves as a guide to severity of respiratory compromise as well as the effect of any therapeutic intervention.
Arterial blood gas (ABG) analysis provides more accurate information on oxygenation as well as determining ventilatory efficacy and acid-base status.
Microbiological samples should be taken for culture and sensitivity in patients presenting with pulmonary exacerbations. These include sputum and blood culture.
Haematological indices may provide supporting evidence for infection (although WBC, CRP and ESR are often normal in respiratory exacerbations). Haemoglobin levels may reflect blood loss in haemoptysis, especially over several days. Prothrombin time is often prolonged due to liver disease or vitamin K deficiency.
Chest x-rays are useful in determining whether new consolidation is present in pulmonary exacerbations or haemoptysis (although longitudinal correlation is often required). In addition, lobar atelectasis/collapse and pneumothoraces may be demonstrated.
CT scanning of the thorax is not usually undertaken in the ED, but studies have shown that it is more sensitive and specific than chest x-ray in demonstrating bronchiectasis and other abnormalities. CT of the thorax can also facilitate the diagnosis and management of pneumothorax in patients with complex cystic disease .
Chest x-rays are useful in the diagnosis and evaluation of respiratory complications of CF, however comparison with previous films is often required
(ii) The gastrointestinal system
Haematological abnormalities such as a raised WBC may result from compromised bowel due to DIOS or intussusception, as well as from appendicitis or C diff colitis. Haemoglobin levels may reflect anaemia of chronic disease, nutritional iron deficiency, and chronic upper GI loss or can indicate acute severe blood loss in haematemesis.
Biochemical assays such as liver function tests can be useful in determining whether symptoms are attributable to cholelithiasis, although alkaline phosphatase and GGT are often elevated in patients with CF because of intrinsic liver disease. Amylase or lipase may also be elevated in pancreatitis. Hypokalaemia and hypomagnesaemia are commonly found due to chronic aminoglycoside use.
Abdominal x-rays can show loaded bowel consistent with constipation. A colon distended with granular or bubbly/foamy contents in the right iliac fossa is seen in DIOS. Dilatation of the ileum with air fluid levels and an empty distal colon is sometimes seen.
Ultrasound scans of the abdomen are useful in investigating upper abdominal pain in CF patients due to the high incidence of biliary tract disease. Ultrasound can also demonstrate an obstructing mass in DIOS, and identify intussusception.
CT scan of the abdomen can be useful when there is diagnostic uncertainty.
CF is one of a few conditions where plain abdominal x-rays are recommended for evaluation of abdominal pain
(iii) The musculoskeletal system
Plain x-rays should be performed where there is any clinical suspicion of a fracture, particularly since osteoporosis is common in patients with CF.
Joint aspiration should be considered in CF patients with acute monoarthritis to exclude sepsis. This should be sent for microscopy, gram staining and culture.
(iv) Other investigations
Blood glucose (BM) assay should be checked in all patients presenting acutely unwell due to the high incidence (up to 35%, increasing with age) of CF-related diabetes (CFRD) in adult CF patients.
(i) General points
Patients with CF are generally managed in regional CF centres. They should be managed according to agreed protocols and advice should be sought from the centre as soon as is practical when these patients present to the ED.
Adult patients with CF are likely to be familiar with their symptoms and when they are clinically worsening listen to their concerns as they are likely to be right about their diagnosis and treatment. They will often carry an Alert card indicating that they have CF and any specific pertinent issues related to their illness.
Many patients will have access ports, as IV access is sometime difficult. These should not be accessed other than by trained staff with the appropriate equipment. Establish alternate IV access if necessary.
TIVADs should only be accessed by staff that are trained to do so.
(ii) The respiratory system
Oxygen should be administered guided by alert cards (if carried). Otherwise aim for an oxygen saturation (SpO2) of 88-92% with a 28% Venturi mask pending ABG measurement. Increase the flow rate by 50% if the RR >30/min .The SpO2 can be adjusted to 94-98% if the pCO2 is normal. ABG assay should be rechecked after 30-60 mins.
Non-invasive ventilation may be helpful in patients with acute Type II respiratory failure or acute on chronic respiratory failure in the short term. The evidence for any benefit of however is inconclusive . Clearly, patients with massive haemoptysis or pneumothorax should not have NIV instituted. Ventilation with endotracheal intubation is associated with poor outcome when used as an emergency .
Antibiotic treatment for respiratory exacerbations (including moderate or severe haemoptysis) should be based on the most recent sensitivities of the surveillance sputum cultures if available. Otherwise treatment should include coverage of both Staphylococcus and Pseudomonas species. Usually an aminoglycoside (tobramycin) is combined with a beta lactam (ceftazidime, piperacillin-tazobactam, aztreonam or a carbapenem such as meropenem) .
As most patients would have been on several classes of antibiotic previously, check for allergies, as these are common.
Bronchodilator therapy with agonists and antimuscuranic agents are used in many patients with CF although there is little evidence of efficacy . In patients with clinical features of bronchial lability, there is little harm in trying nebulised therapy.
Antibiotic treatment is required for most respiratory complications of CF. Be aware of drug allergies when selecting the appropriate antibiotic
Special respiratory scenarios in CF
Airway protection and circulatory support should be urgently implemented if deemed necessary on primary assessment in the ED.
Although most cases of major bleeding will stop spontaneously, patients with massive haemoptysis who are clinically unstable should be urgently referred for Bronchial Artery Embolisation (BAE). Failure of BAE should prompt consideration of lung resection.
Of note, investigations such as CT or bronchoscopy should not precede BAE in massive haemoptysis16.
The treatment for pneumothorax in patients with CF is similar to that for secondary pneumothorax in non-CF patients. Asymptomatic small pneumothoraces ( 2cm) can be observed or aspirated but larger pneumothoraces require a chest drain. An apparently small pneumothorax in a symptomatic patient with advanced CF may need to be drained using CT guidance for symptom relief.
The collapsed lung can be stiff and is associated with sputum retention, thus requiring a longer time to re-expand. During this time other general measures such as supplemental oxygen and appropriate antibiotic treatment are recommended . Non percussive physiotherapy without use of PEP should continue. NIV can be used if a functioning chest drain is sited either as an adjunct to airway clearance or to treat respiratory failure.
(iii) The gastrointestinal system
The management of most causes of abdominal pain in CF is similar to the general population. Pancreatitis, GORD, gastritis/peptic ulcer disease, variceal bleeding and biliary disease are managed in line with recommendations for nonCF patients .
Non-opiate analgesia should be used whenever possible because opiates can precipitate DIOS. Antiemetics should be considered when appropriate.
Abdominal pain, which is common in CF, is often associated with anorexia and nausea; consequently these patients are at risk of dehydration which must be prevented or corrected if present; in particular, dehydration worsens DIOS.
Special gastrointestinal scenario in CF
Distal Intestinal Obstruction Syndrome (DIOS)
Different CF centres may have their own protocols for managing DIOS. The goals of management are early recognition and prompt treatment to avoid the need for surgical intervention .
Mild cases, as well as uncomplicated constipation often respond to laxatives such as Lactulose, Senna or Movicol . Careful attention to adequate hydration is important.
Oral or nasogastric diatrizoate (Gastrograffin ), N-acetylcysteine (NAC) or PEG solution is used to thin bowel contents . NAC acts as a mucolytic and can help break up the protein matrix of the inspissate.
In more severe cases, phosphate enemas or Gastrograffin directed into the lumen of the ascending colon by means of either an enema or colonoscopy may be successful.
If there are signs of peritoneal irritation or complete intestinal obstruction, then a surgical review is warranted. The patient should be kept NPO other than a small dose of pancreatic enzymes every 3-4 hrs to avoid further obstruction. IV fluids and nasogastric (or PEG) drainage should be instituted .
DIOS is managed medically in most cases, with surgical treatment generally resulting from failed, delayed or inappropriate medical therapy
Prognosis & Followup strategies
Key Learning Points
- Patients with CF are surviving longer and are more likely to present to the ED with a complication of their disease. (Level 2)
- Almost 1 in 5 adults with CF will suffer a secondary spontaneous pneumothorax. (Level 4)
- The cause of death in 90% of patients with CF is respiratory infection and the most common colonising bacteria are P aeruginosa and S aureus. (Level 2)
- Adults with CF have twice the risk of fractures compared with the normal population. (Level 4)
- Pulmonary exacerbations may present without pyrexia, new x-ray changes or leucocytosis. (Level 4)
- A high index of suspicion will be required to identify pneumothorax in patients with CF, in whom this condition is common, as the presentation may be a typical. (Level 5)
- DIOS and fibrosing colonopathy are unique to CF all other causes of abdominal pain in the general population also present in patients with CF and with the same signs and symptoms. (Level 4)
- Have a high index of suspicion for fractures in patients with CF presenting with seemingly innocuous mechanisms of injury. (Level 5)
- Just because a young adult is not known to have CF, doesnt mean that they cannot have CF: primary diagnosis in adulthood is becoming more frequent. (Level 5)
- Chest x-rays are useful in the diagnosis and evaluation of respiratory complications of CF, however comparison with previous films is often required. (Level 5)
- CF is one of a few conditions where plain abdominal x-rays are recommended for evaluation of abdominal pain. (Level 5)
- TIVADs should only be accessed by staff that are trained to do so. (Level 5)
- Antibiotic treatment is required for most respiratory complications of CF. Be aware of drug allergies and recent sensitivities when selecting the appropriate antibiotic. (Level 5)
- DIOS is managed medically in most cases, with surgical treatment generally resulting from failed, delayed or inappropriate medical therapy. (Level 4)
Safety pearls and Pitfalls
- Failure to discuss patients with CF presenting to the ED with the regional CF centre.
- Failure to consider respiratory infection in the absence of new chest signs, and in the absence of any new chest X-ray changes.
- Failure to consider respiratory infection in the absence of a raised WBC count.
- Failure to recognise DIOS as a cause of abdominal pain in patients with CF.
- Failure to consider causes of abdominal pain presenting in the general population in patients with CF.
- Failure to consider a diagnosis of CF in adults presenting with recurrent respiratory infections or pancreatitis.
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