Cystic Fibrosis

Cystic fibrosis is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, and pancreatic insufficiency. The gold standard for diagnosis is the sweat chloride test, which can be complemented by genetic testing. Cystic fibrosis ultimately leads to chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and multisystem organ failure. Management includes CFTR modulator therapy and system-specific strategies for supportive care. Prognosis varies depending on treatment and complications. With optimal medical care, patients can live into their mid-40s.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology

  • Synonyms: mucoviscidosis, fibrosa cystica
  • Incidence differs significantly among ethnicities:
    • Caucasians: 1 in 3,000–4,000 live births
    • Latin Americans: 1 in 4,000–10,000 live births
    • African Americans: 1 in 15,000–20,000 live births
    • Asian Americans: 1 in 100,000 live births
  • Most common autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisease in white populations
  • Incidence in the United States: 1 in 3,400 live births
  • Cystic fibrosis (CF) screening is part of the newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn screening in many countries with a high prevalence of the condition.
  • More than 75% of people with CF are diagnosed by the age of 2.

Etiology and Pathophysiology

Etiology

  • Autosomal recessive inheritance 
  • Over 1,500 causative mutations have been identified.
  • The most common mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in Central Europe and North America is the delta F508 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations on chromosome 7. This deletion causes the loss of phenylalanine in position 508.
Type of mutation on cystic fibrosis

Types of mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in cystic fibrosis

Image by Lecturio.
  • The type of mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is crucial in determining the severity of the disease.
    There are 4 distinct classes:
    1. No gene expression of CFTR
    2. The CFTR channel can be constructed, but cannot be built into the membrane or be located (applies to the delta F508 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations).
    3. The channel is expressed and built-in, but cannot open due to the mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.
    4. The protein does not fold correctly, and therefore the channel does not open properly.
  • CFTR encodes an important component of ATP-gated chloride channel in cell membranes.
    • Usually found in epithelial cells throughout the body (e.g., gastrointestinal and respiratory epithelia, sweat glands, exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas, exocrine glands of reproductive organs)

Pathophysiology

  • Mutated CFTR → absent or dysfunctional chloride channel → dysfunctional transport of chloride → abnormal secondary transport of sodium and water
  • In sweat glands: inability to reabsorb chloride from the lumen → reduced reabsorption of sodium and water → sweat with elevated levels of sodium chloride + excessive loss of salt
  • In rest of exocrine glands: inability to secrete chloride into the lumen → accumulation of intracellular chloride → increased sodium and water reabsorption → formation of hyperviscous mucus → accumulation of secretions → blockage of small passages → chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation → multiple organ damage

Impact on organ systems

  • Lung
    • Ineffective mucociliary clearance; obstruction of the alveoli/bronchioles with an increased risk of infection 
    • Destruction of the lung and reformation into a honeycomb parenchymal pattern due to chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Pancreas
    • Blockage of the exocrine gland’s secretion outlets
    • Fibrotic and cystic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
    • Loss of exocrine function
  • Gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
    • Obstruction of bile drainage
    • Development of biliary cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Intestines
    • Obstipation

Clinical Presentation

Respiratory system

  • Chronic/recurrent sinus infections, nasal polyps
  • Recurrent pulmonary infections, especially with Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa 
    • Increasing lung insufficiency leads to exertional dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, anoxia, and bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis
    • Clubbing of fingers and nails
    • 10%–50 % of patients develop polyposis nasi and chronic pansinusitis 
    • Expiratory wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing and barrel chest

Gastrointestinal system

Small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine Thick secretions impair absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption, increasing the risk of obstruction.
  • Fails to pass meconium within 48 hrs of life in newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Bowel obstruction, unable to pass gas, abdominal distention, nausea, vomiting
Large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix Incompletely digested macronutrients lead to thick stool, predisposing patient to impaction, obstruction, intussusception Intussusception Intussusception occurs when a part of the intestine (intussusceptum) telescopes into another part (intussuscipiens) of the intestine. The condition can cause obstruction and, if untreated, progress to bowel ischemia. Intussusception is most common in the pediatric population, but is occasionally encountered in adults. Intussusception.
Pancreas
  • Thick secretions block pancreatic duct and impair fat absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption, leading to a deficiency of fat-soluble vitamins A, D, E, and K.
  • Decreased bicarbonate damages digestive lining and impairs absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.
  • Pancreatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes slowly destroy pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, leading to fibrosis and impaired endocrine function (diabetes).
Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain; abdominal cramping; bloating; frequent bulky, oily stools; weight loss; flatulence
Hepatobiliary
  • Bile is dehydrated, leading to gallstones.
  • Chronic cholestasis leads to inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and fibrosis, which results in cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis and portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension.
Right upper quadrant pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain after large, fatty meals; nausea; vomiting; jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice

Reproductive system

  • Males 
    • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility and delayed secondary sexual development due to:
      • Obstructive azoospermia due to bilateral aplasia/atresia of the deferent duct
      • Undescended testicle; 15 times more likely than in the general population 
  • Females
    • Reduced fertility due to:
      • Viscous cervical mucus 
      • Amenorrhea

Urinary system

  • Nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis
  • Stress incontinence (frequent coughing)

Mnemonic device

To recall the most common clinical features of cystic fibrosis, remember the acronym CF PANCREAS:

  • C: Chronic cough
  • F: Failure to thrive
  • P: Pancreatic insufficiency (exocrine)
  • A: Alkalosis and hypotonic dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration
  • N: Nasal polyps, neonatal dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration
  • C: Clubbing of fingers (Hippocratic fingers and nails)
  • R: Rectal prolapse Rectal prolapse Rectal prolapse, also known as rectal procidentia, is the protrusion of rectal tissue through the anus. The tissue may include just the mucosa or the full thickness of the rectal wall. Common risk factors include chronic straining, constipation, bowel motility disorders, and weakening of the pelvic floor muscles. Rectal Prolapse
  • E: Electrolyte elevation (sweat)
  • A: Atresia, absence of vas deferens
  • S: Sputum with Staphlococcus aureus or Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas

Complications

Exacerbation of pulmonary disease
  • No single set criteria; defined as an acute change in pulmonary status
    • New or increased cough or sputum production, decreased exercise tolerance, increased respiratory rate
  • Can include loss of appetite, weight loss, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and fatigue
  • May lead to a spontaneous pneumothorax Pneumothorax A pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam. Pneumothorax
  • May lead to hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis (hemorrhage of pulmonary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries, with potentially lethal outcome if blood loss > 0.5 L in 24 hours)
Chronic microbial colonization
  • Evidence of 1 pathogenic microorganism in at least 3 sputum cultures over at least 6 months
  • Toddlers:
    • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus infection
    • Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae
  • Children and teenagers:
    • Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa (biofilm formation)
    • Stenotrophomonas maltophilia
  • Viral infections
Allergic bronchopulmonary aspergillosis Aspergillosis Aspergillosis is an opportunistic fungal infection caused by Aspergillus species, which are common spore-forming molds found in our environment. As Aspergillus species are opportunistic, they cause disease primarily in patients who are immunocompromised. The organs that are most commonly involved are the lungs and sinuses. Aspergillus/Aspergillosis Aspergillus airway colonization, followed by vigorous IgE- and IgG-mediated immune response, varied presentation which can include worsening fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, malaise, mucous plugging that may not improve with antibiotics
Biliary cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis Bile duct obstruction in adults
Endocrine pancreatic insufficiency Development of diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, including the destruction of the islets of Langerhans in adulthood

Diagnosis

Cystic fibrosis testing algorithm

Testing algorithm for CF as conducted in many countries. IRT: immunoreactive trypsinogen Trypsinogen The inactive proenzyme of trypsin secreted by the pancreas, activated in the duodenum via cleavage by enteropeptidase. Pancreatic Parameters

Image by Lecturio.

Newborn screening

  • CF testing is part of the newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn screening in most high-prevalence countries (North America, Australia, many European countries).
  • Involves multiple steps of testing on dried blood spots
  • Measurement of immunoreactive trypsinogen Trypsinogen The inactive proenzyme of trypsin secreted by the pancreas, activated in the duodenum via cleavage by enteropeptidase. Pancreatic Parameters, if positive → mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations analysis of CFTR
  • If results indicate CF, the next step is a sweat chloride test when the infant is at least 2 weeks of age and weighs over 2 kg.

Sweat chloride test: gold-standard of diagnosis 

  •  Pilocarpine iontophoresis used to determine sweat chloride concentration
  •  > 60 mmol/L in 2 tests: diagnosis of CF
Newborn screening

Principle and conduction of a sweat chloride test

Image by Lecturio.

Further testing

If the diagnosis remains unclear, further testing can be done.

Nasal potential difference

  • Specialized test only at CF centers; further evaluates CFTR dysfunction
  • Electrodes Electrodes Electric conductors through which electric currents enter or leave a medium, whether it be an electrolytic solution, solid, molten mass, gas, or vacuum. Normal Electrocardiogram (ECG) are placed in the nasal cavity, which is then bathed in a series of solutions with different salts designed to change ion flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure across the membrane in predictable ways.
  • Patients with CF have a more negative baseline difference and react differently to the other salts because of defective chloride transport.

Fecal elastase

Pancreatic insufficiency can be detected when screening the stool for pancreatic elastase Pancreatic Elastase A protease of broad specificity, obtained from dried pancreas. Molecular weight is approximately 25, 000. The enzyme breaks down elastin, the specific protein of elastic fibers, and digests other proteins such as fibrin, hemoglobin, and albumin. Pancreatic Parameters-1, which is absent in 80% of people with CF.

Imaging

  • Sinus CT: panopacification, nasal polyps
  • Chest CT: bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis typically in upper lobes, may progress to be visible on radiographs

Airway culture

  • Persistent detection of the following bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview in respiratory secretion and sputum
  • 80% grow S. aureus or Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa
  • Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae, Burkholderia Burkholderia Burkholderia species are gram-negative bacilli with 2 clinically relevant pathogens: B. pseudomallei (causing melioidosis) and B. cepacia complex (causing opportunistic infections). Melioidosis is commonly seen in Asia and Australia. Infection is transmitted by contact with contaminated soil or water (via skin wounds). Burkholderia cepacia, Stenotrophomonas maltophilia
    • All (except S. aureus) would be unusual in healthy people without CF

Treatment

Management of CF should be multidisciplinary and include specialized physicians, physiotherapists, dieticians, and/or psychological support.

Organ system Approach to therapy
Lung infections, respiratory lung insufficiency
  • Promote lung health: CFTR modulator, endurance sports
  • Enhance airway clearance: inhaled DNase, inhaled hypertonic saline, chest physiotherapy
  • Prevention of infection: all routine childhood vaccines, annual influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination, high-risk protocol for pneumococcal vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination, palivizumab to prevent respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus infection, contact precautions in all healthcare settings
  • Bronchodilators: beta-2 adrenergic agonist before chest physio, inhaled meds or if symptomatic
  • Anti-inflammatory measures: oral azithromycin 3x/week, high-dose ibuprofen if under the age of 18 with good lung function
  • Prevention of acute exacerbations: treatment of chronic P. aeruginosa infection with inhaled tobramycin
  • Treatment of acute exacerbation: systemic antibiotics guided by culture data, intensified airway clearance, steroids only if concurrent asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma is present
  • Referral to transplant center: previously thought of as “last resort” but now recommended earlier in disease course if:
    • Rapid decline in FEV1
    • Hypoxia (paO2 < 88)
    • Hypercarbia (pCO2 > 50 on ABG)
    • Significant pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension OR
    • Exacerbation needing positive pressure ventilation
Hypotonic dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration/hypochloremic alkalosis
  • Adequate hydration, liberal salt intake at baseline
  • Increase salt intake if patient or environmental factors are expected to encourage fluid loss (e.g., high heat, sweating, vomiting, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever)
Exocrine pancreatic insufficiency A dose of pancreatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (defined lipase and protease concentration) with every meal
Failure to thrive
  • High-calorie diet, rich in fats
  • Enteral nutrition via feeding tube
Vitamin and mineral deficits Prophylactic substitution of liposoluble vitamins in supranormal doses, replace minerals and trace elements Trace elements Trace elements are minerals required in small amounts (1-100 mg/day in adults) to carry out biologic functions. These elements act as cofactors for essential enzymes as well as being components of hormones and antioxidant molecules. Iron, chromium, copper, and iodine are among these elements. Trace Elements
CF-related diabetes
  • Different from Type 1 and Type 2 diabetes, different dietary recommendations
  • Treat with insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin

Prognosis

  • With optimal treatment, CF patients have a median life expectancy of 45 years.
  • 50% of patients die before the age of 18 from respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure.
  • The prognosis depends on several factors:
    • Age 
    • Female sex
    • Gene variant 
    • Colonization by multi-drug resistant pathogens 
    • Lung function
    • Complications
    • Access to medical care 

Differential Diagnosis

The following conditions are related to cystic fibrosis:

  • Bronchiectasis: a chronic condition in which the bronchi walls thicken as a result of inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and infection. This condition is characterized by the permanent enlargement of sections of the airways within the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs. Patients often have flare-ups of breathing difficulties, displaying chronic cough with mucus production.
  • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: acute or chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of lung tissue caused by infection with bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, viruses, or fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology: Overview. Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia can be also due to toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.
  • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion: a disorder involving the inability to absorb nutrients from food, such as carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates, fats, minerals, proteins, or vitamins. Lactose intolerance Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance and celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease are related to malabsorption.
  • Failure to thrive: children who are gaining weight or height more slowly compared with other children of similar age or sex. Usually, they present with underdevelopment of motor skills gained in early childhood, such as rolling over, standing, and walking.
  • Dehydration: a condition caused by excessive loss of body fluids. Water is lost out of the individual cells of the body, leading to a net decrease in the total volume of water in the body.
  • Rectal prolapse Rectal prolapse Rectal prolapse, also known as rectal procidentia, is the protrusion of rectal tissue through the anus. The tissue may include just the mucosa or the full thickness of the rectal wall. Common risk factors include chronic straining, constipation, bowel motility disorders, and weakening of the pelvic floor muscles. Rectal Prolapse: a condition in which the rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal loses its normal attachments inside the body, thereby turning itself inside-out through the anus. Definitive treatment requires surgery.
  • Allergic bronchopulmonary aspergillosis Aspergillosis Aspergillosis is an opportunistic fungal infection caused by Aspergillus species, which are common spore-forming molds found in our environment. As Aspergillus species are opportunistic, they cause disease primarily in patients who are immunocompromised. The organs that are most commonly involved are the lungs and sinuses. Aspergillus/Aspergillosis: a hypersensitivity response to the fungus Aspergillus. Patients most often affected are those with asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma or cystic fibrosis.
  • Biliary cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis: a chronic disease in which bile ducts are slowly degraded. With the backup of bile in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, patients often suffer from cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis.
  • Asthma: a chronic inflammatory condition characterized by reversible obstruction to airflow in the lower airways. Patients present with intermittent or persistent wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, cough, and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Diagnosis is usually confirmed with pulmonary function testing that shows a reversible obstructive pattern. Treatment varies based on the severity and includes bronchodilators and inhaled corticosteroids for control of inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation.
  • Primary ciliary dyskinesia Primary Ciliary Dyskinesia Primary ciliary dyskinesia (PCD), also known as immotile-cilia syndrome, is an autosomal recessive disorder leading to an impairment that affects mucociliary clearance. Primary ciliary dyskinesia is caused by defective ciliary function in the airways and is characterized by the loss of oscillation (immotility), abnormal oscillation (dyskinesia), or absence of cilia (aplasia). Primary Ciliary Dyskinesia (PCD): a rare autosomal-recessive genetic disorder leading to dysfunction of the ciliated epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium. Patients present early in childhood with recurring rhinosinusitis, otitis, respiratory infections, and eventual bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis. PCD is often associated with situs inversus and infertility.

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