What Types of New Therapies are Available for Cystic Fibrosis?

Patient Presentation
A 10 day-old female came to clinic for her health supervision visit. She was breastfeeding well and her minimal jaundice had improved since her previous visit at 5 days of life. The parents and physician had been notified that her newborn screening test was positive for possible cystic fibrosis. The parents had been reassured that currently there was nothing specific to do for her but that a sweat chloride test would need to be completed for diagnosis. A pulmonary clinic appointment had already been made.

The past medical history showed a full-term infant without any concerns during the pregnancy and delivery. She was the second child for the married parents.
The family history was negative for cystic fibrosis or any lung diseases. There was diabetes and heart disease in older family members. The family was of northern European ancestry and the parents were not related. There were no miscarriages or infants with genetic diseases or who died young in either family.

The pertinent physical exam revealed a female who was 1% above her birth weight at 3765 grams, with a head circumference of 35 cm and length of 48 cm. All were around 50% for age. Her examination was normal.

The diagnosis of a normal female infant with an abnormal newborn screening test for possible cystic fibrosis was made. The pediatrician offered handouts that had been sent to her by the state newborn screening clinic about cystic fibrosis. The parents didn’t have many questions as they had already done some research online and had been re-assured by the newborn screening professional when they had called to tell them about the diagnosis. The patient’s clinical course showed that her initial sweat test was between 30-60 mmol/L but there had been an inadequate amount of sweat collected. A repeated test with adequate samples was normal.

Discussion
Cystic fibrosis (CF) was identified in 1938 by Dr. Dorothy Andersen who described 49 patients with pancreatic insufficiency. Since that time significant achievements in the knowledge about the disease and treatments for patients have changed the mortality from a few months to patients living into middle adulthood or even later. Quality of life for patients and their families and friends has also markedly improved.

CF is the classic Mendelian autosomal recessive genetic disorder which is a worldwide disorder but affects people of north European ancestry more often where the main mutation is more common. There are more than 2000 variants, but the main mutation is known as Phe508del or F508del. This codes for the cystic fibrosis transmembrane conductance regulator gene (CFTR). Simplistically the CFTR codes for a protein that leaves the endoplasmic reticululum and attaches to the chloride and anion channel at the apical cell membrane which facilitates anion transport out of the cell. This regulates chloride, bicarbonate (needed for respiratory cell protection and pancreatic enzyme activation) and maintains epithelial surface hydration.

In countries with a high prevalence, newborn screening provides most of the diagnoses. Location specific protocols can include testing for immunoreactive trypsinogen, pancreatitis-associated protein testing and DNA mutation analysis. Newborn screening is a screening test and a sweat chloride test is considered the gold standard for diagnosis (> 60 mmol/L is abnormal). However there is a wide-variation in testing and in disease presentation, especially the older the patient is. Therefore CF should still be considered in the proper circumstances and in adults can include bronchiectasis, pancreatitis or infertility as presentations.

There are 7 classes of the CFTR mutation. “Class I, II, and III mutations are associated with no residual CFTR function and patients with these mutations on average have a severe phenotype, whereas individuals with class IV, V, VI mutations have some residual function of DFTR protein and have a mild lung phenotype and pancreatic sufficiency.” F508del is a class II variant. In the lung increased thick secretions along with infections and inflammation can cause lung damage as early as a few months. In the pancreas, increased mucus obstruction and inability to activate pancreatic enzymes can cause pancreatic insufficiency, malnutrition and diabetes (up to 40% of patients particularly females). Osteopenia and renal dysfunction and infertility are also potential problems. Infectious agents often colonize the lung and can cause disease and potentiate inflammatory responses. In children Haemophilus influenzae and Staphylococcus aureus are common. Over time, more gram-negative bacteria become prevalent and especially Pseudomonas aeruginosa are important to manage

Learning Point
Standard of care in high-income countries may be different than middle- and low-income countries because of available resources. Multi-specialty, designated care centers generally have the best outcomes but they are not always available. Patients should be referred for specialty care as soon as the diagnosis is made. Treatment for very young infants does make a difference in long-term outcomes as the effects of the disease appear to be additive over time. For pancreatic disease, a patient’s nutritional status is monitored closely and pancreatic enzyme replacement therapy completed daily. For lung disease, patients are encouraged to exercise which helps with pulmonary toilet. Specific pulmonary toilet physiotherapy is often initiated again to improve movement of secretions. Hypertonic saline inhalation is very effective in adults and data is also positive for children. Prophylactic antibiotics help prevent colonization and pulmonary infections. Regimens for this vary. Azithromycin is used as an anti-infective (especially against Pseudomonas aeruginosa) but has immunomodulatory activity as well.

Treating the underlying cause of CF appears to have made a significant leap in the past 2-3 years with trials of different modulator medications. For minimal function mutations where there is little function, medications are called “correctors” can be used which can be thought of as increasing the overall protein availability in some manner. For residual function mutations where some function is retained but is not overall effective enough, the medications are “potentiators” which can be thought of as improving the protein function in some manner. Combinations of these medications including “triple therapy” with ivacator (a potentiator), tezacaftor (a corrector) and elexacaftor (a corrector) can significantly improve lung functions. Other corrector medications are available including lumacaftor. Governmental approval of various drugs and combinations depends on location and also on specific CFTR variants. There is also the cost of these medications which currently is significant.

Patients’ whose disease leads to end-stage lung disease may be eligible for lung transplantation. Gene therapy is also being researched.

Questions for Further Discussion
1. How is cystic fibrosis managed in your location?
2. How are positive newborn screening results handled in your location?
3. What is the pediatrician’s role in rare or not so rare diseases? A review can be found here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Cystic Fibrosis and Newborn Screening.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Elborn JS. Cystic fibrosis. The Lancet. 2016;388(10059):2519-2531. doi:10.1016/S0140-6736(16)00576-6

Doull I. Cystic fibrosis 2019: Year in review. Paediatr Respir Rev. 2020;35:95-98. doi:10.1016/j.prrv.2020.04.001

De Boeck K. Cystic fibrosis in the year 2020: A disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

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Dacrocystitis in a Teenager?

Patient Presentation
A 13-year-old female came to clinic with a history of swelling medially on her left eye for the past 2 days. She said that it was painful but it improved after expressing some “pus” from the area when she pushed on it. She had had some facial trauma about 4 days prior to this when she was hit on the nose playing volleyball. She had some bruising but had not sought care. She endorsed increased tearing but had no redness or irritation of the eye. Her vision was normal and she had no problems moving her eyes. She denied any fever, chills, nausea, changes in mentation, rhinorrhea, facial or dental pain.
The past medical history was positive for a chalazion on the left eye about 2 years previously.

The pertinent physical exam revealed a well appearing female with normal vital signs. Along the lateral area of the nose/medial area of the left eye she had a 1 cm red/purplish mass. It was not warm but was just slightly tender. No pus could be seen after palpation of the area. The puncta looked clear. There was no conjunctival or scleral injection. Extraocular movements were normal and pupils were 3 mm and reacted briskly to light. Her nose had normal structures with some bruising at the bridge without abnormal discharge. Teeth had no pain with tapping.

The diagnosis of of dacrocystitis was made. Because this seemed mild but in an older child, ophthalmology was consulted by phone. They agreed to starting antibiotics and followed her up the next day. She continued to do well and this eventually resolved. It was felt this occurred because of swelling due to the nasal injury.

Discussion
Tears are produced in the lacrimal gland which resides in the upper outer quadrant of the eye. The tears flow across the eye medially and are collected in the superior and inferior puncta which drain into their respective canaliculi, and these drain into a common canaliculus. Tears then pass through the valve of Rosenmuler into the lacrimal sac where they are collected. Tears then pass through the nasolacrimal duct, through the distal valve of Hasner and into the nasal cavity. Vascular connections are extensive in this anatomic area and veins do not have valves. Therefore infections can spread easily through direct or indirect spread from the nasolacrimal duct system to other adjacent systems.

Dacrocystitis is an inflammation of the nasolacrimal sac that is usually caused by obstruction, leading to tear stagnation which then provides a good environment for proteinaceous material to form and infectious organisms to propagate. Dacrocystitis can be acute or congenital or acquired and acute or chronic. Congenital dacrocystitis is usually due to obstruction or stenosis in the distal anatomy particular the valve of Hasner. “Before delivery [of an infant] the nasolacrimal system is filled with amniotic fluid. When the amniotic fluid fails to be expressed forom the nasolacrimal system, it becomes purulent with a few days of delivery and becomes pathologic.” Acquired disease is caused by trauma, surgery, foreign bodies, neoplasms or medications. Chronic disease is due to chronic obstruction due to a systemic disease such as sarcoidosis or lupus erythematosus. Acute disease is usually due to an acute infectious cause with Staphylococcus(most common) species, Streptococcus species, Haemophilus influenzae and Pseudomonas aeruginosa being the most common causes. Polymicrobial infections are also common.

Not surprisingly given the pathophysiology and causes of dacrocystitis, there is a bimodal distribution with cases occurring around birth (mainly congenital and more acute) and then again in adults > 40 years old (acquired and may be acute or chronic).

Diagnosis is usually clinical. Symptoms can occur over hours to days. The area around the medial canthus swells and is tender and usually erythematous or even more purple colored. Purulent material can sometimes be expressed from the puncta. There often is an increase in tears which may also cause conjunctival injection. Constitutional symptoms such as fever or elevated inflammatory markers may be present but aren’t necessary for diagnosis. A full examination of the ophthalmologic and nasal structures is important. Culture of purulent material may be helpful to identify an offending organism. Imaging of the anatomic area may be necessary if there is extensive disease or involvement of the posterior orbital structures or complications are suspected. Potential morbidities can be severe with mortality a possibility as well because of the number of important structures that lie adjacent to this area including orbital cellulitis, meningitis, brain abscess, cavernous sinus thrombosis, lacrimal duct fistulas, sinusitis, or permanent vision loss.

Learning Point
Acute dacrocystitis can be a very serious infection and especially younger patients may need more evaluation or treatment. All require close monitoring. Congenital dacrocystitis usually resolves by 6 months. Nasolacrimal duct probing or intubation or balloon dacroplasty or stenting may be necessary depending on the underlying cause and types of previous treatment. Sometimes a dacrocystorhinostomy may be necessary.

The differential diagnosis includes:

  • Capillary hemangioma
  • Cellulitis – preseptal or orbital
  • Dacroadenitis – or inflammation of the nasolacrimal sac
  • Dacrocoele
  • Dermoid cyst
  • Ectropian or eversion of the lower lid
  • Encephalocoele
  • Sebaceous cyst
  • Sinusitis
  • Severe acne or medical chalazion usually can be eliminated as possibilities but in the right circumstances can be considered.

Questions for Further Discussion
1. What causes general eyelid swelling? A review can be found here
2. What is the difference between a hordeolum, chalazion and stye? A review can be found here
3. List emergencies related to the eye.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Eye Infections and Tears.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Ali MJ. Pediatric Acute Dacryocystitis. Ophthalmic Plast Reconstr Surg. 2015;31(5):341-347. doi:10.1097/IOP.0000000000000472.

Chung SY, Rafailov L, Turbin RE, Langer PD. The microbiologic profile of dacryocystitis. Orbit. 2019;38(1):72-78. doi:10.1080/01676830.2018.1466901.

Taylor RS, Ashurst JV. Dacryocystitis. In: StatPearls. StatPearls Publishing; 2021. Accessed April 5, 2021. http://www.ncbi.nlm.nih.gov/books/NBK470565/.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What Are Some Indications for Using Dexamethasone?

Patient Presentation
An 18-month-old male came to clinic after a bad night where he had sudden onset of a harsh, seal-like cough and difficulty breathing. The mother had taken him into the bathroom and made a steam bath which helped to calm him. He was able to drink and eventually go back to sleep but did awaken several times and needed the mother’s help to go back to sleep. “I’ve done this before, but he was up all night. We got a medicine for his brother once and that’s why I came in – to see if we can get some,” she said. He had a runny nose for the 24 hours before but was eating/drinking well and had no fever or other symptoms. He went to a group childcare and there was one child with similar symptoms. There were no known COVID-19 contacts. The past medical history was non-contributory.

The pertinent physical exam showed a slightly tired male with growth parameters in the 50-90%. His respiratory rate was 24 with an oxygen saturation of 97-99%. His voice and cry were hoarse sounding. He had moderate rhinorrhea. The rest of his examination was normal. The diagnosis of croup was made. The toddler was given one dose of dexamethasone in the clinic to help prevent worsening symptoms. Symptoms to monitor for were reviewed with the mother.

Discussion
Corticosteroids are a group of drugs which can be naturally or synthetically produced. Naturally occurring substances are produced in the adrenal gland, and are protein-bound (primarily corticosteroid-binding globulin and albumin). In the target tissues, they may need to be converted to an active substance. They are then reduced, oxidized, hydroxylated or conjugated as measures to inactivate them. Synthetic steroids have less protein binding and depending on their structure are more or less resistant to inactivation. Prednisone is the glucocorticoid most often used for treatment, especially as it has a short half-life. Prednisone must be converted to prednisolone to create any glucocorticoid effect. Asthma, acute severe dermatitis (e.g. poison ivy), chronic dermatitis (e.g. atopic dermatitis) are common uses of it for the primary care provider.

Systemic corticosteroids comparison:

  • Short acting
    • Cortisol or hydrocortisone, cortisone acetate
    • Lasts 8-12 hours
    • Anti-inflammatory activity = hydrocortisone is considered the standard
  • Intermediate
    • Prednisone, prednisolone, methylprednisolone, triamcinolone
    • Lasts 12-36 hours
    • Anti-inflammatory activity is increased 4-5 times, therefore an equivalent dose is less than hydrocortisone dosing (specific dosing must be checked)
  • Long acting
    • Betamethasone, dexamethasone
    • Lasts 36-72 hours
    • Anti-inflammatory activity is increased ~30 times, therefore an equivalent dose is substantially less than hydrocortisone dosing (specific dosing must be checked)

Topical steroids are also commonly used by primary care providers.
Their percutaneous absorption and therefore the overall potential efficacy depends on several factors:

  • Specific corticosteroid and its bioavailability
  • Vehicle – ointments generally are more potent than creams, lotions, gels, solutions or foam. A review of these vehicles can be found here.
  • Skin barrier integrity and/or inflammation – irritated, inflamed or broken skin has increased absorption
  • Surface area – more surface area increases absorption
  • Occlusive dressings – use under occlusal dressings increases absorption
  • Anatomic area – areas with thin epidermis have increased absorption (e.g. eyelids, face, genitalia)
  • Frequency and duration of use – more frequent or longer use increases absorption
  • Age – infants and young children’s skin has increased absorption

A fingertip unit (FTU) is the “amount of ointment or cream expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin crease to the tip of the index finger of an adult” is about 0.5 grams. FTU is a convenient way to measure the amount of topical medication being applied.
The general topical dosing in FTUs for an adult is:

    One hand – 0.5
    One arm – 3
    One leg – 6
    One foot – 2
    Trunk (front or back) – 7
    Face and neck – 2.5

A review of croup can be found here.

Learning Point
Dexamethasoneis a synthetic, fluoridated, potent glucocorticoid which has little mineralocorticoid effect. It is metabolized by the liver, excreted mainly in the urine and has a half-life of ~ 3 hours. Onset of action is rapid if given intravenously. It is available in tablets, oral solution or injectable suspension. Dexamethasone decreases white blood cell proliferation and migration and causes capillaries become less permeable. Various inflammatory proteins are inhibited and it also increases pulmonary circulation and surfactant production.

Some uses for dexamethasone include:

  • Acute hypersensitivity/allergies
  • Altitude sickness
  • Cancer treatment
  • Cerebral edema
  • Croup
  • Extubation
  • Inflammation, other
  • Multiple sclerosis
  • Prenatal maternal use before delivery of premature infants
  • Shock
  • Testing for Cushing syndrome
  • Spinal cord compression due to cancer metastasis

Side effects include:

  • Insomnia – most frequently reported
  • Immune suppression
  • Cardiac – arrhythmias, increased blood pressure
  • Central nervous system – increased intracranial pressure, pseudotumor cerebri, anxiety, depression
  • Dermatologic – acne
  • Endocrine/metabolic – adrenal suppression, hypothalmic-adrenal axis suppression, hyperglycemia, hypokalemia
  • Gastrointestinal problems – weight gain, anorexia, indigestion, nausea, emesis
  • Genitourinary – spermatogenic changes
  • Ophthalmologic – glaucoma
  • Orthopaedic – bone marrow suppression
  • Pulmonary – pulmonary edema

Contraindications include cerebral malaria, systemic fungal infections, or hypersensitivity. Dexamethasone should be used with caution with many underlying renal, gastrointestinal or myasthenia gravis diseases. Latent infectious diseases can be activated due to immune suppression. Use during pregnancy has an associated risk of increased oral clefts in the fetus. Use of live-virus vaccine administration is often delayed if dexamethasone or systemic corticosteroids are being used.

Questions for Further Discussion
1. Why are systemic corticosteroids usually tapered when discontinuing the medication?
2. What are indications for consultation with a pharmacist?
3. What are some mineralocorticoid effects?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Steroids and Croup.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Riney LC, Shah M, Lopez Domowicz DA. Visual Diagnosis: An Adolescent Male With Severe Facial Swelling and Scalp Infection. Pediatr Rev. 2015;36(11):e39-42. doi:10.1542/pir.36-11-e39.

Sarinho ESC, Melo VMPP. Glucocorticoid-induced Bone Disease: Mechanisms and Importance in Pediatric Practice. Rev Paul Pediatr. 2017;35(2):207-215. doi:10.1590/1984-0462;2017/;35;2;00007.

Scott SM, Rose SR. Use of Glucocorticoids for the Fetus and Preterm Infant. Clin Perinatol. 2018;45(1):93-102. doi:10.1016/j.clp.2017.11.002.

Gates A, Johnson DW, Klassen TP. Glucocorticoids for Croup in Children. JAMA Pediatr. 2019;173(6):595-596. doi:10.1001/jamapediatrics.2019.0834.

Nieman LK. Pharmacologic Use of Glucocorticoids. UpToDate. Updated 3/2/2019, Accessed 2/25/21.

Goldstein BG, Goldstein AO. Topical Corticosteroids. Use and Adverse Effects. UpToDate. Updated 2/10/20, Accessed 2/25/21.

Johnson DB, Lopez MJ, Kelley B. Dexamethasone. In: StatPearls. StatPearls Publishing; 2021. Accessed March 2, 2021. http://www.ncbi.nlm.nih.gov/books/NBK482130/.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa