Australian Doctor 16th June 2023 16JUNE2023 issue | Page 30

16 JUNE 2023 ausdoc . com . au

Mucus clearance

a ) Normal CFTR b ) CFTR mutation

Figure 1 . Cystic fibrosis transmembrane regulator ( CFTR ) defect . A mutation in the CFTR gene stops chloride ( Cl- ) being secreted out of the cell and unrestrained sodium ( Na +) absorption through the epithelial sodium channel ( ENaC ), resulting in the airway surface layer becoming dehydrated and causing defective mucus clearance .

microbes seen in sputum of patients with CF include Stenotrophomonas maltophilia , Achromabactor xylosoxidans and the filamentous fungus fumigatus . 9 More difficult-to-treat organisms — such as Burkholderia cepacia complex and non-TB mycobacterium ( especially Mycobacterium avium complex and Mycobacteriun abscessus ) — are also cultured and require more specialised management to eradicate . 9 Those with CF are not encouraged to socialise with each other because of the risk of cross-infections and exacerbation of lung conditions , and protective isolation is important in the hospital setting .

DIAGNOSIS AND INVESTIGATION

HISTORICALLY , the diagnosis of CF relied on clinical presentation of the disease , but now most patients ( 64.2 % of Australian cohort ) are diagnosed after a positive NBS . 9

Antenatal diagnosis

Current RANZCOG guidelines recommend that genetic carrier screening is offered to all families planning a pregnancy . 15 It is estimated that one in 25 Australians are carriers for genes that cause CF , and most are unaware they are carriers . 11 The Federal Government has announced that reproductive carrier testing for three conditions — CF , spinal muscular atrophy and fragile X syndrome — will be available on the MBS in November 2023 .

Prenatal testing for CF is offered to couples where both parents are confirmed CF carriers . A range of pregnancy options are available and require discussion with a genetic counsellor . Options include prenatal testing ( performed via chorionic villus sampling or amniocentesis ) and pre-implantation genetic diagnosis . 15

Rarely , CF may be suspected during pregnancy when meconium ileus or peritonitis are noted at the routine 18-20-week morphology scan .

Postnatal diagnosis

CF is most commonly diagnosed on NBS . It was introduced in NSW in 1981 and has been performed for almost 20 years in all Australian states . 11 NBS was developed in New Zealand , where Crossley et al analysed dried blood spots for immunoreactive trypsinogen ( IRT ). 16 IRT , a digestive chemical from the pancreas , is elevated in the blood in most infants with CF .

Figure 2 . Different classes of cystic fibrosis transmembrane regulator ( CFTR ) gene mutations and their mechanism of action . Class I and Class VII mutations result in no protein production ( stop-codon mutation and no mRNA transcription respectively ). 7 They are the most severe and cannot be rescued by corrective therapy . Class II mutations ( including Phe508del ) result in misfolding of the protein at the endoplasmic reticulum and prevent trafficking of CFTR to the cell surface . 8 Class III mutation affects channel regulation and impairs channel opening . Class VI mutation causes substantial plasma membrane instability , resulting in high turnover of the protein . Class V mutations result in reduced synthesis of CFTR as a result of a reduction in mRNA . 10 Class IV mutations result in a defective CFTR channel . 10 Classes IV , V and VI are associated with mild phenotypes .

In NSW , infants with the highest 1 % of IRT values for each day are then tested for copies of the most common Australian CF mutations . If variants are identified , the NBS will directly refer these infants to a CF clinic or paediatrician . A sweat test is then performed . If this is positive , or two variants are identified , then a CF mutation panel is performed by a molecular genetics laboratory .

Because of the high correlation between meconium ileus and CF , it is important to be aware that IRT can be falsely low in children with meconium ileus , thus resulting in a negative NBS . 1 A sweat test is recommended in this situation .

A sweat test measures the concentration of chloride produced in the skin in response to heat . Testing needs to be performed in a reliable laboratory ( usually attached to a children ’ s hospital ) and should be performed as soon as possible after the infant is 10 days old — ideally , before the end of the neonatal period . 17 A minimum of 75mg of sweat is required , and the test is diagnostic if the level is greater than 60mmol / L . 17

A wide variety of symptoms can lead to a diagnosis of CF if this is not

detected on NBS . The most common include respiratory signs and symptoms ( such as chronic or recurrent respiratory tract infections ), meconium ileus or intestinal obstruction , faltering growth , malnutrition , steatorrhoea or male infertility . 18 , 19 Table 2 list the symptoms in the different age groups .

If CF is suspected , refer the child to a paediatrician for a sweat test . If the child has respiratory symptoms , then send a sputum sample ( if they can expectorate ) for microscopy , culture and sensitivities , and prescribe a broad-spectrum antibiotic , such as amoxycillin plus clavulanic acid . If P . aeruginosa is cultured from sputum samples in the absence of other underlying respiratory issue , investigate the patient for CF .

MANAGEMENT

THERE have been significant advances in clinical care , including formalised airway clearance therapy , pancreatic enzyme replacement , inhaled antibiotics and new modulator medications . Centre-based care is important and has become the norm in high-income countries , allowing patients to benefit from the skills of expert members of multidisciplinary teams ( see figure 8 ).

Regular investigations performed by CF team

At the Sydney Children ’ s Hospitals Network , children with CF are reviewed in outpatient clinics a minimum of every three months . At each appointment , their lung function is checked using spirometry and sputum specimen or cough swab is collected . Each child undergoes an annual check and investigation with pulmonary function tests , FBC , LFTs , renal function and electrolyte tests , immunoglobulin E ( IgE ), vitamin levels ( A , D , E and K ) and oral glucose tolerance test . Radiology includes a chest X-ray , liver ultrasound and dual-energy X-ray absorptiometry scan when appropriate . At some institutions , children will have an annual bronchoscopy if aged under five as they are often unable to produce sputum samples .

Lung function

Monitoring of lung function plays a significant role in maintaining lung health in those with CF . Spirometry ( see figure 9 ) is performed at every clinic visit and during inpatient admissions . The test is usually reliable from the age of six . Changes in

FEV 1 are used to assess the severity of lung disease . FEV 1 is a well-documented predictor of mortality and is used as an outcome in clinical trials to indicate or monitor response to treatments and to diagnose pulmonary exacerbations and the response to antibiotics , as well as for transplant referral ( FEV 1 about 30 % predicted ). 19 However , FEV 1 is an insensitive marker in early disease .

Physiotherapy

Physiotherapy techniques to promote mucociliary clearance are generally