Diagnosis of cystic fibrosis

Currently, the diagnosis of cystic fibrosis is based on the following criteria proposed by di Sanl'Agnese.

• chronic bronchopulmonary process;
• characteristic intestinal syndrome;
• increased electrolyte content in sweat;
• family history (having brothers and sisters with cystic fibrosis).

A combination of any 2 signs is sufficient. New criteria for cystic fibrosis diagnostics have been developed and proposed for implementation, including 2 blocks:

• one of the characteristic clinical symptoms, or a case of cystic fibrosis in the family, or a positive result of neonatal screening for immunoreactive trypsin;
• elevated sweat chloride concentration (>60 mmol/L), or 2 identified mutations, or a nasal potential difference value in the range of -40 to -90 mV.

The diagnosis is considered confirmed if at least one criterion from each block is met.

A number of methods are used to diagnose cystic fibrosis, differing in their information content and labor intensity. These include determination of sodium and chlorine concentration in sweat, coprological examination, DNA diagnostics, measurement of nasal potential difference, determination of elastase-1 activity in feces.

The basis for the diagnosis of cystic fibrosis, as a rule, is the typical clinical manifestations of the disease in combination with a high content of sodium chloride in the secretion of the sweat glands.

Anamnesis

Great importance is attached to the family history for the diagnosis of cystic fibrosis, during the collection of which it is necessary to clarify the presence of:

• established diagnosis or symptoms of cystic fibrosis in siblings;
• similar clinical manifestations in close relatives;
• deaths of children in the first year of life.

Physical examination

A thorough examination of patients may reveal rapid breathing, an increase in the anteroposterior size of the chest, and a mild but persistent retraction of the lower intercostal muscles. Auscultation may reveal dry and moist fine and large bubbling rales. Often, pathological changes cannot be detected during auscultation of the lungs.

Laboratory research

Sweat test

The sweat test is the most specific diagnostic test for cystic fibrosis. According to the standard method, a sweat sample is taken after preliminary iontophoresis with pilocarpine on the skin area to be examined. The concentration of sodium chloride in the sweat gland secretion normally does not exceed 40 mmol/l. The result of the sweat test is considered positive if the concentration of sodium chloride in the sample exceeds 60 mmol/l. The sweat test should be repeated if the first sweat test:

• positive;
• dubious;
• negative, but clinical manifestations allow us to assume with a high degree of probability the presence of cystic fibrosis.

To make a final diagnosis, it is necessary to obtain positive results from 2-3 sweat tests. False negative sweat test results are most often associated with:

• conducting a sweat test on newborns;
• technical errors made by medical personnel during the test - carelessness in collecting and transporting sweat, cleaning the skin, weighing and determining the concentration of electrolytes (most often, such errors occur in laboratories that rarely conduct sweat test analysis);
• taking sweat samples from patients with hypoproteinemic edema or hypoproteinemia (in patients with cystic fibrosis, the sweat test becomes positive after the edema has resolved);
• conducting a test while the patient was being treated with cloxacillin.

Coprological examination

Insufficiency of the exocrine function of the pancreas, expressed in extremely low activity or complete absence of pancreatic enzymes (lipase, amylase and trypsin) in the duodenum, is characteristic of the absolute majority of patients with cystic fibrosis. In this case, during a simple coprological examination, it is possible to detect pronounced steatorrhea (up to the detection of drops of neutral fat in the feces).

The "gold standard" for determining the degree of exocrine pancreatic insufficiency in cystic fibrosis, independent of the replacement therapy with pancreatic enzymes, is considered to be the determination of the concentration of elastase-1 in feces. Normally, the content of this enzyme exceeds 500 μg/g of sample. The specificity of this method is 100%, the sensitivity for determining the degree of exocrine pancreatic insufficiency in patients with cystic fibrosis is 93%, and for diagnosing cystic fibrosis - 87%. A decrease in the concentration of elastase-1 serves as an indication for the appointment of replacement enzyme therapy in patients with cystic fibrosis and can help in selecting the dosage of enzymes.

Instrumental research

Chest X-ray

When analyzing chest X-rays, it is possible to detect compaction of the bronchial walls, as well as varying degrees of compaction or increased airiness of the lung tissue. In addition, it is possible to detect signs of atelectasis of segments and lobes of the lungs, and damage to the right upper lobe is one of the important criteria for diagnosing cystic fibrosis.

Study of external respiratory function

FVD is one of the main criteria for the severity of respiratory system damage. In patients with cystic fibrosis, it is also used as an early objective criterion for assessing the effectiveness of treatment. In children over 5-8 years of age, FVD testing has a significantly greater diagnostic value. FVD testing allows us to determine the response of the bronchi to bronchodilators and identify patients for whom the administration of these drugs would be appropriate.

Children with cystic fibrosis sometimes develop bronchial hyperreactivity. As the chronic infectious and inflammatory process in the bronchopulmonary system progresses, the forced expiratory volume in 1 s, vital capacity of the lungs, and forced vital capacity of the lungs decrease. Destruction of the lung parenchyma and the increase in restrictive disorders lead to a sharp decrease in these indicators in the late stages of the disease.

Measuring the nasal potential difference

This is an informative method of additional diagnostics of cystic fibrosis in children over 6-7 years old and adults. It is aimed at identifying the main defect that causes the development of cystic fibrosis. The essence of the method is to measure the difference in the bioelectric potential of the nasal mucosa and the skin of the forearm. The potential difference indicators in healthy people vary from -5 to -40 mV, in patients with cystic fibrosis - from -40 to -90 mV.

Genetic analysis

Conducting genetic tests for all known mutations (more than 1,000 mutations that cause cystic fibrosis have already been discovered) is impractical because each test is too expensive. In addition, by excluding the 10 most common mutations in a given region, the probability of cystic fibrosis in a given patient is significantly reduced.

Prenatal diagnosis

The probability of having a child with cystic fibrosis again is quite high - 25%. DNA diagnostics allows to detect this disease already at the intrauterine stage. The decision to continue or terminate the pregnancy is made by the family, however, before pregnancy, DNA diagnostics should be carried out for all its members (the child with cystic fibrosis, as well as both parents) and a consultation with a geneticist should be conducted. With each new pregnancy, the family should contact the prenatal diagnostic center no later than the eighth week of pregnancy. To diagnose cystic fibrosis in the fetus, a genetic (at 8-12 weeks of pregnancy) or biochemical (at 18-20 weeks of pregnancy) study can be carried out. Negative test results allow in 96-100% of cases to guarantee the birth of a healthy child.

Neonatal diagnostics

The neonatal period in patients with cystic fibrosis often proceeds asymptomatically (even if it subsequently develops severely) or the clinical picture is so blurred that it does not allow the doctor to suspect this disease.

In the 1970s, scientists discovered that the concentration of immunoreactive trypsin in the blood plasma of patients with cystic fibrosis was elevated. This discovery made it possible to develop and implement a program for mass screening of newborns for cystic fibrosis.

At the first stage of screening, the concentration of immunoreactive trypsin in a dried drop of blood of the newborn is determined. The test, carried out during the first week of the life of the subject, is very sensitive (85-90%), but non-specific. Therefore, a repeat test, which allows to exclude a false positive result of the first, is carried out at the 3-4th week of the life of the subject. The "gold standard" of lifetime diagnostics of cystic fibrosis - a sweat test is used as the main stage of neonatal screening in the overwhelming majority of protocols.

Unfortunately, despite significant advances in the treatment and diagnosis of cystic fibrosis, when the clinical picture of the disease develops in the first year of life, only a third of all patients receive a timely diagnosis.

The cystic fibrosis screening protocol includes four steps, with only the first three being mandatory:

• first determination of the concentration of immunoreactive trypsin;
• repeat determination of the concentration of immunoreactive trypsin;
• conducting a sweat test;
• DNA diagnostics.

Two systems that measure the electrical conductivity of sweat are successfully used to conduct a sweat test. The Macrodact sweat collection and analysis system in combination with the Sweat-Chek sweat analyzer from Vescor (USA) allows for a sweat test to be conducted outside the laboratory; the sweat collection time is 30 minutes; it is successfully used in children from the first months of life. The Nanodact device was developed by Vescor specifically for examining newborns. Due to the minimal amount of sweat fluid required for the test, only 3-6 µl, this device is indispensable when examining newborns as part of mass screening.

If the sweat test result is positive (less than 40 mmol/l using the classic Gibson-Cook method and/or 60 mmol/l when using sweat analyzers), the child is observed at the place of residence during the first year of life with a diagnosis of neonatal hypertrypsinogenemia to exclude cases of underdiagnosis. If the sweat test results are borderline (40-60 mmol/l using the Gibson-Cook method and 60-80 mmol/l when using sweat analyzers), the sweat test should be repeated 2-3 times. In addition, to confirm the diagnosis in such cases, it is advisable to conduct DNA diagnostics. If the sweat test result is positive, as well as if mutations in the cystic fibrosis transmembrane conductance regulator gene are detected (with a borderline sweat test result), the child is diagnosed with cystic fibrosis. In doubtful cases, additional examination methods should be used (stool analysis for pancreatic elastase-1, microscopic coprological examination, CT or chest X-ray, throat smear culture).

For proper monitoring of the condition of patients with cystic fibrosis, including those without symptoms of the disease, regular observation by specialists of the Cystic Fibrosis Center is necessary. Newborns under 3 months should be examined every 2 weeks, until the child reaches 6 months - once a month, until the end of infancy - once every 2 months, at an older age - quarterly. Regular examinations allow dynamic assessment of weight gain and monitoring of the rate of physical development, with the necessary frequency of laboratory tests:

• coprological - at least once a month during the first year of the child's life;
• determination of the concentration of pancreatic elastase-1 in feces - once every 6 months with initially normal results;
• microscopic examination of smears from the oropharynx - once every 3 months;
• clinical blood test - once every 3 months.

If a chronic infectious and inflammatory process develops in the lungs, a more in-depth examination is necessary (chest X-ray or CT scan, stool lipidogram, biochemical blood test, proteinogram, etc.).

Differential diagnosis of cystic fibrosis

Cystic fibrosis must be differentiated from other diseases in which the sweat test may be positive:

• pseudohypoaldosteronism;
• congenital dysfunction of the adrenal cortex;
• adrenal insufficiency;
• hypothyroidism;
• hypoparathyroidism;
• nephrogenic diabetes insipidus;
• Mauriac syndrome;
• cachexia;
• nervous anorexia;
• glycogenosis type II;
• glucose-6-phosphatase deficiency;
• atopic dermatitis;
• ectodermal dysplasia;
• AIDS;
• Down syndrome;
• Klinefelter syndrome;
• familial cholestatic syndrome;
• fucosidosis;
• mucopolysaccharidosis;
• chronic pancreatitis;
• hypogammaglobulinemia;
• celiac disease.

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