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 content of electrolytes in sweat;
• family history (the presence of brothers and sisters, patients with cystic fibrosis).

It is enough to combine any 2 signs. Developed and proposed for the introduction of new criteria for diagnosis of cystic fibrosis, including 2 blocks:

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

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

For diagnosis of cystic fibrosis, a number of methods are used, differing in informativeness and labor intensity. These include the determination of the concentration of sodium and chlorine in the sweat, coprologic examination, DNA-diagnostics, measurement of the difference in nasal potentials, determination of elastase-1 activity in stool.

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

Anamnesis

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

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

Physical examination

With careful examination of patients, rapid breathing, an increase in the anteroposterior size of the thorax and a weak but persistent retraction of the lower intercostal muscles can be detected. With auscultation, you can listen to dry and wet small- and large-bubbling rales. Often, pathological changes in the auscultation of the lungs can not be detected.

Laboratory research

Sample Test

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

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

For the final diagnosis, it is necessary to obtain positive results when carrying out 2-3 blood tests. False negative results of sweat sampling are most often associated with:

• conducting a sweat test in newborns;
• technical mistakes of the medical staff admitted during the sample - inaccuracy 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 an analysis of sweat samples);
• taking sweat samples in patients with hypoproteinemic edema or hypoproteinemia (in patients with cystic fibrosis, the sweat test becomes positive after the edema disappears);
• carrying out the test against the background of treatment of the patient with cloxacillin.

Coprological examination

Insufficiency of exocrine pancreatic function, expressed in the extremely low activity or complete absence of pancreatic enzymes (lipase, amylase and trypsin) in the duodenum, is typical for the absolute majority of patients with cystic fibrosis. In the course of a simple coprologic examination, it is possible to detect pronounced steatorrhea (up to the detection of neutral fat in the stool).

The "gold standard" for determining the degree of insufficiency of the exocrine pancreatic function in cystic fibrosis, independent of the pancreatic enzyme replacement therapy, is the determination of the concentration of elastase-1 in stool. 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 insufficiency of the exocrine pancreatic function in patients with cystic fibrosis is 93%, and 87% for the diagnosis of cystic fibrosis. Reducing the concentration of elastase-1 serves as an indication for the appointment of substitution enzyme therapy in patients with cystic fibrosis and can help in selecting the dosage of enzymes.

Instrumental research

Chest X-ray

When analyzing chest radiographs, it is possible to identify the compaction of the walls of the bronchi, as well as the degree 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 the defeat of the upper right lobe is one of the important criteria for diagnosis of cystic fibrosis.

Examination of respiratory function

FVD is one of the main criteria for the severity of the defeat of the respiratory system. In patients with cystic fibrosis, it is also used as an early objective criterion for evaluating the effectiveness of treatment. In children older than 5-8 years, the FVD study has a significantly greater diagnostic value. The FVD test allows to determine the bronchial response to bronchodilators and to identify patients who will be appropriate for the purpose of these medications.

In children with cystic fibrosis, hyperreactivity of the bronchi sometimes appears. As the chronic infectious-inflammatory process progresses in the bronchopulmonary system, the volume of forced expiratory flow decreases in 1 s, the vital capacity of the lungs and the forced vital capacity of the lungs. The destruction of the lung parenchyma and the growth of restrictive disorders lead to a sharp decrease in these indicators in the late stages of the disease.

Measuring the difference in nasal potentials

This is an informative method of additional diagnosis of cystic fibrosis in children older than 6-7 years 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 bioelectrical potential of the nasal mucosa and the skin of the forearm. The indices of potential difference in healthy people range 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 1000 mutations determining the development of cystic fibrosis have already been found) are inexpedient because of the high cost of each study. In addition, with the exception of the 10 mutations most common in the region, the probability of cystic fibrosis in this patient is significantly reduced.

Prenatal diagnosis

The probability of the repeated birth of a patient with cystic fibrosis is high enough - 25%. DNA-diagnostics allows to reveal this disease even at the stage of the intrauterine period. The decision to save or terminate pregnancy is taken by the family, but before the pregnancy, DNA-diagnostics should be performed for all its members (a child with cystic fibrosis, and also for both parents) and consult a geneticist. In case of occurrence of each new pregnancy the family should address in the center of antenatal diagnostics not later than the eighth week of pregnancy. For diagnosis of cystic fibrosis in the fetus, you can conduct a genetic (for 8-12 weeks of pregnancy) or biochemical (for 18-20 weeks of pregnancy) study. Negative test results allow in 96-100% of cases to guarantee the birth of a healthy child.

Neonatal Diagnosis

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

In the 70s of the XX century. Scientists found that in the plasma of patients with cystic fibrosis, the concentration of immunoreactive trypsin was increased. This discovery allowed to develop and implement a program of 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 a newborn is determined. The test conducted during the first week of life of the examinee is very sensitive (85-90%), but is nonspecific. Therefore, a second test, which allows to exclude the false positive result of the first, is carried out for the 3-4th week of the life of the subject. The "gold standard" of the intravital diagnosis of cystic fibrosis - a sweat specimen is used as the main stage of neonatal screening in the vast majority of protocols.

Unfortunately, despite significant success in the treatment and diagnosis of cystic fibrosis, with the development of the clinical picture of the disease in the first year of life, only one third of all patients are diagnosed timely.

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

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

Two systems are successfully used to conduct a sweat test, which makes it possible to measure the electrical conductivity of sweat. The system for collection and analysis of sweat Macrodact in conjunction with the Sweat-Chek Sweat-Chek analyzer from Vescor (USA) allows for a swab sample outside the laboratory, sweat collection time is 30 minutes, successfully used in children from the first months of life. Especially for the examination of newborns by Vescor, the Nanodact was developed. Due to the minimum amount of test fluid required for the test, only 3-6 μl, this device is indispensable in the examination of newborns as part of a mass screening.

If a positive result of the swallowing test (less than 40 mmol / L with the classical Gibson-Cook method and / or 60 mmol / L when working with the sweat analyzers) is monitored at the place of residence for the first year of life, neonatal hypertrypsinogenemia is diagnosed to exclude cases of hypodiagnosis. When obtaining the boundary results of the sweat test (40-60 mmol / L by the Gibson-Cook method and 60-80 mmol / L using the 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. With a positive result of the swallowing test, as well as the detection of mutations in the gene of the cystic fibrosis transmembrane conduction regulator (with the boundary result of the sweat test), the child is diagnosed with cystic fibrosis. In case of doubt, additional examination methods should be used (feces analysis for pancreatic elastase-1, microscopic coprologic examination, CT or chest radiography, smear from the throat).

For proper monitoring of the condition of patients with cystic fibrosis, including without symptoms of the disease, regular monitoring by specialists of the Cystic Fibrosis Center is necessary. Newborns younger than 3 months should be examined every 2 weeks, until the child reaches 6 months - 1 time per month, until the end of infancy - 1 time in 2 months, at an older age - every quarter. Regular inspections allow you to dynamically evaluate the increase in body weight and follow the pace of physical development, with the necessary frequency to conduct laboratory tests:

• coprologic - at least 1 time per month during the first year of the child's life;
• determination of the concentration of pancreatic elastase-1 in feces - 1 time in 6 months with initially normal results;
• microscopic examination of swabs from the oropharynx - 1 time per 3 months;
• the clinical analysis of a blood - 1 time in 3 months.

With the development of a chronic infectious and inflammatory process in the lungs, a more in-depth examination is needed (chest X-ray or CT, lipid stool, biochemical blood test, proteinogram, etc.).

Differential diagnosis of cystic fibrosis

Cystic fibrosis must be differentiated with other diseases in which a sweat test can be positive:

• pseudohyperdosteronism;
• congenital dysfunction of the adrenal cortex;
• insufficiency of adrenal function;
• hypothyroidism;
• hypoparathyroidism;
• nephrogenic diabetes insipidus;
• Moriak's syndrome;
• cachexia;
• anorexia nervosa;
• glycogenosis type II;
• insufficiency of glucose-6-phosphatase;
• atopic dermatitis;
• ectodermal dysplasia;
• AIDS;
• Down syndrome;
• Klinefelter's syndrome;
• family cholestatic syndrome;
• fucosidosis;
• mucopolysaccharidosis;
• chronic pancreatitis;
• hypogammaglobulinemia;
• celiac disease.

[1], [2], [3], [4], [5], [6], [7]