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Rom J Morphol Embryol
2020, 61(2):397–406 ISSN (print) 1220–0522, ISSN (online) 2066–8279 doi: 10.47162/RJME.61.2.09
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ORIGINAL PAPER
Multidisciplinary approach to patients with manifestations
and pulmonary complications of cystic fibrosis
V
IOREL
B
ICIUŞCĂ
1),
I
LEANA
O
CTAVIA
P
ETRESCU
2),
C
RISTINA
E
LENA
S
INGER
2),
A
NCA
G
ABRIELA
O
ANCEA
3),
A
NA
-M
ARIA
P
ETRESCU
4),
I
ONELIA
-S
ORINA
S
TAN
5),
P
ATRICIA
D
URAND
5),
C
ITTO
I
ULIAN
T
AISESCU
6),
D
ANIELA
D
UMITRESCU
7),
M
IHAELA
A
MELIA
D
OBRESCU
8),
I
ON
U
DRIŞTOIU
9),
D
IANA
R
ODICA
T
UDORAŞCU
10),
F
LORIN
P
ETRESCU
10)
1)
Department of Internal Medicine, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
2)
Department of Pediatrics, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
3)
Department of Pediatrics, Emergency County Hospital, Craiova, Romania
4)
Department of Obstetrics and Gynecology, Resident Physician, Emergency County Hospital, Craiova, Romania
5)
Department of Internal Medicine, Resident Physician, Emergency County Hospital, Craiova, Romania
6)
Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
7)
Department of Radiology and Medical Imaging, University of Medicine and Pharmacy of Craiova, Romania
8)
Department of Medical Genetics, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
9)
Department of Psychiatry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
10)
Department of Medical Semiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
Abstract
Cystic fibrosis (CF) is a genetic disease, with autosomal recessive transmission, multisystemic, characterized by a remarkable clinical polymorphism
and significant lethal prospective. Respiratory manifestations dominate the clinical picture, being present in all patients. The aim of the paper
was to analyze the incidence of clinical manifestations, especially respiratory ones, as well as the contribution of interdisciplinary consultations
to the positive diagnosis of CF, in a group of 16 patients who were hospitalized and treated in the II
nd
Pediatric Clinic and II
nd
Medical Clinic
of the Emergency County Hospital, Craiova, Romania, in a period of 20 years. The 16 patients diagnosed with and treated of CF had all shown
increased values of sweat chloride concentration of over 60 mmol/L. The main symptoms and clinical signs encountered in these patients
were cough (75%), sputum (62.5%), dyspnea (50%), wheezing (50%), stature hypotrophy (100%), pallor (37.5%), cyanosis (25%). All 16 patients
had an acute exacerbation of chronic pulmonary disease. Of the total hospitalizations, the death was recorded only in the case of one female
patient. The association of some clinical aspects specific with a positive result of the sweat test or the presence of the two pathological alleles
made room for determining a positive diagnosis. The multisystemic nature of this disease requires a multidisciplinary approach to these patients.
Histopathologically, there was a correspondence between lung morphological lesions and the results of imaging investigations.
Keywords: cystic fibrosis, genetic disease, pulmonary manifestations, multisystemic approach.
Introduction
Cystic fibrosis (CF) is an inherited autosomal recessive
disorder, with a significant clinical heterogeneity, that
requires from a complex treatment [1]. In Romania, the
frequency of the disease is estimated in approximately
one in 2500 newborns, with a prevalence of about 1.5
cases per 100 000 inhabitants and a carrier frequency
(heterozygotes) of one in 25 [2]. The disease is caused by
mutations in the cystic fibrosis transmembrane conduc-
tance regulator (CFTR) gene located on the long arm of
chromosome 7 (7q31), which encodes a transmembrane
conductance regulator protein, CFTR, acting as a chloride
channel at the apical membrane of epithelial cells [3]. The
phenotypic features result from the absence or inappropriate
function of the chloride channels at the cellular level,
which involves the presence of viscous secretions adherent
to the epithelium of the excretory ducts difficult to discharge
as well as to their accumulation and the alteration of the
function and destruction of various organs (lungs, pancreas,
liver, intestine, and reproductive organs) [4]. The diagnosis
of CF is based on specific clinical symptoms and anam-
nestic data and then it is confirmed by the sweat test or
the molecular genetic testing [5].
A CF test must be conducted for every child presenting
with severe respiratory distress associated with a chronic
pulmonary disease (chronic cough, mucopurulent or purulent
sputum, expiratory dyspnea, wheezing, pulmonary hyper-
inflation) or a bronchial obstruction with modified values
in the spirometry tests, specific circumstances for a persistent
pulmonary colonization with Staphylococcus aureus and
Pseudomonas aeruginosa, persistent pulmonary radiological
modifications, nasal polyposis, sinusitis or chronic ethmoiditis
[6], but can be found and associated with common gastro-
intestinal and nutritional manifestations: meconium ileus,
rectal prolapse, pancreatic insufficiency with malabsorption
and steatorrhea, recurrent acute pancreatitis or chronic
R J M
E
Romanian Jo urnal of
Morphology & Embryology
http://www.rjme.ro/
Viorel Biciuşcă et al.
398
pancreatitis, persistent neonatal jaundice, distal intestinal
obstruction syndrome, chronic hepatopathy clinically and
biologically manifested or on ultrasonographic and/or
histological assessment by having the aspect of a focal
or lobular biliary cirrhosis, protein-calorie malnutrition
resulting in hypoproteinemic edema, as well as secondary
complications to liposoluble vitamin deficiency (skin or
mucous membrane hemorrhages, rickets, and nocturnal
cecity) [7].
There are other specific manifestations of this disease
such as salt-wasting syndrome, hypochloremic metabolic
alkalosis with hyponatremic dehydration, increased levels
of serum trypsinogen in newborn screening and obstructive
azoospermia in case of congenital absence of vas deferens
[8].
The diagnosis of CF can be determined in the presence
of one or multiple phenotypic traits of the above-mentioned
CF, in a patient that have the proof of the abnormal function
of CFTR by detecting two abnormal values of sweat Cl– by
quantitative pilocarpine iontophoresis test or identification
of diallelic CFTR pathogenic variants [9]. The sweat test
remains the gold standard test for diagnosing the disease
and assessing the concentrations of Cl– and Na+ ions in the
sweat. A sweat Cl– concentration greater than 60 mmol/L,
in two different assessments, can determine the correct
diagnosis [10]. Molecular genetic testing approaches CFTR
mutation panel that includes the most common pathogenic
variants followed by extended CFTR gene sequencing
and evaluation for deletions or duplications if only one or
no pathogenic variant is found [11]. The diagnostic role
of histopathological (HP) investigations was secondary,
confirming the morphological substrate of the clinical
picture in patients who die during hospitalization.
Aim
The aim of the paper is to demonstrate that due to the
multisystemic nature of this disease, a multidisciplinary
approach of patients is required, in order to early diagnose
the complications of the disease and administer appropriate
therapy, so as to increase quality of life and survival.
Patients, Materials and Methods
We have realized a retrospective clinical study of 16
patients who were hospitalized and diagnosed with CF
in the IInd Pediatric Clinic and IInd Medical Clinic of the
Emergency County Hospital, Craiova, Romania, from
2000 to 2020. The diagnosis of CF was achieved based
on the anamnesis and the clinical evaluation of children,
correlated with the paraclinical investigations in infants
and children and confirmed by the sweat test or genetic
testing of these patients. Patients were included in the study
group according to high levels of Cl– ions concentration
in the sweat after stimulating it with quantitative pilocarpine
(a sweat Cl– concentration greater than 60 mmol/L). The
sweat test measures the concentration of Cl– and Na+ ions
in the sweat test. A sweat Cl– concentration greater than
60 mmol/L, in two different assessments, confirmed the
diagnosis. When a patient with hyponatremia and hypo-
chloremia is clinically suspected of having CF, the sweat
test was delayed until an electrolytic balance has been
restored. The normal values of electrolytes in sweat are
less than 40 mmol/L. Positive values were observed in
children >60 mmol/L, while adolescents and teenagers
registered >70 mmol/L; values considered equivocal,
between 40 and 60 mmol/L required repeating the inves-
tigation after a while. Genetic testing was performed in
two Genetics Laboratories (Bucharest and Timişoara).
Peripheral blood samples were collected from each child
testing positive for the sweat test and for healthy controls,
in ethylenediaminetetraacetic acid (EDTA) tubes. The
deoxyribonucleic acid (DNA) extraction was performed
by QIAmp DNA Blood Mini Kit (QIAGEN). All samples
(patients and controls) were analyzed for the 29 common
mutations by Elucigene™ CF29 multiplex ARMS kit
(Tepnel Diagnostics Ltd, UK), as a rapid screening according
to the manufacturer’s instructions. To evaluate the frequency
of the 5T allele of intron 8, amplification and sequencing of
the polypyrimidine tract in front of exon 9 was performed
using primers 9i-5 and 9i-3 [12]. Imagistic investigations
(radiography, tomography, ultrasound exam) were made
with the equipment used by the Laboratory of Radiology
and Medical Imaging, Emergency County Hospital of
Craiova. Laboratory from samples involving hematology,
biochemistry, immunology, bacteriology, and gasometric
methods) were done in the Clinical Laboratory of the
Hospital, using the system known as Celltac Nihon Khoden
and Vitros 250 dry chemistry analyzers. The HP investi-
gations were performed on the specimens harvested from
the patient who died because of the evolution of this disease.
The necropsy fragments of the lungs were processed by the
classic histological technique with 24 hours routine 4%
neutral buffered formalin fixation, and paraffin embedding
in the Laboratory of Pathology from the Emergency County
Hospital of Craiova. Four μm-thick sections from the
resulting paraffin blocks were cut at the microtome, and
then stained with Hematoxylin–Eosin (HE). The stained
sections were examined under a Nikon Eclipse 55i
microscope by two pathologists highlighting the lesions
characteristic of CF. The statistical analysis was performed
using the Microsoft Excel (Microsoft Corp., Redmond,
WA, USA), together with the XLSTAT add-on for MS Excel
(Addinsoft SARL, Paris, France) and IBM Statistical
Package for the Social Sciences (SPSS) Statistics 20.0
(IBM Corporation, Armonk, NY, USA) for data processing.
Because the numerical variables investigated had a normal
data distribution, globally or in each studied group, we
were allowed to use the parametric statistical tests (e.g.,
Student’s t-test) and the results were summarized as the
mean value ± standard deviation (SD). For all statistical
tests, p-values less than 0.05 were considered significant.
All imagistic, hematological, biochemical, immunological,
bacteriological, functional, and genetic investigations were
made after obtaining the informed consent from the tutor
of the hospitalized child or the diagnosed teenager, which
guarantees the fundamental rights of the patient.
Results
The 16 patients suffering from CF (13 children and three
adults) diagnosed and treated in the Emergency County
Hospital of Craiova, from 2000 to 2020. Patients were
between four and 27 years old, with an average age of
12.31±6.27 years. Most patients were male, 12 (75%)
patients, while the minority was female, four (25%) patients.
Multidisciplinary approach to patients with manifestations and pulmonary complications of cystic fibrosis
399
The patients included in the study came from Oltenia
Region, as follows: 10 (62.5%) patients from Dolj County,
four (25%) patients from Olt County, and two (12.5%)
patients from Vâlcea County. The age of mothers when
they gave birth was between 22 and 31 years old, with an
average age of 25.42±5.74 years. The outstanding family
antecedents of the patients were found in the brother’s
case who manifested CF in two (12.5%) cases. The kids
showed first symptoms at an age between one day and
seven months of life, with an average age of debut of
3.088±2.87 months. The symptoms of debut were respiratory
symptoms in four (25%) patients, digestive signs and
symptoms in six (37.5%) patients or association of wheezing
with chronic diarrhea in four (25%) patients, and retarded
growth associated with coughing and diarrhea in two
(12.5%) patients. The average age of the patients at the
time of diagnosis was 3.63±2.72 years, with limits between
0 and 12 years. The average body mass index (BMI) value
was 14.24±1.65 kg/m2, with limits between 12.26 and
16.49 kg/m2.
Clinical manifestations among CF patients hospitalized
and under treatment are shown in the Table 1.
Table 1 – Incidence of clinical manifestations
Symptoms No. of patients/
incidence (%)
Clinical
signs
No. of patients/
incidence (%)
Cough 12 (75%) Stature
hypotrophy 16 (100%)
Expectoration 10 (62.5%) Paleness 6 (37.5%)
Dyspnea 8 (50%) Cyanosis 4 (25%)
Wheezing 8 (50%) Jaundice 2 (12.5%)
Fever 8 (50%)
Persistent skin
crease 8 (50%)
Diarrhea 10 (67.5 %) Clubbing fingers 3 (18.75%)
Constipation 2 (12.5%) Orthopnea 2 (12.5%)
Loss of
appetite 8 (50%) Bronchial
rales 4 (25%)
Weight loss 12 (75%) Bronchoalveolar
rales 2 (12.5%)
Abdominal
pain 6 (37.5%) Abdominal
distension 10 62.5%)
Nausea 4 (25%) Hepatomegaly 4 (25%)
Vomiting 2 (12.5%) Splenomegaly 2 (12.5%)
Oliguria 8 (50%)
Alteration of
consciousness 1 (6.25%)
All 16 patients had exacerbations of chronic broncho-
pulmonary disease. The number of infectious exacerba-
tions registered in these patients was 49 per year, with an
average value of 3.06±0.46 acute symptoms/patient/year.
The total number of hospitalizations of the patients included
in the present study per year was 67, which represents an
average value of 4.18±1.24 hospitalizations/patient/year.
There was only one reported death, a 10-year-old girl,
whose leading cause of death was a cardiorespiratory
arrest resulting from a staphylococcal pneumonia with
acute chronic respiratory failure. All hospitalized patients
showed high levels of Cl– concentration in the sweat test,
over 60 mmol/L, the average value registered with these
patients being 114.75±18.07 mmol/L, with limits between
80 and 193 mmol/L in the sweat test. Genetic analysis was
performed on DNA samples obtained from 14 (87.5%)
patients. Two mutations were found in all patients. Six
different CFTR mutations were detected: ΔF508 at 18
(53.57%) out of 28 CFTR alleles tested, N1303K at four
(14.28%) out of 28 CFTR alleles, G85E at three (10.71%)
out of 28 CFTR alleles, 394delTT and 2184delA in only
one (3.57%) out of 28 CFTR alleles and 5T polymorphism
in one (3.57%) patient. Most patients, nine (56.25%) out of
14 patients, were compound heterozygous, and five (31.25%)
were homozygous. In other two patients, who did not
undergo genetic testing, the sweat test was used to help
diagnose CF.
Modifications present in pulmonary radiography and
computed tomography (CT) are shown in the Table 2.
Table 2 – Incidence of imagistic examination modifi-
cations
Radiological
features
(16 patients)
No. of
patients/
incidence
(%)
CT features
(five from 16
patients)
No. of
patients/
incidence
(%)
Accentuation of the
peribronchovascular
pulmonary
interstitium
12/16
(75%)
Bronchiectasis of
bilateral upper
lobes
3/5
(60%)
Apical bilateral
bronchial
dilatations
4/16
(25%)
Disseminated
bronchiectasis
of both lungs
2/5
(40%)
Pulmonary opacity
with the appearance
of pulmonary
condensation
2/16
(12.5%)
Peribronchovascular
interstitial pulmonary
fibrosis
5/5
(100%)
Pulmonary
hyperinflation
2/16
(12.5%)
Pneumonic-type
condensation
2/5
(40%)
Normal lung
radiograph
appearance
2/16
(12.5%) Lung distention 1/5
(20%)
CT: Computed tomography.
On chest radiographs, the earliest modification was
accentuation of the peribronchovascular pulmonary
interstitium (Figure 1).
On CT images, the most common changes were lung
hyperinflation, pulmonary hypertension, and bronchiectasis
(Figures 2 and 3).
Spirometry was performed for 12 patients and allowed
for a registered forced vital capacity, both with an absolute
and a relative (percentage) value, the forced expiratory
volume in the first second (FEV1) and the index of
bronchial permeability. Low values of forced vital capacity
(FVC) were registered in the investigated patients, less than
80% of standard values were calculated in three (25%)
patients, low levels of FEV1 were less than 80% of standard
values calculated in five (41.66%) patients, low levels of
the index of bronchial permeability less than 70% in three
(25%) patients. Germs involved in the production of infectious
exacerbations (identified in pathological products of
tracheobronchial tree), which complicated the evolution of
the disease, were: Methicillin-sensitive S. aureus (MSSA)
20 (40.81%) infectious episodes, P. aeruginosa 12 (24.48%)
infectious episodes, Methicillin-resistant S. aureus (MRSA)
six (12.24%) infectious episodes, Klebsiella pneumoniae
four (8.16%) infectious episodes, Burkholderia cepacia
two (4.08%) infectious episodes, and Serratia liquefaciens
one infectious episode (2.04%). There were four (7.27%)
mixed infectious episodes with P. aeruginosa and MRSA.
The average, minimum and maximum values of
hematological and biochemical parameters are shown in
the Table 3.
The average, minimum and maximum values of liver
and pancreatic laboratory tests are shown in the Table 4.
Viorel Biciuşcă et al.
400
Figure 1 – Radiological aspects in CF. Chest
radiographs in postero-anterior incidence. (A) Four-
year-old child diagnosed with CF. Pulmonary
hyperinflation. Pulmonary hypertension – vascular
enlargement of pulmonary hilum. Accentuation
of the apical and perihilar pulmonary interstitium,
bilateral. (B) Eighteen-year-old adolescent with CF.
Pulmonary hyperinflation. Pulmonary hypertension
– vascular enlargement of pulmonary hilum.
Bronchial dilatations with a predominant
cylindrical appearance, in the upper half of the
bilateral lung areas. CF: Cystic fibrosis.
Figure 2 – CT scans in CF. Axial CT images. (A)
Pulmonary hyperinflation. Pulmonary hypertension –
vascular enlargement of pulmonary hilum. Bronchi
with thickened walls. Cylindrical bronchiectasis (1).
(B) Cystic dilated bronchi (1) in an 18-year-old
adolescent patient. The “signet ring of
bronchiectasis” (2), with the cystic dilated bronchus
representing the “ring” and the adjacent smaller
artery representing the “jewel” on the ring. CT:
Computed tomography; CF: Cystic fibrosis.
Figure 3 – Coronal reformatted CT image in CF. CT
images shows corresponding dilated bronchi with
thickened walls and dilated bronchi: (A) Cylindrical
bronchiectasis in a 14-year-old patient; (B) Cystic
bronchiectasis in an 18-year-old patient. CT:
Computed tomography; CF: Cystic fibrosis.
Table 3 – The average, minimum and maximum values
of the hematological and biochemical parameters
Parameter
Average value,
minimum and
maximum
values
Parameter
Average value,
minimum and
maximum
values
Hb [g/dL] 11.43±3.43
(7.7
–
14.5) γ-Globulin [g%] 15.87±6.91
(6
–
34)
MEV [fL] 83.8±14.68
(66
–
105) pH 7.42±0.05
(7.35
–
7.51)
MCH [pg/mL] 25.4±3.51
(20
–
29) PaO2 [mmHg] 72.8±22.88
(37
–
99)
Leukocyte
count [/mm
3
]
11550.63±
5290.67
(7500
–
28 000)
PaCO2 [mmHg] 33.6±5.22
(27–36)
Platelet
count [/mm
3
]
387 540.43±
112 400.62
(180 000–
540 000)
HCO
3–
[mEq/L] 33.6±5.22
(27–36)
Fe [μg/dL] 48.5±22.98
(12
–
113) D-dimers [μg/mL] 1.24±0.48
(0.5
–
1.8)
ESR [mm/1 h] 26.56±11.07
(5
–
52)
NT-proBNP
[pg/mL]
54.42±23.45
(30
–
120)
Fb [mg/dL] 435.07±113.14
(250
–
750) Urea [mg/dL] 28.5±14.45
(13
–
98)
CRP [mg/L] 2.975±1.78
(0.3
–
9) Uric acid [mg/dL] 0.46±0.12
(0.3
–
0.9)
Hb: Hemoglobin; MEV: Mean erythrocyte volume; MCH: Mean
corpuscular hemoglobin; Fe: Serum iron; ESR: Erythrocyte sedi-
mentation rate; Fb: Fibrinogen; CRP: C-reactive protein; PaO2:
Partial pressure of oxygen; PaCO2: Partial pressure of carbon
dioxide; HCO
3–
: Serum bicarbonate; NT-proBNP: N-terminal pro-
brain natriuretic peptide.
Table 4 – The average, minimum and maximum values
of liver and pancreatic laboratory tests
Parameter
Average value,
minimum and
maximum
values
Parameter
Average value,
minimum and
maximum
values
TBIL [mg%] 1.31±1.13
(0.5
–
6.8) Am [U/L] 42.8±28.72
(20
–
97)
DBIL [mg%] 0.63±0.37
(0.2
–
2.73) Lip [U/L] 30.66±10.14
(23
–
45)
ALP [U/L] 286.46±148.76
(125
–
576) Ca [mg/dL] 8.36±0.84
(7.4
–
10.6)
GGT [U/L] 77.78±14.06
(12
–
477) Ca
2+
[mg/dL] 3.32±0.78
(1.2
–
4.4)
ALT [U/L] 42.5±28.55
(13
–
100) Mg [mg/dL] 1.75±0.26
(1.4
–
2.1)
AST [U/L] 42.8±28.72
(20
–
197) VitD3 [U/L] 38.8±13.91
(24
–
54)
TP [g%] 6.29±1.35
(4.4
–
9.5) Na [mEq/dL] 130.22±8.8
(118
–
137)
S-alb [g%] 3.72±0.65
(2.9
–
4.8) K [mEq/dL] 4.3±0.9
(3.1
–
5.1)
PT [%] 77.93±11.66
(68
–
100) Cl [mEq/dL] 95.87±9.94
(76
–
104)
TBIL: Total bilirubin; DBIL: Direct bilirubin; ALP: Alkaline phosphatase;
GGT: Gamma-glutamyltransferase; ALT: Alanine transaminase;
AST: Aspartate transaminase; TP: Total proteins; S-alb: Serum
albumin; PT: Prothrombin time; Am: Amylasemia; Lip: Lipasemia;
Ca: Serum calcium; Ca
2+
: Ionized calcium; Mg: Magnesium; VitD3:
Vitamin D3; Na: Sodium; K: Potassium; Cl: Chloride.
The modifications resulted from the stool test were as
follows: presence of drops of undigested fats in eight (50%)
Multidisciplinary approach to patients with manifestations and pulmonary complications of cystic fibrosis
401
patients, presence of undigested fat drops and muscular
fibers in four (25%) patients, presence of fat drops and
undigested starch in three (18.75%) patients. The average
value of the fecal pancreatic elastase performed on six
patients was 78.42±43.36, with limits between 29–100 mg/dL.
Abdominal ultrasound exam performed on the tested
patients revealed: hepatomegaly in four (25%) patients,
modifications of hepatic echogenicity in six (37.5%)
patients, modifications of hepatic structure in six (37.5%)
patients, modifications of hepatic contour in one (6.25%)
patient, caudate lobe hypertrophy in one (6.25%) patient,
increase in portal vein diameter in one (6.25%) patient,
splenomegaly in three (18.75%) patients and an increase
in the splenic vein diameter in one (6.25%) patient. The
endocrinology exam performed on these children confirmed
the following results: postural hypotrophy in 16 (100%)
patients, osteopenia in four (25%) patients, and delayed
menarche in two (12.5%) patients. The ear, nose, and throat
(ENT) exam performed on most hospitalized patients
described acute nasopharyngitis in four (25%) patients,
acute tonsillitis in four (25%) patients, nasal polyposis in
four (25%) patients, acute otitis in three (18.75%) patients,
acute rhino-adenoiditis in two (12.5%) patients, chronic
tonsillitis in six (37.5%) patients, and chronic rhinosinusitis
in four (25%) patients.
HP examination of pulmonary necropsy fragments
revealed the presence of a large lesion diversity. Thus, the
predominant lesions have been hypertrophy of the bronchial
glands, mucous cell hyperplasia of the trachea and main
bronchi (Figure 4A), the presence of intraluminal mucous
plugs, acute and chronic inflammation of bronchi, with
the presence of mucopurulent exudate with microbial
colonization in the lumen of lower respiratory airways
and the presence of a diverse inflammatory cell population
with neutrophils, histiocytes, lymphocytes, and plasma cells
(Figure 4B). Others associated lesions were the ulcerations
of the bronchial and bronchiolar mucosa, endobronchial
abscesses, bronchiectasis, and atelectasis.
Figure 4 – Lung necropsy fragments (HE staining, ×40): (A) A main bronchus with mucous cell hyperplasia, mucous
gland hypertrophy, fibrosis predominantly in the submucosa and in the intima of the pulmonary arterial branches;
(B) A bronchiole with ulcerated areas of the epithelium, extensive fibrosis starting from the basement membrane of the
bronchial epithelium and extending into the pulmonary interstitium associated with fibrosis in the intima and hypertrophy
of the middle layer of the branches of the pulmonary artery. HE: Hematoxylin–Eosin.
Discussions
Amongst the patients hospitalized in the IInd Pediatric
Clinic and IInd Medical Clinic of the Emergency County
Hospital of Craiova and diagnosed with CF, the most
majority were males, the male/female ratio being 3:1,
which clearly shows a male genetic predisposition to this
disease, an aspect which has been also highlighted by the
specialists [13]. The average age of the investigated patients
was 12.31±6.27 years, with limits between four and 27 years
[13]. The reported average age of the onset of the disease
was 3.088±2.87 months, with value limits of one day and
seven months [14]. The onset symptoms of the disease
were respiratory manifestations in four (25%) patients,
digestive symptoms and signs in six (37.5%) patients or
the association of wheezing with chronic diarrhea in four
(25%) patients, and the growth retardation with cough
and diarrhea in two (12.5%) patients [14]. The average age
of the patients at the time of diagnosis of the disease was
3.63±2.72 years, with limits in between zero and 12 years.
The incidence of the main symptoms and clinical signs
recorded in these children was cough in 12 (75%) patients,
expectoration in 10 (62.5%) patients, dyspnea in eight (50%)
patients, wheezing in eight (50%) patients, diarrhea in 10
(62.5%) patients, loss of appetite in eight (50%) patients,
growth retardation in 12 (75%) patients, abdominal pain
in six (37.5%) patients, postural hypotrophy in 16 (100%)
patients, pallor in six (37.5%) patients, cyanosis in four
(25%) patients, persistent skin fold in eight (50%) patients,
mucosal dryness in eight (50%) patients, bronchial rales
in four (25%) patients, tachycardia in eight (50%) patients,
abdominal distension in 10 (62.5%) patients and hepato-
megaly in four (25%) patients.
Iontophoresis (sweat test) was the basic exploration
for the diagnosis of mucoviscidosis. All patients presented
sweat Cl– concentration values of over 60 mmol/L, the
average value recorded in these patients being of 114.75±
18.07 mmol/L, with limits in between 80 and 193 mmol/L
[3]. These results were in accordance with the genotyping
tests, the patients showing genetic changes specific to this
disease [15]. Genetic analysis performed in 14 patients
revealed six allelic mutations, each patient analyzed had
Viorel Biciuşcă et al.
402
two different alleles on chromosome 7 q31.2 locus. The
frequency of mutations found was: ΔF508 in 18 (53.57%)
situations, N1303K mutation in four (14.28%) situations,
G85E mutation found in three (10.71%) situations, 5T
polymorphism in one situation (7.14%), deletion 394TT in
one case (3.57%), and deletion 2184A in another situation
(3.57%), frequency similar to that found in a study
conducted on 777 samples collected from patients [16].
Most patients, nine (56.25%) patients, presented with a
heterozygous status, while a homozygous status was
identified in five (31.25%) patients. In our study, in two
(12.5%) patients who did not undergo genetic testing, the
sweat test was used to help diagnose CF.
Conventional chest radiographs are usually adequate to
detect the salient radiographic features of CF and provide
objective parameters for longitudinal disease progression
[17]. On the radiographs, the earliest change is the accen-
tuation of the pulmonary interstitium. Also, pulmonary
hypertransparency is a change that occurs quite early.
Changes in lung imaging are due to thickening of the
bronchial walls by infiltration of the bronchial submucosa
with lymphocytes and plasma cells. In many cases, recurrent
pneumonia, cylindrical or cystic bronchiectasis and multiple
small abscesses developed in the bronchiolar walls appear
[18]. Advanced complications of CF are atelectasis, pneumo-
thorax, pneumomediastinum, pulmonary hemorrhage,
cardiomegaly, and dilation of the pulmonary artery with
the appearance of radiographic signs of chronic pulmonary
heart [17]. High-resolution computed tomography (HRCT)
is more sensitive and secure than standard chest radiography
in establishment the presence and severity of bronchiectasis
and other parenchymal and airway changes in CF [17]. There
are scoring systems using HRCT to assess bronchiectasis
severity in CF. These systems rely on a subjective evaluation
of the presence, extent, and severity of different lesions of
the CF, including bronchial wall thickening, bronchiectasis,
mucous plugging, and emphysema [19]. Pulmonary function
measurements showed low values of FVC less than 80%
of the standard values calculated in three (25%) patients,
low values of FEV1 less than 80% of the standard values
calculated in five (41.66%) patients, low values of bronchial
permeability index less than 70% in three (25%) patients.
The analysis of the values of the spirometric indices obtained
at the pulmonary function tests allowed the description of
the obstructive ventilatory dysfunction syndrome in three
(25%) patients and mixed in two (12.5%) patients. The
chronic bronchial infection (colonization) and a persistent
inflammatory response leading to the appearance of pro-
gressive bronchiectasis and obstructive and restrictive lung
disease [20]. The measurement of FEV1 by spirometry
is currently the essential parameter for monitoring lung
function, assessing its severity and progression [21]. Lung
function tests play an important role in the management
of CF patients of all ages. We must be aware of the
reference values used for spirometry since according to
the chosen one, the respiratory functional diagnosis can
be variable [22]. The bacteriological examination of the
pathological respiratory disorders should occur whenever
the patients present an inflammatory process of the respi-
ratory symptomatology (intense coughing, increasing
thickness and quantity of sputa, which intermingles with
mucopurulent matter, the occurrence or disappearance of
dyspnea), considering the risk of pulmonary colonization
of these patients, mainly with extremely pathogenic,
antibiotic resistant stems. Early sustained therapy with
antibiotics of respiratory infections contributed to the
longevity of patients with CF [23].
The low hemoglobin values, found in seven (43.75%)
patients could be explained by malabsorption syndrome,
acute or chronic infectious phenomena, immunological
phenomena recorded in patients with hypergamma-
globulinemia [24]. The increased values of erythrocyte
sedimentation rate (ESR) recorded in 14 (87.5%) children
were the consequence of acute inflammatory processes
caused by infection, which complicated the evolution of
the disease of these patients, the highest values being
observed in bacterial lung infections (pneumonia) [24].
High γ-globulin levels in two (12.5%) patients suffering
from CF can be explained via the chronic infectious disease,
which can cause local immunological reaction followed by
a systemic one from the immunity system. Under these
circumstances, a larger number of immunological tests is
needed in order to be able to exclude an autoimmune
pathology or a simultaneous hematological one [25]. High
levels of pH determined in four patients (25%), associated
with low levels of electrolytes in blood (Na+ and Cl–) and
high bicarbonate levels determined the suspicion and
diagnosis of CF, based on hypochloremic and hyponatremic
metabolic alkalosis, mainly in patients who, at the debut,
presented episodes of diarrhea associated with dehydration
with hydroelectrolytic imbalance and acid–base disorders
[26]. Low levels of partial pressure of oxygen (PaO2) in six
(37.5%) patients affected by advanced bronchopulmonary
disease (especially those suffering from bronchiectasis)
determined chronic hypoxemia as well as the risks it
generates, which necessitates a plan completion for caring
and treating these patients [27]. Low levels of partial
pressure of carbon dioxide (PaCO2) (hypocapnea) were
present in those four (25%) patients diagnosed with
metabolic alkalosis, attributed to chronic diarrhea, which
caused the suspicion and early diagnosis of CF. High
levels of PaCO2 (hypercapnea) correctly defined the type
of hypercapnic respiratory insufficiency manifested in
two (12.5%) of the hospitalized patients, with the occasion
of infectious exacerbations of the chronic bronchopulmonary
disease and helped to set up an appropriate treatment
[28]. Unfortunately, this type of respiratory insufficiency
which complicated the evolution of the disease in the
deceased child could not be corrected and was noted
down as the immediate cause of death. The biochemical
evaluation of the myocardial function, by determining
the serum N-terminal pro-brain natriuretic peptide (NT-
proBNP), is useful for early diagnosis of the contractile
dysfunction of the right ventricular myocardium, when
the completion of the therapeutic plan is indicated [29].
Renal functional exploration, along with an assessment of
the water-electrolyte imbalance and acid–base disorders
highlighted electrolyte imbalances in patients manifesting
dehydration, eight (50%) patients and the one suffering
from acute pyelonephritis in one (6.25%) patient, which
allowed the implementation of a correct therapeutic
Multidisciplinary approach to patients with manifestations and pulmonary complications of cystic fibrosis
403
approach. The functional exploration of the liver, which
was of major importance in these patients revealed
biochemical modifications specific for cytolysis in five
(31.25%) patients and intrahepatic cholestasis in four (25%)
patients, pathological aspects common in such cases [30].
These modifications must be highlighted any time they
appear, since in patients who are hospitalized for infectious
exacerbations of mucoviscidosis and who need antibio-
therapy, the antibacterial drugs must be chosen according
to the level of hepatotoxicity. The evaluation of the exocrine
pancreatic function was necessary both for the diagnosis
of pancreatic insufficiency, but mostly for establishing an
appropriate therapeutic care. In these patients, the medi-
cation for pancreatic substitution must replace the nutritional
deficiency of patients, while it is acknowledged that protein-
calorie malnutrition has its own supplementary contribution
to the alteration of the pulmonary function [31]. Establishing
the levels of albuminemia and oligoelements (calcium, iron,
and magnesium blood levels) had a significant meaning
in the therapeutic management of these patients, knowing
that an early improvement in the manifestations of the
syndrome of malabsorption will prevent metabolic and
hematological disorders from occurring, since these had
a negative impact on the evolution of the disease [25]. The
investigation of the function of the endocrine pancreas is
indicated by the glucose tolerance test, especially in patients
with a history of prolonged pulmonary diseases. It is
necessary and useful for the early diagnosis of diabetes
associated with CF, knowing that a delay in the introduction
of the antidiabetic treatment will result in irreversible
modifications at the level of small and large vessels [32].
CF is an autosomal recessive disorder with a varied
penetrance and wide clinical variability. Interdisciplinary
examinations were extremely important in these patients
given the multisystemic nature of the disease, the role of
the pediatrician being the most important, because he
must recognize all the manifestations of the disease and
request these examinations at the right time [33]. The
neonatologist was requested whenever the newborn
presented either respiratory distress at birth that required
oxygen supply, or delayed appearance of meconium. The
collaboration of the neonatologist with the pediatric
surgeon was necessary and lifesaving in the case of
newborns with meconium ileus, who did not respond to
drug therapy or in the case of the newborn with jejunal
atresia. In such cases, early indication for sweat test was
beneficial to diagnose the disease since the first days of
life [34]. ENT examination was indicated and provided
useful information if the child had specific manifestations
of acute adenoiditis, nasal polyposis, ethmoiditis, and
acute/chronic sinusitis. These diseases required immediate
performance of the sweat test and early diagnosis of this
disease [35]. The pneumological examination helped
establish the correct type and degree of respiratory failure
and established, together with the pediatrician, the
therapeutic conduct in the transition of childhood to
adulthood [36]. Cardiological examination was required in
all children diagnosed with CF who showed manifestations
of severe respiratory failure and who were hospitalized
for clinical and biological evaluation. It is necessary to
develop a periodic cardiological exploration plan that allows
the early detection of secondary pulmonary hypertension,
which will indicate the establishment of new therapeutic
measures particularly useful in preventing the installation
of chronic pulmonary heart disease [37]. Periodic pediatric
examination with clinical–biological evaluation will help
for early diagnosis of malabsorption syndrome, establishing
the degree of pancreatic damage by correct morpho-
functional examination of the pancreas, early identification
of hepatobiliary suffering and the establishment of appro-
priate hepatoprotective and anti-cholestatic therapy for this
type of disease [38]. Urological examination in adulthood
will be required whenever a young man with CF will
want to start a family. Infertility induced by the absence of
vas deferens can be overcome by intracytoplasmic injection
of sperm after transcutaneous harvesting the sperm from
the epididymis [39]. Neurological examination proved to
be particularly necessary in agitated patients, in exacer-
bation of chronic respiratory failure, in whom hypoxic,
but especially hypercapnic cerebral distress, required the
exclusion of an organic neurological pathology [40].
Endocrinological examination was practiced in most
children, given the endocrine and metabolic manifestations
of malabsorption syndrome. The endocrinologist will
establish the therapeutic conduct in girls who have delayed
menarche, but especially the counseling of young man with
azoospermia [41]. Psychological examination should not
be missing from the exploration plan of these young patients,
considering the special psychological problems that occur
during the diagnosis of this chronic disease, and especially
for the family of the patient in time of the transition of
the patient to adulthood [42]. Genetic counseling is very
important for families where one of the children has been
diagnosed with CF, or if a patient with CF wants to start
a family [43]. Screening for carrier status and prenatal
testing for pregnancies at increased risk are possible.
The HP examination highlighted the morphological
substrate of the clinical and imaging manifestations of
the patients investigated by us, emphasizing the existence
of a correspondence between the imaging picture and the
HP one. Most HP lung lesions detected by us in the child
who died of CF were mucous cell hyperplasia, mucosal
gland hypertrophy and acute and chronic inflammation of
the lower respiratory tract. Changes such as bronchiectasis,
atelectasis, emphysema, and pulmonary fibrosis are more
the prerogative of older children and young people affected
by this disease. Many authors have shown that the lungs
are normal at birth [44], but that even before the infectious
clinical picture became evident in the airways were observed:
hypertrophy of the submucosal glands, obstruction of the
excretory ducts, hyperplasia of mucous cells in the trachea
and large bronchi and mucus hypersecretion [45]. In overt
clinical forms of bronchiolitis, the airway lumen is filled
with mucopurulent secretions and bacterial colonies, and
the respiratory epithelium proliferates endoluminal as
papillary projections. Over time, reinfections change the
morphopathological picture to a chronic bronchial type
with a mixed inflammatory infiltrate, which includes
neutrophils and histiocytes, lymphocytes and plasma cells,
and quite often is associated with follicular bronchiolitis
Viorel Biciuşcă et al.
404
[46]. The formation of endobronchial abscesses is the first
step towards the development of bronchiectasis, their
number increasing with age. They are more numerous in
the proximal pulmonary airways, affecting especially the
upper lobes, the middle lobe of the right lung, and the
lower lobes [45, 46]. In children, atelectatic lesions are
also quite common, being the result of obstructive mucus
plugs and lymphoid follicle hyperplasia adjacent to the
bronchi [47]. In contrast, emphysematous lesions appear
to develop at older ages, so that they become present in
41% of patients aged between 10–24 years old [45]. At
the same time, if in young children the HP picture is
dominated by acute pneumonia, in the older children and
youths the morphopathological picture is dominated by
appearance of chronic inflammatory interstitial infiltrate,
lymphocytes and plasma cell, interstitial fibrosis and the
presence of lung cystic structures. It is discussed the
existence of four types of pulmonary cystic structures
developed in the CF evolution, respectively: (i) bronchi-
ectatic type, the most common, in which there is a direct
communication with the bronchi, (ii) interstitial type, located
in the visceral pleura and interlobular septa, frequently
associated with pneumothorax, (iii) pneumatocele type,
and (iv) emphysematous type [46]. In older patients, with
the increase of bronchiectasis number, and as well as due
to fibrous obliterative bronchiolitis, was noticed a decrease
in the density of small airways [48]. At the same time,
it seems that there is a prevalence of lesions such as
pulmonary atelectasis, bronchial obliteration with mucus
plugs and air cysts for the upper lung lobes [49, 50]. Over
time, pulmonary hypertension develops, due to the medial
hypertrophy and intimal fibrosis of the pulmonary artery
branches, which is often incriminated in the death of
some of these patients due to rupture of dilated arteries
and bronchial veins in the airway walls or bronchiectasis
[51]. The severity of lung lesions increases with age, with
emphysematous changes, pneumothorax, chronic pulmo-
nary arterial hypertension, and severe chronic respiratory
failure on the foreground [52]. Pulmonary amyloidosis
with a diffuse interstitial pattern was also found in patients
with a longer survival time [53].
Conclusions
The association of some phenotypic aspects specific for
CF (recurrent pulmonary infections, MRSA or P. aeruginosa
respiratory tract colonization, fat soluble vitamin malab-
sorption, the hyponatremic dehydration syndrome associated
with hypochloremic metabolic alkalosis, or the connection
between diarrhea and recurrent wheezing) with a positive
result of the sweat test or the presence of the two patho-
logical alleles made room for determining a positive
diagnosis. The multisystemic character of CF requires a
multidisciplinary approach to the problems of the patients
involved in research, with a view to early diagnosis and
guiding of the appropriate and timely treatment, which
will alleviate and improve the quality of our lives and will
increase life expectancy. A HP approach to this study
revealed a connection between morphological characte-
ristics of pulmonary lesions and the results of the imagistic
investigations.
Conflict of interests
The authors declare that they have no conflict of
interests.
Acknowledgments
Viorel Biciuşcă and Ileana Octavia Petrescu equally
contributed to the manuscript.
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Corresponding authors
Citto Iulian Taisescu, Associate Professor, MD, PhD, Department of Physiology, Faculty of Medicine, University of
Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Romania; Phone +40722–520 531,
e-mail: taisescu@yahoo.com
Mihaela Amelia Dobrescu, Lecturer, MD, PhD, Department of Medical Genetics, Faculty of Medicine, University of
Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Romania; Phone +40741–194 395,
e-mail: amelia_dobrescu@yahoo.com
Received: March 28, 2020
Accepted: December 19, 2020
