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Contents
67 Management of Laryngeal Papillomatosis in Children . . . . . . . . . . . . . 817
Mustafa Nuhut and Sema Zer Toros
Part VII Miscellaneous
68 The Role of the Critical Airway Team . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
Zeynel Öztürk, Nuray Bayar Muluk, and Felicia Manole
69 Epidermolysis Bullosa: ENT Involvement . . . . . . . . . . . . . . . . . . . . . . . 839
Oğuzhan Oğuz, Nuray Bayar Muluk,
and Gabriela Kopacheva-Barsova
70 Pierre Robin Sequence: Controversies in Management . . . . . . . . . . . . 847
Zeynel Öztürk, Nuray Bayar Muluk, and Felicia Manole
71 Herpes Simplex Viruses in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
Rahime Koca and Erdem Atalay Çetinkaya
72 COVID: Upper Respiratory Involvement . . . . . . . . . . . . . . . . . . . . . . . . 881
Rezarta Taga Senirli and Erdem Atalay Çetinkaya
Part I
General Concepts of Upper Respiratory Tract
for Pediatric Pulmonology
Embryological Origins oftheUpper
andLower Respiratory Tract
ŞeydaDemirYüksel, GeorginaSiordia,
andH.AlperBağrıyanık
1.1 Introduction toUpper Respiratory System
The development of the upper respiratory tract begins very early during the embryonic period and involves the embryonic leaves from the pharyngeal arches and the
intermediate lamina from the primitive intestine. The organization and differentiation
of laryngotracheal primordia are induced by the migration of neural crest- derived
cells under the control of many genes. The laryngotracheal structures are present from
the end of the embryonic period, but their maturation continues throughout the fetal
period [1].
1
Ş. D. Yüksel
Department of Histology and Embryology, Faculty of Medicine, Dokuz Eylul University,
Balcova, Izmir, Türkiye
Department of Histology and Embryology, Health Sciences Institute, Dokuz Eylul University,
Balcova, Izmir, Türkiye
G. Siordia
Department of Pathology, UMAE Hospital de Pediatría, CMN-SXXI, IMSS,
Ciudad de México (CdMx), Mexico
H. A. Bağrıyanık (*)
Department of Histology and Embryology, Faculty of Medicine, Dokuz Eylul University,
Balcova, Izmir, Türkiye
Department of Histology and Embryology, Health Sciences Institute, Dokuz Eylul University,
Balcova, Izmir, Türkiye
Stem Cell and Organoid Technologies Lab, Izmir Biomedicine and Genome Center (iBGizmir), Balcova, Izmir, Türkiye
e-mail: alper.bagriyanik@deu.edu.tr
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2024
H. Yüksel et al. (eds.), Pediatric Airway Diseases, Comprehensive ENT,
https://doi.org/10.1007/978-3-031-74853-0_1
3
4
Ş. D. Yüksel et al.
1.1.1 Oral Cavity
The primordium of the mouth (stomodeum) is identied from the third week, rostrally by a bilaminar oropharyngeal or oronasal membrane, composed of ectoderm
in its external layer and endoderm in the internal layer, separating the amniotic cavity from the anterior primitive intestine and the primitive pharynx. This membrane
will disappear between 26 and 30days after embryogenesis. At this moment, the
oor is already well delimited by the mandible, the lateral walls by the maxillary
processes and the caudal region by the frontonasal process [2].
1.1.2 Nasal Cavity
They form from the nasal placodes, which are thickenings of the surface ectoderm that form during the fth week of development. The nasal placodes invaginate giving rise to the nasal foveas, which expand dorsally cranial to the
stomodeum, until they converge to form a single cavity that will later be divided.
The nasal passages continue to deepen until, during the sixth week, they are
separated from the oral cavity by a temporary membrane called the oronasal
membrane [3].
When the oronasal membrane disappears, communication between the nasal
passages and the oral cavity is established through two openings called nasal choanae, which open on both sides of the midline in the most dorsal region of the roof of
the oral cavity [3].
The mesenchyme surrounding the epithelium of the nasal cavity is a derivative of
neural crest cells; In subsequent stages, this mesenchyme forms a cartilage capsule
(nasal capsule) that will give rise to the nasal septum in the midline and the lateral
nasal wall [4]. Shortly after the degeneration of the oronasal membrane, a plug of
epithelial cells forms in the external region of the primitive nasal cavity, so this
communication with the outside is temporarily occluded. At the end of the fourth
month, this plug disappears [5].
1.1.3 Palate
During the initial stages, there is communication between the nasal cavity and the
oral cavity until the formation of the palate, which is usually in the rostral region
since the posterior part maintains extensive communication with the pharynx. The
separation of both cavities begins during the sixth week with the fusion of the nasal
prominences and the maxillary prominences.
The primary palate will also give rise to the anterior triangular third of the incisive foramen and will include the four maxillary incisors.
At the end of the eighth week, the two secondary palatine processes will end up
fusing with the primary palate to form the denitive palate. During this same time,
the nasal septum grows to separate the left and right nasal passages, and its lower
portion will merge with the denitive palate [6].
1 Embryological Origins oftheUpper andLower Respiratory Tract
5
1.1.4 Primitive Pharynx
It corresponds to the most cranial region of the primitive intestine that originates
from the oropharyngeal membrane to the respiratory diverticulum. The neural
crest cells migrate to this site during the fourth week and are arranged around the
endoderm, which, when they proliferate, give rise to the pharyngeal arches.
Toward the fourth week, you can see the four pairs of pharyngeal arches formed
by the nucleus of the mesenchyme surrounded by the supercial ectoderm and
covered inside by the endoderm of the pharyngeal intestine, the latter invaginates
between the pharyngeal arches to give rise to the pouches, pharyngeal, which
participates in the formation of the glands of the neck. The invagination of the
ectoderm will give rise to the grooves or clefts and the muscles will originate from
the presomitic mesoderm and the precordial plate that migrate toward the pharyngeal arches [2].
1.1.5 Upper Airway Anomalies
Upper respiratory tract anomalies represent a broad group of pathological entities
whose early diagnosis and timely treatment greatly reduce fetal and neonatal mortality. Although there are currently imaging studies that are routinely performed on
pregnant women, there is still work to be done to signicantly reduce morbidity and
mortality in the perinatal period.
1.1.6 Cleft Lip/Palate
Orofacial clefts are the most common orofacial malformations in humans and
include cleft lip, cleft lip with or without cleft palate, and cleft palate only. Cleft
palate only is a birth defect that occurs when only the secondary palate is involved
and can affect the hard palate and/or the soft palate, sometimes limited to one cleft
uvula, due to a failure in the fusion of facial processes during crucial periods in the
embryonic development. It represents one-third of all oral clefts and affects about
1–25 per 10,000 newborns worldwide [7, 8].
The etiology of the cleft palate only is multifactorial and involves both genetic
and environmental risk factors [9]. Multiple recognized syndromes associated with
cleft lip and palate have been identied [10] and they can be alone or in combination
with other malformations, mainly cardiac [11].
1.1.7 Choanal Atresia
A rare anomaly, dened as anatomical narrowing of the posterior openings of the
nasal cavity, associated with hypoplasia of the nasopharynx, an anomaly that usually occurs in cases of craniofacial and mandibulofacial dysostosis [12].
6
It can occur unilaterally or bilaterally and be associated with other obstructive
anomalies of the upper airway. Its clinical presentation can vary from acute airway
obstruction to chronic recurrent sinusitis. The exact cause of this congenital anomaly has not yet been described, however, some probable causes have been accepted,
such as the lack of obliteration of the oropharyngeal membrane, the abnormal presence of the mesoderm in the posterior region of the forming nasal cavity, or the
aberrant migration of neural crest cells [13].
This anomaly may be seen associated with other defects remembered by the
mnemonic CHARGE (coloboma, heart disease, atresia choanae, retarded growth
and retarded development and/or CNS anomalies, genital hypoplasia, and ear
anomalies) [6].
Ş. D. Yüksel et al.
1.1.8 Laryngomalacia
It is another of the most frequent anomalies of the upper airway and represents the
main cause of respiratory stridor in newborns. It occurs during inspiration and worsens during feeding, crying, supine position, and when the infant is agitated [14].
Although the cause of the illness is not entirely understood, short aryepiglottic
folds, a lengthy, curved epiglottis, and extra arytenoid mucosa prolapsing into the
glottis are also present with anatomical anomalies usually linked to it [14].
There are multiple classications 1165 [15] although the most practical current
classication of this pathology corresponds to the one proposed by Holinger and
Konior [16], which takes into account the direction in which the collapse of the
supraglottic region occurs: Type A, which occurs toward the posterolateral region,
in which there is a collapse of the arytenoid and aryepiglottic folds; Type B, in
which there is a complete collapse of the supraglottic structures; Type C, in which a
collapse of the anterior region occurs, in this case, the epiglottis is the one that collapses during the inspiration process [16].
1.1.9 Laryngeal Atresia
Laryngeal atresia, categorized as a variant of congenital high airway obstruction syndrome (CHAOS), represents a rare and frequently life-threatening medical condition.
Laryngeal atresia arises due to the failure of laryngeal recanalization during the
embryological period. The mortality rate of laryngeal atresia is high. Over the last
decade, advancements in the early detection of the condition during the antenatal
period, coupled with the implementation of diverse antenatal and peripartum management strategies, have contributed signicantly to enhancing its outcomes [17].
1.1.10 Laryngeal Webs
Laryngeal web is an uncommon congenital condition leading to airway stenosis.
The symptoms exhibited by individuals with a laryngeal web vary widely, ranging
from asymptomatic cases to severe respiratory dysfunction that poses a potentially
1 Embryological Origins oftheUpper andLower Respiratory Tract
life-threatening situation, often necessitating emergency tracheostomy shortly after
birth, depending on the extent of atresia severity [18].
The origin of the congenital laryngeal web stems from the abnormal development of the larynx by the tenth week of gestation, often associated with syndromes
such as 22q11.2 deletion syndrome. 22q11.2 deletion syndrome is present in 30%
of individuals diagnosed with the congenital laryngeal web [19].
7
1.1.11 Congenital Subglottic Stenosis
Congenital subglottic stenosis (SGS) refers to the constriction of the subglottic
space beneath the vocal cords. This condition arises due to a deformity in the cricoid
cartilage and the inability of the laryngeal lumen to undergo proper rechanneling
during embryogenesis [20].
Congenital subglottic stenosis (SGS) is the primary laryngeal anomaly that often
leads to the need for tracheostomy in children under one. Detecting subglottic stenosis prenatally is not a standard practice. In cases where severe difculty in breathing emerges at birth, immediate intubation is essential, followed by a prompt
tracheotomy to ensure proper ventilation and oxygenation for the newborn [21].
However, for individuals with mild to moderate congenital subglottic stenosis
(SGS), the condition tends to ameliorate with age. Tracheostomy is needed for
fewer than 50% of such patients.
1.1.12 Laryngeal Cleft
Laryngeal cleft is a congenital anomaly where a gap in the posterior laryngotracheal
wall enables the passage of food and liquid from the esophageal lumen to the airway, resulting in aspiration. The incidence of laryngeal cleft anomaly is rare, estimated to be between 1in 10,000 to 1in 20,000.
The severity of the anomaly can vary from mild to severe, depending on how
large the gap is between the esophagus and the airway.
Patients with small clefts do not need surgery. If there is aspiration and difculty
breathing, the cleft is closed with sutures [22, 23].
1.1.13 Tracheoesophageal Fistula
Tracheoesophageal stula (TEF) is a foregut malformation that causes an abnormal
connection between the trachea, bronchus, and esophagus. It is a rare, lifethreatening congenital anomaly. TEF treatment is usually performed through surgical intervention in the rst days following birth. Nevertheless, it is crucial not to
overlook the substantial rates of recurrence and mortality linked with the surgical
procedure, with recurrent TEF reported in 3–20% of infants following the repair of
TEF. The etiology of TEF is largely unknown but is thought to be multifactorial.
However, it has been reported that 10% of TEF patients have chromosomal anomalies, most commonly trisomy [23, 24].
8
Ş. D. Yüksel et al.
1.1.14 Tracheal Bronchus
Tracheal bronchus (TB) is a rare congenital anomaly. Children diagnosed with a
tracheal bronchus commonly exhibit symptoms such as recurring pneumonia and
atelectasis. Surgical interventions in pediatrics are the preferred approach for
patients dealing with tracheal bronchus, tracheal stenosis, recurrent pneumonia, and
atelectasis. No treatment is necessary for individuals without tracheal stenosis or
those experiencing minimal or no symptoms (Shi-Min [25]).
1.2 Introduction toLower Respiratory System
The respiratory system consists of the lungs and their conducting airways.
Facilitating the exchange of gases between blood and air, it provides oxygen to the
organism while enabling the removal of carbon dioxide. The development of the
respiratory system is intricate, involving coordinated epithelial morphogenesis and
mesenchymal development. The lower respiratory tract is early in development in
mammals, yet critical steps in alveolar maturation occur after birth. The components of the lower respiratory tract encompass the larynx, trachea, bronchi, and lungs.
The development of the human lung is initiated with the emergence of the tracheal bud from the primitive foregut endoderm during the fourth week of intrauterine life and continues until early childhood. Survival at birth hinges on adequate
lung development and maturation during the intrauterine period. Aberrations in
bronchopulmonary development lead to congenital lung malformations, and inadequate development is believed to contribute to bronchopulmonary dysplasia [26–28].
1.2.1 General Overview ofLower Respiratory
System Development
The lung endoderm becomes specialized within the ventral endoderm of the primitive foregut, approximately during weeks 4–5 of gestation in humans [29]. This
specication occurs through the expression of the transcription factor NKX2.1. The
respiratory bud, positive for NKX2.1, starts to elongate in the ventral direction, giving rise to the future tracheal tube [30]. Simultaneously, early growth and differentiation are facilitated by growth factors such as FGF10, produced from the pulmonary
mesenchyme [31]. Immediately following the formation of the tracheal tube, the
hedgehog (shh) signaling pathway, present within the endoderm, is activated to promote the development of extensively branched airways [32]. There are several
molecular signaling pathways that regulate cellular differentiation within these airways. SOX2 is necessary for epithelial differentiation in the airways, and the loss of
expression has been observed to lead to the loss of secretory and ciliated cells [33].
The activation of the Notch signaling pathway, in turn, leads to an increase in
mucus-secreting cells [34]. FOXJ1, on the other hand, has been shown to be necessary for the differentiation of multi-ciliated epithelium in the airways [35]. The
branching of developing lobular and segmental bronchi from the trachea concludes
with the formation of distal alveoli.
1 Embryological Origins oftheUpper andLower Respiratory Tract
9
1.2.2 Mesenchyme Development
Upon its formation, the respiratory bud becomes encircled by lateral plate mesoderm. Subsequently, this lateral plate mesoderm will give rise to various mesenchymal lineages within the lungs and trachea. The signaling factors secreted by
this mesenchyme, such as FGFs, WNTs, BMPs, and TGFβ, enable branching
morphogenesis, epithelial and endothelial differentiation, as well as postnatal
alveogenesis to occur [36]. In addition, throughout all stages of endodermal
development, lung mesoderm (mesenchyme) interacts with lung endoderm [37]
giving rise to mesenchymal- derived cells within the lung, including smooth muscle cells, vascular smooth muscle cells, interstitial broblasts, and pericytes
[38, 39].
1.2.3 Larynx andTrachea Development
The larynx originates from the fourth and sixth pharyngeal arches. Around the
fourth week, the laryngotracheal diverticulum, formed in the caudal part of the foregut, serves as the initial respiratory primordium, progressively giving rise to the
formation of the larynx, trachea, and lungs. Initially, it emerges as a laryngotracheal
groove beneath the primitive foregut, and subsequently elongates and develops into
the laryngotracheal diverticulum. The mesenchyme surrounding the region where
the larynx will form later contributes to the formation of the laryngeal cartilages:
thyroid, cricoid, arytenoid, and epiglottis The epithelium of the larynx, on the other
hand, derives from the endoderm. Initially elongated, the laryngeal orice transforms into a “T” shape later on [40]. The epithelial cells lining the canal begin to
rapidly proliferate, and this swift proliferation leads to a temporary closure of the
laryngeal lumen. By the tenth week, re-canalization recreates the channel. During
re-canalization, the laryngeal ventricle forms a pair of lateral depressions, which are
surrounded by tissue that will eventually give rise to the vocal and vestibular
folds [27].
The trachea, as described earlier, arises from the separation of the laryngotracheal diverticulum from the foregut. This separation involves the initial formation
of tracheoesophageal ridges, which later grow and fuse with each other, creating the
tracheoesophageal septum. This septum divides the cranial portion of the foregut
into ventral and dorsal segments. From the ventral portion, the trachea and subsequently the bronchi leading to the lungs develop, while the dorsal portion gives rise
to the esophagus (Fig.1.1) [41].
1.2.4 Lung Development
The aim of bronchopulmonary development is to establish an efcient gas exchange
organ with a broad surface area where blood and air remain in close contact with the
outside environment. Lung development has traditionally been categorized into ve
histological stages. These are the embryonic, pseudoglandular, canalicular, saccular, and alveolar stages (Fig.1.2).
10
ab cd ef
Fig. 1.1 Respiratory system development. (a) The initial emergence of the respiratory draft from
the ventral aspect of the primitive gut as the laryngotracheal groove. (b) Subsequently, the separation of the primitive trachea from the primitive gut through tracheoesophageal folds. (c) The separation of the embryonic larynx and the two main branches of the trachea from the primitive gut. (d)
The formation of primitive lobar bronchi by branching from the primary bronchi. (e) The branching of segmental bronchi. (f) The development of bronchioles and alveoli
Fig. 1.2 Lung
development stages.
(Figure was created with
BioRender.com)
Ş. D. Yüksel et al.
1.2.4.1 Embryonic Stage
Following the formation of the primitive gut, the lung bud emerges as an epithelial
outgrowth on the ventral aspect of the future esophagus. During organogenesis in
weeks 4–7, this primitive lung bud undergoes branching to give rise to two lung buds
located on either side of the future esophagus. The epithelium of the lung derives from
the endoderm and the mesodermal germ layer of the connective tissue. By the seventh
week, the initial branching of the primary lobar and segmental bronchi becomes more
distinct, signifying the segmental branching of the airways. Experimental studies have
demonstrated that this branching is directed by the mesenchyme [41].
1.2.4.2 Pseudoglandular Stage
By the end of the seventh week, each lung resembles a small tubulo-acinar gland,
thus this stage is termed “Pseudoglandular.” Between weeks 7 and 17 of gestation,
lung buds undergo branching, leading to the formation of pre-acinar airways. In this