Review

Middle lobe syndrome in children today

Vittorio Romagnoli
1
, Kostas N. Priftis
2
, Fernando M. de Benedictis
1,
*
1
Department of Mother and Child Health, Salesi University Childrens Hospital, Ancona, Italy
2
Pulmonology Unit, 3
rd
Department of Paediatrics, University General Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens,
Athens, Greece
Middle lobe syndrome (MLS) is a distinct clinical and radio-
graphic entity that has been well described in the pediatric
literature. The clinical and radiological aspects of the lung
involvement were illustrated by Brock et al. [1] in 1937 in
children with tuberculous mediastinal lymphadenitis, but Graham
et al. [2] rst used the term MLS to describe a series of 12 patients
with middle lobe atelectasis due to compression of the middle lobe
bronchus by peribronchial lymph nodes. The process can also occur
in other areas of the lung, particularly in the lingula [3,4]. It should
be emphasized that much of the knowledge on MLS is speculative
and not based on scientic evidence.
The exact prevalence of MLS is unknown. In childhood, it is
more frequent in preschool years, with a median age at diagnosis
ranging from 3.3 to 5.5 years [5,6]. An increased prevalence in
females has been reported in most studies [7,8]. Familial
occurrence has been occasionally described [9].
MLS is frequently misdiagnosed in clinical practice, and delay in
the diagnosis is responsible for both high economic burden due to
over-prescription of drugs and potential poor long-term outcome.
The aim of this article is therefore to illustrate the clinical and
imaging features of MLS in order to help physicians to recognize
this condition early and treat it accordingly.
ETIOLOGY AND PATHOPHYSIOLOGIC MECHANISMS
The causes of atelectasis in childhood are summarized in
Table 1. Traditionally, atelectasis has been classied into obstructive
and nonobstructive, but pathophysiologic mechanisms can occa-
sionally interact. Obstructive MLS can be caused by extrinsic
compression of the middle lobe bronchus or by endobronchial
lesions. In children, the most common cause of bronchial compres-
sion is enlargement of peribronchial, hilar or mediastinal lymph
nodes; this is usually the consequence of mycobacterial or fungal
infection, immunodeciency syndrome, lymphoma or metastasis
[5]. Mediastinal tumors and cardiomegaly in congenital heart
disease are rare causes of extrinsic obstruction. Aspirated foreign
bodies, recurrent aspiration and, less frequently, endobronchial
Paediatric Respiratory Reviews 15 (2014) 188193
A R T I C L E I N F O
Keywords:
Middle lobe
Lingula
Atelectasis
S U M M A R Y
Middle lobe syndrome in children is a distinct clinical and radiographic entity that has been well
described in the pediatric literature. However, issues regarding its etiology, clinical presentation, and
management continue to puzzle the clinical practitioner. Pathophysiologically, there are two forms of
middle lobe syndrome, namely obstructive and nonobstructive. Middle lobe syndrome may present as
symptomatic or asymptomatic, as persistent or recurrent atelectasis, or as pneumonitis or bronchiectasis
of the middle lobe and/or lingula. A lower threshold of performing a chest radiograph is warranted in
children with persistent or recurrent nonspecic respiratory symptoms, particularly if there is clinical
deterioration, in order to detect middle lobe syndrome and to initiate a further diagnostic and therapeutic
workup.
2014 Elsevier Ltd. All rights reserved.
EDUCATIONAL AIMS
Review the pathophysiologic mechanisms.
Illustrate the clinical and imaging features.
Emphasize the diagnostic and therapeutic intervention in order to help physicians to recognize MLS early and treat it accordingly.
* Corresponding author. Division of Pediatrics, Salesi Childrens Hospital, 11, via
Corridoni, I-60123 Ancona, Italy Tel.: +39 071 5962351; fax: +39 071 5962234.
E-mail address: debenedictis@ospedaliriuniti.marche.it (F.M. de Benedictis).
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
1526-0542/$ see front matter 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.prrv.2014.01.002
tumors represent the main causes of intrabronchial obstruction in
childhood [10]. In aspiration lung disease in infancy, the most
frequently affected lobes are the posterior areas of the upper and
lower lobes, because the infants lie supine for much of the day; in
toddlers or older children, who spend more time vertical, the lower
lobes, the lingula and the middle lobe are more frequently affected
[11]. In the nonobstructive type of MLS, the middle lobe bronchus is
patent but several anatomical as well as functional factors make it
susceptible to collapse [12]. They include: the narrow diameter and
long length of the middle lobe bronchus; its angular take-off from
the intermediate bronchus [13]; the deep ssures of both the middle
lobe and lingula with only scanty parenchymal bridges which
determine a relative anatomical isolation [3]; and nally, the poor
development of the inter-alveolar pores of Kohn and brochoalveolar
canals of Lambert in early life, that may impair collateral
ventilation of the middle lobe [14]. The physiologic absence of
collateral communication at the more proximal bronchial level
may also lead to air trapping in lung areas peripheral to occlusion.
All the above mentioned factors may contribute to an impaired or
absent drainage of secretions from the middle lobe and to
subsequent atelectasis when inammation and/or edema due to
lower respiratory tract infections intervene [15]. Some patients
have mucus hypersecretion, as their dominant phenotype,
worsening the conditions. This process is particularly frequent
in children with asthma, cystic brosis and ciliary dyskinesia
[16,17]. In such patients, the airway inammation and the
concomitant airway epithelium involvement may affect the
periciliary uid, thus reducing the effect of surfactant and
enhancing the tendency to bronchial collapse.
Bronchial obstruction leads to non-ventilation of the distal
airways, where the gas is completely absorbed by pulmonary blood
owing through that area. The rate of absorption into the blood
stream depends on the solubility of the trapped gases: while
atmospheric air is absorbed in 2 to 3 hours, 100 per cent oxygen is
absorbed in few minutes, thus explaining the high risk of
atelectasis in the postoperative period. In atelectasis, compression
of the parenchyma and/or increased surface tension produces an
extrusion of the gas out of the alveoli and reduces the capability of
the involved parenchyma to re-inate. Atelectasis induces alveolar
hypoxia and pulmonary vasoconstriction to prevent ventilation-
perfusion mismatching and minimize arterial hypoxia. The
vascular response is less effective when a large part of the lung
is collapsed; if the blood cannot be diverted, it ows through the
atelectatic non-ventilated region and produces intrapulmonary
shunting [18]. The mechanical effect of a collapsed segment may
result in the distension of adjacent unobstructed alveoli.
If the underlying causes promptly resolve, the atelectasis may
recover spontaneously, but complications often supervene when
atelectasis persists. The accumulation of secretions distal to the
obstructed area is an important factor which creates a favorable
site for the growth of microorganisms. In such cases, a vicious cycle
of recurrent inammation, infection and obstruction may occur
and bronchiectasis may develop. Inadequate bronchial wall
integrity in bronchiectasis may lead in turn to progressive airway
obstruction. When alveoli are collapsed, a great effort is required to
expand lung tissue, especially if it has been collapsed for a long
period.
Priftis et al. [19] were the rst to investigate the allergic
component and the inammatory state of airway in patients with
MLS. They compared 53 children with MLS to a group with asthma
but no MLS, and to non-asthmatic controls. They found that the
prevalence of skin test sensitization was not different between
MLS and non-asthmatics, but was lower than in children with
asthma. A positive response to methacholine challenge was more
common among children with MLS than either the asthmatic or
Table 1
Causes of atelectasis in childhood
1. Obstructive
Bronchial compression
Lymph nodes
Tumors
Cardiomegaly
Endobronchial obstruction
Exogenous
Foreign body
Recurrent aspiration
Histoplasmosis
Endogenous
Polyps
Papillomas
Adenomas
Granulomas
2. Nonobstructive
Mucus plugs
Asthma
Cystic brosis
Immotile cilia syndrome
Bronchiectasis
Pneumonia
Bronchopulmonary dysplasia
Surfactant deciency or dysfunction
Hyaline membrane disease
Pulmonary edema
Near-drowning
Respiratory distress syndrome
Chest wall defects and neuromuscular diseases
Abnormalities of diaphragm
Spinal muscular atrophy
Werding-Hoffman disease
Muscular dystrophies
Guillan-Barre` syndrome
Intrathoracic compression
Pleural effusion
Chylothorax
Hemothorax
Pneumothorax
Table 2
Diagnostic and therapeutic strategies in different conditions causing middle lobe syndrome
Predisposing conditions Evaluation Intervention
Asthma Spirometry, bronchoprovocation tests Inhaled bronchodilators inhaled corticosteroids
Cystic brosis Sweat test, genetics Airway clearance regimen (i.e. chest physiotherapy, aerosol therapy)
Primary ciliary dyskinesia Ciliary beat analysis, electron microscopy, genetics
Neuromuscular diseases Electromyography, electroneurography, genetics Removal with the rigid bronchoscope
Immunodeciency syndromes Immunologic tests Immunoglobulin replacement, if indicated
Inhaled foreign body Flexible bronchoscopy Rigid bronchoscopy removal
Recurrent aspiration Flexible endoscopic evaluation of swallowing, reux
monitoring (PH and impedance)
Treatment of the underlying condition (i.e.: laryngeal cleft repair,
swallowing therapy)
Mediastinal mass CT-scan, tuberculin skin test Treatment of the underlying condition (i.e.: anti-TB drugs,
chemotherapy)
Cardiomegaly Echocardiography Treatment of heart disease
V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188193 189
non-asthmatic children. For the children with MLS, an increased
count of eosinophils in the bronchoalveolar lavage uid was
predictive of resolution of symptoms after aggressive manage-
ment, but not of radiographic improvement. This suggests that
factors other than asthmatic inammation are responsible for
bronchial hyperresponsiveness in children with MLS, but alter-
native explanations cannot be excluded [20].
WHEN MLS SHOULD BE SUSPECTED
MLS may present as symptomatic or asymptomatic. The clinical
presentation is not linked to specic respiratory symptoms but
rather to common ones, such as chronic or recurrent cough,
sputum production, intermittent wheezing, and recurrent or
persistent pneumonia [5,21]. It is therefore not surprising that
such nonspecic symptoms may result in the underestimation of
latently developed atelectasis in anatomically predisposed pul-
monary segments. In more than half of children, MLS went
unnoticed by physicians for an unknown period of time, although
symptoms, albeit nonspecic, persisted for many months [5].
Therefore, any postponement in obtaining a chest radiograph in
patients with nonspecic, often mild, persistent respiratory
symptoms may result in a failure to diagnose longstanding MLS.
Low-grade fever, hemoptysis, chest pain, weight loss, and fatigue
may indicate complications related to suppurative infections
[22,23]. There is often a history of multiple treatments with
antibiotics, mucolytics and antiasthmatic drugs for recurrent
pneumonia or asthma. Physical examination may be completely
normal, but loss of breath sound in the middle lobe, localized
wheeze and crackles may be revealed [5,24,25].
Asthma may be associated with MLS and this can cause a
diagnostic dilemma. When a viral infection occurs in an asthmatic
patient, the poor clearance of inammatory debris, smooth muscle
constriction and edema of the bronchial wall can occlude the
lumen of the airway, especially the right middle bronchus, causing
partial or complete obstruction. Unfortunately, these radiographic
signs are often interpreted (and improperly treated) as pneumo-
nia. The role of secondary bacterial infections in these patients is
unclear, but it has been claimed to be of importance [26]. In case of
recurrent or persistent consolidation of the middle lobe with no
evidence of asthma, other disease such as cystic brosis, primary
ciliary dyskinesia, plastic bronchitis or immunodeciency should
be ruled out.
FROM THE CLINICAL SUSPICION TO DIAGNOSIS
The diagnosis of MLS is difcult only for physicians who do not
think of it. If not recognized early, atelectasis of the middle lobe
may persist unnoticed for a prolonged period of time and repeated
episodes of infection/inammation may develop.
Chest radiograph is the rst-line diagnostic tool for diagnosing
MLS. The postero-anterior view may show obscuring of the right
cardiac border (silhouette sign) (Figure 1). The collapse of the
middle lobe is often difcult to detect on this view, both because
the lobe is relatively thin and compensatory overdistention of
nonobstructed alveoli. Radiological abnormalities are more
apparent in the lateral view: a wedge-shaped area of increased
density with the apex is at the hilum and the base towards the
pleura, and occasionally a concomitant hyper-ination of the
adjacent lobes can be seen (Figure 2) [27]. In some cases, the loss of
volume in the lobe is so small that it may appear as a dense band,
suggesting pleural thickening rather than an atelectatic lobe [28].
Radiographically, there can be problems differentiating atelectasis
from simple lobar consolidation. In consolidated areas, the alveoli
are full of exudate and there is no signicant loss of lung volume.
However, as the pneumonia clears, atelectasis may develop
because of mucus plugs or surfactant dysfunction. In such cases
a clinical history may be helpful. If confusion remains, chest
radiographic follow-up may be useful to demonstrate rapid
resolution, which is more rapid in atelectasis.
High-resolution, thin-section computed tomography scans may
identify endobronchial abnormalities, bronchiectasis and other
parenchymal abnormalities, as well as provide information on
bronchial patency, lymph node enlargement and calcications, or
other causes of extrinsic compression of airway [29]. A recent
study suggests that magnetic resonance imaging of the chest may
represent a feasible and radiation-free option for an overall
assessment of the lung in the follow-up of patients with MLS [30].
Several studies evaluated the role of ultrasound in the diagnosis
and follow-up of pneumonia and atelectasis, but its role in the
evaluation of MLS needs to be claried [31].
Flexible bronchoscopy plays a key role in the investigation of
children with airway diseases including persistent atelectasis [32].
In patients with MLS it may reveal foreign body aspiration, mucus
plugging, endobronchial tumors or even signs of extrinsic compres-
sion of airways (Figure 3) and also allows the collection of specimens
for diagnosis of infectious causes [33]. Bronchoalveolar lavage can be
Figure 1. Chest X-ray, postero-anterior view: Ill-dened opacity obscuring the right
cardiac border.
Figure 2. Chest X-ray, lateral view: Wedge-shaped area of increased density with
apex at the hilum and the base towards the pleura.
V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188193 190
concurrently performed to determine cellular elements and assess
the presence of infection [34].
Blood samples (circulating blood cell count with differential,
total serum immunoglobulins and subclasses, specic antibodies
after vaccination), sweat test and tuberculin skin test may be
helpful tools in the diagnostic evaluation of MLS and may suggest
the diagnosis of an underlying cause.
HOW MLS SHOULD BE MANAGED
Since several causes may underlie MLS and the characteristics
of the process may vary between patients, treatment should be
individualized. Conservative intervention should be the rst-line
treatment. In case of a suspected or proven lung infection,
antibiotic therapy is recommended. Antibiotics are chosen on
microbial culture or sensitivity results from bronchoalveolar
lavage uid or sputum. Otherwise, oral broad-spectrum anti-
biotics such as amoxicillin-clavulanate or a second generation
cephalosporin should be used, covering the most common
respiratory bacteria (Streptococcus pneumoniae, Haemophilus
inuenzae, Moraxella catarralis).[7] If Mycoplasma pneumoniae is
suspected, macrolide therapy should be considered [35]. Specic
antimicrobial agents are necessary in case of unusual infections,
such as Pseudomonas aeruginosa, atypical mycobacteria or fungi.
There is no evidence to guide the duration of treatment, but
antibiotics are usually continued for several weeks, until there is
denite evidence of clinical and radiological improvement [36].
The use of nebulized antibiotics in MLS is anecdotal. Despite the
frequent use of antibiotic therapy in MLS, the exact role of these
agents is still uncertain and should be better evaluated in future
by controlled studies.
Tubercular lymph nodes adjacent to bronchi can inltrate the
airways, causing ulceration and granulation tissue formation and
eventually leading to atelectasis or bronchial perforation. If started
early and continued for 6 to 12 weeks, prednisone (12 mg/kg/d)
can prevent brous tissue formation and may be a useful adjuvant
to antituberculous drugs. Rifampicin induces the hepatic enzymes
that catabolize corticosteroids, effectively reducing bioavailability
by 50% [37].
When asthma is suspected, treatment with inhaled broncho-
dilators and even inhaled corticosteroids is a reasonable option.
Antibiotics agents should be added to antiasthmatic therapy only if
bacterial infection is present or suspected as a concomitant factor.
It is widely believed that a routine airway clearance regimen is
an important component of the management of individuals who
have chronic productive cough and/or evidence of mucus plugging.
The benet is thought to be due to mobilization of secretions by
hufng and coughing from the smaller to the more central airways.
Chest physiotherapy includes multiple techniques to improve
mucus clearance in conjunction with spontaneous or directed
cough. The active cycle of breathing techniques is the most
commonly used method. Alternative modalities such as positive
expiratory pressure, oscillating positive expiratory pressure,
autogenic drainage and intermittent positive pressure breathing
may be also used. Chest physiotherapy has been traditionally
recommended as rst-line therapy in the management of MLS,
especially if mucus plugging is suspected [38]. Despite its large use,
scientic evidence on the effect of physiotherapy in improving
atelectasis is lacking [39], and it is hard to say whether individuals
with MLS may benet from seeing a physiotherapist. Until
denitive answer will be obtained from controlled clinical studies,
it seems wise to advocate teaching an airway clearance technique
by an expert physiotherapist in children with MLS suspected to
have mucus plugging.
Aerosol therapy by inhalation of jet-nebulized saline increases
sputum volume and clearance compared to physiotherapy alone.
In concentrations of 3-14%, hypertonic saline and dry powder
mannitol [40] have been shown to improve tracheobronchial
clearance in patients with chronic bronchitis, cystic brosis,
asthma and normal individuals [41]. It is thought that it may work
by inducing liquid ux from the epithelium into the mucus,
thereby increasing hydration of airway surface so that secretions
are cleared more easily by cough. The effect of hypertonic solution
in children with MLS has not been formally evaluated, but there is a
rationale if increased bronchial secretions are present. Pretreat-
ment with a bronchodilator may be necessary for those with
bronchial hyper-reactivity. The use of classical mucolytics and new
agents such as recombinant human DNase and tissue plasminogen
activator has not been studied in patients with MLS.
Flexible bronchoscopy plays an important role in treating MLS.
In a relevant study, 92% of children with nonobstructive atelectasis
of the middle lobe and/or lingula were cured or their symptom
were improved after both exible bronchoscopy and bronchoal-
veolar lavage [5]. Such a benet may be the result of the
combination of performing bronchoscopy, which restores the
patency of the atelectatic segment per se, with an aggressive
therapeutic protocol. The proper timing for such combined
intervention is not known, but current data support that
Figure 3. Flexible bronchoscopy: Orice of the middle lobe bronchus before (a) and
after removal (b) of a purulent mucus plug.
V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188193 191
intervention delayed more than 3 to 7 months is associated with
poor clinical and radiographic outcome. Rigid bronchoscopy is the
main therapeutic tool in case of foreign body aspiration, mucus
plugging or endobronchial tumors [30,31]. This procedure usually
results in a resolution of the atelectasis with a prompt re-
expansion of the involved lung parenchyma [42]. Non surgical
techniques such as intrabronchial air insufation, balloon dilata-
tion, stent placement, cryosurgery and laser therapy may represent
promising bronchoscopic options in selected conditions [43,44].
The main diagnostic and therapeutic strategies in different
conditions causing MLS are shown in Table 2.
There is no consensus regarding the indication for surgical
intervention in MLS, especially in children [8]. Indeed, there have
been few studies, and most of them are not randomized or enrolled
a small number of patients [3]. Surgical removal of the middle lobe
or lingula is advocated for patients with failure of the lung to re-
expand accompanied by persistent symptoms after prolonged (at
least 6 months), aggressive medical therapy or who have frequent
relapses of lobar atelectasis and established bronchiectasis.
Surgery should be also considered in patients with persistent
lung infection, clinically problematic bronchiectasis or abscesses,
lung scarring and brosis [8,45]. The surgical procedure is usually
more successful if the disease is limited to the middle lobe only
[46]. Thoracoscopic techniques are minimally invasive and should
be preferred in children, when possible [47]. The decision of
performing lung resection in children is a widely debated topic due
to the risk of impaired lung function. Such a decision requires
careful discussion of individualized cases between highly experi-
enced physicians in this eld.
THE OUTCOME
MLS usually has a favorable outcome with complete recovery of
symptoms and re-expansion of the collapsed lung parenchyma.
There is a paucity of information on the long-term pulmonary
consequences of MLS in childhood. Although few evidence based
data are available on this matter, it is commonly believed that
delaying the diagnosis and denying a patient with an appropriate
treatment may lead to an unfavorable outcome in some cases. In a
study on 17 children diagnosed with MLS in early childhood, about
one third continued to have respiratory symptoms in later
childhood, most commonly mild obstructive airway disease [6].
Cylindrical bronchiectasis only occurred in one patient and none of
these children had been operated during a 10 year follow-up.
Abnormal pulmonary function tests consistent with mild obstruc-
tive airway disease and hyperreactive airway disease were more
frequent in children with ongoing respiratory symptoms. In
addition, age at the initial diagnosis tended to be younger in
patients with symptoms at follow-up. In a recent, retrospective
evaluation of 55 children with MLS, bronchiectasis were docu-
mented in 27.3% of the patients [5]. The authors showed that the
earlier the management protocol, including exible bronchoscopy
and bronchoalveolar lavage, was implemented, the lower was the
risk of bronchiectatic lesions; after bronchiectasis had been
established, the clinical and radiographic outcomes became less
favorable. It is hoped that prospective studies are implemented
with the aim to clear this still uncertain aspect of long-term
outcome of MLS.
In conclusion, MLS is characterized by a spectrum of diseases
from recurrent atelectasis and pneumonitis to bronchiectasis of
the middle lobe. Thinking of MLS is a prerequisite for diagnosis.
Most patients respond to medical treatment consisting of
bronchodilators, inhaled corticosteroids and antibiotics. However,
some patients do not show therapeutic response and may suffer
irreversible damage of the middle lobe or lingula. These selected
patients can be offered an aggressive and timely therapeutic
protocol, including bronchoscopy and bronchoalveolar lavage.
Surgical resection should be reserved to the rare children who have
persistent lung infection in spite of the aggressive medical
treatment.
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