Paediatric Respiratory Reviews 15 (2014) 188–193

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

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 Children’s Hospital, Ancona, Italy
2
Pulmonology Unit, 3rd Department of Paediatrics, University General Hospital ‘‘Attikon’’, School of Medicine, National and Kapodistrian University of Athens,
Athens, Greece

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.

A R T I C L E I N F O S U M M A R Y

Keywords: Middle lobe syndrome in children is a distinct clinical and radiographic entity that has been well
Middle lobe
described in the pediatric literature. However, issues regarding its etiology, clinical presentation, and
Lingula
management continue to puzzle the clinical practitioner. Pathophysiologically, there are two forms of
Atelectasis
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 nonspecific respiratory symptoms, particularly if there is clinical
deterioration, in order to detect middle lobe syndrome and to initiate a further diagnostic and therapeutic
workup.
ß 2014 Elsevier Ltd. All rights reserved.

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] first 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 scientific 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].
* Corresponding author. Division of Pediatrics, Salesi Children’s 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).
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 classified 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, immunodeficiency 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

1526-0542/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.prrv.2014.01.002
 V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188–193 189

Table 1 canals of Lambert in early life, that may impair collateral

Causes of atelectasis in childhood
ventilation of the middle lobe [14]. The physiologic absence of
1. Obstructive collateral communication at the more proximal bronchial level
Bronchial compression
may also lead to air trapping in lung areas peripheral to occlusion.
Lymph nodes
Tumors All the above mentioned factors may contribute to an impaired or
Cardiomegaly absent drainage of secretions from the middle lobe and to
Endobronchial obstruction subsequent atelectasis when inflammation and/or edema due to
Exogenous lower respiratory tract infections intervene [15]. Some patients
Foreign body
Recurrent aspiration
have mucus hypersecretion, as their dominant phenotype,
Histoplasmosis worsening the conditions. This process is particularly frequent
Endogenous in children with asthma, cystic fibrosis and ciliary dyskinesia
Polyps [16,17]. In such patients, the airway inflammation and the
Papillomas
concomitant airway epithelium involvement may affect the
Adenomas
Granulomas periciliary fluid, thus reducing the effect of surfactant and
enhancing the tendency to bronchial collapse.
2. Nonobstructive
Bronchial obstruction leads to non-ventilation of the distal
Mucus plugs
Asthma airways, where the gas is completely absorbed by pulmonary blood
Cystic fibrosis flowing through that area. The rate of absorption into the blood
Immotile cilia syndrome stream depends on the solubility of the trapped gases: while
Bronchiectasis atmospheric air is absorbed in 2 to 3 hours, 100 per cent oxygen is
Pneumonia
Bronchopulmonary dysplasia
absorbed in few minutes, thus explaining the high risk of
Surfactant deficiency or dysfunction atelectasis in the postoperative period. In atelectasis, compression
Hyaline membrane disease of the parenchyma and/or increased surface tension produces an
Pulmonary edema extrusion of the gas out of the alveoli and reduces the capability of
Near-drowning
the involved parenchyma to re-inflate. Atelectasis induces alveolar
Respiratory distress syndrome
Chest wall defects and neuromuscular diseases hypoxia and pulmonary vasoconstriction to prevent ventilation-
Abnormalities of diaphragm perfusion mismatching and minimize arterial hypoxia. The
Spinal muscular atrophy vascular response is less effective when a large part of the lung
Werding-Hoffman disease is collapsed; if the blood cannot be diverted, it flows through the
Muscular dystrophies
Guillan-Barrè syndrome
atelectatic non-ventilated region and produces intrapulmonary
Intrathoracic compression shunting [18]. The mechanical effect of a collapsed segment may
Pleural effusion result in the distension of adjacent unobstructed alveoli.
Chylothorax If the underlying causes promptly resolve, the atelectasis may
Hemothorax
recover spontaneously, but complications often supervene when
Pneumothorax
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
tumors represent the main causes of intrabronchial obstruction in of recurrent inflammation, infection and obstruction may occur
childhood [10]. In aspiration lung disease in infancy, the most and bronchiectasis may develop. Inadequate bronchial wall
frequently affected lobes are the posterior areas of the upper and integrity in bronchiectasis may lead in turn to progressive airway
lower lobes, because the infants lie supine for much of the day; in obstruction. When alveoli are collapsed, a great effort is required to
toddlers or older children, who spend more time vertical, the lower expand lung tissue, especially if it has been collapsed for a long
lobes, the lingula and the middle lobe are more frequently affected period.
[11]. In the nonobstructive type of MLS, the middle lobe bronchus is Priftis et al. [19] were the first to investigate the allergic
patent but several anatomical as well as functional factors make it component and the inflammatory state of airway in patients with
susceptible to collapse [12]. They include: the narrow diameter and MLS. They compared 53 children with MLS to a group with asthma
long length of the middle lobe bronchus; its angular take-off from but no MLS, and to non-asthmatic controls. They found that the
the intermediate bronchus [13]; the deep fissures of both the middle prevalence of skin test sensitization was not different between
lobe and lingula with only scanty parenchymal bridges which MLS and non-asthmatics, but was lower than in children with
determine a relative anatomical isolation [3]; and finally, the poor asthma. A positive response to methacholine challenge was more
development of the inter-alveolar pores of Kohn and brochoalveolar common among children with MLS than either the asthmatic or

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 fibrosis
Primary ciliary dyskinesia
Neuromuscular diseases
Immunodeficiency syndromes
Inhaled foreign body
Recurrent aspiration
Mediastinal mass
Cardiomegaly
Sweat test, genetics Airway clearance regimen (i.e. chest physiotherapy, aerosol therapy)
Ciliary beat analysis, electron microscopy, genetics
Electromyography, electroneurography, genetics Removal with the rigid bronchoscope
Immunologic tests Immunoglobulin replacement, if indicated
Flexible bronchoscopy Rigid bronchoscopy removal
Flexible endoscopic evaluation of swallowing, reflux Treatment of the underlying condition (i.e.: laryngeal cleft repair,
monitoring (PH and impedance) swallowing therapy)
CT-scan, tuberculin skin test Treatment of the underlying condition (i.e.: anti-TB drugs,
chemotherapy)
Echocardiography Treatment of heart disease
190 V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188–193
non-asthmatic children. For the children with MLS, an increased
count of eosinophils in the bronchoalveolar lavage fluid was
predictive of resolution of symptoms after aggressive manage-
ment, but not of radiographic improvement. This suggests that
factors other than asthmatic inflammation 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 specific 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 nonspecific 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 nonspecific, persisted for many months [5].
Therefore, any postponement in obtaining a chest radiograph in
patients with nonspecific, 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 inflammatory 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 fibrosis, primary
ciliary dyskinesia, plastic bronchitis or immunodeficiency should
be ruled out.
Figure 1. Chest X-ray, postero-anterior view: Ill-defined 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.
FROM THE CLINICAL SUSPICION TO DIAGNOSIS
The diagnosis of MLS is difficult 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/inflammation may develop.
Chest radiograph is the first-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 difficult 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-inflation 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 significant 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 calcifications, 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 clarified [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
 V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188–193
Figure 3. Flexible bronchoscopy: Orifice of the middle lobe bronchus before (a) and
after removal (b) of a purulent mucus plug.
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, specific 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 first-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 fluid 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
influenzae, Moraxella catarralis).[7] If Mycoplasma pneumoniae is
suspected, macrolide therapy should be considered [35]. Specific
191
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
definite 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 infiltrate 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 (1–2 mg/kg/d)
can prevent fibrous 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 benefit is thought to be due to mobilization of secretions by
huffing 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 first-line therapy in the management of MLS,
especially if mucus plugging is suspected [38]. Despite its large use,
scientific evidence on the effect of physiotherapy in improving
atelectasis is lacking [39], and it is hard to say whether individuals
with MLS may benefit from seeing a physiotherapist. Until
definitive 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 fibrosis,
asthma and normal individuals [41]. It is thought that it may work
by inducing liquid flux 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 flexible bronchoscopy and bronchoal-
veolar lavage [5]. Such a benefit 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
192 V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188–193
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 insufflation, 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 fibrosis [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 field.
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 flexible 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.
PRACTICAL POINTS
 MLS is frequently unrecognized in children.
 Nonspecific clinical presentation of MLS leads to delayed
diagnosis.
 A low threshold of performing a chest radiograph is
warranted in children with suspected MLS.
 Medical intervention should mainly focus on the preven-
tion of bronchiectasis.
 Therapeutic intervention should be instituted as soon as
possible.
UNMET NEEDS AND FUTURE RESEARCH
 Evaluation of chest physiotherapy programs.
 Well controlled studies on traditional (ie. bronchodilators,
inhaled corticosteroids) and new (ie. DNAse, hypertonic
saline, dry powder mannitol) drugs.
 Evaluation of new nonsurgical therapeutic techniques (ie.
positive pressure ventilation via flexible bronchoscopy).
 Evaluation of radiation-free imaging techniques for
follow-up.
 Re-evaluation of threshold for surgical treatment.
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