Paediatric Respiratory Reviews 15 (2014) 188–193

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

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 Lingula Atelectasis

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 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 radiographic 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: [email protected] (F.M. de Benedictis). 1526-0542/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2014.01.002

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 occasionally 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 compression 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

V. Romagnoli et al. / Paediatric Respiratory Reviews 15 (2014) 188–193 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 fibrosis Immotile cilia syndrome Bronchiectasis Pneumonia Bronchopulmonary dysplasia Surfactant deficiency 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

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 fissures of both the middle lobe and lingula with only scanty parenchymal bridges which determine a relative anatomical isolation [3]; and finally, the poor development of the inter-alveolar pores of Kohn and brochoalveolar

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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 inflammation 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 fibrosis and ciliary dyskinesia [16,17]. In such patients, the airway inflammation and the concomitant airway epithelium involvement may affect the periciliary fluid, 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 flowing 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-inflate. Atelectasis induces alveolar hypoxia and pulmonary vasoconstriction to prevent ventilationperfusion 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 flows 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 inflammation, 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 first to investigate the allergic component and the inflammatory 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 2 Diagnostic and therapeutic strategies in different conditions causing middle lobe syndrome Predisposing conditions

Evaluation

Intervention

Asthma Cystic fibrosis Primary ciliary dyskinesia Neuromuscular diseases Immunodeficiency syndromes Inhaled foreign body Recurrent aspiration

Inhaled bronchodilators  inhaled corticosteroids Airway clearance regimen (i.e. chest physiotherapy, aerosol therapy)

Mediastinal mass

Spirometry, bronchoprovocation tests Sweat test, genetics Ciliary beat analysis, electron microscopy, genetics Electromyography, electroneurography, genetics Immunologic tests Flexible bronchoscopy Flexible endoscopic evaluation of swallowing, reflux monitoring (PH and impedance) CT-scan, tuberculin skin test

Cardiomegaly

Echocardiography

Removal with the rigid bronchoscope Immunoglobulin replacement, if indicated Rigid bronchoscopy removal Treatment of the underlying condition (i.e.: laryngeal cleft repair, swallowing therapy) Treatment of the underlying condition (i.e.: anti-TB drugs, chemotherapy) Treatment of heart disease

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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 management, but not of radiographic improvement. This suggests that factors other than asthmatic inflammation are responsible for bronchial hyperresponsiveness in children with MLS, but alternative 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 pulmonary 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 ‘‘pneumonia’’. 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 compression of airways (Figure 3) and also allows the collection of specimens for diagnosis of infectious causes [33]. Bronchoalveolar lavage can be

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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 antibiotics 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

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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 bronchodilators 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. Pretreatment 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 bronchoalveolar 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

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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 reexpansion of the involved lung parenchyma [42]. Non surgical techniques such as intrabronchial air insufflation, balloon dilatation, 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 reexpand 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 experienced 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 obstructive 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 documented 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 prevention 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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