Keywords

Introduction

Follicular bronchiolitis (FB) and lymphoid interstitial pneumonia (LIP) represent a pathophysiological continuum of lymphocytic infiltration from hyperplasia of bronchus-associated lymphoid tissue to cellular expansion of the interstitium with fibrosis [1]. In other words, LIP is a clinicopathologic term that describes diffuse involvement of the lung parenchyma by reactive pulmonary lymphoid tissue, whereas FB refers to a pattern of lymphoid follicular hyperplasia centered on airways, vessels, and interlobular septa consistent with a lymphatic distribution [2]. Although LIP can be difficult to distinguish from FB, we will review the clinical, radiologic, and pathologic presentation of both entities in this continuum. We will also review what little is known regarding their etiopathogenesis and treatment.

Lymphoid Interstitial Pneumonia

LIP was first described by Carrington and Liebow in 1966 [3]. It is a benign lymphoproliferative disorder that is characterized by diffuse infiltration of small mature lymphocytes, plasma cells, and histiocytes that spread diffusely into the alveolar septae.

Clinical Presentation

LIP is an uncommon disorder that is rarely idiopathic; rather, it is thought to be an expression of systemic immunologic disorders in the lung [4]. The diagnosis of LIP should be considered in anyone with lung cysts and an immunologic abnormality (Table 8.1). A thorough evaluation for an underlying systemic condition, especially autoimmune and immunodeficiency states, should be undertaken after a radiological or histopathological diagnosis of LIP is established [5].

Table 8.1 Clinical and radiologic features of follicular bronchiolitis and lymphoid interstitial pneumonia
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LIP has a bimodal distribution. In children less than 13, LIP is generally associated with human immunodeficiency virus (HIV) and is an acquired immunodeficiency syndrome (AIDS)-defining illness [6]. Whereas in adults, LIP most commonly affects women in the fourth to sixth decade with an underlying autoimmune disorder or immunodeficiency [7, 8]. The female to male prevalence in adults is 2:1 [8]. Most non-HIV adults presenting with LIP are white [8], whereas in the context of HIV, LIP is more commonly seen in those of black African or Afro-Caribbean origin, particularly those from Haiti [9].

Patients may have constitutional symptoms including fevers, chills, night sweats, weight loss, and fatigue [7, 10]. Patients may also present with pleuritic chest pain possibly indicating a pneumothorax [11]. On examination, patients may have bibasilar end inspiratory crackles [12], or the chest may be silent as it often is in children. Clubbing of the fingers and toes frequently occurs in children, but may not be present in adults [13,14,15]. Splenomegaly is commonly associated with LIP in the setting of common variable immune deficiency (CVID) [16]. When LIP occurs in the setting of HIV, it may be associated with other features of diffuse infiltrative lymphocytic syndrome (DILS) including xerophthalmia and xerostomia, nontender parotid and salivary gland involvement, widespread lymphadenopathy, hepatosplenomegaly, or discomfort after eating if lymphocytic gastritis is a feature. There may also be facial numbness or weakness caused by seventh cranial nerve palsy. Patients may also present neck stiffness and headache due to aseptic meningitis [9].

Pulmonary function may show a restrictive ventilatory defect with a reduced diffusion [17]. Approximately 80% of patients with LIP have serum dysproteinemias; most commonly hypergammaglobulinemia [8] but hypogammaglobulinemia can occur in the setting of CVID. The cause of this is unknown but likely reflects chronic systemic autoimmune inflammation [18]. Serum lactate dehydrogenase (LDH) may be elevated, but this is a nonspecific finding [9].

Associated Conditions

Many affected patients have immune dysregulation or an underlying autoimmune disease, and thus, LIP is thought to represent a nonspecific response to multiple stimuli or antigens [7, 19]. Tertiary lymphoid neogenesis, which is associated with chronic inflammatory conditions, is seen in the distinct B- and T-cell areas of cellular proliferation found in LIP [20, 21]. Although the specific immunologic pathogenesis for LIP is unknown, an immunologic pathogenesis is further supported by an association with major histocompatibility complex antigens [9] and the presence of immune complex deposition [22].

Viral Associations

Chronic antigenic stimulation as a cause of LIP is suggested by the association of several viruses (EBV, HIV, HHV-8, hepatitis B, hepatitis C) with LIP [19, 23]. Epstein-Barr virus (EBV) is frequently found in the lungs of children and some adults with LIP [24]. EBV infects B lymphocytes, inducing proliferation of these cells, and patients with various types of immunodeficiency are at increased risk for developing a sustained EBV-related proliferation response, resulting in B-cell lymphoproliferative disorders [25]. EBV is also often found in the lungs of children with LIP and AIDS [26], and the titers of EBV antibodies are significantly higher in adult patients with AIDS and LIP compared to AIDS patients without LIP [27]. The predilection for EBV and/or HIV being associated with LIP in children is likely due to the presence of bronchus-associated lymphoid tissue, which is less commonly seen in healthy adult lungs [15]. Viral-related LIP may be associated with a cellular immune response against the viral antigen as CD8+ lymphocytes, in particular, are considered to play a major role in the pathology of LIP, with increased CD8+ lymphocytes found in BAL fluid [15].

Autoimmune Disease

Another hypothesis suggests that LIP is due to loss of self-tolerance; a clonality of autoreactive T cells develops in response to lung antigens [28]. This is most evident by the strong association between LIP (and follicular bronchiolitis) and Sjögren’s syndrome (SS): nearly 1% of adults with SS have LIP, and 30% to 60% of adults with LIP have SS [29,30,31,32]. LIP is also associated with a number of other autoimmune disorders including rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid disease, primary biliary cirrhosis, myasthenia gravis, hemolytic and pernicious anemia, idiopathic thrombocytopenic purpura, erythrocyte sensitization syndrome, autoimmune glomerulonephritis, ulcerative colitis, celiac sprue, and diabetes mellitus [7, 8, 33,34,35,36,37]. Because of this strong association with autoimmune disease, the presence of LIP is one of the criteria for the new entity “interstitial pneumonia with autoimmune features (IPAF),” which describes patients with an idiopathic interstitial pneumonia and features suggestive of, but not definitive for, a connective tissue disease [38].

Immunodeficiencies

A polyclonal hypergammaglobulinemia is typically present when LIP is associated with an underlying autoimmune condition. However, LIP also occurs in the setting of other immunodeficiencies in addition to that seen in HIV/AIDS, and dysgammaglobulinemia syndrome is frequently linked to LIP.

LIP may be seen in approximately 10% of patients with CVID [16, 39]. Pathologic specimens from patients with CVID frequently contain both granulomatous and lymphoproliferative histopathologic patterns, otherwise called granulomatous-lymphocytic interstitial lung disease (GLILD). Lymphoid hyperplasia, follicular bronchiolitis, and LIP may “represent different ends of a spectrum of the same disease” [5, 16, 40]. The presence of GLILD decreases survival by 50% compared to patients with CVID and no evidence of GLILD [16].

LIP may occur after allogeneic hematopoietic stem cell transplantation, often following a viral infection or in the context of chronic graft versus host disease [41,42,43]. LIP may also be seen in the immunodeficiency syndrome ataxia-telangiectasia [44].

Other Associations

LIP has also been associated with Castleman disease, another rare lymphoproliferative disorder, which may result in systemic inflammatory symptoms, lymphadenopathy, and multi-organ involvement [45]. This has been reported primarily in patients with Asian ancestry [8, 53].

Radiology

The classic radiologic findings of LIP are bilateral interstitial infiltrates of the lower lobes. Alveolar and reticulonodular infiltrative patterns are also seen [8]. However, the chest radiograph is neither sensitive nor specific for LIP and may miss characteristic imaging findings that may be detected by high-resolution computed tomography (HRCT) of the chest.

HRCT typically shows a combination of ill-defined centrilobular and subpleural micronodules, ground-glass opacities, basilar reticulation, peribronchovascular interstitial thickening, and pulmonary cysts. Cysts are present in 60%–80% of patients and are thin walled and regular shaped (round) (Fig. 8.1). They vary in size and are often large (up to 3 cm) [46]. Typically, cysts comprise <10% of the lung parenchyma. They occur randomly in all lung zones but are often basilar and subpleural or along the peribronchovascular bundle [47]. Cysts are postulated to be a consequence of bronchiolar obstruction by lymphocytic infiltrates accompanied by postobstructive ectasia/dilatation [5]. Ischemia is another process that can induce cystic change in the lungs. The obstruction of small capillaries that supply the terminal bronchiole leads to necrosis of the airways and ischemic dilatation.

Fig. 8.1
figure 1

High-resolution chest computed tomography of a patient with lymphoid interstitial pneumonia showing multiple thin-walled round cysts

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Ground-glass opacities may represent areas of alveolar septal infiltrates, whereas centrilobular nodules represent foci of peribronchiolar infiltrates [13]. Although micronodules are characteristic, 40% of patients may have larger nodules up to 2 cm. Nodules are typically subpleural and in a perilymphatic distribution [48]. Ground-glass opacities and nodules may evolve into consolidation, architectural distortion, and honeycombing [9]. The reverse halo sign (atoll sign) may be seen [49]. Mediastinal and hilar adenopathy are also seen in approximately 65% of patients with LIP [13, 50,51,52]. The regular (as opposed to bizarre) shape of the cysts, presence of adenopathy, and septal thickening help to distinguish LIP from pulmonary Langerhans cell histiocytosis, whereas the presence of centrilobular nodules allows differentiation of LIP from lymphangioleiomyomatosis [47, 50].

Radiologic findings may wax and wane with a chronic, indolent course [5]. Radiologic findings that may be reversible include ground-glass attenuation, airspace consolidation, centrilobular small nodules, subpleural small nodules, large nodules, thickening of the interlobular septa, thickening of bronchovascular bundles, and lymph node enlargement [52], whereas cysts and architectural distortion may stay stable or progress on imaging follow-up. Often, new cysts develop in areas of previous centrilobular nodules [52].

Diagnosis

LIP should be considered when there is a characteristic HRCT in the correct clinical context. However, in the absence of a clearly diagnosed systemic disease, it is recommended that the diagnosis of LIP be confirmed histologically [2, 53].

Bronchoscopy is most useful for establishing an alternative diagnosis. Bronchoalveolar lavage (BAL) will reveal a lymphocytosis with a shift in favor of CD3 T lymphocytes, often with a mild increase in eosinophils and alveolar macrophages [33]. More importantly, the BAL should be negative for viral, bacterial, and fungal pathogens and neoplastic (clonal) cells [9].

As the yield of transbronchial biopsies is low in making a diagnosis of LIP, surgical lung biopsy (Fig. 8.2) is the procedure of choice. The macroscopic appearance of the lung may be normal, but histopathologic examination generally shows a diffuse interstitial inflammatory infiltrate composed of mature small lymphocytes, plasma cells, and occasional histiocytes [12]. This pattern is most characteristically present in the areas surrounding lymphatic channels, such as the alveolar septa, interstitial septa, peribronchovascular regions, and subpleural lung [7]. Alveolar aggregates of lymphoid tissue may cause bronchiolitis and small airway plugging leading to cysts [9]. The interstitial lymphoid cells are mainly T cells (CD3+) mixed with histiocytes and plasma cells, while B cells (CD20+) are more prominent in peribronchial germinal centers [54]. Scattered multinucleated giant cells or ill-formed granulomas are seen in the lymphoid infiltrates in about half of the cases [9, 12]. There is no evidence of vasculitis or necrosis. Hyperplasia of type II pneumocytes is commonly seen, and fibrosis may develop in more advanced cases [9, 12].

Fig. 8.2
figure 2

Lymphoid interstitial pneumonia. Chronic lymphoplasmacytic inflammation extends from the bronchovascular area to the adjacent lobule. Germinal centers can be seen both around the airway and also in more distal areas of the lobule (arrowheads). Hematoxylin and eosin: 20×

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The histopathologic differential diagnosis of LIP includes lymphomatoid granulomatosis, hypersensitivity pneumonitis, small lymphocytic lymphoma, and MALTomas [5, 18]. Immunohistochemical studies and flow cytometry should be performed in order to distinguish between the polyclonal populations of lymphocytes seen in LIP and a monotypic cell population seen in malignant lymphoproliferative disorders. In the past, LIP was considered a risk factor for the development of malignant lymphoma; however, many of the previously described cases were reclassified as lymphoma, and only a small number of definite LIP cases are felt to have undergone malignant transformation. Due to its association with immunocompromised states, stains for Pneumocystis jiroveci pneumonia (PJP) must be carried out in all patients.

Treatments

The natural history of LIP is variable, and it may often be stable for many months without specific treatment, although approximately one-third of cases may progress to pulmonary fibrosis and respiratory failure [12, 52]. The reported median survival times range from 5 years [5] to 11.5 years [53].

Patients with mild or indolent disease may not require therapy [55]. However, treatment should be considered in patients with disabling symptoms or a progressive decline in pulmonary function [39]. There are no randomized, placebo-controlled clinical trials to inform treatment decisions. Instead, treatment recommendations are based on case reports and case series. Approximately 50% to 60% of patients stabilize or improve with corticosteroids [8]. Suggested prednisone regimens range from 1 to 2 mg/kg/day for 2 to 12 weeks followed by a slow taper over another 6–12 weeks [56]. Variable improvement and treatment responses have also been reported with hydroxychloroquine, azathioprine, rituximab, cyclophosphamide, and chlorambucil [8, 39, 55, 57,58,59]. There may be a role for gamma globulin therapy in patients with hypogammaglobulinemia [8, 60]. LIP associated with HIV often resolves with highly active antiretroviral drug treatment [61].

Follicular Bronchiolitis

Follicular bronchiolitis (FB) is considered one of the reactive lymphoid disorders that affect the lungs, along with nodular lymphoid hyperplasia (NLH) – which is synonymous with pseudolymphoma, and LIP [62].

Histologically, FB is characterized by nonneoplastic, polyclonal [63] lymphoid hyperplasia of the bronchus-associated lymphoid tissue (BALT). Lymphoid follicles containing reactive germinal centers lie in the walls of the small airways (<2 mm, non-cartilaginous) leading to progressive narrowing and eventual obliteration of the bronchioles. There is little to no extension to the alveolar septa and interstitium. BALT is itself not native to adult human airways and can be considered an ectopic lymphoid tissue that appears to develop as a result of antigenic stimulation [64]. This might suggest that FB reflects a pathologically exaggerated inflammatory response with BALT and lymphoplasmacytic infiltration in the susceptible host with an aberrant immune system (Table 8.1). NLH and LIP share the same reactive lymphoid and plasmacytic inflammation but are distinguished from each other based on the diffuseness and the predominant compartments of the lung affected. Whereas FB is primarily bronchiolocentric, LIP is characterized by more extensive interstitial involvement. However, these entities are not mutually exclusive, and FB may coexist with LIP and NLH, which can dominate over FB in the affected patient’s clinical and radiographic presentation.

Clinical Presentation

Clinically, FB is most commonly associated with connective tissue diseases (CTD), particularly rheumatoid arthritis (RA) and Sjögren’s syndrome (SS), as well as congenital and acquired immunodeficiencies such as HIV infection and CVID. Other associations include hypersensitivity reactions, diffuse panbronchiolitis, granulomatosis with polyangiitis (GPA), interstitial pneumonias, multicentric Castleman disease, infections, and bronchiectasis [65,66,67,68]. Infrequently, FB may exist in a “primary” idiopathic form without any identifiable associated conditions or derangements of the immune system [68]. However, as a result of overlapping clinical features, multiple clinical associations, and the need for a biopsy for definitive confirmation of FB, its precise prevalence and epidemiology remain unknown and are dependent on the underlying associated condition. For example, FB will be more prevalent in the pediatric population among those with congenital immune deficiency syndromes, whereas it may be more prevalent later in life in adult women affected by SS. Most, but not all, series appear to indicate FB being identified after recognition of the associated disorder [65, 68], although FB as a presenting manifestation of SS has been described [78].

Attributable respiratory symptoms are commonly cough and dyspnea. However, they may be mild or, in some cases, asymptomatic. Among those with respiratory symptoms, evidence of small airway disease can be found in over half of the patients with SS [69, 70]; however, it is not clear how many may be asymptomatic or have only mild impairment [68, 69, 71, 72].

Pulmonary function testing (PFT) should include both lung volumes and diffusion capacity, in addition to the standard spirometry. As with other causes of bronchiolitis where the small airways are predominantly affected, obstructive physiology by classic definitions may not always be present as might be expected, but depending on the severity of the disease and the specific type of bronchiolitis, the PFTs may be normal, restricted, and nonspecific or have mixed defects [60, 68, 72, 73]. Lung volumes may demonstrate air trapping, and the diffusion capacity for carbon monoxide may be reduced, which may be the most sensitive indicator [68]. Among the newer techniques, impulse oscillometry may be a promising technique to detect peripheral airway disease, but is not readily available [74].

Radiology

Short of a lung biopsy, the most specific objective clues for FB are found radiographically. However, a plain chest radiograph is typically inadequate, as it may be normal. In the symptomatic patient suspected of, or at risk for, having bronchiolitis, HRCT imaging is required (Fig. 8.3). Micronodules ranging from 1 to 3 mm are universal, with up to half between 3 and 12 mm [75]. They can be greater than a centimeter but are less common prompting consideration for other processes. They are most commonly diffuse and less commonly basilar predominant or equally distributed [75]. They can appear solid and also with ground-glass opacities, often in a centrilobular, tree-in-bud, or peribronchial distribution [75, 76]. Additional evidence of airway disease can be appreciated with bronchial wall thickening and dilation (i.e., bronchiolectasis), sometimes evolving into more obvious features of bronchiectasis. Indirect features of small airway disease typically include evidence of air trapping suggested by mosaicism that can be accentuated on expiratory CT imaging. Although this is fairly characteristic in constrictive bronchiolitis and bronchiolitis of hypersensitivity pneumonitis, it does not appear to be a common feature for follicular bronchiolitis [75, 77]. A more unique feature to FB and LIP among the different types of bronchiolitis and idiopathic interstitial pneumonias is that patients can present with diffuse cystic lung disease, particularly in the clinical context of SS [71, 78]. In a series of four patients with SS who presented with cystic lung disease, SSA was positive in all, and surgical lung biopsy in three showed two cases of FB and one case of LIP [78]. These rounded or oval cysts were described to be variable in size (5 mm to 5 cm), basilar predominant if not diffuse, perivascular, and sometimes with internal septations. The authors propose that these characteristic findings in established SS may obviate the need for a biopsy to confirm FB or LIP. However, lymphoma and amyloid can complicate cystic lung disease and should be considered in the context of associated nodularity [79, 80]. Cystic lung disease in FB may not be as common of a finding when associated with other disorders such as RA or in immunodeficiencies [75, 81], but is considered a common feature of LIP [52].

Fig. 8.3
figure 3

High-resolution chest computed tomography of a patient with follicular bronchiolitis showing multiple solid and ground-glass nodules in a peribronchial distribution and tree-in-bud distribution. Bronchial wall thickening, bronciolectasis, and bronchiectasis are also present

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Diagnosis

Although the CT features in the appropriate clinical context may suggest the presence of FB, a formal diagnosis still requires a surgical lung biopsy (Fig. 8.4). The decision to do a biopsy may lie largely on the clinical context of whether alternative considerations that have important prognostic or treatment implications are being considered, such as lymphoma or amyloid. Progressive disease may also prompt the need for definitive histologic diagnosis, especially if there is no specific context such as SS to guide the clinician. As surgical lung biopsy is associated with some morbidity and mortality, a period of observation may also be appropriate. Increasing expertise and availability of bronchoscopic transbronchial cryobiopsy may prove to be a more cost-effective, if not a safer, alternative to a surgical lung biopsy, particularly since the FB abnormalities are airway centered [82, 83]. The diagnostic yield may further improve with a multidisciplinary review.

Fig. 8.4
figure 4

Follicular bronchiolitis. Thoracoscopic wedge excision reveals chronic bronchiolitis with germinal centers (arrow) adjacent to small airways, features consistent with follicular bronchiolitis. Hematoxylin and eosin: 200×

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If there is no clinical pressure to achieve a firm histological diagnosis, a confident working diagnosis might be achieved based on the clinical context and HRCT features, as described previously. Thus, it is imperative to evaluate thoroughly for clues to underlying connective tissue disease, immune deficiency states, hypersensitivity exposures, and other associated disorders.

Treatment

As most cases of FB are secondary to another primary disorder, treatment is often related to treating the underlying disease. Although no formal randomized controlled trials exist specifically targeting FB, there are observational data to support that treating the underlying immune derangement may be of benefit, particularly in acquired immunodeficiency syndromes such as HIV [84, 85] and CVID [86]. However, in some cases, treatment targeting the underlying disorder may be ineffective including in systemic inflammatory disorders such as in RA [73] and SS [29]. Many have treated empirically, regardless of the mechanism, with prednisone or cytotoxic agents including azathioprine, mycophenolate, and cyclophosphamide, with anecdotal benefit [64, 68, 71, 87]. As with the literature in diffuse panbronchiolitis and bronchiectasis, macrolides may be of help in idiopathic FB or possibly even when associated with other disorders [46, 68, 88,89,90,91]. Finally, there is rationale for, but little experience with, more specific targeted therapies such with rituximab and other biologic agents that target the lymphoplasmacytic inflammation [56].

Conclusion

Follicular bronchiolitis and lymphoid interstitial pneumonia represent a pathologic continuum arising from benign reactive lymphoid reaction of the BALT leading to formation of nodules and luminal narrowing and to expansion of the interstitium with fibrosis and, in some cases, cyst formation. Multiple disorders have been associated with LIP and FB including autoimmune disorders and immunodeficiencies, but they can also occur in an idiopathic form. Additionally, LIP and FB may be overshadowed by other features of these other disorders or by other injury patterns, such as interstitial pneumonias, that may coexist and dominate the clinical and radiographic presentation. Diagnostic evaluation thus requires a careful evaluation for associated conditions, and given the variable patterns on pulmonary function testing and an insensitive chest radiograph, HRCT imaging is necessary to identify the suggestive features for FB and LIP. Cystic disease in well-established SS may be specific for FB and/or LIP, but a definitive diagnosis in most other contexts requires a surgical biopsy. Treatment should initially target any underlying conditions, and in refractory or idiopathic variants, prednisone, macrolides, cytotoxic medications, and biologic agents have been used with variable success.

Key Learning Points

  • Follicular bronchiolitis and lymphoid interstitial pneumonia are characterized by polyclonal infiltration of the lung by mature lymphocytes. Follicular bronchiolitis is primarily bronchiolocentric, whereas lymphoid interstitial pneumonia extends into the interstitium with fibrosis.

  • Follicular bronchiolitis and lymphoid interstitial pneumonia are rarely idiopathic and are generally associated with an immunodeficiency or autoimmune condition.

  • Lymphoid interstitial pneumonia is an AIDS-defining illness in children.

  • There is a strong association between lymphoid interstitial pneumonia and follicular bronchiolitis and Sjögren’s syndrome with nearly 1% of Sjögren’s syndrome patients having LIP or FB and 30%–60% of patients with LIP having Sjögren’s syndrome.

  • The diagnosis of LIP should be considered in anyone with lung cysts and an immunologic abnormality.

  • The diagnosis of follicular bronchiolitis should be considered in anyone with micronodules in a peribronchial distribution with an underlying immunologic abnormality.

  • Treatment of follicular bronchiolitis and lymphoid interstitial pneumonia is focused on treating the underlying/associated condition.