INTRODUCTION — Lymphocytic interstitial pneumonia (LIP) remains in the differential diagnosis for interstitial lung disease (ILD) in childhood, although it is actually a form of pulmonary lymphoproliferative disease. LIP may be part of a spectrum with other relatively benign lymphoid disorders of the lung, which include follicular bronchiolitis, intraparenchymal lymph nodes, bronchial-associated lymphoid hyperplasia, and nodular lymphoid hyperplasia. It is important to distinguish LIP from angioimmunoblastic lymphadenopathy (now classified as angioimmunoblastic lymphoma), which is a rare lymphoproliferative disorder that can also occur in association with forms of leukemia and has different treatment regimens and prognostic significance [1].
The epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of LIP in infants and children will be presented here. LIP in adults is discussed separately. (See "Lymphoid interstitial pneumonia in adults".)
EPIDEMIOLOGY — The incidence and prevalence of LIP in children are not known. Relatively little has been published about LIP in children. In a 2017 report from a large European registry, only three cases of LIP were reported among 346 total cases of interstitial lung disease (ILD) in children that were submitted over a three-year period [2]. LIP most often occurs in association with underlying conditions, such as autoimmune disease and immunodeficiencies [3-7], but also occurs in familial and idiopathic forms (table 1) [8,9]. LIP occurs in a substantial number of children with perinatally acquired HIV if they are not treated with antiretroviral agents [10] and usually presents in the second or third year of life. The frequency of LIP in children with HIV was lower in those born between 2007 and 2016 (1 percent) compared with those born between 1997 and 2006 (4.9 percent) [11].
PATHOLOGY — LIP is characterized by a diffuse infiltrate of mature and immature lymphocytes, plasma cells, and histiocytes in the alveolar septae and pulmonary interstitium (picture 1). Nodular formation of lymphocytes is commonly seen, occasionally with germinal centers. The cellular infiltrate is polyclonal, including both B and T cells, usually with a predominance of CD8 lymphocytes [12]. Fibrosis is not a typical feature. However, if there is a significant nodular component, it may distort the pulmonary architecture [10]. Further, the blood vessels and airways are not involved in classic LIP. However, some cases demonstrate a spectrum of lymphoid hyperplasia including airway involvement, resulting in findings that may be described as follicular bronchiolitis [7,13].
A form of LIP, known as granulomatous and lymphocytic interstitial lung disease (GLILD), has been described in patients with certain immunodeficiencies, especially common variable immunodeficiency. (See "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease'.)
PATHOGENESIS — Although the pathogenesis of LIP is unknown, several theories have been suggested. LIP may result from an exaggerated immunologic response to inhaled or circulating antigens and/or caused by a primary infection with Epstein-Barr virus (EBV) [14,15], HIV, or an unknown source [4]. Immune dysregulation may play a role in the pathogenesis of LIP, and in some cases, LIP may be a premalignant state [16]. An immunogenetic basis also has been postulated since HLA-DR5 markers have been found in adults with LIP [17]. Cytokines including tumor necrosis factor alpha and interleukin-1 are elevated to a greater extent in children with HIV and LIP than in children with HIV without LIP [18].
Role of Epstein-Barr virus infection — Numerous investigations, limited by the small number of included patients, have shown evidence of EBV in patients with HIV infection and LIP [14,15,19,20]. However, the role of EBV infection in the development of LIP remains unclear. As examples:
●In a study examining lung biopsy specimens from 17 patients with acquired immunodeficiency syndrome (AIDS), EBV DNA was detected in 8 of the 10 biopsy specimens diagnosed with LIP [14].
●In a case-control study of HIV infected children, serologic evidence of recrudescent or primary EBV infection was observed in all 7 children with LIP but in only 2 of 13 children (15 percent) without LIP [20].
●In a study of nine children vertically infected with HIV-1 subtype E who had biopsy-proven LIP, all had EBV identified in the lung by EBV-encoded RNA in situ hybridization. Interestingly, in six of nine cases, EBV was found in 30 to 50 percent of Langerhans and related dendritic cells, whereas only 30 percent of T and B cells were infected, suggesting that Langerhans cells are more readily infected and may be a reservoir for EBV [21].
●In a study of 20 children with HIV-1 and chronic lung disease, EBV expression was detected in the majority of lung samples but without significant association with pulmonary lymphoid hyperplasia/LIP [22].
The role of EBV infection in non-HIV-related LIP also is unclear. EBV-associated LIP has been reported in adults [23] and children [24,25] without HIV infection. In one study of seven lung biopsy specimens from patients with LIP, EBV DNA was detected in three specimens by polymerase chain reaction [23]. This suggests that EBV may be associated with some, but not all, cases of non-HIV-related LIP [23].
Genetic mutations — A growing number of specific genetic mutations have been identified that are associated with a spectrum of pulmonary disease in children with immunodeficiencies and immune dysfunction, including mutations in STAT3, GATA-2, COPA, and LRBA [7,26-29]. In particular, mutations in STAT3 have been shown to lead to autoimmunity and LIP [26]. Mutations in LRBA, which encodes a protein involved in trafficking of CTLA4 in Treg cells, have also been identified in patients with common variable immunodeficiency and LIP [29,30]. The clinical availability of genetic testing for new disorders is rapidly evolving, and consultation with an immunologist and/or genetic counselor can aid in decisions regarding the approach to genetic testing. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Genetic testing'.)
Association with immunodeficiencies or systemic inflammatory disease — LIP also may be associated with underlying immunodeficiencies (especially HIV infection) or systemic inflammatory diseases (especially juvenile idiopathic arthritis) (table 1) [31]. (See "Pediatric HIV infection: Classification, clinical manifestations, and outcome" and "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and 'Evaluation for associated diseases' below.)
CLINICAL MANIFESTATIONS — Although there are many similarities, it is important to distinguish HIV-related from non-HIV-related LIP since the treatment varies. In addition, lung biopsy, which is required for diagnosis of non-HIV-related LIP, may not be necessary in children with HIV. (See 'Diagnosis' below.)
HIV-related lymphocytic interstitial pneumonia — LIP is more common in perinatally acquired than in transfusion-acquired HIV. Before intervention to prevent perinatal transmission of HIV infection became widely available in the United States, children with perinatally acquired HIV infection typically presented in the second to third year of life. In one retrospective review of 172 children with perinatally acquired HIV, 17 percent presented with LIP [32]. The median age of presentation with LIP was 14 months, with a range of 5 to 60 months [32].
The onset of HIV-related LIP generally is insidious. Cough and tachypnea are often noted. However, auscultation of the chest reveals few abnormalities. Digital clubbing occurs commonly [33]. Extrapulmonary manifestations include generalized lymphadenopathy, hepatosplenomegaly, and salivary gland enlargement [34]. Hypergammaglobulinemia, which is usually present, is thought to be secondary to an imbalance of immunoregulatory cells in the lung [3].
The clinical course is variable. Spontaneous clinical remission sometimes is observed [35]. Exacerbation of clinical signs and symptoms may occur in association with intercurrent viral respiratory illnesses. In severe cases, progressive hypoxia and respiratory failure occur.
Non-HIV-related lymphocytic interstitial pneumonia — Non-HIV-related LIP is less common than HIV-related LIP. Non-HIV-related LIP shares the classic presentation of other forms of ILD, including symptoms of tachypnea, cough, dyspnea, exercise intolerance, and frequent respiratory infections (see "Approach to the infant and child with diffuse lung disease (interstitial lung disease)") [7]. In the absence of HIV, other causes of immunodeficiency and autoimmune disorders should be considered.
On physical examination, the most common findings include retractions, tachypnea, and basilar crackles. Evidence of growth failure, cyanosis, clubbing, and increased intensity of the second component of the second heart sound (P2) are present in the more severe cases [36]. Generalized lymphadenopathy is rare; if it is detected, malignancy should be considered. Hypogammaglobulinemia is present occasionally [3].
DIAGNOSIS — Lung biopsy is usually necessary to diagnose LIP and to distinguish it from benign lymphoid disorders of the lung. However, in patients with documented HIV infection, the presentation of dyspnea with associated hypoxia and classic radiographic findings of micronodular infiltrates may be enough for the diagnosis of LIP, without further invasive procedures [37].
Pulmonary function tests — Pulmonary function testing in both HIV-related and non-HIV-related LIP, as in other forms of ILD, typically demonstrates a pattern of restrictive disease, with reduced forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) as well as normal FEV1/FVC ratio [1]. Obstructive lung disease may also be present when overlapping pathologies such as follicular bronchiolitis are present. Measurement of oxygen saturation with pulse oximetry helps to determine the severity of illness and may have prognostic significance [38]. (See "Overview of pulmonary function testing in children" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Clinical course and outcome'.)
Radiographic studies — Chest radiography in HIV-related LIP typically reveals a diffuse symmetric reticulonodular or nodular pattern, occasionally associated with mediastinal or hilar adenopathy [37,39]. The nodular pattern can wax and wane and has been noted to disappear completely [40]. In some cases, hyperinflation may be the only radiographic abnormality [41]. Air space consolidation, bronchiectasis, and cystic lung changes have been observed in advanced disease [39,42].
Non-HIV-related LIP is also characterized by a diffuse reticulonodular pattern, most prominent in the lower lobes, but may vary from a purely linear interstitial process affecting the bases and perihilar regions to a more nodular process [7,43]. However, a ground glass abnormality may be the only radiographic finding (image 1). Cystic lung disease may also occur. Mediastinal or hilar adenopathy is rarely found and if detected, should warrant further investigation for a malignancy. (See "Overview of common presenting signs and symptoms of childhood cancer".)
High-resolution computed tomography scans provide important details about the extent and distribution of the parenchymal disease (image 1) and may aid in selection of biopsy sites [44].
Lung biopsy — Lung biopsy remains the gold standard for the diagnosis of non-HIV-related LIP and is important in confirming the diagnosis of HIV-related LIP, particularly in cases with an unusual presentation. Transbronchial biopsy is used primarily to diagnose infections or rejection in patients after transplantation [45] but has limited use in the primary diagnosis of LIP.
Transthoracic lung biopsy via video-assisted thoracoscopy (VATS) is the preferred method to obtain lung tissue for diagnosis [46,47]. The diagnostic yield of VATS and open lung biopsy are similar. However, because VATS has less morbidity with respect to duration of surgery, chest tube drainage, and hospitalization, it is becoming the method of choice for lung biopsy in children [48]. Whatever method is used, the lung biopsy specimen must be processed in a consistent manner and should be analyzed by an experienced pediatric pathologist. The characteristic pathologic findings are described above (picture 1). (See 'Pathology' above.)
Evaluation for associated diseases — Children in whom LIP is diagnosed should undergo an evaluation for underlying immunodeficiencies or autoimmune diseases that are associated with LIP, if not already known (table 1). The immune evaluation should include HIV testing and immunoglobulin levels and vaccine titers (to evaluate for common variable immunodeficiency). (See "Common variable immunodeficiency in children" and "Primary humoral immunodeficiencies: An overview" and "Pediatric HIV infection: Classification, clinical manifestations, and outcome", section on 'Other'.)
An evaluation for autoimmune disease should be guided by clinical symptoms. Associations include Sjögren's syndrome (characterized by diminished lacrimal and salivary gland function), juvenile idiopathic arthritis, and, rarely, other connective tissue diseases [31]. (See "Interstitial lung disease associated with Sjögren syndrome: Clinical manifestations, evaluation, and diagnosis" and "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)
To guide this work-up, consultation with an immunologist and/or rheumatologist should be considered in children with unexplained LIP.
TREATMENT — The treatment for patients with pediatric LIP involves both supportive care and pharmacologic therapy.
Supportive therapy — Supportive therapy for children with LIP is the same as it is for children with other forms of interstitial lung disease (ILD) and is discussed separately. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Supportive therapy'.)
Pharmacologic therapy — The pharmacologic therapy for pediatric LIP differs for HIV-related and non-HIV-related illness. For those with LIP and HIV infection, use of antiviral agents to control the underlying HIV infection is critical. In addition, periodic intravenous gamma globulin has shown to be useful for slowing and even halting progression of LIP [16].
For both HIV-related and non-HIV-related LIP, corticosteroid therapy has been shown to be beneficial in uncontrolled studies, with improved respiratory symptoms and decreased oxygen requirement [7,49]. Pulse therapy with intravenous methylprednisolone (10 to 30 mg/kg per day [maximum 1000 mg], administered over one hour for three consecutive days each month) is an alternative to daily therapy and may be equally or more effective, with fewer side effects [50,51]. Children with HIV-related LIP should receive prophylaxis for Pneumocystis jirovecii pneumonia (previously known as Pneumocystis carinii pneumonia) if they are receiving systemic corticosteroid treatment.
Hydroxychloroquine is an alternative to corticosteroid therapy. In anecdotal reports, it has been effective in HIV-related LIP and in LIP related to other immune deficiencies [52,53]. The recommended dose in children is 10 mg/kg per day. In severely immunocompromised patients, hydroxychloroquine may be preferred to prednisone.
More targeted immunomodulatory therapies including rituximab, cyclosporine, tacrolimus, and others are emerging in the treatment of ILD associated with connective tissue diseases [54]. Targeted immunomodulatory therapy may also be possible for cases where a specific underlying immune defect is identified, such as the use of abatacept for patients with LRBA deficiency [29].
Further studies are needed to determine the role of steroid-sparing therapies in children with LIP.
PROGNOSIS — The prognosis for children with LIP is variable. The overall long-term mortality rate is high and depends in part on the extent of any associated immunodeficiency. Spontaneous resolution has been noted, but more commonly, episodic worsening leading to progression of frank respiratory failure is seen [7,16].
LIP is no longer considered an acquired immunodeficiency syndrome (AIDS)-defining illness in children with HIV infection. However, there is evidence of considerable chronic respiratory morbidity associated with LIP and HIV. The incidence of acute lower respiratory tract infection in children with LIP is twice the rate of those infected with HIV without LIP and tenfold higher than reported in non-HIV infected children [55]. (See "Pediatric HIV infection: Classification, clinical manifestations, and outcome".)
In addition, LIP infection can lead to bronchiectasis and cystic changes within the lung, resulting in chronic respiratory infections and even respiratory failure [56]. Death in both HIV-related and non-HIV-related LIP may occur secondary to infectious complications of treatment, end-stage pulmonary fibrosis, or, rarely, malignant lymphoma [3].
SUMMARY AND RECOMMENDATIONS
●Lymphocytic interstitial pneumonia (LIP) remains a form of pulmonary lymphoproliferative disease. LIP most often occurs in association with underlying conditions, such as autoimmune disease and immunodeficiencies, but also occurs in familial and idiopathic forms. LIP occurs in 25 to 40 percent of children with perinatally acquired HIV and usually presents in the second or third year of life. (See 'Epidemiology' above.)
●LIP may result from an exaggerated immunologic response to inhaled or circulating antigens and/or caused by a primary infection with Epstein-Barr virus (EBV), HIV, or an unknown source. (See 'Pathogenesis' above.)
●In children with perinatally acquired HIV infection, LIP typically presents in the second or third year of life. The onset of HIV-related LIP generally is insidious, with cough and tachypnea and sometimes digital clubbing and hypergammaglobulinemia. The clinical course is variable, and spontaneous clinical remission sometimes is observed. (See 'HIV-related lymphocytic interstitial pneumonia' above.)
●Non-HIV-related LIP is less common than HIV-related LIP. Non-HIV-related LIP shares the classic presentation of other forms of interstitial lung disease (ILD), including symptoms of tachypnea, cough, dyspnea, exercise intolerance, and frequent respiratory infections. In the absence of HIV, other causes of immunodeficiency and autoimmune disorders should be considered. Generalized lymphadenopathy is rare; if it is detected, malignancy should be considered. (See 'Non-HIV-related lymphocytic interstitial pneumonia' above.)
●Chest radiography in LIP typically reveals a diffuse symmetric reticulonodular or nodular pattern occasionally associated with mediastinal or hilar adenopathy. Lung biopsy remains the gold standard for the diagnosis of non-HIV-related LIP and is important in confirming the diagnosis of HIV-related LIP. In patients with documented HIV infection, the presence of typical clinical and radiographic features may be sufficient to make the diagnosis without lung biopsy. (See 'Diagnosis' above.)
●Children in whom LIP is diagnosed should undergo an evaluation for underlying immunodeficiencies or autoimmune diseases that are associated with LIP, if not already known (table 1). To guide this work-up, consultation with an immunologist and/or rheumatologist should be considered in children with unexplained LIP. (See 'Evaluation for associated diseases' above.)
●The pharmacologic therapy for pediatric LIP differs for HIV-related and non-HIV-related illness. (See 'Pharmacologic therapy' above.)
•For both HIV-related and non-HIV-related LIP, corticosteroid therapy has been shown to be beneficial in uncontrolled studies.
•For children with HIV-related LIP, use of antiviral agents to control the underlying HIV infection is critical. In addition, periodic intravenous gamma globulin has shown to be useful for slowing and even halting progression of LIP. Hydroxychloroquine is an alternative to corticosteroid therapy.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Cynthia Epstein, MD and Leland Fan, MD, who contributed to an earlier version of this topic review.
