COMMENTARY
The Clinical Respiratory Journal
Clinical approach to endogenous lipoid pneumonia
Key words crazy paving pattern – interstitial lung disease – lipoid pneumonia Correspondence James W. Antoon, MD, PhD, Division of General Pediatrics and Adolescent Medicine, UNC Hospitals, University of North Carolina School of Medicine, 260 MacNider Building CB# 1593 Chapel Hill, NC 27599-7220, USA. Tel: 919 966 3172 Fax: 919 966 8419 email: [email protected]
Received: 10 August 2014 Accepted: 11 August 2014
Conflict of interest Authors have no potential conflicts of interest.
DOI:10.1111/crj.12203
Abbreviations: ELP endogenous lipoid pneumonia PAP pulmonary alveolar proteinosis
Authorship and contributorship Dr. Antoon drafted the manuscript. Julie S. Byerley, Michelle L. Hernandez and Margaret W. Leigh contributed to the proposed management plan and critically reviewed the manuscript.
Introduction Endogenous lipoid pneumonia (ELP) is an underreported and underdiagnosed condition, with a high percentage of cases found on autopsy or late-stage disease (1). The etiology of ELP varies widely and includes obstructive, hematologic, oncologic, rheumatologic, infectious, idiopathic, inflammatory and immunologic diseases (Table 1) (2). Early diagnosis of ELP is critical because of serious and life-threatening complications of late-stage disease. Treatment and prognosis also vary based on underlying etiology of lipoid pneumonia and delayed diagnosis, which affect later treatment strategies. Unfortunately, there is no standard workup or established empiric treatment for ELP. We recently reported a case of ELP associated with non-specific interstitial pneumonitis and pulmonary alveolar proteinosis (PAP), which resulted in the death of the patient 10 months after ELP diagnosis (3). Based on an extensive review of the literature and experience with clinical cases of ELP, a standard diagnostic approach to ELP is proposed below in hopes of preventing a delay in diagnosis and treatment in future cases.
Diagnosis and empiric management of ELP Lipoid pneumonia is an uncommon pediatric complaint characterized by lipid deposition in the alveoli and pulmonary macrophages. The disease is categorized as exogenous or endogenous based on lipid origin. Exogenous lipoid pneumonia is more common
The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 The
© 2014 John John Wiley Wiley&&Sons SonsLtd Ltd C 2014 V
in the pediatric and geriatric populations and caused by aspiration of fatty substances, including mineral oil, laxatives, nasal drops and lip balm (1, 2). While a comprehensive patient history often reveals exogenous lipoid pneumonia, the endogenous form has a more insidious presentation. The presentation of ELP various widely and often includes non-specific symptoms such as cough or dyspnea. Early identification of the disease is difficult, and most patients are diagnosed with communityacquired pneumonia prior to further workup when symptoms do not resolve with therapy (4). Symptoms can progress to chest pain, tachypnea and respiratory distress and death in late-stage disease. Radiologic findings vary based on underlying pathologic mechanism but commonly include consolidative opacities with or without central obstructing lesion (4). A ‘crazy paving pattern’ is often seen on computed tomography, although this finding is neither sensitive nor specific for the disease (Fig. 1A) (5). Definitive diagnosis is made with histopathology, which demonstrates lipidladen macrophages and intra-alveolar lipid deposition (Fig. 1B) (5, 6). The mainstay of therapy for ELP is treatment of the underlying cause. There have been reports of successful treatment and resolution of lipoid pneumonia with pharmacologic tumor necrosis factor inhibition, whole-lung lavage and lung transplantation in severe cases of lipoid pneumonia associated with specific diseases (7–9). We present here a diagnostic strategy for working up and empirically treating lipoid pneumonia (Fig. 2). The causes of ELP vary widely but can generally be
1 259
Approach Approach to to lipoid lipoid pneumonia pneumonia
Byerley Byerley et et al. al.
Table 1. Non-obstructive etiologies of endogenous lipoid pneumonia (ELP) Etiology
Age
Gender
CT
Treatment
Resolution of ELP
Chronic myelomonocytic leukemia (27) Idiopathic (11–13)
61
M
Prednisolone/amphotericin
No
40 33
M M
Prednisolone Prednisolone
Yes No
57 21, 5
F M
Antibiotics Steroids/infliximab
No No
5
F
Etanercept
Yes
Lung cancer (10, 29, 30)*
39–82
M and F
Interstitial reticular, ground-glass and granular lesions in whole-lung fields Mass lesion of mixed attenuation Bilateral reticulonodular shadows and bronchiectasis N/A Interlobular thickening and ground-glass opacities Reticulonodular and fibrotic changes located in the centrolobular region Variable
Variable
Hodgkin’s lymphoma (21) Atypical mycobacterial infection (7, 19)
34 29
M M
Anticancer/antibacterial agents Chemotherapy/steroids Lung transplantation
Yes Yes
63
F
Antimycobacterials
Yes
Neiman–Pick type II (9)
48
M
Whole-lung lavage
Yes
Non-specific interstitial pneumonitis (3)
16
F
Immunosuppression
No
Primary sclerosing cholangitis (20) Pulmonary alveolar proteinosis (3, 15–17)
63
F
Yes
1–31
M
Ursodeoxycholic acid/atorvastatin Prednisolone
No
34
F
Prednisolone
Yes
Adults
M and F
Variable
Variable
Juvenile rheumatoid arthritis (8, 28)
Undifferentiated connective tissue disease (31) Wegener’s granulomatosis (22–24)
Interstitial infiltrates Bilateral hyperinflated lung fields with superimposed fibrosis and patchy infiltrates Alveolar interstitial infiltrate and patchy infiltrate with pleural effusions Extensive bilateral ground-glass attenuation, with some focal areas of consolidation and thickening of the interlobular septa Smooth perilobular septal thickening with multifocal ground-glass opacities Consolidation of the lingula and the middle lobe region Diffuse, small reticular opacities and increase in alveolar and interstitial densities Atelectatic area and infiltrates bilaterally Variable
*Often have secondary obstructive component. CT, computed tomography.
categorized into obstructive, idiopathic or systemic etiologies. The first step in the workup of lipoid pneumonia involves determination of the extent of organ involvement. Idiopathic and obstructive causes generally present with intrathoracic symptoms only while systemic etiologies exhibit extrathoracic signs and symptoms (4). A comprehensive patient history often distinguishes between obstructive and idiopathic etiologies. Evidence of obstruction includes recent surgeries, blockages, aspiration or foreign body ingestion suggests obstruction (2, 4). In adults, lung cancer and bronchiolitis obliterans are common causes of obstructive ELP, although there are no reported cases 260 2
of these etiologies in children (10). There is a strong association between ELP and PAP, and ELP can be both an early and late finding of PAP. Therefore, thorough evaluation for PAP, including serum and tissue testing, should be considered when ELP is present, even in the absence of PAP on biopsy. The time course of symptom onset and progression is shorter in those with obstructive disease compared with idiopathic etiology. Patients with idiopathic disease have a more insidious presentation of symptoms and tend to be less acute than with obstructive or systemic disease-related lipoid pneumonia (2, 11). Treatment for obstructive etiology remains relief of
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Byerley Byerley et et al. al.
Figure 1. Radiographic and histopathology findings of endogenous lipoid pneumonia. (A) High-resolution computed tomography scan demonstrating a pattern of perilobular septal thickening with multifocal ground glass opacities or ‘crazy paving pattern’. (B) Alveolar accumulation of foamy macrophages consistent with endogenous lipoid pneumonia.
obstruction and therapeutic broncholavage in moderate to severe cases (2, 4). Idiopathic disease tends to resolve over several months with supportive or mild medical intervention. While there have been reports of both successful and unsuccessful treatment of idiopathic disease with systemic steroids, natural disease progression cannot be ruled out in these cases (11–13). However, given the limited reported cases and documented follow up of idiopathic ELP, it is likely that ELP is the initial presentation of a systemic disease (14–17). If patients have extrapulmonary symptoms, or symptoms that cannot be wholly attributed to lung disease, then investigation of an underlying systemic disease is warranted. Systemic diseases associated with The The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981
C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Approach Approach to to lipoid lipoid pneumonia pneumonia
ELP include infectious, rheumatologic, oncologic and inflammatory conditions (Table 1). Early identification of systemic pathology is paramount as these diseases can have poor outcomes if not diagnosed and treated early. Furthermore, treatments for these diseases vary widely based on the underlying pathophysiology and stage of disease. Yet, given the lack of large scale clinical studies, systemic diseases not yet associated with ELP cannot be ruled out in the many cases. Therefore, we recommend a high index of suspicion for systemic diseases with known pulmonary complications, including sarcoidosis and undifferentiated connective tissue disease. Laboratory and histologic analysis for several of these, including Neimann–Pick type II, undifferentiated connective tissue disease and Wegener’s granulomatosis, can take days to weeks to return. If the patient remains stable, conservative therapy is recommended until a final diagnosis is determined. However, if the patient is unstable or has rapidly worsening disease, therapeutic intervention is warranted. There is currently no empiric treatment strategy for patients with ELP with progressive disease. While some report that whole-lung lavage is of benefit in cases of obstruction and Neimann–Pick type II, patients with severe systemic disease are unlikely to be stable enough for whole lung broncholavage (9, 18). Similarly, maintenance systemic steroids are not likely to overcome worsening ELP. Therefore, in cases of worsening severe ELP, a treatment triad of high dose, lympholytic corticosteroids, macrolide antibiotics and statin therapy is reasonable. Case reports suggest empiric treatment with macrolides and statins may be beneficial in atypical mycobacterial infection and primary sclerosing cholangitis, respectively, associated with ELP (19, 20). High-dose steroids are beneficial in the treatment of juvenile idiopathic arthritis, Wegener’s granulomatosis, connective tissue disease and lymphomas (21–24). Lympholytic steroid dosing may also empirically treat diseases not yet associated with ELP that have pathologic inflammatory, rheumatologic and autoimmune processes (25, 26). If symptoms worsen following medical treatment, more invasive therapeutic interventions such as whole-lung lavage, lung transplantation, plasmapheresis and further immune suppression may be considered, although a comprehensive risk–benefit analysis should be performed prior to implementation.
Acknowledgement We thank Dr. William K. Funkhouser for assistance with histopathology. 2613
Approach Approach to to lipoid lipoid pneumonia pneumonia
Byerley Byerley et et al. al.
Figure 2. Diagnostic approach to lipoid pneumonia.
References 1
2
Julie S. Byerley , Michelle L. Hernandez , Margaret W. Leigh3 and James W. Antoon1 1 Division of General Pediatrics and Adolescent Medicine, UNC Hospitals, University of North Carolina School of Medicine, Chapel Hill, NC, USA 2 Division of Allergy, Immunology, Rheumatology and Infectious Diseases, UNC Hospitals, University of North Carolina School of Medicine, Chapel Hill, NC, USA 3 Division of Pulmonology, Department of Pediatrics, UNC Hospitals, University of North Carolina School of Medicine, Chapel Hill, NC, USA 262 4
1. Wright BA, Jeffrey PH. Lipoid pneumonia. Semin Respir Infect. 1990;5(4): 314–21. 2. Hadda V, Khilnani GC. Lipoid pneumonia: an overview. Expert Rev Respir Med. 2010;4(6): 799–807. 3. Antoon JW, Hernandez ML, Roehrs PA, Noah TL, Leigh MW, Byerley JS. Endogenous lipoid pneumonia preceding diagnosis of pulmonary alveolar proteinosis. Clin Respir J. 2014;August 8. doi: 10.1111/crj.12197. PMID: 25103284. 4. Betancourt SL, Martinez-Jimenez S, Rossi SE, Truong MT, Carrillo J, Erasmus JJ. Lipoid pneumonia: spectrum of clinical and radiologic manifestations. AJR Am J Roentgenol. 2010;194(1): 103–9. 5. De Wever W, Meersschaert J, Coolen J, Verbeken E, Verschakelen JA. The crazy-paving pattern: a
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Byerley Byerley et et al. al.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
radiological-pathological correlation. Insights into Imaging. 2011;2(2): 117–32. Waddell WR, Sniffen RC, Whytehead LL. The etiology of chronic interstitial pneumonitis associated with lipid deposition; an experimental study. J Thorac Surg. 1954;28(2): 134–44. Au WY, Lie AK, Cheng VC, Cheng LC, Wang EP, Wong CF. Successful lung transplantation for post-BMT bronchiolitis obliterans and lipoid pneumonia associated with atypical mycobacterium and aspergillosis infection. J Heart Lung Transplant. 2007;26(8): 870–2. Leber A, Carette S, Chapman KR, Hwang DM, Singer LG, Marras TK. A 21-year-old man with systemic-onset juvenile rheumatoid arthritis, cough and progressive dyspnea. Can Respir J. 2010;17(3): e42–4. Nicholson AG, Wells AU, Hooper J, Hansell DM, Kelleher A, Morgan C. Successful treatment of endogenous lipoid pneumonia due to Niemann-Pick Type B disease with whole-lung lavage. Am J Respir Crit Care Med. 2002;165(1): 128–31. Tamura A, Hebisawa A, Fukushima K, Yotsumoto H, Mori M. Lipoid pneumonia in lung cancer: radiographic and pathological features. Jpn J Clin Oncol. 1998;28(8): 492–6. Chin NK, Hui KP, Sinniah R, Chan TB. Idiopathic lipoid pneumonia in an adult treated with prednisolone. Chest. 1994;105(3): 956–7. Sharma A, Ohri S, Bambery P, Singh S. Idiopathic endogenous lipoid pneumonia. Indian J Chest Dis Allied Sci. 2006;48(2): 143–5. Griffith Pearson F, Mark EJ. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 19–1984. A 57-year-old woman with recurrent pneumonia. N Engl J Med. 1984;310(19): 1245–52. Brasch F, Griese M, Tredano M, et al. Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. Eur Respir J. 2004;24(1): 30–9. Fisher M, Roggli V, Merten D, Mulvihill D, Spock A. Coexisting endogenous lipoid pneumonia, cholesterol granulomas, and pulmonary alveolar proteinosis in a pediatric population: a clinical, radiographic, and pathologic correlation. Pediatr Pathol. 1992;12(3): 365–83. McDonald JW, Roggli VL, Bradford WD. Coexisting endogenous and exogenous lipoid pneumonia and pulmonary alveolar proteinosis in a patient with neurodevelopmental disease. Pediatr Pathol. 1994;14(3): 505–11.
The The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981
C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Approach Approach to to lipoid lipoid pneumonia pneumonia
17. Sato K, Takahashi H, Amano H, Uekusa T, Dambara T, Kira S. Diffuse progressive pulmonary interstitial and intra-alveolar cholesterol granulomas in childhood. European Respir J. 1996;9(11): 2419–22. 18. Chang HY, Chen CW, Chen CY, et al. Successful treatment of diffuse lipoid pneumonitis with whole lung lavage. Thorax. 1993;48(9): 947–8. 19. Ahmed A, Gupta V, Fleming DA, Aggarwal K. Pulmonary tuberculosis causing lipoid pneumonia. Mo Med. 2007;104(5): 446–7. 20. Berghaus TM, Haeckel T, Wagner T, von Scheidt W, Schwaiblmair MG. Endogenous lipoid pneumonia associated with primary sclerosing cholangitis. Lancet. 2007;369(9567): 1140. 21. van der Hoven B, Stiegelis WF, van der Linden AN, Giard RW. Lipoid pneumonitis complicating treatment of Hodgkin’s disease. Neth J Med. 1993;43(3–4): 183–6. 22. Fienberg R. Necrotizing granulomatosis and angiitis of the lungs and its relationship to chronic pneumonitis of the cholesterol type. Am J Pathol. 1953;29(5): 913–31. 23. French WO, Civin WH. Cholesterol pneumonitis and Wegener’s granulomatosis. AMA Arch Intern Med. 1956;97(6): 798–802. 24. Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci AS. Surgical pathology of the lung in Wegener’s granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. 1991;15(4): 315–33. 25. Antoon JW, Chakraborti C. Corticosteroids in the treatment of alcohol-induced rhabdomyolysis. Mayo Clin Proc. 2011;86(10): 1005–7. 26. Barnes PJ. Corticosteroids: the drugs to beat. Eur J Pharmacol. 2006;533(1–3): 2–14. 27. Itoh Y, Segawa H, Kito K, et al. Lipoid pneumonia with chronic myelomonocytic leukemia. Pathol Res Pract. 2009;205(2): 143–7. 28. Schultz R, Mattila J, Gappa M, Verronen P. Development of progressive pulmonary interstitial and intra-alveolar cholesterol granulomas (PICG) associated with therapy-resistant chronic systemic juvenile arthritis (CJA). Pediatr Pulmonol. 2001;32(5): 397–402. 29. De Navasquez S, Haslewood GA. Endogenous lipoid pneumonia with special reference to carcinoma of the lung. Thorax. 1954;9(1): 35–7. 30. Felson B, Ralaisomay G. Carcinoma of the lung complicating lipoid pneumonia. AJR Am J Roentgenol. 1983;141(5): 901–7. 31. Barta Z, Szabo GG, Bruckner G, Szegedi G. Endogenous lipoid pneumonia associated with undifferentiated connective tissue disease (UCTD). Med Sci Monit. 2001;7(1): 134–6.
2635
The Clinical Respiratory Journal
Clinical approach to endogenous lipoid pneumonia
Key words crazy paving pattern – interstitial lung disease – lipoid pneumonia Correspondence James W. Antoon, MD, PhD, Division of General Pediatrics and Adolescent Medicine, UNC Hospitals, University of North Carolina School of Medicine, 260 MacNider Building CB# 1593 Chapel Hill, NC 27599-7220, USA. Tel: 919 966 3172 Fax: 919 966 8419 email: [email protected]
Received: 10 August 2014 Accepted: 11 August 2014
Conflict of interest Authors have no potential conflicts of interest.
DOI:10.1111/crj.12203
Abbreviations: ELP endogenous lipoid pneumonia PAP pulmonary alveolar proteinosis
Authorship and contributorship Dr. Antoon drafted the manuscript. Julie S. Byerley, Michelle L. Hernandez and Margaret W. Leigh contributed to the proposed management plan and critically reviewed the manuscript.
Introduction Endogenous lipoid pneumonia (ELP) is an underreported and underdiagnosed condition, with a high percentage of cases found on autopsy or late-stage disease (1). The etiology of ELP varies widely and includes obstructive, hematologic, oncologic, rheumatologic, infectious, idiopathic, inflammatory and immunologic diseases (Table 1) (2). Early diagnosis of ELP is critical because of serious and life-threatening complications of late-stage disease. Treatment and prognosis also vary based on underlying etiology of lipoid pneumonia and delayed diagnosis, which affect later treatment strategies. Unfortunately, there is no standard workup or established empiric treatment for ELP. We recently reported a case of ELP associated with non-specific interstitial pneumonitis and pulmonary alveolar proteinosis (PAP), which resulted in the death of the patient 10 months after ELP diagnosis (3). Based on an extensive review of the literature and experience with clinical cases of ELP, a standard diagnostic approach to ELP is proposed below in hopes of preventing a delay in diagnosis and treatment in future cases.
Diagnosis and empiric management of ELP Lipoid pneumonia is an uncommon pediatric complaint characterized by lipid deposition in the alveoli and pulmonary macrophages. The disease is categorized as exogenous or endogenous based on lipid origin. Exogenous lipoid pneumonia is more common
The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 The
© 2014 John John Wiley Wiley&&Sons SonsLtd Ltd C 2014 V
in the pediatric and geriatric populations and caused by aspiration of fatty substances, including mineral oil, laxatives, nasal drops and lip balm (1, 2). While a comprehensive patient history often reveals exogenous lipoid pneumonia, the endogenous form has a more insidious presentation. The presentation of ELP various widely and often includes non-specific symptoms such as cough or dyspnea. Early identification of the disease is difficult, and most patients are diagnosed with communityacquired pneumonia prior to further workup when symptoms do not resolve with therapy (4). Symptoms can progress to chest pain, tachypnea and respiratory distress and death in late-stage disease. Radiologic findings vary based on underlying pathologic mechanism but commonly include consolidative opacities with or without central obstructing lesion (4). A ‘crazy paving pattern’ is often seen on computed tomography, although this finding is neither sensitive nor specific for the disease (Fig. 1A) (5). Definitive diagnosis is made with histopathology, which demonstrates lipidladen macrophages and intra-alveolar lipid deposition (Fig. 1B) (5, 6). The mainstay of therapy for ELP is treatment of the underlying cause. There have been reports of successful treatment and resolution of lipoid pneumonia with pharmacologic tumor necrosis factor inhibition, whole-lung lavage and lung transplantation in severe cases of lipoid pneumonia associated with specific diseases (7–9). We present here a diagnostic strategy for working up and empirically treating lipoid pneumonia (Fig. 2). The causes of ELP vary widely but can generally be
1 259
Approach Approach to to lipoid lipoid pneumonia pneumonia
Byerley Byerley et et al. al.
Table 1. Non-obstructive etiologies of endogenous lipoid pneumonia (ELP) Etiology
Age
Gender
CT
Treatment
Resolution of ELP
Chronic myelomonocytic leukemia (27) Idiopathic (11–13)
61
M
Prednisolone/amphotericin
No
40 33
M M
Prednisolone Prednisolone
Yes No
57 21, 5
F M
Antibiotics Steroids/infliximab
No No
5
F
Etanercept
Yes
Lung cancer (10, 29, 30)*
39–82
M and F
Interstitial reticular, ground-glass and granular lesions in whole-lung fields Mass lesion of mixed attenuation Bilateral reticulonodular shadows and bronchiectasis N/A Interlobular thickening and ground-glass opacities Reticulonodular and fibrotic changes located in the centrolobular region Variable
Variable
Hodgkin’s lymphoma (21) Atypical mycobacterial infection (7, 19)
34 29
M M
Anticancer/antibacterial agents Chemotherapy/steroids Lung transplantation
Yes Yes
63
F
Antimycobacterials
Yes
Neiman–Pick type II (9)
48
M
Whole-lung lavage
Yes
Non-specific interstitial pneumonitis (3)
16
F
Immunosuppression
No
Primary sclerosing cholangitis (20) Pulmonary alveolar proteinosis (3, 15–17)
63
F
Yes
1–31
M
Ursodeoxycholic acid/atorvastatin Prednisolone
No
34
F
Prednisolone
Yes
Adults
M and F
Variable
Variable
Juvenile rheumatoid arthritis (8, 28)
Undifferentiated connective tissue disease (31) Wegener’s granulomatosis (22–24)
Interstitial infiltrates Bilateral hyperinflated lung fields with superimposed fibrosis and patchy infiltrates Alveolar interstitial infiltrate and patchy infiltrate with pleural effusions Extensive bilateral ground-glass attenuation, with some focal areas of consolidation and thickening of the interlobular septa Smooth perilobular septal thickening with multifocal ground-glass opacities Consolidation of the lingula and the middle lobe region Diffuse, small reticular opacities and increase in alveolar and interstitial densities Atelectatic area and infiltrates bilaterally Variable
*Often have secondary obstructive component. CT, computed tomography.
categorized into obstructive, idiopathic or systemic etiologies. The first step in the workup of lipoid pneumonia involves determination of the extent of organ involvement. Idiopathic and obstructive causes generally present with intrathoracic symptoms only while systemic etiologies exhibit extrathoracic signs and symptoms (4). A comprehensive patient history often distinguishes between obstructive and idiopathic etiologies. Evidence of obstruction includes recent surgeries, blockages, aspiration or foreign body ingestion suggests obstruction (2, 4). In adults, lung cancer and bronchiolitis obliterans are common causes of obstructive ELP, although there are no reported cases 260 2
of these etiologies in children (10). There is a strong association between ELP and PAP, and ELP can be both an early and late finding of PAP. Therefore, thorough evaluation for PAP, including serum and tissue testing, should be considered when ELP is present, even in the absence of PAP on biopsy. The time course of symptom onset and progression is shorter in those with obstructive disease compared with idiopathic etiology. Patients with idiopathic disease have a more insidious presentation of symptoms and tend to be less acute than with obstructive or systemic disease-related lipoid pneumonia (2, 11). Treatment for obstructive etiology remains relief of
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Byerley Byerley et et al. al.
Figure 1. Radiographic and histopathology findings of endogenous lipoid pneumonia. (A) High-resolution computed tomography scan demonstrating a pattern of perilobular septal thickening with multifocal ground glass opacities or ‘crazy paving pattern’. (B) Alveolar accumulation of foamy macrophages consistent with endogenous lipoid pneumonia.
obstruction and therapeutic broncholavage in moderate to severe cases (2, 4). Idiopathic disease tends to resolve over several months with supportive or mild medical intervention. While there have been reports of both successful and unsuccessful treatment of idiopathic disease with systemic steroids, natural disease progression cannot be ruled out in these cases (11–13). However, given the limited reported cases and documented follow up of idiopathic ELP, it is likely that ELP is the initial presentation of a systemic disease (14–17). If patients have extrapulmonary symptoms, or symptoms that cannot be wholly attributed to lung disease, then investigation of an underlying systemic disease is warranted. Systemic diseases associated with The The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981
C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Approach Approach to to lipoid lipoid pneumonia pneumonia
ELP include infectious, rheumatologic, oncologic and inflammatory conditions (Table 1). Early identification of systemic pathology is paramount as these diseases can have poor outcomes if not diagnosed and treated early. Furthermore, treatments for these diseases vary widely based on the underlying pathophysiology and stage of disease. Yet, given the lack of large scale clinical studies, systemic diseases not yet associated with ELP cannot be ruled out in the many cases. Therefore, we recommend a high index of suspicion for systemic diseases with known pulmonary complications, including sarcoidosis and undifferentiated connective tissue disease. Laboratory and histologic analysis for several of these, including Neimann–Pick type II, undifferentiated connective tissue disease and Wegener’s granulomatosis, can take days to weeks to return. If the patient remains stable, conservative therapy is recommended until a final diagnosis is determined. However, if the patient is unstable or has rapidly worsening disease, therapeutic intervention is warranted. There is currently no empiric treatment strategy for patients with ELP with progressive disease. While some report that whole-lung lavage is of benefit in cases of obstruction and Neimann–Pick type II, patients with severe systemic disease are unlikely to be stable enough for whole lung broncholavage (9, 18). Similarly, maintenance systemic steroids are not likely to overcome worsening ELP. Therefore, in cases of worsening severe ELP, a treatment triad of high dose, lympholytic corticosteroids, macrolide antibiotics and statin therapy is reasonable. Case reports suggest empiric treatment with macrolides and statins may be beneficial in atypical mycobacterial infection and primary sclerosing cholangitis, respectively, associated with ELP (19, 20). High-dose steroids are beneficial in the treatment of juvenile idiopathic arthritis, Wegener’s granulomatosis, connective tissue disease and lymphomas (21–24). Lympholytic steroid dosing may also empirically treat diseases not yet associated with ELP that have pathologic inflammatory, rheumatologic and autoimmune processes (25, 26). If symptoms worsen following medical treatment, more invasive therapeutic interventions such as whole-lung lavage, lung transplantation, plasmapheresis and further immune suppression may be considered, although a comprehensive risk–benefit analysis should be performed prior to implementation.
Acknowledgement We thank Dr. William K. Funkhouser for assistance with histopathology. 2613
Approach Approach to to lipoid lipoid pneumonia pneumonia
Byerley Byerley et et al. al.
Figure 2. Diagnostic approach to lipoid pneumonia.
References 1
2
Julie S. Byerley , Michelle L. Hernandez , Margaret W. Leigh3 and James W. Antoon1 1 Division of General Pediatrics and Adolescent Medicine, UNC Hospitals, University of North Carolina School of Medicine, Chapel Hill, NC, USA 2 Division of Allergy, Immunology, Rheumatology and Infectious Diseases, UNC Hospitals, University of North Carolina School of Medicine, Chapel Hill, NC, USA 3 Division of Pulmonology, Department of Pediatrics, UNC Hospitals, University of North Carolina School of Medicine, Chapel Hill, NC, USA 262 4
1. Wright BA, Jeffrey PH. Lipoid pneumonia. Semin Respir Infect. 1990;5(4): 314–21. 2. Hadda V, Khilnani GC. Lipoid pneumonia: an overview. Expert Rev Respir Med. 2010;4(6): 799–807. 3. Antoon JW, Hernandez ML, Roehrs PA, Noah TL, Leigh MW, Byerley JS. Endogenous lipoid pneumonia preceding diagnosis of pulmonary alveolar proteinosis. Clin Respir J. 2014;August 8. doi: 10.1111/crj.12197. PMID: 25103284. 4. Betancourt SL, Martinez-Jimenez S, Rossi SE, Truong MT, Carrillo J, Erasmus JJ. Lipoid pneumonia: spectrum of clinical and radiologic manifestations. AJR Am J Roentgenol. 2010;194(1): 103–9. 5. De Wever W, Meersschaert J, Coolen J, Verbeken E, Verschakelen JA. The crazy-paving pattern: a
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Byerley Byerley et et al. al.
6.
7.
8.
9.
10.
11.
12.
13.
14.
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The The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981
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Approach Approach to to lipoid lipoid pneumonia pneumonia
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