|Year : 2016 | Volume
| Issue : 3 | Page : 22-32
Pulmonary alveolar proteinosis in children: An update on pathogenesis, clinical features and review of literature
Ahmad Hamed1, Daniel Rosenbaum1, Esther Cheng1, Rizwana Popatia2
1 Resident Fellow, Weill Cornell-New York Presbyterian
2 Attending Pediatric Pulmonologist, Weill Cornell-New York Presbyterian
|Date of Submission||13-Jun-2016|
|Date of Acceptance||12-Jul-2016|
|Date of Web Publication||21-Jul-2016|
505 East 70th Street HT 3, New York, NY 10021
Source of Support: None, Conflict of Interest: None
Pulmonary alveolar Proteinosis (PAP) is a rare disease whereby the alveolar sacs are filled with a lipoproteinaceous material. The accumulation of this material hinders gas exchange, resulting in a variety of presentations involving all age groups. Symptoms range in severity from mild cough and dyspnea in most patients, to respiratory distress and failure to thrive in infants and young children. Depending on the etiology, PAP cases are classified as being hereditary, secondary, or autoimmune. Despite the different mechanisms underlying these, a unifying pathophysiological concept for PAP exists. Diagnosis is often difficult, and takes time to establish, given the vague nature ofthe presenting symptoms ofthis disease. High resolution computed tomography (HRCT) remains the preferred radiological diagnostic tool. Diagnosis is confirmed by lung biopsy and bronchoalveolar fluid lavage. Management encompasses whole lung lavage (WLL), exogenous GM-CSF therapy, supportive respiratory measures where necessary, and even lung transplant in some severe cases. Children affected with PAP remain a population with high mortality. Pediatric literature is scarce in comparison to PAP described in adults. This paper focuses on reviewing the pathophysiology in context to recent advances in molecular genetics, diagnosis, and management in children with this disease.
Keywords: pulmonary alveolar proteinosis, granulocyte macrophage colony-stimulating factor, surfactant protein, lipoproteinaceous material, crazy paving, whole lung lavage
|How to cite this article:|
Hamed A, Rosenbaum D, Cheng E, Popatia R. Pulmonary alveolar proteinosis in children: An update on pathogenesis, clinical features and review of literature. J Pediatr Crit Care 2016;3:22-32
|How to cite this URL:|
Hamed A, Rosenbaum D, Cheng E, Popatia R. Pulmonary alveolar proteinosis in children: An update on pathogenesis, clinical features and review of literature. J Pediatr Crit Care [serial online] 2016 [cited 2022 Dec 8];3:22-32. Available from: http://www.jpcc.org.in/text.asp?2016/3/3/22/282624
| Introduction|| |
Pulmonary alveolar proteinosis (PAP) is an uncommon disorder characterized by inapt accumulation of lipoproteinaceous material in the alveoli, leading to impaired gas exchange and respiratory insufficiency. Being a rare disease, most of the evidence comes from case reports and small case series. However, the majority of PAP cases are autoimmune and are found in adults, making information regarding the other forms of PAP, especially in children, much more scarce in comparison.
S. Rosen first described this disease in 1958 as an unusual disease of the lung in which the alveoli were filled with PAS-positive protein rich material. PAP is a heterogenous disease but has been primarily classified in to three categories - hereditary, secondary and autoimmune. Current global estimate is one case per two million. The disease also features a worldwide distribution and occurs in all age groups - neonates, children,,,, and adults. Autoimmune PAP remains the most common and comprises almost 90% of all cases of PAP. There is a male preponderance of 2-3:1, but an equal sex distribution in non-smoker population. The estimated incidence is 0.5 million, and prevalence ranges from 6 to 7 per million.,, Clinical presentations may range from dyspnea and cough to cyanosis and clubbing, with about a third of the patients being asymptomatic at diagnosis. Secondary PAP is the next most common form of PAP and it accounts for approximately 8-9% of total PAP cases. It usually occurs secondary to hematological malignancies,,,,, infections, rheumatological diseases,,,, and toxic inhalation,,,. The hereditary form is most commonly seen in children, and occurs as a result of mutations in surfactant protein (SFTPB, SFTPC, ABCA3),,,,, GM-CSF receptor units·,, or lysurinic protein intolerance. With increasing evidence of a pediatric form of this disease, as seen in multiple case reports and recent advances in molecular genetics· our understanding of pediatric PAP has improved considerably. In this paper we review the pathophysiology in context to recent advances in molecular genetics and immunohistochemistry, clinical features and management of this disease.
| Pathophysiology, Molecular Genetics & Immunohistochemistry|| |
1) Hereditary PAP
| Normal Surfactant Metabolism|| |
Surfactant homeostasis is an extremely complex process involving alveolar type II cells and macrophages. Surfactant proteins are a lipoprotein complex secreted by type II alveolar cells. It plays an important role in reducing surface tension at the air-liquid interface of the gas exchange areas of the lung (hydrophobic surfactant proteins -B and C) and provides innate immunity (hydrophilic surfactant proteins - A and D). Both the lipid and protein components of surfactant are stored in lamellar bodies, which are then secreted into the alveolar space by a process called exocytosis. Once secreted, surfactant undergoes a series of complex transformations in the alveoli by a pathway that is not well understood, into a lattice-like structure, called tubular myelin. This structure serves as the precursor to the formation of a monolayer film, rich in dipalmitoylphosphatidyl choline, which ultimately helps in the reduction of alveolar surface tension and collapse of alveoli. Type II cells and alveolar macrophages play a vital role in the degradation and recycling of surfactant. Studies have shown that surfactant proteins regulate the uptake and recycling of surfactant phospholipids by receptor-mediated endocytosis.
A fine balance between its production and clearance sustains surfactant homeostasis. Alveolar macrophages play a primary role in clearance of surfactant proteins and lipids. GM-CSF (Granulocyte Macrophage Colony-Stimulating Factor) is a hematopoietic cytokine released by a variety of leukocytes, including macrophages, fibroblasts and lymphocytes in addition to serving as a modulator of white blood cell function. The GM-CSF receptor is found on alveolar macrophages. It is composed of two main subunits; alpha (α) and beta (β), coded by Colony Stimulating Factor 2 Receptor Alpha subunit (CSF2RA) and Receptor Beta subunit (CSF2RB) respectively. CSF2RB also functions as a receptor for IL-3 and IL-5. One of the functions that are induced through its activation is the clearance of alveolar surfactant.,,,
| Surfactant Dysfunction|| |
As mentioned earlier, surfactant components function as cohesive particles, holding together the phospholipid-dominant surfactant material, which is referred to as ‘lateral stability.‘ Mutations in the genes coding for these surfactant proteins have been implicated in PAP.
The SFTPB gene (chromosome 2) codes for surfactant protein B (SP-B). These mutations are usually autosomal recessive, but can also arise de novo as nonsense, missense, and frame-shift mutations. Within pneumocytes, they result in the formation of disorganized vesicles due to an incompletely formed surfactant aggregate, instead of normally arranged lamellar bodies. Ultimately, when the content of these vesicles is released, they fail to form the thin film that would otherwise coat the alveolar surface. Interestingly, investigations on SP-B deficient patients have also revealed incomplete SP-C function and deficiency.
SFTPC (chromosome 8) mutations have been widely described to cause diffuse lung disease in children and adults.,, After being translated into pro-SP-C further modifications are made to yield the final SP-C protein. An autosomal dominant pattern of inheritance was described for this mutation, though de novo mutations have been widely reported. In addition to its shared function with the other surfactant proteins, SP-C exhibits an additional benefit whereby it maintains surfactant homeostasis by facilitating surfactant uptake by type-II pneumocytes. The observation of hypertrophied pneumocytes in murine biopsy samples lent evidence to this mechanism. In addition, due to the dysfunctional structure of the pro-SP-C product of mutated SFTPC genes, this protein tends to aggregate within the alveolar cell, inducing cellular toxicity.
Mutations of proteins involving trafficking and transport ofsome other surfactant components are also implicated. ABC (ATP-based cassette) transporters are membrane bound structures that hydrolyze ATP to shuttle different substances across plasma membranes. ABCA3 is a gene (chromosome 16) that codes for a specific transporter found on the surface of the lamellar bodies within type-II pneumocytes. Their dysfunction results in mislocalization of surfactant proteins and resultant PAP., Analysis of the structure and function of the ABCA3 mutated gene product revealed two mechanisms by which this occurs: (a) inappropriate intracellular trafficking, and/or (b) normal trafficking, but with decreased ATP hydrolysis activity of the transporter. These mutations are inherited in an autosomal recessive pattern. Family members that are heterozygotes for these mutations are asymptomatic, indicating sufficient function of the normal gene product.
| GM-CSF Receptor Mutations (CSF2RA, CSF2RB)|| |
Mutations in the CSF2RA gene (chromosome X) affect the α subunit, whereas those in the CSF2RB (chromosome 22) gene affect the β subunit.
Mutations of CSF2RA have been described in eight children ranging from 1.5-9 years and are inherited in an autosomal recessive manner. Some mutations may have incomplete penetrance, and were described in two asymptomatic children of the affected family in the same study.
CSF2RB mutations were first described in 1995 in mice that were transplanted with bone marrow cells containing a defective CSF2RB gene, which resulted in a hypocellular bone marrow and lung pathology consistent with PAP. Mutations of CSF2RB have been reported in various case reports ranging from neonatal age to adults.,,
The mechanism by which this receptor dysfunction causes PAP is not yet fully understood. It is hypothesized that activation of the GM-CSF receptor, via JAK-STAT signaling, triggers a cascade down multiple other activation pathways. This signaling is believed to then promote the uptake of surfactant by alveolar macrophages. The final result of all GM-CSF mutations is therefore the inability of alveolar macrophages to efficiently clear excess surfactant, disrupting its homoeostasis, and leading to its abnormal accumulation.
2) Secondary PAP
Secondary PAP, as the name suggests, occurs secondary to hematological malignancies, immune deficiencies, rheumatological disorders, infections and toxic inhalation. Recently, GATA 2 mutations have been implicated in some hematological and infectious conditions associated with PAP.,
| GATA2 Mutations|| |
First discovered in the late 1980s in chicken globin genes, GATA2 (chromosome 3) is among a family of DNA transcription factors that feature zinc finger domains. It plays a direct role in the differentiation and maturation of cells of the hematopoietic lineage. Different types of mutations in this gene’s locus as well as its regulatory sequences have been identified. These mutations arise spontaneously, and are inherited in an autosomal dominant pattern. Heterozygous individuals demonstrate haploinsufficiency, whereby the remaining functional gene cannot generate a normal phenotype on its own. Given the gene’s early involvement in the hematopoietic process, a subsequent dysfunction down all the cell lines can manifest.
3) Autoimmune PAP
Autoimmune PAP is characterized by increased levels of circulating anti-GM-CSF antibodies. These are IgG antibodies that have increased affinity for binding GM-CSF, thus blocking its function.,, GM-CSF serves as a stimulus for alveolar macrophages. Reduction of this cytokine in the blood causes dysfunction of alveolar macrophages, and thereby, reduced surfactant clearance and abnormal accumulation., It also modifies the neutrophils and lymphocytes, causing increased rates of opportunistic infections associated with this type of PAP.
| Diagnosis|| |
1) Hereditary PAP
| Surfactant Protein Dysfunction|| |
Mutations of SFTPB usually present in the neonatal period with signs and symptoms of respiratory distress syndrome (RDS). However, they are found to be non-responsive to interventions of exogenous surfactant and steroids. This disease therefore carries the burden of high mortality and patients usually do not survive beyond the neonatal period. Some novel mutations have been described with increased survival to early childhood, found to be due to a decrease in functional SP-B protein, rather than complete deficiency.
SFTPC mutations on the other hand are less lethal, and generally do not present early on in life. Interestingly however, these mutations in isolation are less likely to result in PAP. Rather, they tend to cause a picture consistent with interstitial lung diseases (ILD), including pulmonary fibrosis and nonspecific interstitial pneumonitis.,, These patients would preset with dyspnea, cough and failure to thrive. A presentation with a mixed picture of both PAP and ILD is also possible, as in the case of an 8-month- old boy with a homozygous SFTPC mutation who presented with cough and cyanosis. The SFTPC product and precursor protein pro-SP-C, has been found to aggregate and cause clinical PAP in patients. ABCA3 mutations also present in the neonatal period, with a picture much like RDS. They affect the structural development of the fetal lungs, and are almost always fatal. Of note, some cases of homozygous ABCA3 mutations are not lethal, as reported in adolescents and young adults, but with manifestations of interstitial pneumonitis.
| GM-CSF Receptor Mutations|| |
CSF2RA mutations can present from early infancy to late childhood with insidious symptoms of progressively worsening dyspnea. Though they present similar to auto-immune PAP, they are negative for anti-GM-CSF antibodies, but an increased concentration of alveolar and serum GM- CSF is found. In a case series described by Suzuki et al, two out of 8 patients with these mutations were asymptomatic. Mutations of CSF2RB present from neonatal age to adulthood, with varying degrees of respiratory distress., Symptoms may eventually progress to respiratory failure in untreated patients.
| Lysinuric Protein Intolerance|| |
Lysinuric protein intolerance is an autosomal- recessive disease caused by mutations of the SLC7A7 gene, manifesting as failure to thrive and chronic renal and pancreatic insufficiency., Pulmonary symptoms range from mild interstitial lung disease, to respiratory failure. These patients have reduced function of alveolar macrophages, leading to inadequate surfactant clearance and features of PAP.
2) Secondary PAP
Secondary PAP has been reported less frequently in children than in adults. Symptoms are typically insidious and progressive in nature. They comprise up to 10% of pulmonary manifestations during the course of primary disease (malignancies, immune deficiencies, organ transplant, infections, rheumatological conditions, toxic inhalation).,,,,,,,
| GATA2 Deficiency|| |
Consequently, GATA2 deficiency presents with a very broad phenotype. These presentations include those that are hematological (familial myelodysplastic syndromes, acute myelocytic leukemias, MonoMAC syndrome, Emberger syndrome), pulmonary (PAP, pulmonary arterial hypertension), and infectious (mycobacterial, fungal, viral).,,,,
3) Autoimmune PAP
Autoimmune PAP can occur anywhere from neonatal to older age groups., Though it is the most common form of PAP, only less than 2% of patients have other associated autoimmune disease. Dyspnea is the most common presentation (40-70%), followed by cough. Inoue et al showed that about one-third of patients were asymptomatic. Crackles on examination are the most common physical sign (50%) and cyanosis is present in up to one third of cases.,,,,
On chest radiography, the appearance of congenital PAP mimics that of respiratory distress syndrome., Though nonspecific, findings in primary and secondary PAP typically include bilateral symmetric reticular or indistinct opacities with a central predominance [Figure 1]. Less common appearances range from asymmetric multifocal opacities to diffuse consolidation., Pleural effusions and lymphadenopathy are uncommon. A clinicoradiologic discrepancy has been described, with relatively poor correlation between symptomatology and severity of imaging findings.,
|Figure 1: Chest radiograph in an 8-year-old patient with primary PAP demonstrates diffuse bilateral reticular opacities with a central predominance.|
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HRCT yields superior anatomic detail, and is the test of choice in characterizing and determining extent of disease. While CT is not routinely performed for congenital alveolar proteinosis due to severity of disease, diffuse groundglass opacity with prominent septal thickening and fibrosis may be seen. The distinctive pattern of “crazy-paving,” manifested by smooth thickening of the interlobular septa and intralobular lines on a background of groundglass opacity interspersed with geographic or lobular areas of sparing, has been well described in adult patients with both primary and secondary PAP [Figure 2]., While the appearance in children may be more variable, the majority of patients exhibit a crazy-paving pattern [Figure 3]., Children may also demonstrate hyperinflation, consolidation, thickening of fissures, and rarely subpleural or interlobular cystic changes [Figure 4].,, Whereas septal thickening and groundglass opacity tends to be widespread throughout the lung zones, consolidations may show a basilar predominance. Primary differential considerations for the crazy- paving pattern include pulmonary hemorrhage, exogenous lipoid pneumonia, diffuse alveolar damage, and pulmonary edema., Following therapeutic bronchoalveolar lavage, CT may show decrease in the extent of groundglass opacity and interlobular septal thickening, even in the absence of appreciable improvement on chest radiography.
|Figure 2: Chest CT in a patient with primary PAP demonstrates a typical crazy-paving pattern, with multifocal areas of groundglass opacity (asterisk), intralobular lines (solid arrows), and interlobular septal thickening (dotted arrow), as well as geographic areas of relative sparing.|
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|Figure 3: Chest CT in an 8-year-old patient with biopsy-proven PAP shows interspersed areas of geographic groundglass opacity and sparing, widespread interlobular septal thickening (solid arrows), as well as thickening of the fissures (arrowheads).|
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|Figure 4: Chest CT in a 4-year-old patient with juvenile idiopathic arthritis and biopsy-proven secondary PAP demonstrates bilateral lower lobe consolidations (asterisks) in addition to more typical finding of septal thickening (solid arrows) and groundglass opacity (dotted arrow)|
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[TAG:2]Bronchoscopy with Bronchoalveolar Lavage,,,,[/TAG:2]
Bronchoalveolar lavage (BAL) fluid usually appears milky in patients with PAP and it stains positive with periodic acid - schiff (PAS). BAL cytology shows preponderance of macrophages, many of which appear large and foamy and stain positive on PAS staining. Electron microscopy of BAL may reveal lamellar bodies with structural similarity to tubular myelin.
| Biopsy & Histopathology|| |
In the initial characterization of this disease by Rosen et al, the majority of the biopsy material showed gross features of yellow-gray subpleural nodules ranging in size of several millimeters to 2.0 cm. Palpation of cut sections caused oozing of milky yellow material. The histological findings consisted of lipoproteinaceous eosinophilic material within the alveolar space with small acicular spaces, otherwise also described as cholesterol clefts. The surrounding epithelium is largely intact though it may also be denuded into the alveolar space. The macrophages within the alveolar space are “bubbly” or vacuolated and may show concentrically laminated surfactant aggregates. The eosinophilic material is periodic acid-Schiff positive and diastase (PAS-D) resistant. The histopathological findings from a left lung biopsy of a 4-year-old patient with hereditary PAP demonstrate the typical accumulation of the eosinophilic material within the alveolar spaces [Figure 5]. Hyperplasia of type II pneumocytes is seen [Figure 6], and on higher power, disruption of the alveolar macrophage structure can be appreciated [Figure 7].
|Figure 5: The left lung biopsy shows diffuse involvement of the intra-alveolar airspaces by amorphous, granular, eosinophilic material. The interstitium is expanded by chronic inflammatory cells that form dense aggregates (arrows).|
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|Figure 6: The alveolar spaces are filled with eosinophilic, foamy macrophages surrounded by an amorphous eosinophilic and granular material. Numerous cholesterol clefts (“acicular spaces”) are seen in the alveolar spaces. Type II pneumocyte hyperplasia with expansion of the interstitium by lymphocytes and plasma cells are seen.|
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|Figure 7: Higher magnification of the alveolar space with granular eosinophilic debris and degenerated macrophages. Occasional lymphocytic aggregates are seen. The eosinophilic material contains cholesterol clefts and oncocytoid macrophages with vacuolated cytoplasm. Degenerated macrophages show disrupted cytoplasmic membranes with release of the inner granular content into the alveolar space.|
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|Figure 8: Serial lavage specimens labelled from 1-11 shows clearing of proteinaceous fl uid. Image courtsey Dr Alicia Casey, Children's Hospital Boston.|
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| Pulmonary Function Tests|| |
Restrictive ventilatory defect with reduction in lung volumes, and reduced diffusion impairment, are the most common pulmonary function abnormalities in patients with PAP. Hypoxemia is common in advanced disease along with increased alveolar- arterial pressure gradient (A-a gradient), which worsens with exercise. These abnormalities correlate with the severity and progression of the disease, and also serve as a prognostic marker during treatment.
| Management|| |
Whole Lung Lavage,,,,,,
Whole lung lavage remains the standard of care for all types of PAP with moderate to severe symptoms. This was implemented as early as the 1960’s, but more sophisticated techniques have evolved over a period of time with improved outcomes. This procedure is performed under general anesthesia in an operating room or an intensive care setting, by a multidisciplinary staff involving a pulmonologist and/or intensivist, anesthetist, physiotherapist and respiratory therapist. This procedure becomes more challenging in pediatric patients, as it requires anesthetist expertise of selective intubation of a single lung while lavaging the other, and is also limited by the availability of special endotracheal tubes. The patient is usually intubated with a doublelumen endotracheal tube. Flexible bronchoscopy for baseline evaluation and confirmation of tube position is done. Patient is then placed in lateral decubitus position, with the intubated lung on the top and the lung being lavaged in the bottom position. A circuit is established, wherein pre-warmed saline (500 ml - 1Liter) is instilled in the lung to be lavaged, after which it is closed while the patient receives manual or mechanical intensive chest physiotherapy. The circuit is then opened to drain the fluid via gravity. The process is then repeated until the fluid eventually becomes clear. The contralateral lung can be lavaged 24-48 hours later.
This procedure has shown significant improvement in various studies with symptomatic, radiographic and physiological improvement as well as improved survival. There has been an improvement in lung volumes and arterial oxygen gradients reported with whole lung lavage. Repeat procedure may be needed depending on progression of the disease and symptomatic impairment. Diffusing capacity (DLCO) has been reported as an important marker to assess the need for future lavage in one of the recent studies. Fever, infection, pleural effusion, hypoxemia and pneumothorax are usual complications.
| Recombinant GM-CSF|| |
GM-CSF therapy remains a safer and non-invasive alternative to whole lung lavage in patients with GM-CSF receptor mutations, or those with anti-GM- CSF antibodies. There are no identified clinical or biological markers to date that can foresee response to GM-CSF. It can be used via a sub-cutaneous or an inhalation route. Different studies have shown significantly improved response with GM-CSF via different routes and different dosage protocols, ranging from 50 - 90%. The main objective parameter for response was improvement in PaO2 (partial pressure of oxygen in arterial blood) and the results were comparable to that with whole lung lavage. Side effects were minor and non-specific, and included edema and erythema at the local site, fever, malaise and transient respiratory symptoms.,,,,,,
| Immunosuppressive Therapy|| |
Few case reports and case series have shown plasmapheresis and Rituximab (monoclonal antibody against CD20 B-lymphocytes) to result in some improvement in patients with anti-GM-CSF antibody.,,,,
| Anti-Inflammatory Therapy|| |
In children with underlying disorders such as SP-C deficiency, corticosteroids and hydroxychloroquine have been used in isolated cases with variable improvement.
| Mechanical Ventilation|| |
Neonates and infants with SP-B or ABCA3 mutations require mechanical ventilation, owing to worsening respiratory insufficiency and respiratory failure. These children may not respond adequately to whole lung lavage, and lung transplant remains the only option to improve survival.
| Prognosis|| |
Prognosis of PAP depends on the severity of the disease and underlying etiology. The most common cause of mortality is due to infection with opportunistic organisms.,,,,,,,, The natural course of disease involves spontaneous resolution,, to interstitial fibrosis and respiratory failure., Generally, it carries an excellent prognosis with whole lung lavage.,
| Summary|| |
Pulmonary alveolar proteinosis (PAP) represents a heterogenous group of disorders across all age group with varied severity of presentation. The advent of molecular genetics in recent times has increased our understanding of the pathogenesis of this disease. Keeping high suspicion for the disease and early diagnosis remains key for improved outcomes and better prognosis. Whole lung lavage remains the treatment of choice and carries an excellent prognosis. GM-CSF treatment for those who are deficient remains a promising and safe treatment option. Due to a wide spectrum of presentation, with some of the patients being asymptomatic at diagnosis, the disease would have been widely underreported. More efforts need to be done to work-up this disease in appropriate patients and maintain a registry to report all such cases that can help in future research. Gene therapy targeting GM-CSF receptors remains an important milestone to be achieved for the future.
| Abbreviations|| |
- ABCA3 – ATP-based cassette subfamily A member 3
- BAL – bronchoalveolar lavage
- CSF2RA/B – colony stimulating factor 2 receptor alpha/beta subunit
- DLCO – diffusion capacity of the lungs for carbon monoxide
- GM-CSF – granulocyte macrophage colony- stimulating factor
- HRCT – high resolution computed tomography
- ILD – interstitial lung disease
- PAP – pulmonary alveolar proteinosis
- RDS – respiratory distress syndrome
- SFTPB/C – surfactant protein B/C (gene)
- SP-B/C – surfactant protein B/C (protein)
- WLL – whole lung lavage
Conflict of Interest: None
Source of Funding: None
| References|| |
Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N
Engl J Med 1958;258:1123-42.
Shah PL, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax 2000;55:67-77.
Coleman M, et al. Pulmonary alveolar proteinosis: an uncommon cause of chronic neonatal respiratory distress. Am Rev Respir Dis 1980;121:583-6.
Suzuki T, et al. Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med 2010;182:1292-304.
Mahut B, et al. Pulmonary alveolar proteinosis: experience with eight pediatric cases and a review. Pediatrics 1996;97:117-22.
Wilkinson RH, Blanc WA, Hagstrom JW. Pulmonary alveolar proteinosis in three infants. Pediatrics1968;41:510-5.
Prakash UB, et al. Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review. Mayo Clin Proc1987;62:499-518.
Inoue Y, et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med2008;177:752-62.
Briens E, et al. [Pulmonary alveolar proteinosis]. Rev Mal Respir 2002;19:66-82.
Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002;166:215-35.
Ben-Dov I, Segel MJ. Autoimmune pulmonary alveolar proteinosis: clinical course and diagnostic criteria. Autoimmun Rev2014;13:513-7.
Ishii H, et al. Clinical features of secondary pulmonary alveolar proteinosis: pre-mortem cases in Japan. Eur Respir J 2011; 37:65-8.
Cordonnier C, et al. Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 1994;149:788-94.
Pamuk GE, et al. Pulmonary alveolar proteinosis in a patient with acute lymphoid leukemia regression after G-CSF therapy. Leuk Lymphoma2003;44:71-4.
Chung JH, et al. Secondary pulmonary alveolar proteinosis: a confusing and potentially serious complication of hematologic malignancy. J Thorac Imaging 2009;24:115-8.
Vella FS, et al. Case of multiple myeloma mimicking an infectious disease with fever, intrahepatic cholestasis, renal failure, and pulmonary insufficiency. Am J Hematol 2003;72:38-42.
Tran Van Nhieu J, et al. Pulmonary alveolar proteinosis associated with Pneumocystis carinii. Ultrastructural identification in bronchoalveolar lavage in AIDS and immunocompromised non-AIDS patients. Chest 1990;98:801-5.
Samuels MP, Warner JO. Pulmonary alveolar lipoproteinosis complicating juvenile dermatomyositis. Thorax 1988;43:939-40.
Wardwell NR Jr., Miller R, Ware LB. Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug. Respirology 2006;11:663-5.
Uchiyama M, et al. Pulmonary alveolar proteinosis in a patient with Behcet’s disease. Respirology 2009;14:305-8.
Cummings KJ, et al. Pulmonary alveolar proteinosis in workers at an indium processing facility. Am J Respir Crit Care Med 2010;181:458-64.
Lison D, et al. Sintered indium-tin-oxide (ITO) particles: a new pneumotoxic entity. Toxicol Sci 2009;108:472-81.
Tredano M, et al. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A 2004; 126:18-26.
Mechri M, et al. Surfactant protein C gene (SFTPC) mutation-associated lung disease: high-resolution computed tomography (HRCT) findings and its relation to histological analysis. Pediatr Pulmonol 2010;45:1021-9.
Young LR, et al. Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest 2008;134:192-5.
Hamvas A. Surfactant protein B deficiency: insights into inherited disorders of lung cell metabolism. Curr Probl Pediatr 1997;27:325-45.
Thouvenin G, et al. Characteristics of disorders associated with genetic mutations of surfactant protein C. Arch Dis Child 2010;95:449-54.
Tanaka T, et al. Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB. J Med Genet 2011;48:205-9.
Dirksen U, et al. Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J Clin Invest 1997;100:2211-7.
Suzuki T, et al. Hereditary pulmonary alveolar proteinosis caused by recessive CSF2RB mutations. Eur Respir J 2011;37:201-4.
Williams MC, Hawgood S,. Hamilton RL. Changes in lipid structure produced by surfactant proteins SP-A, SP-B, and SP-C. Am J Respir Cell Mol Biol 1991;5:41-50.
Suzuki Y, Fuj ita Y, Kogishi K. Reconstitution of tubular myelin from synthetic lipids and proteins associated with pig pulmonary surfactant. Am Rev Respir Dis 1989;140:75-81.
Wright JR, Dobbs LG. Regulation of pulmonary surfactant secretion and clearance. Annu Rev Physiol 1991;53:395-414.
Whitsett JA, Wert SE, Weaver TE. Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu Rev Med 2010;61:105-19.
Hercus TR, et al. The granulocyte-macrophage colony- stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood2009 ;114:1289-98.
Hansen G, et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 2008;134:496-507.
Sakamaki K, et al. Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation. EMBO J 1992;11: 3541-9.
Shibata Y, et al. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 2001;15: 557-67.
Yoshida M, et al. GM-CSF regulates protein and lipid catabolism by alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2001;280: L379-86.
Trapnell BC, Whitsett JA. Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu Rev Physiol 2002;64: 775-802.
Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N
Engl J Med 2003;349:2527-39.
Cochrane CG. Pulmonary surfactant in allergic inflammation: new insights into the molecular mechanisms of surfactant function. Am J Physiol Lung Cell Mol Physiol 2005;288: L608-9.
Deutsch GH, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med 2007;176:1120-8.
Tredano M, et al. Compound SFTPB 1549C-->GAA (121ins2) and 457delC heterozygosity in severe congenital lung disease and surfactant protein B (SP-B) deficiency. Hum Mutat 1999;14:502-9.
Edwards V, et al. Ultrastructure of lamellar bodies in congenital surfactant deficiency. Ultrastruct Pathol 2005;29: 503-9.
Tredano M, et al. Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism. Clin Chem Lab Med 2001;39: 90-108.
van Moorsel CH, et al. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med 2010;182: 1419-25.
Tredano M, et al. Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB. Am J Med Genet A 2003;119:324-39.
Amin RS, et al. Surfactant protein deficiency in familial interstitial lung disease. J Pediatr 2001;139: 85-92.
Glasser SW, et al. Pneumonitis and emphysema in sp-C gene targeted mice. J Biol Chem 2003;278:14291-8.
Thomas AQ, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002;165: 1322-8.
Doan ML, et al. Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax 2008;63: 366-73.
Matsumura Y, et al. Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency. J Biol Chem 2006; 281:34503-14.
Shulenin S, et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N
Engl J Med 2004;350: 1296-303.
Bruder E, et al. Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation. Mod Pathol2007;20: 1009-18.
Nishinakamura R, et al. Mice deficient for the IL-3/GM- CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor- deficient mice are normal. Immunity 1995;2:211-22.
Spinner MA, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 2014;123:809-21.
Collin M, Dickinson R, BigleyVl. Haematopoietic and immune defects associated with GATA2 mutation. Br J Haematol 2015;169:173-87.
Heicklen-Klein A, McReynolds LJ, Evans T. Using the zebrafish model to study GATA transcription factors. Semin Cell Dev Biol 2005;16: 95-106.
Leonard M, et al. Dynamics of GATA transcription factor expression during erythroid differentiation. Blood 1993;82:1071-9.
Cortes-Lavaud X, et al. GATA2 germline mutations impair GATA2 transcription, causing haploinsufficiency: functional analysis of the p. Arg396Gln mutation. J Immunol 2015;194:2190-8.
Kitamura T, et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med 1999;190:875-80.
Uchida K, et al. High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood 2004;103:1089-98.
Kitamura T, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 162: 658-62.
Greenhill SR, Kotton DN. Pulmonary alveolar proteinosis: a bench-to-bedside story of granulocyte-macrophage colony- stimulating factor dysfunction. Chest 2009;136:571-7.
Uchida K, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N
Engl J Med 2007;356:567-79.
Tredano M, et al. Clinical, biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism: SP-B deficiency and alveolar proteinosis. Ann Biol Clin (Paris) 2001;59:131-48.
Dunbar AE, 3rd, et al. Prolonged survival in hereditary surfactant protein B (SP-B) deficiency associated with a novel splicing mutation. Pediatr Res 2000;48:275-82.
Wert, S.E., J.A. Whitsett, and L.M. Nogee, Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol, 2009. 12(4): p. 253-74.
Nogee LM, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N
Engl J Med 2001;344:573-9.
Arikan-Ayyildiz Z, et al. Survival of an infant with homozygous surfactant protein C (SFTPC) mutation. Pediatr Pulmonol 2014;49: E112-5.
Bullard JE, et al. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 2005; 172:1026-31.
Sperandeo MP, Andria G, Sebastio G. Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene. Hum Mutat 2008;29:14-21.
Broer S, et al. Lysinuric protein intolerance: one gene, many problems. Am J Physiol Cell Physiol 2007;293:C540-1.
Barilli A, et al. In Lysinuric Protein Intolerance system y+L activity is defective in monocytes and in GM-CSF- differentiated macrophages. Orphanet J Rare Dis 2010;5: 32.
Tomonari A, et al. Acquired pulmonary alveolar proteinosis after umbilical cord blood transplantation for acute myeloid leukemia. Am J Hematol 2002;70:154-7.
Pollack SM, Gutierrez G, Ascensao J. Pulmonary alveolar proteinosis with myeloproliferative syndrome with myelodysplasia: bronchoalveolar lavage reduces white blood cell count. Am J Hematol 2006;81: 634-8.
Dai MS, et al. Impact of open lung biopsy for undiagnosed pulmonary infiltrates in patients with hematological malignancies. Am J Hematol 2001;68:87-90.
Hsu AP, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood 2013;121:3830-7, S1-7.
Camargo JF, et al. MonoMAC syndrome in a patient with a GATA2 mutation: case report and review of the literature. Clin Infect Dis 2013;57: 697-9.
Ostergaard P, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 2011;43: 929-31.
Du Bois RM, McAllister WA, Branthwaite MA. Alveolar proteinosis: diagnosis and treatment over a 10-year period. Thorax 1983;38:360-3.
Kariman K, Kylstra JA, Spock A. Pulmonary alveolar proteinosis: prospective clinical experience in 23 patients for 15 years. Lung 1984;162:223-31.
Albafouille V, et al. CT scan patterns of pulmonary alveolar proteinosis in children. Pediatr Radiol 1999;29:147-52.
Newman B, et al. Congenital surfactant protein B deficiency-emphasis on imaging. Pediatr Radiol 2001;31:327-31.
Frazier AA, et al. From the archives of the AFIP: pulmonary alveolar proteinosis. Radiographics 2008;28:883-99.
McCook TA, et al. Pulmonary alveolar proteinosis in children. AJR Am J Roentgenol 1981;137:1023-7.
Berteloot L, et al. Primary pulmonary alveolar proteinosis: computed tomography features at diagnosis. Pediatr Radiol 201; 44:795-802.
Murch CR, Carr DH. Computed tomography appearances of pulmonary alveolar proteinosis. Clin Radiol 1989;40:240-3.
Godwin JD, Muller NL, Takasugi JE. Pulmonary alveolar proteinosis: CT findings. Radiology 1988;169: 609-13.
Copley SJ, Padley SP. High-resolution CT of paediatric lung disease. Eur Radiol 2001;11:2564-75.
Guillerman RP. Imaging of Childhood Interstitial Lung Disease. Pediatr Allergy Immunol Pulmonol 2010;23:43-68.
Zontsich T, et al. Pulmonary alveolar proteinosis in a child: HRCT findings before and after bronchoalveolar lavage. Eur Radiol 1998;8:1680-2.
Verma H, et al. Alveolar proteinosis with hypersensitivity pneumonitis: a new clinical phenotype. Respirology 2010:15:1197-202.
Wang BM, et al. Diagnosing pulmonary alveolar proteinosis. A review and an update. Chest 1997;111: 460-6.
Baro A, et al. Pulmonary alveolar proteinosis in a 10-year- old girl masquerading as tuberculosis. Oxf Med Case Reports 2015;2015:300-2.
Rogers RM, et al. Physiologic effects of bronchopulmonary lavage in alveolar proteinosis. Am Rev Respir Dis 1978;118:255-64.
Ramirez J, Campbell GD. Pulmonary Alveolar Proteinosis. Endobronchial Treatment. Ann Intern Med 1965;63:429-41.
Michaud G, Reddy C, Ernst A. Whole-lung lavage for pulmonary alveolar proteinosis. Chest 2009;136:1678-81.
Tan Z, Tan KT, Poopalalingam R. Anesthetic Management for Whole Lung Lavage in Patients with Pulmonary Alveolar Proteinosis. A A Case Rep 2016; 6:234-7.
Zhao YY, et al. Whole Lung Lavage Treatment of Chinese Patients with Autoimmune Pulmonary Alveolar Proteinosis: A Retrospective Long-term Follow-up Study. Chin Med J (Engl) 2015;128:2714-9.
Seymour JF, et al. Therapeutic efficacy of granulocyte- macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med 2001;163:524-31.
Kavuru MS, et al. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000;161:1143-8.
Venkateshiah SB, et al. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest 2006;130:227-37.
Wylam ME, et al. Aerosol granulocyte-macrophage colony- stimulating factor for pulmonary alveolar proteinosis. Eur Respir J 2006;27:585-93.
Robinson TE, et al. Quantitative analysis of longitudinal response to aerosolized granulocyte-macrophage colony- stimulating factor in two adolescents with autoimmune pulmonary alveolar proteinosis. Chest 2009:135: 842-8.
Rodriguez Portal JA, E. Rodriguez Becerra, Sanchez Garrido A. Response to inhaled granulocyte-macrophage colony-stimulating factor in a patient with alveolar proteinosis. Arch Bronconeumol 2009;45:150-2.
Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol 1999;10:2446-53.
Kavuru MS, Bonfield TL, Thomassen MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit Care Med 2003;167: 1036; author reply 1036-7.
Luisetti M, et al. Plasmapheresis for treatment of pulmonary alveolar proteinosis. Eur Respir J 2009;33: 1220-2.
Amital A, et al. Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis. Thorax 2010;65:1025-6.
Borie R, et al. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J 2009;33:1503-6.
Rosen DM, Waltz DA, Hydroxychloroquine and surfactant protein C deficiency. N
Engl J Med 2005;352: 207-8.
Palomar LM, et al. Long-term outcomes after infant lung transplantation for surfactant protein B deficiency related to other causes of respiratory failure. J Pediatr 2006;149:548-53.
Burbank B, Morrione TG, Cutler SS, Pulmonary alveolar proteinosis and nocardiosis. Am J Med 1960;28:1002-7.
Lathan SR Jr, et al. Pulmonary alveolar proteinosis. Treatment of a case complicated by tuberculosis. Chest1971;59: 452-4.
Reyes JM, Putong PB. Association of pulmonary alveolar lipoproteinosis with mycobacterial infection. Am J Clin Pathol 1980;74:478-85.
Bakhos R, et al. Pulmonary alveolar proteinosis: an unusual association with Mycobacterium avium-intracellulare infection and lymphocytic interstitial pneumonia. South Med J 1996;89: 801-2.
Couderc LJ, et al. Pulmonary alveolar proteinosis and disseminated Mycobacterium avium infection. Respir Med 1996;90: 641-2.
Sunderland WA, Campbell RA, Edwards MJ. Pulmonary alveolar proteinosis and pulmonary cryptococcosis in an adolescent boy. J Pediatr 1972;80:450-6.
Hartung M, Salfelder K. Pulmonary alveolar proteinosis and histoplasmosis: report of three cases. Virchows Arch A Pathol Anat Histol 1975;368:281-7.
Ranchod M, Bissell M. Pulmonary alveolar proteinosis and cytomegalovirus infection. Arch Pathol Lab Med 1979;103:139-42.
Haddad PG, Pankey GA. Pulmonary alveolar proteinosis: a case with spontaneous resolution. J La State Med Soc 1969;121:365-76.
Topchiev Sh R, et al. A case of spontaneous recovery from pulmonary alveolar proteinosis. Probl Tuberk 1988;8:76-8.
Canto MJ, et al. Successful pregnancy after spontaneous remission of familial pulmonary alveolar proteinosis. Eur J Obstet Gynecol Reprod Biol 1995; 63:191-3.
Hudson AR, et al. Pulmonary interstitial fibrosis following alveolar proteinosis. Chest 1974;65: 700-2.
Clague HW, Wallace AC, Morgan WK. Pulmonary interstitial fibrosis associated with alveolar proteinosis. Thorax 1983;38:865-6.
Larson RK, Gordinier R. Pulmonary Alveolar Proteinosis. Report ofSix Cases, Review ofthe Literature, and Formulation of a New Theory. Ann Intern Med 1965;62:292-312.
Davidson JM, Macleod WM. Pulmonary alveolar proteinosis. Br J Dis Chest 1969;63:13-28.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]