Pulmonary alveolar proteinosis is a broad group of rare diseases that are defined by the occupation of a lung’s gas-exchange area by pulmonary surfactants that are not properly removed. The clinical and radiologic phenotypes among them are very similar. The age of manifestation plays a central role in the differential diagnosis of the almost 100 conditions and provides an efficient path to the correct diagnosis. The diagnostic approach is tailored to identify genetic or autoimmune causes, exposure to environmental agents, and associations with numerous other diseases. Whole-lung lavages are the cornerstone of treatment, and children in particular depend on the expertise to perform such therapeutic lavages. Other treatment options and long-term survival are related to the condition causing the proteinosis.

Under pathological conditions, the alveolar airspaces can be filled with various materials, which frequently replace the air necessary for gas exchange and give rise to alveolar filling syndromes (Table 1). These conditions have similar clinical and radiologic presentations. This makes their differential diagnosis difficult.

TABLE 1

Intra-Alveolar Filling With Different Materials Leads to Various Disease Entities

Material Filling the Alveolar SpaceDisease
Surfactant PAP 
Erythrocytes, siderophages Alveolar hemorrhage 
Macrophages Desquamative interstitial pneumonia 
Hyaline membranes Diffuse alveolar damage, RDS 
Eosinophils Eosinophilic pneumonia 
Cholesterol crystals, foreign material Exogenous lipid pneumonia, aspiration pneumonia 
Exsudative neutrophilic alveolitis, progressively replaced by macrophages, giant cells, fibroblasts Meconium aspiration syndrome 
Lipoproteins, Pneumocystis P jiroveci pneumonia 
Calcified microliths Pulmonary alveolar microlithiasis 
Plasma, serum Pulmonary edema 
Material Filling the Alveolar SpaceDisease
Surfactant PAP 
Erythrocytes, siderophages Alveolar hemorrhage 
Macrophages Desquamative interstitial pneumonia 
Hyaline membranes Diffuse alveolar damage, RDS 
Eosinophils Eosinophilic pneumonia 
Cholesterol crystals, foreign material Exogenous lipid pneumonia, aspiration pneumonia 
Exsudative neutrophilic alveolitis, progressively replaced by macrophages, giant cells, fibroblasts Meconium aspiration syndrome 
Lipoproteins, Pneumocystis P jiroveci pneumonia 
Calcified microliths Pulmonary alveolar microlithiasis 
Plasma, serum Pulmonary edema 

Pulmonary alveolar proteinosis (PAP) is defined by the accumulation of pulmonary surfactants in the alveolar space (Fig 1). Mechanistically, these disturbances of surfactant homeostasis may be caused by an altered surfactant production, removal, or both.1 PAP is a heterogeneous group of disorders that is caused by different conditions2 (Table 2). The age of manifestation plays an important role in the diagnostic approach and differential diagnosis (Fig 2). Success of treatment and outcome are related to the underlying condition and, in children, to the technical skills needed to perform whole-lung lavages (WLLs). WLL is the cornerstone of PAP treatment.

FIGURE 1

Diagnosing alveolar pulmonary proteinosis. A, A chest radiograph shows bilateral, often symmetrical alveolar opacities. If a radiograph appears less dense than what is shown here, a “butterfly” appearance may be recognized. B, A crazy paving pattern from ground-glass opacification and overlaid reticulonodular pattern is shown. C, Foamy macrophage from BAL filled with lipid material (May-Grünwad staining) is seen. D, Periodic acid–Schiff (PAS) staining–positive noncellular globules. A large amount of cell debris is characteristic of PAP lavage. E, Histology from a patient with PAP caused by a homozygous GM-CSF-Ra mutation is shown. Note the alveolar filling and normal alveolar walls (haematoxylin-eosin staining). F, The same biopsy with a PAS stain shows amorphous PAS-positive material with abundant oval bodies.

FIGURE 1

Diagnosing alveolar pulmonary proteinosis. A, A chest radiograph shows bilateral, often symmetrical alveolar opacities. If a radiograph appears less dense than what is shown here, a “butterfly” appearance may be recognized. B, A crazy paving pattern from ground-glass opacification and overlaid reticulonodular pattern is shown. C, Foamy macrophage from BAL filled with lipid material (May-Grünwad staining) is seen. D, Periodic acid–Schiff (PAS) staining–positive noncellular globules. A large amount of cell debris is characteristic of PAP lavage. E, Histology from a patient with PAP caused by a homozygous GM-CSF-Ra mutation is shown. Note the alveolar filling and normal alveolar walls (haematoxylin-eosin staining). F, The same biopsy with a PAS stain shows amorphous PAS-positive material with abundant oval bodies.

TABLE 2

Categorization of PAP

Disease Causes of PAPManifestation Reported in Neonates, ChildrenaGenetically CausedbExposure CausedHistologically Intact Lung Interstitial Tissue, Primarily Alveolar Filling
Surfactant-dysfunction syndromes     
 SFTPB mutations 
 SFTPC mutations 
 ABCA3 mutations 
 TTF1 mutations 
Impaired GM-CSF signaling     
 GM-CSF receptor α chain of mutations 
 Turner syndrome with heterozygous GM-CSF receptor α chain mutations 
 GM-CSF receptor β chain mutations 
 Autoimmune GM-CSF antibodies 
Hematologic disorders and other malignancies     
 GATA2 deficiency 
 MDS (most common) 
 Chronic myelomonocytic leukemia n.k. 
 Acute lymphatic leukemia Yc 
 Congenital dyserythropoietic anemia 
 Fanconi’s anemia 
 Hemophagocytic lymphohistiocytosis  
 Sideroblastic anemia Nc Yc 
 Primary myelofibrosis, chronic lymphocytic leukemia, cutaneous T-cell lymphoma, thymic alymphoplasia, adult T-cell leukemia and/or lymphoma, idiopathic thrombocytopenic purpura, aplastic anemia, chronic myeloid leukemia, overlap myeloproliferative neoplasm, acute myeloid leukemia, hairy-cell leukemia, multiple myeloma and/or plasmocytoma, polycythemia vera, essential thrombocythemia, amyloidosis, Hodgkin disease, non-Hodgkin lymphoma, adenocarcinoma, glioblastoma, melanoma, small-cell lung carcinoma, clear-cell renal cell carcinoma, mesothelioma Y or n.k. Nc Yc or n.k. 
Systemic diseases     
 Lysinuric protein intolerance (SLC7A7 mutation) Y (50%), N (50%) 
 MARS mutations 
 Niemann Pick type C2 
 Niemann Pick type B n.d. 
 Bone marrow, stem cell transplant Yc 
 Systemic lupus erythematosus, granulomatosis with polyangiitis, microscopic polyangiitis, membranous nephropathy, dermatomyositis with interstitial lung disease, coincident in many other rheumatologic diseases and interstitial lung diseases, lung transplant Yc or N 
Immunologic diseases     
 Adenosine deaminase deficiency 
 Agammaglobulinemia Yc n.k. 
 DiGeorge syndrome type 2 n.d. 
 Monoclonal gammopathy 
 Selective immunoglobulin A deficiency 
 Severe combined immunodeficiency 
 X-linked hyper–immunoglobulin M syndrome n.d. 
Infections     
 Cytomegalovirus N or Nc 
 Epstein-Barr virus N or Nc 
 HIV N or Nc 
M tuberculosis N or Nc 
 Atypical mycobacteria N or Nc 
Nocardia N or Nc 
P jiroveci N or Nc 
Drugs     
 Chemotherapy, antineoplastic 
 Busulfan, sirolimus, everolimus, tyrosine kinase inhibitors (including imatinib, nilotinib, and dasatinib), mycophenolate and cyclosporine combination, smoked fentanyl patches, leflunomide, hydrofluoric acid (inhaled) 
Types of dust exposure, inorganic     
 Aluminum, cement, marble, indium, iron, silica and silica-leaking breast implants, tin, titanium (and varnish) N (except aluminum, silica) 
Types of dust exposure, organic     
 Bakery flour, chlorine, cleaning products, cotton, fertilizer, agricultural dust, fumes, gasoline, hydrofluoric acid, parrots, pigeons, petroleum, sawdust N or Nc 
Miscellaneous conditions     
 Osteopetrosis caused by TCIRG1 gene mutation Yc 
 Total anomalous pulmonary venous return with coarctation of the aorta (single case) N, Yc Y, pulmonary hypoplasia 
Disease Causes of PAPManifestation Reported in Neonates, ChildrenaGenetically CausedbExposure CausedHistologically Intact Lung Interstitial Tissue, Primarily Alveolar Filling
Surfactant-dysfunction syndromes     
 SFTPB mutations 
 SFTPC mutations 
 ABCA3 mutations 
 TTF1 mutations 
Impaired GM-CSF signaling     
 GM-CSF receptor α chain of mutations 
 Turner syndrome with heterozygous GM-CSF receptor α chain mutations 
 GM-CSF receptor β chain mutations 
 Autoimmune GM-CSF antibodies 
Hematologic disorders and other malignancies     
 GATA2 deficiency 
 MDS (most common) 
 Chronic myelomonocytic leukemia n.k. 
 Acute lymphatic leukemia Yc 
 Congenital dyserythropoietic anemia 
 Fanconi’s anemia 
 Hemophagocytic lymphohistiocytosis  
 Sideroblastic anemia Nc Yc 
 Primary myelofibrosis, chronic lymphocytic leukemia, cutaneous T-cell lymphoma, thymic alymphoplasia, adult T-cell leukemia and/or lymphoma, idiopathic thrombocytopenic purpura, aplastic anemia, chronic myeloid leukemia, overlap myeloproliferative neoplasm, acute myeloid leukemia, hairy-cell leukemia, multiple myeloma and/or plasmocytoma, polycythemia vera, essential thrombocythemia, amyloidosis, Hodgkin disease, non-Hodgkin lymphoma, adenocarcinoma, glioblastoma, melanoma, small-cell lung carcinoma, clear-cell renal cell carcinoma, mesothelioma Y or n.k. Nc Yc or n.k. 
Systemic diseases     
 Lysinuric protein intolerance (SLC7A7 mutation) Y (50%), N (50%) 
 MARS mutations 
 Niemann Pick type C2 
 Niemann Pick type B n.d. 
 Bone marrow, stem cell transplant Yc 
 Systemic lupus erythematosus, granulomatosis with polyangiitis, microscopic polyangiitis, membranous nephropathy, dermatomyositis with interstitial lung disease, coincident in many other rheumatologic diseases and interstitial lung diseases, lung transplant Yc or N 
Immunologic diseases     
 Adenosine deaminase deficiency 
 Agammaglobulinemia Yc n.k. 
 DiGeorge syndrome type 2 n.d. 
 Monoclonal gammopathy 
 Selective immunoglobulin A deficiency 
 Severe combined immunodeficiency 
 X-linked hyper–immunoglobulin M syndrome n.d. 
Infections     
 Cytomegalovirus N or Nc 
 Epstein-Barr virus N or Nc 
 HIV N or Nc 
M tuberculosis N or Nc 
 Atypical mycobacteria N or Nc 
Nocardia N or Nc 
P jiroveci N or Nc 
Drugs     
 Chemotherapy, antineoplastic 
 Busulfan, sirolimus, everolimus, tyrosine kinase inhibitors (including imatinib, nilotinib, and dasatinib), mycophenolate and cyclosporine combination, smoked fentanyl patches, leflunomide, hydrofluoric acid (inhaled) 
Types of dust exposure, inorganic     
 Aluminum, cement, marble, indium, iron, silica and silica-leaking breast implants, tin, titanium (and varnish) N (except aluminum, silica) 
Types of dust exposure, organic     
 Bakery flour, chlorine, cleaning products, cotton, fertilizer, agricultural dust, fumes, gasoline, hydrofluoric acid, parrots, pigeons, petroleum, sawdust N or Nc 
Miscellaneous conditions     
 Osteopetrosis caused by TCIRG1 gene mutation Yc 
 Total anomalous pulmonary venous return with coarctation of the aorta (single case) N, Yc Y, pulmonary hypoplasia 

Y or N indicates highest likelihood and/or firm knowledge from publications; frequently extensive data are lacking and these indications are based on estimation. n.d., not done; n.k., not known.

a

Manifestation of PAP is proven in this age group (not of disease).

b

May be germline or clonal in monocytes.

c

Indicates uncertainty.

FIGURE 2

Schematic of age dependency of the manifestation of various alveolar pulmonary proteinosis forms and qualitative estimates of age at clinical manifestation in the major groups of PAP. Note the size of the graphs does not represent their absolute frequency. Autoimmune PAP represents ∼90% of all cases if age of manifestation is not considered.

FIGURE 2

Schematic of age dependency of the manifestation of various alveolar pulmonary proteinosis forms and qualitative estimates of age at clinical manifestation in the major groups of PAP. Note the size of the graphs does not represent their absolute frequency. Autoimmune PAP represents ∼90% of all cases if age of manifestation is not considered.

PAP is a rare disease complex that affects <5 cases per 100 000 inhabitants.3 The first description of PAP4 as well as the vast majority of data on treatment and prognosis are related to autoimmune PAP. Most pediatric cases are nonautoimmune PAP and distribute almost evenly among many different entities. In childhood, there is a bimodal age distribution; some conditions manifest in the neonatal period (Fig 2, upper portion), whereas others manifest during infancy and childhood.

The expansion of the surfactant pool can be recognized in histopathological specimens. The alveoli are filled with eosinophilic, acellular, and finely granular material (Fig 1E). Clefts made of cholesterol can be found (Fig 1F).4,5 Sometimes, detached type II pneumocytes, foamy macrophages, or neutrophil granulocytes as well as lamellar bodies of normal lungs can be identified (Fig 1 C and D).

Whereas the intra-alveolar filling does not differentiate between different forms of PAP, histopathological examination of the alveolar wall structures may be normal (Fig 1E) or abnormal. The interstitial space is mostly normal; however, several forms show widening from cells or fibrosis.4,6 When the surfactant dysfunction syndromes were first described, the term “congenital alveolar proteinosis” was used in such newborns.7 Particularly in children, the PAP histopattern presents in combination with additional histopatterns,8,9 such as increased cellularity from hyperplasia of type II pneumocytes and collagen fibers or alveolar macrophages.10 In cohort studies in ∼50% to 60% of such biopsies, the PAP histopattern was found,11,12 and the detection rate was higher in biopsies conducted during the early disease phase.12 In TTF1 deficiency, pulmonary histology may also show the PAP pattern in addition to the nonspecific interstitial pneumonia pattern and defects in lung development.13 

PAP presents in 2 types: Most frequently (70%–90% of PAP cases), patients develop slowly increasing dyspnea (initially on exertion) and dry coughing.2 In PAP caused by granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Ra) mutations, 70% had dyspnea at presentation, 15% had tachypnea, 30% had clubbing, 35% had global respiratory failure, and 15% were intubated and ventilated.14 

Less frequently (30%–50% of PAP cases), fever, weight loss, fatigue, and chest pain are observed (numbers are for autoimmune PAP2). Among the children, 45% had infections (mycoplasma, influenza, or respiratory syncytial virus) before PAP because of GM-CSF-Ra mutations, 26% had a cough, 5% had a fever, and 36% had failure to thrive.14 PAP caused by affected surfactant production typically presents with idiopathic respiratory distress syndrome (RDS) or idiopathic pulmonary hypertension in a mature neonate.

The presence of diffuse bilateral mostly symmetrical alveolar, sometimes patchy infiltrates with air bronchograms give first clues to interstitial lung disease due to alveolar filling (Fig 1A). Usually, the perimediastinal regions are more affected than the subpleural regions. Persistence of the cloudy infiltrates after antibiotic treatment is a frequent observation. In neonates with acute RDS, all radiologic stages (including a “white lung”) may develop progressively.

Adults and children who are old enough to perform spirometry have a restrictive pattern with small lung volumes and reduced diffusing capacity of the lung for carbon monoxide, although initial tests may also be normal.6 Of interest, carbon dioxide elimination rarely is a problem in the face of significant hypoxemia. At presentation, 55% of the patients with PAP caused by GM-CSF-Ra mutations had hypoxemia,14 whereas in adults with autoimmune PAP, hypoxemia at rest was present in approximately one-third and during exercise in more than half of the patients.3 With treatment of the alveolar filling, abnormal lung function tests are expected to be reversible; if they are not, then additional pathology should be suspected.

Autoantibodies Against GM-CSF

In all cases of suspected PAP, these should be searched. In adults, >90% of the case results are positive.15,19 Serology has excellent sensitivity and specificity.20 Autoimmune PAP occurs in children, and it needs to be differentiated from GM-CSF antibodies in healthy individuals at low levels and patients with autoinflammatory diseases such as colitis, Crohn disease, malignancies,21 or PAP caused by dust exposure.22,24 Because there is a close correlation between antibody level and PAP development,25,26 a close link to pulmonary manifestation is mandatory when searching for these autoantibodies.

Lactate Dehydrogenase

Lactate dehydrogenase is increased in 82% of patients with autoimmune PAP.6 Of interest, this marker readily responds to changes in disease severity and improves after therapeutic lavages.6,27,29 

Similarly, in serum carcinoembryonic antigen, levels of the surfactant proteins A, D,30 and KL-6 are markers of disease activity, which can be used to monitor its course. Serum KL-6 accurately predicts disease progression in autoimmune PAP.29 

In children and adults, autoantibodies including antinuclear antibody, antineutrophil cytoplasmic antibody (eg, cANCA/PR3 and pANCA/MPO), anti–double-stranded DNA, anticentromere, cyclic citrullinated peptide, extractable nuclear antigen (eg, anti–SS-A [Ro], anti–SS-B [La], anti-RNP, anti–Jo-1, anti-Sm, and Scl-70), and rheumatoid factor should be assessed.

Global and specific immunologic function tests need to be done to diagnose underlying immune deficiencies (Table 2).

In neonates with the characteristic clinical and radiologic presentation (and after the exclusion of other, more frequent causes), testing for mutations in SFTPB, SFTPC, ABCA3, and TTF1 is recommended (www.childeu.net). In infants and older patients, analysis for mutations in SFTPC, ABCA3, CSF2RB, CSF2RA, GATA2, SLC7A7, methionyl–transfer RNA synthetase (MARS), NPC2, and possibly NPB (see Table 2) should be done when appropriate.

With standardized diagnostics, lavage return typically gets milkier on visual inspection. May-Grünwald Giemsa staining shows cellular debris, acellular globules, and foamy macrophages (Fig 1 C and D). In adults with PAP, experienced centers can make the diagnosis by bronchoalveolar lavage (BAL) in 70% to 74% of the patients with acquired PAP.3,16 BAL fluid should be investigated for infections (Table 2).

Crazy paving pattern, which combines ground-glass opacity (a hazy increase in lung opacity that does not obscure the underlying vessels or bronchial structures) and a superimposed reticular pattern (Fig 1B), is characteristic for PAP but not specific to it. Its differential diagnosis includes edema, hemorrhage, acute RDS, acute interstitial pneumonia, eosinophilic pneumonia, diffuse alveolar damage, pneumonias caused by Pneumocystis jirovecii, cytomegalovirus, adenovirus, mycoplasma, bacteria, tuberculosis, nonspecific interstitial pneumonitis, organizing pneumonia, eosinophilic granulomatosis with polyangiitis, radiation pneumonitis, drug-related pneumonitis, sarcoidosis, lipoid pneumonia, and Niemann-Pick disease, among others.31 

It must be kept in mind that computed tomography (CT) imaging in neonates and infants with high breathing rates is very demanding and needs a lot of technical detail to obtain high-quality scans. Therefore, CT scanning should be reserved for the specialized center performing diagnostic imaging in temporal relation to the lung biopsy.

In infants, biopsies are done as open biopsies or sometimes thoracoscopically. In adults and older children, transbronchial biopsies can be done during a bronchoscopy. Lung biopsies were performed in ∼80% of the children to make the diagnosis of PAP.14 In children, reference reading of the biopsy specimens by a specialized pathologist is highly recommended and can be organized via different networks, such as the European Management Platform for Children’s Interstitial Lung Diseases (www.childeu.net).

As with all rare lung diseases, a high degree of suspicion is necessary when taking the diagnosis of PAP into consideration. Red flags in neonates and young infants are nonimproving or slowly improving respiratory distress in the mature neonate (ie, if persistent after 1 or more weeks and excluding cardiac, infectious, central, or metabolic causes). In older infants and children, red flags include slowly developing dyspnea or dyspnea persisting after resolution of an acute respiratory tract infection, together with diffuse alveolar infiltrates on the chest radiograph.

Blood tests are done first, followed by a bronchoscopy with standardized lavage and transbronchial biopsy in most patients (Table 2). When the results obtained are not definitively diagnostic, a lung biopsy is needed to firmly establish the diagnosis.

Categorization of PAP forms according to suspected etiology is helpful for therapy, although frequently the underlying etiology cannot be identified precisely (Table 2).

Mutations in SFTPB, SFTPC, ABCA3, and TTF1 may present with the histologic PAP pattern mostly during the neonatal period,7,9,32,34 when secretion of surfactant is normally increased more than 10-fold35,36 and sometimes later as well but to a smaller degree.37,38 At the same time, the removal of aberrant surfactant may be impaired because of volume- and barotrauma-induced lung injuries,39 and physiologically increased removal may be disturbed, all of which lead to swamped macrophage-removal systems.40 If patients survive, the PAP pattern slowly disappears and is replaced by a more fibrotic pattern of lung disease.10,12 Similarly, such a sequence has been demonstrated for MARS mutations (Table 2).41 Today, fortunately, conditions are diagnosed genetically, which eliminates the need for a biopsy.

GM-CSF is critical for the regulation of surfactant homeostasis, alveolar macrophage maturation and phagocytosis, lung host defense, and innate immunity.42 Disrupted GM-CSF signaling by neutralizing GM-CSF autoantibodies is the cause of the vast majority of adult cases of PAP.43 This autoimmune disease, in the beginning called “adult idiopathic PAP” or “primary PAP,” is now called “autoimmune PAP”44 and can also occur in children.

Interruption of GM-CSF signaling by hereditary factors, such as mutations in the α (CD116) or β (CD131) chain of the GM-CSF receptor (which is also used by the interleukin-3 and interleukin-5 receptors),45,46 will all lead to hereditary PAP forms. These cases most likely manifest in childhood but may also be diagnosed in adults.14,47,48 

Hematologic disorders widely contribute to PAP causes, both in children49 and adults50 (Table 2). Prolonged neutropenia and reduction of alveolar macrophages by myeloablative chemotherapy or leukemic infiltration have been implicated in the pathogenesis of pediatric PAP.51 Autoantibodies against GM-CSF may be elevated in BAL fluid, whereas in sera, they were below sensitivity.52 Among patients with GATA2 haploinsufficiency, ∼20% develop PAP, often in association with familial myelodysplastic syndrome (MDS) (84%); acute myeloid leukemia (14%); chronic myelomonocytic leukemia (8%); severe infections (including mycobacterial and fungal infections); human papillomavirus– or Epstein-Barr virus–associated tumors; venous thrombosis; lymphedema; sensorineural hearing loss; miscarriage; and hypothyroidism.53 

Lysinuric protein intolerance is an inherited defect of cationic amino acid (lysine, arginine, and ornithine) transport at the basolateral membrane of epithelial cells and is caused by mutations in SLC7A7.54 The condition can be considered a disorder of bone marrow–derived monocytes differentiating into dysfunctional alveolar macrophages.55 Lung involvement was observed in 71% of children, which showed fibrosis on histopathology or CT scan in addition to PAP.56 

MARS deficiency by missense mutations leads to PAP, which is endemic on Réunion Island in the Indian Ocean.41 The disease starts in infancy with PAP then frequently progresses to pulmonary fibrosis with cholesterol granulomas.57 

Niemann-Pick diseases are hereditary neurovisceral lysosomal lipid-storage disorders, which can present with respiratory symptoms at any age. In type C2, PAP may be caused by reduced NPC2 protein expression in alveolar macrophages. The composition and function of surfactants in this form of PAP are abnormal.58 PAP has been reported in Niemann-Pick type B; however, it was unclear if this was a coincidence with autoimmune PAP.59 

Of infants with adenosine deaminase deficiency, ∼50% have PAP with typical lung pathology and without additional abnormalities, except for coincident identification of various pathogens.60 For several other immunologic diseases, cases of PAP have been reported (Table 2).

In a recent review of the literature, all reported cases of PAP and opportunistic infections between 1950 and 2010 were searched, and 75 cases were reviewed. Forty-three percent of the patients had nocardia infection, 37% had mycobacterial infection (of those, 75% were Mycobacterium tuberculosis), and 20% had fungal infections.61 Opportunistic infections can either precede or follow a diagnosis of PAP. PAP should be considered in apparently immunocompetent patients who present with an opportunistic infection and diffuse alveolar infiltrates. For Pneumocystis and the viruses indicated in Table 2, individual cases of PAP were reported.

Although PAP caused by dust exposure has not been reported in children, a detailed occupational and environmental history has to be taken for diagnoses in every new patient regardless of age. In adults, between 23% and 39% of patients with PAP were exposed to compounds shown to induce PAP.2,3 

Any disease involving the lungs may potentially cause PAP, and thus PAP needs to be included in the differential diagnosis. Alternatively, PAP could be coincident with another lung disease; thus diagnostic workup for different causes is mandatory.62 

WLL remains the current standard of care for PAP. Over the years, the technique has been improved in dedicated centers.6,63,64 Bilateral sequential WLL in the same treatment session is aimed at, but is dependent on, the clinical condition of the patient. In adults and older children in whom a double-lumen tube can be safely placed repetitively, one of the lungs is ventilated and the other is filled with aliquots of warmed saline by infusion with gravity or gentle pressure via a 50-mL syringe. After recovery of the fluid, the next washing cycle begins.15 For smaller children or infants, we have developed and extensively tested a novel technique.65 In this technique, 1 lung is occluded with a pulmonary artery balloon catheter (which is continuously watched with a small endoscope for its tight fit into the bronchus) and used for lavage of that lung, and the other lung is ventilated.27,66 Indication for WLL is given when respiratory symptoms impair the quality of life (eg, oxygen treatment is necessary), development of weight is impaired, or lung function deviates from normal.

Sometimes, severe hypoxemia precludes immediate WLL, and patients need to be supported by extracorporeal membrane oxygenation to allow for the procedure and recovery or to have it serve as a bridge to the lung transplant.65 Several patients with PAP (in its various forms) have had a lung transplant. However, the recurrence of PAP disease has been reported in some patients.67,68 

Each etiologic group of PAP has its own clinical course, treatments and outcome, and due to rarity of cases, has not been described in detail for most.

In autoimmune PAP, historical comparisons suggest that patients before the advent of therapeutic lung lavages had higher mortality than after therapeutic lung lavages had become an established treatment.6 In ∼5% to 10% of patients, spontaneous remission may occur,3,6 and in ∼50%, only 1 WLL treatment is necessary for long-term remission.2 Mortality during follow-up in large centers is <10%.16 WLL is the standard treatment; however, additional options have been developed.69 To overcome the endogenous GM-CSF autoantibodies that neutralize GM-CSF, recombinant and exogenous GM-CSF has been tested.69,70 Administration of aerosolized GM-CSF appeared more attractive and more effective in a controlled prospective trial of 50 patients with a response rate of 62%.71,72 Of interest are studies with a goal of decreasing the GM-CSF amounts necessary by combining it with WLL.73 Another approach combined WLL and plasmapheresis to reduce the circulating level of GM-CSF autoantibodies; however, the results for clinical efficacy are controversial.74,75 Rituximab, a humanized B-lymphocyte–depleting antibody, is able to reduce neutralizing GM-CSF autoantibodies and showed improved lung function in high-resolution CT scans.2,76,78 There is no rationale for all the latter approaches in nonautoimmune PAP.

WLL treatment is the mainstay of therapy in patients with receptor mutations and has been used in the majority of cases reported so far (78%).14 In some patients with the same mutation, treatment every 4 to 8 weeks over several years was necessary,27 whereas in others, only few or no lavages were sufficient in maintaining a stable clinical course.

The protein amounts recovered from the lungs were similar to those in adults with autoimmune PAP79 (Fig 3). WLLs within a few days are less efficient than lavages repeated at least 2 or more weeks apart (Fig 3C). The amount of protein recovered over time changes with disease activity and with the lavage volume necessary until the effluent is clear (Fig 3 D and E). The outcome depends mainly on WLL treatment, which was successfully performed in ∼90% of all published cases.14 In these forms of PAP, hematopoietic stem cell transplants may be successful to correct a defect that is localized in alveolar macrophages. A recurrence of PAP in such a child (M. Castelle, MD, personal communication, 2015) or an inadvertent outcome have been reported45; however, this scenario needs to be investigated further.

FIGURE 3

Analytical results of WLL effluents in patients with different molecularly defined forms of PAP. A, The total amount of protein removed from the left lung (LL) and right lung (RL) during repetitive WLL. Each dot indicates a single WLL. B, Washout kinetics of protein concentration in lavages from different patients are shown. GM-CSF-Ra #1, n = 26; GM-CSF-Ra #2, n = 28; MDS DiGeorge, n = 9; NPC2, n = 4; SP-C, n = 11. C, WLL protein removed varies with intervals used until next lavage. From day 0 through 180, lavage intervals were 1 to 4 days, then 4 weeks, then 1 to 4 days, etc. Note the low amount of protein removed after a short interval from the previous lavage. From day 180 through 540, lavage intervals were always at least 2 weeks and usually 3 to 4 weeks. D, Over-time variation of volume necessary until clear effluent is shown. E, Over-time variation of protein washed out is shown. The detailed descriptions of the PAP cases used here can be found for GM-CSF-Ra -1 in Griese et al,27 for GM-CSF-Ra -2 in Hildebrandt et al14 (subject I), for NPC2 in Reunert et al80 (subject 1), for SP-C (I73T) in Brasch et al,8 for SP-C (C121F) in van Hoorn et al,81 and for MDS DiGeorge2 in Griese et al49 (subject 7). Ethics approval is documented in the individual studies.

FIGURE 3

Analytical results of WLL effluents in patients with different molecularly defined forms of PAP. A, The total amount of protein removed from the left lung (LL) and right lung (RL) during repetitive WLL. Each dot indicates a single WLL. B, Washout kinetics of protein concentration in lavages from different patients are shown. GM-CSF-Ra #1, n = 26; GM-CSF-Ra #2, n = 28; MDS DiGeorge, n = 9; NPC2, n = 4; SP-C, n = 11. C, WLL protein removed varies with intervals used until next lavage. From day 0 through 180, lavage intervals were 1 to 4 days, then 4 weeks, then 1 to 4 days, etc. Note the low amount of protein removed after a short interval from the previous lavage. From day 180 through 540, lavage intervals were always at least 2 weeks and usually 3 to 4 weeks. D, Over-time variation of volume necessary until clear effluent is shown. E, Over-time variation of protein washed out is shown. The detailed descriptions of the PAP cases used here can be found for GM-CSF-Ra -1 in Griese et al,27 for GM-CSF-Ra -2 in Hildebrandt et al14 (subject I), for NPC2 in Reunert et al80 (subject 1), for SP-C (I73T) in Brasch et al,8 for SP-C (C121F) in van Hoorn et al,81 and for MDS DiGeorge2 in Griese et al49 (subject 7). Ethics approval is documented in the individual studies.

Several infants previously labeled as having congenital PAP have been treated with limited success or without success by WLLs.6 An infant with PAP likely caused by a surfactant-dysfunction disorder was treated with liquid ventilation.82 An infant girl with familial congenital PAP who was not responsive to lavages recovered 3 times from respiratory failure after intravenous immunoglobulin G administration; a mutation in SFTPB was excluded.83 PAP reports from children with molecularly defined surfactant-dysfunction disorders are scarce. In our cohort of patients with SFTPC mutations, we reported 5 patients suffering from PAP who have been treated with WLLs.12 No clinical success was observed in a child with mutation C121F,81 whereas reasonable success was observed in a patient with severe course and mutation I73T.8 The amount of protein recovered in these conditions was much lower than in other PAPs (Fig 3). This clearly indicates that in addition to alveolar filling with surfactants, other disease mechanisms play a major role for respiratory failure.84 We are not aware of WLLs in patients with mutations in SFTPB, ABCA3, or TTF1. The outcomes of these patients are only initially related to PAP severity; and later, pulmonary fibrosis predominates.

These patients present with respiratory insufficiency and fever in 24% of cases, particularly in patients with prolonged neutropenia from chemotherapy,85 which demands suspicion for this complication. Initial attempts to treat PAP caused by MDS with WLLs were not successful,52 although later survival improved.50 WLL may be used as a bridge to bone marrow transplants, as reported for an adult patient86 and also recently for a small 6-year-old child, for whom we performed 14 WLLs over a period of 1 year until a suitable donor was found. PAP resolved rapidly after the transplant.49 The amount of protein recovered in this condition was similar to the amount in autoimmune PAP or GM-CSFR mutations (Fig 3).

Xue et al87 described a patient with PAP and MDS due to idic(20q–) who was too sick to be lavaged. Consider a timely transfer of patients to centers experienced in WLL technique.

An important report indicates that empirical corticosteroid treatment in PAP secondary to MDS is a risk factor for infection and contributes to poor prognosis.88 We had a similar experience in a patient with PAP caused by a GM-CSF-Ra mutation,27 which suggests the need for caution with immunosuppressive therapy in these conditions. In an adult patient with PAP caused by GATA2 deficiency and infection with Mycobacterium avium intracellulare, WLL was not helpful.49 

The outcome of these conditions is strongly determined by the underlying condition and is generally poorer than in autoimmune PAP. Median survival time was only 20 months in a Japanese cohort50,88; in another cohort, the death rate in such subjects was ∼50%.16 The causes of death were hematologic disease (33%), respiratory insufficiency (25%), infection (25%), and unspecified bleeding (13%).

Lysinuric Protein Intolerance (SLC7A7 Mutation)

Children present with failure to thrive and gastrointestinal symptoms from pancreatic insufficiency. In 2 children <2 years old, WLLs were performed without efficacy.56 However, at least 1 case of long-lasting remission after WLL has been described in a PAP associated with lysinuric protein intolerance.55 This suggests that in selected cases, WLL may be helpful and could be attempted by experienced specialists. GM-CSF therapy may be an additional option.89,90 

MARS Mutations

Recently, we identified biallelic missense mutations in MARS as the cause of a specific form of pediatric PAP.41 Patients develop PAP early in their disease course, and several received empirical WLLs.57 An analysis of the cohort of 34 patients suggested that WLL did not have an influence on survival rates.57 The protein content, the composition, and the concentration of surfactant proteins A, B, C, and D as well as lipid composition and material removed from the lungs were not different from autoimmune PAP (M.G., unpublished observations). Overall outcome of this condition is poor, with a median age at death of ∼17 years.57 

Niemann Pick Type C2

Early lung disease in patients with Niemann-Pick disease type C2 may be associated with PAP.58,80 In Griese et al58 and Reunert et al,80 empirical treatment with WLL in those patients was only transiently effective, reducing the need for oxygen and improving imaging. The amount of protein recovered was low, which also differentiated this form of PAP from the others (Fig 3 A and B). Such treatments may be helpful in less severe cases or when bridging to other treatments is the goal. The outcome is frequently determined by other organ complications from the underlying condition.

Immunologic Diseases

PAP caused by immunologic diseases is best treated by correcting the underlying defect if possible60,91 or by symptomatic treatment (eg, immunoglobulin therapy). A 15-year-old boy with agammaglobulinemia and recurrent PAP was treated with additional WLL without any complications.92 A 6-year-old child we treated with bridging WLL until a successful stem cell transplant was performed had underlying syndromic immunodeficiency associated with DiGeorge syndrome type 2.49 

Infection

There is an ongoing “chicken or the egg” debate as to whether specific infections in PAP are causes or symptoms, which may be clarified by therapeutic intervention. The case of a 3-year-old boy with histologically proven PAP, a high load of Epstein-Barr virus, and a response to ganciclovir treatment supports the view that specific infections may induce PAP.93 Early WLL may reduce complications by infections from nocardiosis or mucormycosis.

Drugs

After 9 months of treatment with sirolimus, PAP was diagnosed in a heart-lung transplant patient. The drug was discontinued, GM-CSF therapy was started, and 3 WLLs were performed to relieve respiratory distress.94 A patient treated with the disease-modifying anti–rheumatoid arthritis drug leflunomide developed PAP (verified by a biopsy specimen) and was treated with WLL and subsequently discontinued taking the leflunomide.95 

Dust Exposure

WLL may be symptomatically beneficial, but stopping exposure is pivotal. WLL may be ineffective after long-standing or extensive exposure, as additional pathologies such as cholesterol granuloma and fibrosis may have developed.96 

The label PAP is merely an overall description of alveolar filling with surfactant. It is very important to classify all cases definitively according to etiology and on the basis of new knowledge generated by translational research. PAP of all etiologies known may be observed in children. The diagnostic algorithm as well as treatment options strongly depend on age at presentation (Fig 2, Table 2).

     
  • BAL

    bronchoalveolar lavage

  •  
  • CT

    computed tomography

  •  
  • GM-CSF

    granulocyte-macrophage colony-stimulating factor

  •  
  • MARS

    methionyl–transfer RNA synthetase

  •  
  • MDS

    myelodysplastic syndrome

  •  
  • PAP

    pulmonary alveolar proteinosis

  •  
  • RDS

    respiratory distress syndrome

  •  
  • WLL

    whole-lung lavage

FUNDING: Funded by the German Center for Lung Research, DZL 2.0, the European Management Platform for Children’s Interstitial Lung Disease (FP7, 305653), and E-Rare 2016.

This review is based on my experience as a pediatric pulmonologist caring for children of all ages with PAP, my experience as a researcher interested in PAP running a laboratory for the determination of GM-CSF autoantibodies, and a review of the literature on PAP. Diagnosis and treatment of PAP are the result of a team approach and would not have been possible without the many people involved, including T. Nicolai, K. Reiter, C. Schön, F. Hoffmann, A. Schams, T. Wesselak, E. Kaltenborn, M. Kappler, J. Ripper, J. Hildebrandt, P. Lohse, F. Brasch, M. Hofmann, I. Eckerlein, and the many coworkers on published research projects and the cooperators in internal medicine and pulmonology including M. Luisetti, I. Campo, S.A. Papiris, E.D. Manali, U. Costabel, and F. Bonella. Finally, I thank the families and children for their longstanding confidence. I apologize to other researchers of many excellent articles and reviews of the condition who were not included because of limited space.

1
Griese
M
.
Pulmonary surfactant in health and human lung diseases: state of the art.
Eur Respir J
.
1999
;
13
(
6
):
1455
1476
[PubMed]
2
Bonella
F
,
Theegarten
T
,
Guzman
J
,
Costabel
U
.
Alveolar lipoproteinosis syndromes.
Eur Respir Mon
.
2011
;
54
:
171
186
3
Inoue
Y
,
Trapnell
BC
,
Tazawa
R
, et al;
Japanese Center of the Rare Lung Diseases Consortium
.
Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan.
Am J Respir Crit Care Med
.
2008
;
177
(
7
):
752
762
[PubMed]
4
Rosen
SH
,
Castleman
B
,
Liebow
AA
.
Pulmonary alveolar proteinosis.
N Engl J Med
.
1958
;
258
(
23
):
1123
1142
[PubMed]
5
Travis
WD
,
Colby
TV
,
Koss
MN
,
Rosado-de-Christenson
ML
,
Müller
NL
,
King
TE
.
Non-Neoplastic Disorders of the Lower Respiratory Tract
.
Washington, DC
:
American Registry of Pathology
;
2002
6
Seymour
JF
,
Presneill
JJ
.
Pulmonary alveolar proteinosis: progress in the first 44 years.
Am J Respir Crit Care Med
.
2002
;
166
(
2
):
215
235
[PubMed]
7
Nogee
LM
,
de Mello
DE
,
Dehner
LP
,
Colten
HR
.
Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis.
N Engl J Med
.
1993
;
328
(
6
):
406
410
[PubMed]
8
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
39
[PubMed]
9
Brasch
F
,
Schimanski
S
,
Mühlfeld
C
, et al
.
Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency.
Am J Respir Crit Care Med
.
2006
;
174
(
5
):
571
580
[PubMed]
10
Kröner
C
,
Wittmann
T
,
Reu
S
, et al
.
Lung disease caused by ABCA3 mutations.
Thorax
.
2017
;
72
(
3
):
213
220
[PubMed]
11
Thouvenin
G
,
Abou Taam
R
,
Flamein
F
, et al
.
Characteristics of disorders associated with genetic mutations of surfactant protein C.
Arch Dis Child
.
2010
;
95
(
6
):
449
454
[PubMed]
12
Kröner
C
,
Reu
S
,
Teusch
V
, et al
.
Genotype alone does not predict the clinical course of SFTPC deficiency in paediatric patients.
Eur Respir J
.
2015
;
46
(
1
):
197
206
[PubMed]
13
Hamvas
A
,
Deterding
RR
,
Wert
SE
, et al
.
Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1.
Chest
.
2013
;
144
(
3
):
794
804
[PubMed]
14
Hildebrandt
J
,
Yalcin
E
,
Bresser
HG
, et al
.
Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis.
Orphanet J Rare Dis
.
2014
;
9
(
1
):
171
[PubMed]
15
Bonella
F
,
Bauer
PC
,
Griese
M
,
Wessendorf
TE
,
Guzman
J
,
Costabel
U
.
Wash-out kinetics and efficacy of a modified lavage technique for alveolar proteinosis.
Eur Respir J
.
2012
;
40
(
6
):
1468
1474
[PubMed]
16
Bonella
F
,
Bauer
PC
,
Griese
M
,
Ohshimo
S
,
Guzman
J
,
Costabel
U
.
Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients.
Respir Med
.
2011
;
105
(
12
):
1908
1916
[PubMed]
17
Manali
ED
,
Papadaki
G
,
Konstantonis
D
, et al
.
Cardiovascular risk in pulmonary alveolar proteinosis.
Expert Rev Respir Med
.
2016
;
10
(
2
):
235
240
[PubMed]
18
Papiris
SA
,
Tsirigotis
P
,
Kolilekas
L
, et al
.
Pulmonary alveolar proteinosis: time to shift?
Expert Rev Respir Med
.
2015
;
9
(
3
):
337
349
[PubMed]
19
Latzin
P
,
Tredano
M
,
Wüst
Y
, et al
.
Anti-GM-CSF antibodies in paediatric pulmonary alveolar proteinosis.
Thorax
.
2005
;
60
(
1
):
39
44
[PubMed]
20
Uchida
K
,
Nakata
K
,
Carey
B
, et al
.
Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis.
J Immunol Methods
.
2014
;
402
(
1–2
):
57
70
[PubMed]
21
Sergeeva
A
,
Ono
Y
,
Rios
R
,
Molldrem
JJ
.
High titer autoantibodies to GM-CSF in patients with AML, CML and MDS are associated with active disease.
Leukemia
.
2008
;
22
(
4
):
783
790
[PubMed]
22
Nakano
M
,
Omae
K
,
Tanaka
A
, et al
.
Causal relationship between indium compound inhalation and effects on the lungs.
J Occup Health
.
2009
;
51
(
6
):
513
521
[PubMed]
23
Noguchi
S
,
Eitoku
M
,
Kiyosawa
H
,
Suganuma
N
.
Fibrotic gene expression coexists with alveolar proteinosis in early indium lung.
Inhal Toxicol
.
2016
;
28
(
9
):
421
428
[PubMed]
24
Omae
K
,
Nakano
M
,
Tanaka
A
,
Hirata
M
,
Hamaguchi
T
,
Chonan
T
.
Indium lung–case reports and epidemiology.
Int Arch Occup Environ Health
.
2011
;
84
(
5
):
471
477
[PubMed]
25
Nei
T
,
Urano
S
,
Itoh
Y
, et al
.
Light chain (κ/λ) ratio of GM-CSF autoantibodies is associated with disease severity in autoimmune pulmonary alveolar proteinosis.
Clin Immunol
.
2013
;
149
(
3
):
357
364
[PubMed]
26
Arai
T
,
Hamano
E
,
Inoue
Y
, et al
.
Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF.
Respir Med
.
2004
;
98
(
12
):
1227
1230
[PubMed]
27
Griese
M
,
Ripper
J
,
Sibbersen
A
, et al
.
Long-term follow-up and treatment of congenital alveolar proteinosis.
BMC Pediatr
.
2011
;
11
:
72
[PubMed]
28
Seymour
JF
,
Doyle
IR
,
Nakata
K
, et al
.
Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis.
Thorax
.
2003
;
58
(
3
):
252
257
[PubMed]
29
Bonella
F
,
Ohshimo
S
,
Miaotian
C
,
Griese
M
,
Guzman
J
,
Costabel
U
.
Serum KL-6 is a predictor of outcome in pulmonary alveolar proteinosis.
Orphanet J Rare Dis
.
2013
;
8
:
53
[PubMed]
30
Griese
M
,
Lorenz
E
,
Hengst
M
, et al
.
Surfactant proteins in pediatric interstitial lung disease.
Pediatr Res
.
2016
;
79
(
1–1
):
34
41
[PubMed]
31
Webb
WR
,
Müller
NL
,
Naidich
DP
.
High Resolution CT of the Lung
. 4th ed.
Netherlands
:
Wolter Kluver
;
2009
32
Nogee
LM
,
Dunbar
AE
 III
,
Wert
SE
,
Askin
F
,
Hamvas
A
,
Whitsett
JA
.
A mutation in the surfactant protein C gene associated with familial interstitial lung disease.
N Engl J Med
.
2001
;
344
(
8
):
573
579
[PubMed]
33
Kleinlein
B
,
Griese
M
,
Liebisch
G
, et al
.
Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis.
Arch Dis Child Fetal Neonatal Ed
.
2011
;
96
(
6
):
F453
F456
[PubMed]
34
Wirtz
HR
,
Dobbs
LG
.
Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells.
Science
.
1990
;
250
(
4985
):
1266
1269
[PubMed]
35
Wright
JR
,
Dobbs
LG
.
Regulation of pulmonary surfactant secretion and clearance.
Annu Rev Physiol
.
1991
;
53
:
395
414
[PubMed]
36
Griese
M
,
Gobran
LI
,
Rooney
SA
.
Ontogeny of surfactant secretion in type II pneumocytes from fetal, newborn, and adult rats.
Am J Physiol
.
1992
;
262
(
3 pt 1
):
L337
L343
[PubMed]
37
Young
LR
,
Deutsch
GH
,
Bokulic
RE
,
Brody
AS
,
Nogee
LM
.
A mutation in TTF1/NKX2.1 is associated with familial neuroendocrine cell hyperplasia of infancy.
Chest
.
2013
;
144
(
4
):
1199
1206
[PubMed]
38
Tredano
M
,
Griese
M
,
Brasch
F
, et al
.
Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease.
Am J Med Genet A
.
2004
;
126A
(
1
):
18
26
[PubMed]
39
Robertson
B
,
Curstedt
T
,
Herting
E
,
Sun
B
,
Akino
T
,
Schäfer
KP
.
Alveolar-to-vascular leakage of surfactant protein A in ventilated immature newborn rabbits.
Biol Neonate
.
1995
;
68
(
3
):
185
190
[PubMed]
40
Griese
M
,
Beck
J
,
Feuerhake
F
.
Surfactant lipid uptake and metabolism by neonatal and adult type II pneumocytes.
Am J Physiol
.
1999
;
277
(
5 pt 1
):
L901
L909
[PubMed]
41
Hadchouel
A
,
Wieland
T
,
Griese
M
, et al
.
Biallelic mutations of methionyl-tRNA synthetase cause a specific type of pulmonary alveolar proteinosis prevalent on Réunion Island.
Am J Hum Genet
.
2015
;
96
(
5
):
826
831
[PubMed]
42
Carey
B
,
Trapnell
BC
.
The molecular basis of pulmonary alveolar proteinosis.
Clin Immunol
.
2010
;
135
(
2
):
223
235
[PubMed]
43
Kitamura
T
,
Tanaka
N
,
Watanabe
J
, et al
.
Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor.
J Exp Med
.
1999
;
190
(
6
):
875
880
[PubMed]
44
Costabel
U
,
Guzman
J.
Pulmonary alveolar proteinosis: a new autoimmune disease.
Sarcoidosis Vasc Diffuse Lung Dis
.
2005
;
22
(
suppl 1
):
S67
S73
45
Martinez-Moczygemba
M
,
Doan
ML
,
Elidemir
O
, et al
.
Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1.
J Exp Med
.
2008
;
205
(
12
):
2711
2716
[PubMed]
46
Notarangelo
LD
,
Pessach
I
.
Out of breath: GM-CSFRalpha mutations disrupt surfactant homeostasis.
J Exp Med
.
2008
;
205
(
12
):
2693
2697
[PubMed]
47
Tanaka
T
,
Motoi
N
,
Tsuchihashi
Y
, et al
.
Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB.
J Med Genet
.
2011
;
48
(
3
):
205
209
[PubMed]
48
Ito
M
,
Nakagome
K
,
Ohta
H
, et al
.
Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile.
BMC Pulm Med
.
2017
;
17
(
1
):
40
[PubMed]
49
Griese
M
,
Zarbock
R
,
Costabel
U
, et al
.
GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders.
BMC Pulm Med
.
2015
;
15
:
87
[PubMed]
50
Ishii
H
,
Tazawa
R
,
Kaneko
C
, et al
.
Clinical features of secondary pulmonary alveolar proteinosis: pre-mortem cases in Japan.
Eur Respir J
.
2011
;
37
(
2
):
465
468
[PubMed]
51
Inaba
H
,
Jenkins
JJ
,
McCarville
MB
, et al
.
Pulmonary alveolar proteinosis in pediatric leukemia.
Pediatr Blood Cancer
.
2008
;
51
(
1
):
66
70
[PubMed]
52
Ohnishi
T
,
Yamada
G
,
Shijubo
N
, et al
.
Secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome.
Intern Med
.
2003
;
42
(
2
):
187
190
[PubMed]
53
Spinner
MA
,
Sanchez
LA
,
Hsu
AP
, et al
.
GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity.
Blood
.
2014
;
123
(
6
):
809
821
[PubMed]
54
Ogier de Baulny
H
,
Schiff
M
,
Dionisi-Vici
C
.
Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder.
Mol Genet Metab
.
2012
;
106
(
1
):
12
17
[PubMed]
55
Ceruti
M
,
Rodi
G
,
Stella
GM
, et al
.
Successful whole lung lavage in pulmonary alveolar proteinosis secondary to lysinuric protein intolerance: a case report.
Orphanet J Rare Dis
.
2007
;
2
:
14
[PubMed]
56
Valimahamed-Mitha
S
,
Berteloot
L
,
Ducoin
H
,
Ottolenghi
C
,
de Lonlay
P
,
de Blic
J
.
Lung involvement in children with lysinuric protein intolerance.
J Inherit Metab Dis
.
2015
;
38
(
2
):
257
263
[PubMed]
57
Enaud
L
,
Hadchouel
A
,
Coulomb
A
, et al
.
Pulmonary alveolar proteinosis in children on La Réunion Island: a new inherited disorder?
Orphanet J Rare Dis
.
2014
;
9
:
85
[PubMed]
58
Griese
M
,
Brasch
F
,
Aldana
VR
, et al
.
Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis.
Clin Genet
.
2010
;
77
(
2
):
119
130
[PubMed]
59
Sideris
GA
,
Josephson
M
.
Pulmonary alveolar proteinosis and Niemann Pick disease type B: an unexpected combination.
Respir Med Case Rep
.
2016
;
19
:
37
39
60
Grunebaum
E
,
Cutz
E
,
Roifman
CM
.
Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency.
J Allergy Clin Immunol
.
2012
;
129
(
6
):
1588
1593
[PubMed]
61
Punatar
AD
,
Kusne
S
,
Blair
JE
,
Seville
MT
,
Vikram
HR
.
Opportunistic infections in patients with pulmonary alveolar proteinosis.
J Infect
.
2012
;
65
(
2
):
173
179
[PubMed]
62
Su
KC
,
Lay
SL
,
Perng
RP
,
Chang
SC
,
Chen
YM
.
Lung cancer may develop subsequently or coincidently with pulmonary alveolar proteinosis.
Lung Cancer
.
2007
;
58
(
1
):
144
148
[PubMed]
63
Campo
I
,
Luisetti
M
,
Griese
M
, et al;
WLL International Study Group
.
A global survey on whole lung lavage in pulmonary alveolar proteinosis.
Chest
.
2016
;
150
(
1
):
251
253
[PubMed]
64
Campo
I
,
Luisetti
M
,
Griese
M
, et al;
WLL International Study Group
.
Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures.
Orphanet J Rare Dis
.
2016
;
11
(
1
):
115
[PubMed]
65
Wilson
CA
,
Wilmshurst
SL
,
Black
AE
.
Anesthetic techniques to facilitate lung lavage for pulmonary alveolar proteinosis in children-new airway techniques and a review of the literature.
Paediatr Anaesth
.
2015
;
25
(
6
):
546
553
[PubMed]
66
Reiter
K
,
Schoen
C
,
Griese
M
,
Nicolai
T
.
Whole-lung lavage in infants and children with pulmonary alveolar proteinosis.
Paediatr Anaesth
.
2010
;
20
(
12
):
1118
1123
[PubMed]
67
Parker
LA
,
Novotny
DB
.
Recurrent alveolar proteinosis following double lung transplantation.
Chest
.
1997
;
111
(
5
):
1457
1458
[PubMed]
68
Takaki
M
,
Tanaka
T
,
Komohara
Y
, et al
.
Recurrence of pulmonary alveolar proteinosis after bilateral lung transplantation in a patient with a nonsense mutation in CSF2RB.
Respir Med Case Rep
.
2016
;
19
:
89
93
69
Bonella
F
,
Campo
I
.
Pulmonary alveolar proteinosis.
Pneumologia
.
2014
;
63
(
3
):
144
, 147–155
[PubMed]
70
Campo
I
,
Mariani
F
,
Rodi
G
, et al
.
Assessment and management of pulmonary alveolar proteinosis in a reference center.
Orphanet J Rare Dis
.
2013
;
8
:
40
[PubMed]
71
Papiris
SA
,
Tsirigotis
P
,
Kolilekas
L
, et al
.
Long-term inhaled granulocyte macrophage-colony-stimulating factor in autoimmune pulmonary alveolar proteinosis: effectiveness, safety, and lowest effective dose.
Clin Drug Investig
.
2014
;
34
(
8
):
553
564
[PubMed]
72
Tazawa
R
,
Trapnell
BC
,
Inoue
Y
, et al
.
Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.
Am J Respir Crit Care Med
.
2010
;
181
(
12
):
1345
1354
[PubMed]
73
Yamamoto
H
,
Yamaguchi
E
,
Agata
H
, et al
.
A combination therapy of whole lung lavage and GM-CSF inhalation in pulmonary alveolar proteinosis.
Pediatr Pulmonol
.
2008
;
43
(
8
):
828
830
[PubMed]
74
Kavuru
MS
,
Bonfield
TL
,
Thomassen
MJ
.
Plasmapheresis, GM-CSF, and alveolar proteinosis.
Am J Respir Crit Care Med
.
2003
;
167
(
7
):
1036
, author reply 1036–1037
[PubMed]
75
Luisetti
M
,
Rodi
G
,
Perotti
C
, et al
.
Plasmapheresis for treatment of pulmonary alveolar proteinosis.
Eur Respir J
.
2009
;
33
(
5
):
1220
1222
[PubMed]
76
Amital
A
,
Dux
S
,
Shitrit
D
,
Shpilberg
O
,
Kramer
MR
.
Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis.
Thorax
.
2010
;
65
(
11
):
1025
1026
[PubMed]
77
Malur
A
,
Kavuru
MS
,
Marshall
I
, et al
.
Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis.
Respir Res
.
2012
;
13
:
46
[PubMed]
78
Nagasawa
J
,
Kurasawa
K
,
Hanaoka
R
.
Rituximab improved systemic lupus erythematosus-associated pulmonary alveolar proteinosis without decreasing anti-GM-CSF antibody levels.
Lupus
.
2016
;
25
(
7
):
783
784
[PubMed]
79
Paschen
C
,
Reiter
K
,
Stanzel
F
,
Teschler
H
,
Griese
M
.
Therapeutic lung lavages in children and adults.
Respir Res
.
2005
;
6
:
138
[PubMed]
80
Reunert
J
,
Lotz-Havla
AS
,
Polo
G
, et al
.
Niemann-Pick type C-2 disease: identification by analysis of plasma cholestane-3β,5α,6β-triol and further insight into the clinical phenotype.
JIMD Rep
.
2015
;
23
:
17
26
[PubMed]
81
van Hoorn
J
,
Brouwers
A
,
Griese
M
,
Kramer
B
.
Successful weaning from mechanical ventilation in a patient with surfactant protein C deficiency presenting with severe neonatal respiratory distress.
BMJ Case Rep
.
2014
;
2014
(
1
):
bcr2013203053
82
Tsai
WC
,
Lewis
D
,
Nasr
SZ
,
Hirschl
RB
.
Liquid ventilation in an infant with pulmonary alveolar proteinosis.
Pediatr Pulmonol
.
1998
;
26
(
4
):
283
286
[PubMed]
83
Cho
K
,
Nakata
K
,
Ariga
T
, et al
.
Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration.
Respirology
.
2006
;
11
(
suppl
):
S74
S77
[PubMed]
84
Wittmann
T
,
Schindlbeck
U
,
Höppner
S
, et al
.
Tools to explore ABCA3 mutations causing interstitial lung disease.
Pediatr Pulmonol
.
2016
;
51
(
12
):
1284
1294
[PubMed]
85
Cordonnier
C
,
Fleury-Feith
J
,
Escudier
E
,
Atassi
K
,
Bernaudin
JF
.
Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients.
Am J Respir Crit Care Med
.
1994
;
149
(
3 pt 1
):
788
794
[PubMed]
86
Tabata
S
,
Shimoji
S
,
Murase
K
, et al
.
Successful allogeneic bone marrow transplantation for myelodysplastic syndrome complicated by severe pulmonary alveolar proteinosis.
Int J Hematol
.
2009
;
90
(
3
):
407
412
[PubMed]
87
Xue
Y
,
Han
Y
,
Li
T
, et al
.
Pulmonary alveolar proteinosis as a terminal complication in a case of myelodysplastic syndrome with idic(20q-).
Acta Haematol
.
2010
;
123
(
1
):
55
58
[PubMed]
88
Ishii
H
,
Seymour
JF
,
Tazawa
R
, et al
.
Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan.
BMC Pulm Med
.
2014
;
14
(
1
):
37
[PubMed]
89
Barilli
A
,
Rotoli
BM
,
Visigalli
R
, 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
(
1
):
32
[PubMed]
90
Tanner
LM
,
Kurko
J
,
Tringham
M
, et al
.
Inhaled sargramostim induces resolution of pulmonary alveolar proteinosis in lysinuric protein intolerance [published online ahead of print October 26, 2016].
JIMD Rep
. doi:
[PubMed]
91
Gallagher
J
,
Adams
J
,
Hintermeyer
M
, et al
.
X-linked hyper IgM syndrome presenting as pulmonary alveolar proteinosis.
J Clin Immunol
.
2016
;
36
(
6
):
564
570
[PubMed]
92
Patiroglu
T
,
Akyildiz
B
,
Patiroglu
TE
,
Gulmez
IY
.
Recurrent pulmonary alveolar proteinosis secondary to agammaglobulinemia.
Pediatr Pulmonol
.
2008
;
43
(
7
):
710
713
[PubMed]
93
Edwards
C
,
Primhak
R
,
Cohen
MC
.
Pulmonary alveolar proteinosis associated with Epstein-Barr virus infection.
Eur Respir J
.
2010
;
36
(
5
):
1214
1216
[PubMed]
94
Narotzky
S
,
Kennedy
CC
,
Maldonado
F
.
An unusual cause of respiratory failure in a 25-year-old heart and lung transplant recipient.
Chest
.
2015
;
147
(
5
):
e185
e188
[PubMed]
95
Wardwell
NR
 Jr
,
Miller
R
,
Ware
LB
.
Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug.
Respirology
.
2006
;
11
(
5
):
663
665
[PubMed]
96
Masuko
H
,
Hizawa
N
,
Chonan
T
, et al
.
Indium-tin oxide does not induce GM-CSF autoantibodies.
Am J Respir Crit Care Med
.
2011
;
184
(
6
):
741
, author reply 741–742
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.