PulmonaryMatthias Griese, MD Alveolar Proteinosis: A abstract Comprehensive’ Clinical Perspective 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.
3 Under pathological conditions, the inhabitants4 . The first description of alveolar airspaces can be filled with PAP as well as the vast majority of various materials, which frequently data on treatment and prognosis are replace the air necessary for gas related to autoimmune PAP. Most Department of Pediatric Pneumology, Dr von Hauner exchange and give rise to alveolar pediatric cases are nonautoimmune Children’s Hospital, Ludwig-Maximilians-University of Munich and the German Center for Lung Research, Munich, filling syndromes (Table 1). These PAP and distribute almost evenly Germany conditions have similar clinical and among many different entities. In radiologic presentations. This makes childhood, there is a bimodal age DOI: https://doi.org/10.1542/peds.2017-0610 their differential diagnosis difficult. distribution; some conditions manifest Accepted for publication Apr 11, 2017 in the neonatal period (Fig 2, upper Address correspondence to Matthias Griese, MD, Pulmonary alveolar proteinosis (PAP) portion), whereas others manifest Dr von Hauner Children’s Hospital, University of is defined by the accumulation of during infancy and childhood. Munich, Lindwurmstr 4, 80337 München, Germany. pulmonary surfactants in the alveolar E-mail: [email protected] space (Fig 1). Mechanistically, these Pathology PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, disturbances of surfactant homeostasis 1098-4275). Copyright 2017 by the American Academy of may be caused by an altered surfactant1 © production, removal, or both. PAP is The expansion of the surfactant pool Pediatrics can be recognized in histopathological FINANCIAL DISCLOSURE: The author has indicated a heterogeneous group of disorders 2 that is caused by different conditions specimens. The alveoli are filled with he has no financial relationships relevant to this (Table 2). The age of manifestation eosinophilic, acellular, and finely article to disclose. plays an important role in the granular material (Fig 1E). Clefts FUNDING: Funded by the German Center for Lung Research, DZL 2.0, the European Management diagnostic approach and differential made4,5 of cholesterol can be found (Fig 1F). Sometimes, detached type II Platform for Children’s Interstitial Lung Disease diagnosis (Fig 2). Success of treatment (FP7, 305653), and E-Rare 2016. and outcome are related to the pneumocytes, foamy macrophages, or neutrophil granulocytes as well as POTENTIAL CONFLICT OF INTEREST: The author has underlying condition and, in children, to indicated he has no potential conflicts of interest the technical skills needed to perform lamellar bodies of normal lungs can be to disclose. whole-lung lavages (WLLs). WLL is the identified (Fig 1 C and D). cornerstone of PAP treatment. Epidemiology Whereas the intra-alveolar filling does To cite: Griese M. Pulmonary Alveolar Proteinosis: not differentiate between different A Comprehensive Clinical Perspective. Pediatrics. forms of PAP, histopathological 2017;140(2):e20170610
PAP is a rare disease complex examination of the alveolar wall that affects <5 cases per 100000 structures may be normal (Fig 1E) Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 2, August 2017:e20170610 STATE-OF-THE-ART REVIEW ARTICLE or abnormal. The interstitial space idiopathic pulmonary hypertension occurs in children, and it needs is mostly normal; however, several in a mature neonate. to be differentiated from GM-CSF forms show4, 6widening from cells Investigations and Differential antibodies in healthy individuals or fibrosis. When the surfactant Diagnosis at low levels and patients with “ dysfunction syndromes were first autoinflammatory diseases such as ” Chest Radiography – 21 described, the term congenital colitis, Crohn disease, malignancies,22 24 alveolar proteinosis7 was used or PAP caused by dust exposure. in such newborns. Particularly Because there is a close correlation in children, the PAP histopattern The presence of diffuse bilateral between antibody level and PAP mostly symmetrical alveolar, 25,26 presents in combination 8,with9 development, a close link additional histopatterns, such sometimes patchy infiltrates with to pulmonary manifestation is as increased cellularity from air bronchograms give first clues mandatory when searching for these to interstitial lung disease due to hyperplasia of type II pneumocytes autoantibodies.Lactate Dehydrogenase and collagen fibers or alveolar alveolar filling (Fig 1A). Usually, ∼ 10 macrophages. In cohort studies in the perimediastinal regions are 50% to 60% of such biopsies, the more affected than the subpleural 11,12 Lactate dehydrogenase is increased PAP histopattern was found, regions. Persistence of the cloudy in 82% of patients with autoimmune and the detection rate was higher in infiltrates after antibiotic treatment 6 is a frequent observation. In neonates PAP. Of interest, this marker biopsies conducted during the early “ ” 12 readily responds to changes in disease phase. In TTF1 deficiency, with acute RDS, all radiologic stages – disease severity and improves after pulmonary histology may also show (including a white lung ) may 6,27 29 develop progressively. therapeutic lavages. the PAP pattern in addition to the Lung Function Tests nonspecific interstitial pneumonia Similarly, in serum carcinoembryonic antigen, levels of the surfactant pattern and defects13 in lung 30 proteins A, D, and KL-6 are markers development. Adults and children who are old of disease activity, which can be Clinical Presentation enough to perform spirometry have used to monitor its course. Serum a restrictive pattern with small KL-6 accurately predicts disease lung volumes and reduced diffusing 29 – progression in autoimmune PAP. PAP presents in 2 types: Most capacity of the lung for carbon frequently (70% 90% of PAP cases), monoxide, although 6initial tests In children and adults, autoantibodies patients develop slowly increasing may also be normal. Of interest, including antinuclear antibody, dyspnea (initially2 on exertion) and carbon dioxide elimination rarely is antineutrophil cytoplasmic antibody – dry coughing. In PAP caused by a problem in the face of significant (eg, cANCA/PR3 and pANCA/ granulocyte-macrophage colony- hypoxemia. At presentation, 55% MPO), anti double-stranded DNA, stimulating factor receptor alpha of the patients with PAP caused anticentromere, cyclic citrullinated – – (GM-CSF-Ra) mutations, 70% had by GM-CSF-Ra mutations had peptide, extractable nuclear antigen 14 – dyspnea at presentation, 15% had hypoxemia, whereas in adults with (eg, anti SS-A [Ro], anti SS-B [La], tachypnea, 30% had clubbing, 35% autoimmune PAP, hypoxemia at anti-RNP, anti Jo-1, anti-Sm, and Scl- had global respiratory failure, and 14 rest was present in approximately 70), and rheumatoid factor should be 15% were intubated and ventilated. – one-third and during exercise 3in assessed. more than half of the patients. With Global and specific immunologic Less frequently (30% 50% of PAP treatment of the alveolar filling, function tests need to be done cases), fever, weight loss, fatigue, abnormal lung function tests are to diagnose underlying immune and chest pain are observed expected to be reversible; if they are Geneticdeficiencies Testing (Table 2). (numbers2 are for autoimmune not, then additional pathology should PAP ). Among the children, 45% had beLaboratory suspected. Blood Tests infections (mycoplasma, influenza, or respiratory syncytial virus) Autoantibodies Against GM-CSF In neonates with the characteristic before PAP because of GM-CSF-Ra clinical and radiologic presentation mutations, 26% had a cough, 5% (and after the exclusion of other, had a fever,14 and 36% had failure In all cases of suspected PAP, these– more frequent causes), testing for to thrive. PAP caused by affected should be searched. In adults, >90%15 19 mutations in SFTPB, SFTPC, ABCA3, surfactant production typically of the case results are positive. and TTF1 is recommended (www. presents with idiopathic respiratory Serology has excellent20 sensitivity childeu.net). In infants and older distress syndrome (RDS) or and specificity. Autoimmune PAP patients, analysis for mutations in Downloaded from www.aappublications.org/news by guest on October 1, 2021 2 Griese TABLE 1 Intra-Alveolar Filling With Different Materials Leads to Various Disease Entities Material Filling the Alveolar Space Disease excluding cardiac, infectious, central, Surfactant PAP or metabolic causes). In older infants Erythrocytes, siderophages Alveolar hemorrhage Macrophages Desquamative interstitial pneumonia and children, red flags include slowly Hyaline membranes Diffuse alveolar damage, RDS developing dyspnea or dyspnea Eosinophils Eosinophilic pneumonia persisting after resolution of an acute Cholesterol crystals, foreign material Exogenous lipid pneumonia, aspiration pneumonia respiratory tract infection, together Exsudative neutrophilic alveolitis, progressively Meconium aspiration syndrome with diffuse alveolar infiltrates on the replaced by macrophages, giant cells, fibroblasts Lipoproteins, Pneumocystis P jiroveci pneumonia chest radiograph. Calcified microliths Pulmonary alveolar microlithiasis Blood tests are done first, followed Plasma, serum Pulmonary edema by a bronchoscopy with standardized lavage and transbronchial biopsy in most patients (Table 2). When the – results obtained are not definitively SFTPC, ABCA3, CSF2RB, CSF2RA, pneumonitis, sarcoidosis, lipoid diagnostic, a lung biopsy is needed to GATA2, SLC7A7, methionyl transfer pneumonia, and Niemann-Pick31 firmly establish the diagnosis. RNA synthetase (MARS), NPC2, and disease, among others. Etiology possibly NPB (see Table 2) should be It must be kept in mind that done when appropriate. Bronchoalveolar Lavage computed tomography (CT) imaging in neonates and infants with high Categorization of PAP forms according breathing rates is very demanding to suspected etiology is helpful With standardized diagnostics, ü and needs a lot of technical detail to for therapy, although frequently lavage return typically gets milkier obtain high-quality scans. Therefore, the underlying etiology cannot be on visual inspection. May-Gr nwald CT scanning should be reserved for Surfactantidentified precisely Dysfunction (Table Syndromes 2). Giemsa staining shows cellular the specialized center performing debris, acellular globules, and foamy diagnostic imaging in temporal macrophages (Fig 1 C and D). Lungrelation Biopsy to the lung biopsy. Mutations in SFTPB, SFTPC, In adults with PAP, experienced ABCA3, and TTF1 may present with centers can make the diagnosis by – the histologic PAP pattern mostly bronchoalveolar lavage (BAL) in 7,9, 32 34 In infants, biopsies are done during the neonatal period, 70% to 74% of the patients with 3,16 as open biopsies or sometimes when secretion of surfactant is acquired PAP. BAL fluid should be thoracoscopically. In adults and older normally increased more than investigated for infections (Table 2). 35,36 High-Resolution Computed children, transbronchial biopsies can 10-fold and sometimes later as ∼ 37,38 Tomography be done during a bronchoscopy. Lung well but to a smaller degree. biopsies were performed in 80% At the same time, the removal of
of the children14 to make the diagnosis aberrant surfactant may be impaired Crazy paving pattern, which of PAP. In children, reference because of volume- and39 barotrauma- combines ground-glass opacity (a reading of the biopsy specimens by induced lung injuries, and hazy increase in lung opacity that a specialized pathologist is highly physiologically increased removal does not obscure the underlying recommended and can be organized may be disturbed, all of which lead via different networks, such as the to swamped macrophage-removal vessels or bronchial structures) and ’ 40 a superimposed reticular pattern (Fig European Management Platform for systems. If patients survive, the 1B), is characteristic for PAP but not Children s Interstitial Lung Diseases PAP pattern slowly disappears and is specific to it. Its differential diagnosis (www.childeu.net). replaced by a more10,12 fibrotic pattern includes edema, hemorrhage, acute Diagnosis of PAP of lung disease. Similarly, such a RDS, acute interstitial pneumonia, sequence has been demonstrated41 for MARS mutations (Table 2). Today, eosinophilicPneumocystis pneumonia, jirovecii diffuse alveolar damage, pneumonias As with all rare lung diseases, a high fortunately, conditions are diagnosed caused by , degree of suspicion is necessary genetically, which eliminates the cytomegalovirus, adenovirus, when taking the diagnosis of PAP into need for a biopsy. mycoplasma, bacteria, tuberculosis, consideration. Red flags in neonates Impaired GM-CSF Signaling nonspecific interstitial pneumonitis, and young infants are nonimproving organizing pneumonia, eosinophilic or slowly improving respiratory granulomatosis with polyangiitis, distress in the mature neonate (ie, if GM-CSF is critical for the regulation radiation pneumonitis, drug-related persistent after 1 or more weeks and of surfactant homeostasis, alveolar Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 2, August 2017 3 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.
43 “ macrophage maturation and GM-CSF signaling by neutralizing PAP. This autoimmune disease, in ” “ ” phagocytosis, lung host42 defense, GM-CSF autoantibodies is the cause the beginning called adult idiopathic and innate immunity. DisruptedDownloaded fromof www.aappublications.org/newsthe vast majority of adult bycases guest of on OctoberPAP 1, 2021 or primary PAP, is now called 4 Griese TABLE 2 Categorization of PAP Disease Causes of PAP Manifestation Genetically Exposure Histologically Intact Reported in Causedb Caused Lung Interstitial Tissue, Neonates, Primarily Alveolar Filling Childrena Surfactant-dysfunction syndromes SFTPB mutations Y Y N N SFTPC mutations Y Y N N ABCA3 mutations Y Y N N TTF1 mutations Y Y N N Impaired GM-CSF signaling GM-CSF receptor α chain of mutations Y Y N Y Turner syndrome with heterozygous GM-CSF receptor α chain mutations Y Y N Y GM-CSF receptor β chain mutations Y Y N Y Autoimmune GM-CSF antibodies Y N N Y Hematologic disorders and other malignancies GATA2 deficiency Y Y N Y MDS (most common) Y Y N Y Chronic myelomonocytic leukemia Y Y N n.k. Acute lymphatic leukemia Y Y N Yc Congenital dyserythropoietic anemia Y Y N Y Fanconi’s anemia Y Y N Y Hemophagocytic lymphohistiocytosis Y N N Sideroblastic anemia Y Nc N Yc Primary myelofibrosis, chronic lymphocytic leukemia, cutaneous -cellT N Y or n.k. Nc Yc or n.k. 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 Systemic diseases Lysinuric protein intolerance (SLC7A7 mutation) Y Y N Y (50%), N (50%) MARS mutations Y Y N N Niemann Pick type C2 Y Y N N Niemann Pick type B Y Y N n.d. Bone marrow, stem cell transplant Y N N Yc Systemic lupus erythematosus, granulomatosis with polyangiitis, N N N Yc or N microscopic polyangiitis, membranous nephropathy, dermatomyositis with interstitial lung disease, coincident in many other rheumatologic diseases and interstitial lung diseases, lung transplant Immunologic diseases Adenosine deaminase deficiency Y Y N Y Agammaglobulinemia Y Yc N n.k. DiGeorge syndrome type 2 Y Y N n.d. Monoclonal gammopathy N N N Y Selective immunoglobulin A deficiency N N N Y Severe combined immunodeficiency Y Y N Y X-linked hyper–immunoglobulin M syndrome Y Y N n.d. Infections Cytomegalovirus Y N Y N or Nc Epstein-Barr virus Y N Y N or Nc HIV Y N Y N or Nc M tuberculosis Y N Y N or Nc Atypical mycobacteria Y N Y N or Nc Nocardia N N Y N or Nc P jiroveci Y N Y N or Nc Drugs Chemotherapy, antineoplastic Y N Y Y
Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 2, August 2017 5 TABLE 2 Continued Disease Causes of PAP Manifestation Genetically Exposure Histologically Intact Reported in Causedb Caused Lung Interstitial Tissue, Neonates, Primarily Alveolar Filling Childrena Busulfan, sirolimus, everolimus, tyrosine kinase inhibitors (including N N Y Y 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 N N Y N (except aluminum, implants, tin, titanium (and varnish) silica) Types of dust exposure, organic Bakery flour, chlorine, cleaning products, cotton, fertilizer, agricultural N N Y N or Nc dust, fumes, gasoline, hydrofluoric acid, parrots, pigeons, petroleum, sawdust Miscellaneous conditions Osteopetrosis caused by TCIRG1 gene mutation Y Y N Yc Total anomalous pulmonary venous return with coarctation of the aorta Y N, Yc N Y, pulmonary hypoplasia (single case) 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.
“ ” 44 autoimmune PAP and can also occur in children. Interruption of GM-CSF signaling by α β hereditary factors, such as mutations in the (CD116) or (CD131) chain of the GM-CSF receptor (which is also used by the interleukin-345,46 and interleukin-5 receptors), will all lead to hereditary PAP forms. These cases most likely manifest in childhood14, but47, 48 may also be diagnosed inHematologic adults. Disorders and Other Malignancies
Hematologic disorders widely contribute 49to PAP causes,50 both in children and adults (Table 2). Prolonged neutropenia and reduction of alveolar macrophages FIGURE 2 by myeloablative chemotherapy Schematic of age dependency of the manifestation of various alveolar pulmonary proteinosis forms or leukemic infiltration have been and qualitative estimates of age at clinical manifestation in the major groups of PAP. Note the size of implicated in the pathogenesis of the graphs does not represent their absolute frequency. Autoimmune PAP represents ∼90% of all 51 cases if age of manifestation is not considered. pediatric PAP. Autoantibodies against GM-CSF may be elevated in BAL fluid, whereas in sera, 52 – they were below sensitivity. ∼ – Among patients with GATA2 myeloid leukemia (14%); papillomavirus or Epstein- haploinsufficiency, 20% chronic myelomonocytic Barr virus associated tumors; develop PAP, often in association leukemia (8%); severe infections venous thrombosis; lymphedema; with familial myelodysplastic (including mycobacterial and sensorineural hearing loss; 53 syndrome (MDS) (84%); acute fungal infections); human miscarriage; and hypothyroidism. Downloaded from www.aappublications.org/news by guest on October 1, 2021 6 Griese Systemic Diseases
opportunistic infections between one of the lungs is ventilated and 1950 and 2010 were searched, and the other is filled with aliquots of Lysinuric protein intolerance is 75 cases were reviewed. Forty-three warmed saline by infusion with an inherited defect of cationic percent of the patients had nocardia gravity or gentle pressure via a amino acid (lysine, arginine, Mycobacteriuminfection, 37% had tuberculosis mycobacterial 50-mL syringe. After recovery of the15 and ornithine) transport at the infection (of those, 75% were fluid, the next washing cycle begins. basolateral membrane of epithelial ), 61 For smaller children or infants, we and 20% had fungal infections. have developed and extensively cells and is54 caused by mutations 65 in SLC7A7. The condition can Opportunistic infections can either tested a novel technique. In this – be considered a disorder of bone precede or follow a diagnosis of technique, 1 lung is occluded with a marrow derived monocytes PAP. PAP should be considered pulmonary artery balloon catheter in apparently immunocompetent (which is continuously watched with differentiating into dysfunctional55 alveolar macrophages. Lung patients who present withPneumocystis an a small endoscope for its tight fit into involvement was observed in 71% of opportunistic infection and diffuse the bronchus) and used for lavage children, which showed fibrosis on alveolar infiltrates. For of that lung,27, and66 the other lung is and the viruses indicated in Table ventilated. Indication for WLL is histopathology56 or CT scan in addition to PAP. 2, individual cases of PAP were given when respiratory symptoms reported. impair the quality of life (eg, oxygen Drugs and Dust Exposure MARS deficiency by missense treatment is necessary), development é mutations leads to PAP, which is of weight is impaired, or lung endemic on R union Island in the functionExtracorporeal deviates M fromembrane normal. 41 Oxygenation and Lung Transplants Indian Ocean. The disease starts Although PAP caused by dust in infancy with PAP then frequently exposure has not been reported in children, a detailed occupational progresses to pulmonary fibrosis57 with cholesterol granulomas. and environmental history has to Sometimes, severe hypoxemia be taken for diagnoses in every precludes immediate WLL, and new patient regardless of age. In patients need to be supported Niemann-Pick diseases are adults, between 23% and 39% of by extracorporeal membrane hereditary neurovisceral lysosomal patients with PAP were exposed to oxygenation to allow for the lipid-storage disorders, which can 2,3 compounds shown to induce PAP. procedure and recovery or to have present with respiratory symptoms Miscellaneous Conditions it serve as a bridge to the lung at any age. In type C2, PAP may be 65 transplant. Several patients caused by reduced NPC2 protein with PAP (in its various forms) expression in alveolar macrophages. have had a lung transplant. The composition and function of Any disease involving the lungs However, the recurrence of PAP surfactants in this form of PAP are may potentially cause PAP, and thus 58 disease has been reported in some abnormal. PAP has been reported PAP needs to be included in the 67,68 patients. in Niemann-Pick type B; however, it differential diagnosis. Alternatively, Natural Course, Specific was unclear if this was a coincidence PAP could be coincident with another 59 Treatment Options, and Outcome Immunologicwith autoimmune Diseases PAP. lung disease; thus diagnostic workup62 for different causes is mandatory. General Treatment Approach Each etiologic group of PAP has its ∼ Of infants with adenosine deaminase Therapeutic WLL own clinical course, treatments and deficiency, 50% have PAP with outcome, and due to rarity of cases, typical lung pathology and without has not been described in detail for additional abnormalities, except for WLL remains the current standard most.Autoimmune PAP coincident 60identification of various of care for PAP. Over the years, the pathogens. For several other technique has been6, 63,improved64 in immunologic diseases, cases of PAP dedicated centers. Bilateral In autoimmune PAP, historical comparisons suggest that patients Infectionshave been reported (Table 2). sequential WLL in the same treatment session is aimed at, but is before the advent of therapeutic dependent on, the clinical condition lung lavages had higher mortality than after therapeutic lung lavages of the patient. In adults and older ∼ In a recent review of the literature, children in whom a double-lumen had become6 an established all reported cases of PAP and tube can be safely placed repetitively, treatment. In 5% to 10% of Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 2, August 2017 7 PAP Caused by Hematologic ∼ Disorders patients, spontaneous3,6 remission necessary until the effluent is clear may occur, and in 50%, only 1 (Fig 3 D and E). The outcome depends ∼ WLL treatment is necessary for long- mainly on WLL treatment, which 2 These patients present with term remission. Mortality during 16 was successfully performed14 in 90% follow-up in large centers is <10%. of all published cases. In these respiratory insufficiency and fever in WLL is the standard treatment; forms of PAP, hematopoietic stem 24% of cases, particularly in patients with prolonged85 neutropenia from however, additional69 options have cell transplants may be successful to been developed. To overcome the correct a defect that is localized in chemotherapy, which demands endogenous GM-CSF autoantibodies alveolar macrophages. A recurrence suspicion for this complication. Initial attempts to treat PAP caused by MDS that neutralize GM-CSF, recombinant of PAP in such a child (M. Castelle, 52 with WLLs were not successful, and exogenous GM-CSF has been MD, personal communication, 2015) 50 69,70 although later survival improved. tested. Administration of or an inadvertent45 outcome have been aerosolized GM-CSF appeared more reported ; however, this scenario WLL may be used as a bridge to bone marrow transplants, as reported for attractive and more effective in a needs to be investigated further. 86 controlled prospective trial of 50 an adult patient and also recently PAP Caused by Affected Surfactant for a small 6-year-old child, for whom patients71,72 with a response rate of 62%. Of interest are studies with Production we performed 14 WLLs over a period a goal of decreasing the GM-CSF of 1 year until a suitable donor was found. PAP resolved rapidly after the amounts necessary by combining 49 73 transplant. The amount of protein it with WLL. Another approach Several infants previously labeled recovered in this condition was combined WLL and plasmapheresis as having congenital PAP have been similar to the amount in autoimmune to reduce the circulating level of treated with limited success or 6 PAP or GM-CSFR mutations (Fig 3). GM-CSF autoantibodies; however, without success by WLLs. An infant the results for clinical74,75 efficacy with PAP likely caused by a surfactant- 87 – – Xue et al described a patient with are controversial. Rituximab, dysfunction disorder was82 treated a humanized B-lymphocyte with liquid ventilation. An infant girl PAP and MDS due to idic(20q ) who depleting antibody, is able to reduce with familial congenital PAP who was was too sick to be lavaged. Consider a neutralizing GM-CSF autoantibodies– not responsive to lavages recovered timely transfer of patients to centers experienced in WLL technique. and showed improved lung 2,function76 78 3 times from respiratory failure in high-resolution CT scans. after intravenous immunoglobulin G An important report indicates that There is no rationale for all the latter administration;83 a mutation in SFTPB approaches in nonautoimmune PAP. was excluded. PAP reports from empirical corticosteroid treatment GM-CSF Receptor α or β Chain in PAP secondary to MDS is a risk Mutation–Caused PAP children with molecularly defined surfactant-dysfunction disorders factor for infection88 and contributes are scarce. In our cohort of patients to poor prognosis. We had a similar with SFTPC mutations, we reported experience in a patient with PAP 27 WLL treatment is the mainstay of caused by a GM-CSF-Ra mutation, therapy in patients with receptor 5 patients suffering from PAP 12who have been treated with WLLs. No which suggests the need for caution mutations and has been used in the with immunosuppressive therapy in majority of cases reported so far clinical success was observed81 in a 14 these conditions. In an adult patient (78%). In some patients with the child with mutation C121F, whereas Mycobacterium reasonable success was observed aviumwith PAP intracellulare caused by GATA2 deficiency same mutation, treatment every 4 and infection with in a patient with8 severe course and to 8 weeks27 over several years was mutation I73T. The amount of 49 , WLL was not necessary, whereas in others, only helpful. few or no lavages were sufficient in protein recovered in these conditions maintaining a stable clinical course. was much lower than in other PAPs (Fig 3). This clearly indicates that The outcome of these conditions The protein amounts recovered from in addition to alveolar filling with is strongly determined by the the lungs were similar to those79 in surfactants, other disease mechanisms underlying condition and is generally adults with autoimmune PAP (Fig 3). play a major84 role for respiratory poorer than in autoimmune PAP. WLLs within a few days are less failure. We are not aware of WLLs Median survival time was only50,88 20 efficient than lavages repeated at months in a Japanese cohort ; in in patients with mutations in SFTPB, ∼ least 2 or more weeks apart (Fig 3C). ABCA3, or TTF1. The outcomes of another cohort, the death16 rate in such The amount of protein recovered these patients are only initially related subjects was 50%. The causes over time changes with disease to PAP severity; and later, pulmonary of death were hematologic disease activity and with the lavage volume fibrosis predominates. (33%), respiratory insufficiency Downloaded from www.aappublications.org/news by guest on October 1, 2021 8 Griese 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.
41 (25%), infection (25%), and WLL has been described in a PAP PAP. Patients develop PAP early unspecified bleeding (13%). associated with lysinuric protein in their disease course, and several Systemic Diseases 55 57 intolerance. This suggests that in received empirical WLLs. An Lysinuric Protein Intolerance (SLC7A7 selected cases, WLL may be helpful and analysis of the cohort of 34 patients Mutation) could be attempted by experienced suggested that WLL did not57 have an specialists. GM-CSF89, therapy90 may be an influence on survival rates. The additional option. protein content, the composition, MARS Mutations Children present with failure to thrive and the concentration of surfactant and gastrointestinal symptoms from proteins A, B, C, and D as well as lipid pancreatic insufficiency. In 2 children composition and material removed
<2 years old, WLLs56 were performed Recently, we identified biallelic from the lungs were not different from without efficacy. However, at least missense mutations in MARS as the autoimmune PAP (M.G., unpublished 1 case of long-lasting remission after cause of a specific form of pediatric observations). Overall outcome of this Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 2, August 2017 9 Drugs ö ∼ condition is poor, with57 a median age at K. Reiter, C. Sch n, F. Hoffmann, A. death of 17 years. Schams, T. Wesselak, E. Kaltenborn, Niemann Pick Type C2 After 9 months of treatment with M. Kappler, J. Ripper, J. Hildebrandt, sirolimus, PAP was diagnosed in P. Lohse, F. Brasch, M. Hofmann, I. a heart-lung transplant patient. Eckerlein, and the many coworkers The drug was discontinued, Early lung disease in patients with on published research projects and GM-CSF therapy was started, Niemann-Pick disease type C2 may the cooperators in internal medicine 58,80 and 3 WLLs were performed to be associated with PAP. In Griese 94 and pulmonology including M. 58 80 relieve respiratory distress. A et al and Reunert et al, empirical – Luisetti, I. Campo, S.A. Papiris, E.D. patient treated with the disease- treatment with WLL in those patients Manali, U. Costabel, and F. Bonella. modifying anti rheumatoid arthritis was only transiently effective, Finally, I thank the families and drug leflunomide developed PAP reducing the need for oxygen and children for their longstanding (verified by a biopsy specimen) improving imaging. The amount of confidence. I apologize to other and was treated with WLL and protein recovered was low, which researchers of many excellent articles subsequently discontinued taking the also differentiated this form of PAP 95 and reviews of the condition who leflunomideDust Exposure. from the others (Fig 3 A and B). were not included because of limited Such treatments may be helpful in space. less severe cases or when bridging Abbreviations WLL may be symptomatically to other treatments is the goal. The beneficial, but stopping exposure is outcome is frequently determined by pivotal. WLL may be ineffective after other organ complications from the BAL: bronchoalveolar lavage long-standing or extensive exposure, underlying condition. CT: computed tomography Immunologic Diseases as additional pathologies such as GM-CSF: granulocyte-macro - cholesterol granuloma and fibrosis 96 phage colony-stimulat- may have developed. – ing factor Conclusions PAP caused by immunologic MARS: methionyl transfer RNA diseases is best treated by synthetase correcting60, the91 underlying defect MDS: myelodysplastic syndrome if possible or by symptomatic The label PAP is merely an overall PAP: pulmonary alveolar treatment (eg, immunoglobulin description of alveolar filling with proteinosis therapy). A 15-year-old boy with surfactant. It is very important RDS: respiratory distress agammaglobulinemia and recurrent to classify all cases definitively syndrome according to etiology and on the PAP was treated with additional 92 WLL: whole-lung lavage basis of new knowledge generated WLL without any complications. References A 6-year-old child we treated with by translational research. 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Downloaded from www.aappublications.org/news by guest on October 1, 2021 Pulmonary Alveolar Proteinosis: A Comprehensive Clinical Perspective Matthias Griese Pediatrics 2017;140; DOI: 10.1542/peds.2017-0610 originally published online July 20, 2017;
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