A Comprehensive Outlook on Pulmonary Alveolar Proteinosis-A Review.

Pulmonary alveolar proteinosis (PAP) is an ultra-rare disease caused by impaired pulmonary surfactant clearance due to the dysfunction of alveolar macrophages or their signaling pathways. PAP is categorized into autoimmune, congenital, and secondary PAP, with autoimmune PAP being the most prevalent. This article aims to present a comprehensive review of PAP classification, pathogenesis, clinical presentation, diagnostics, and treatment. The literature search was conducted using the PubMed database and a total of 67 articles were selected. The PAP diagnosis is usually based on clinical symptoms, radiological imaging, and bronchoalveolar lavage, with additional GM-CSF antibody tests. The gold standard for PAP treatment is whole-lung lavage. This review presents a summary of the most recent findings concerning pulmonary alveolar proteinosis, pointing out specific features that require further investigation.

Role of rituximab as neoadjuvant therapy in a difficult case of relapsing pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare disease which involves the accumulation of insoluble lipoproteinaceous material in the alveoli leading to impaired gas exchange and even respiratory failure. Autoimmune PAP is the most common type and is characterized by the presence of anti-granulocyte-monocyte colony stimulating factor (anti GM-CSF) antibody. Whole lung lavage has been traditionally used as first-line management of PAP but there is a lack of clarity especially in the treatment of relapsing cases of PAP. Rituximab is an anti Cluster of Differentiate 20 (CD 20) monoclonal antibody that has been tried as salvage therapy for relapsing cases of PAP. We present a case of 35 years old female patient who was diagnosed as a case of relapsing PAP who was managed initially with neoadjuvant rituximab. This is a retrospective observational report showing novel use of neoadjuvant rituximab in a difficult case of relapsing PAP.

Pulmonary alveolar proteinosis in Taiwan.

BACKGROUND/PURPOSE: Pulmonary alveolar proteinosis (PAP) is rare disease manifested as alveolar macrophage dysfunction and abnormal accumulation of surfactant protein in the alveoli. In this nationwide, population-based study, we investigated the epidemiology of PAP in Taiwan, and discovered the comorbidities and prognostic factors of PAP. METHODS: From the National Health Insurance Research Database (NHIRD), we obtained comprehensive information about all patients of PAP in Taiwan between 1995 and 2013. The incidence, baseline characteristics comorbidities, and prognostic factors of PAP were investigated. RESULTS: The annual incidence rate of PAP was around 0.79 (range: 0.49-1.17) patients per million people after 2000, and the prevalence rate was 7.96 patients per million people by the end of 2013. In total, 276 patients of PAP were identified, including 177 (64%) and 99 (36%) patients with primary and secondary PAP, respectively. The median age of diagnosis was 53.8 years. The median survival was 9.6 years after the initial PAP diagnosis, and the 5-year survival rate was 65.96%. Twenty (7%) patients received whole lung lavage (WLL) within three months after the diagnosis had significantly better survival compared to the others. Multivariable Cox regression analyses showed that elder age, secondary PAP, and malignancy were associated with poorer survival, while WLL within 3 months of diagnosis might greatly improve the survival. CONCLUSION: We demonstrated the epidemiology of PAP in Taiwan, showing several poor prognostic factors and the potential effectiveness of WLL. Further prospective studies based on registry are warranted to improve the diagnosis and treatment of PAP.

A mini-whole lung lavage to treat autoimmune pulmonary alveolar proteinosis (PAP).

BACKGROUND: PAP is an ultra-rare respiratory syndrome characterized by the accumulation of surfactant within the alveoli. Whole lung lavage (WLL) is the current standard of care of PAP, however it is not a standardized procedure and the total amount of fluid used to wash each lung is still debated. Considering ICU hospitalization associated risks, a "mini-WLL" with anticipated manual clapping and reduced total infusion volume and has been proposed in our center. The aim of the study is to retrospectively analyze the efficacy of mini-WLL compared to standard WLL at the Pavia center. METHODS: 13 autoimmune PAP patients eligible for WLL were included: 7 patients were admitted to mini-WLL (9 L total infusion volume for each lung) and 6 patients underwent standard WLL (14 L of infusion volume). Functional data (VC%, FVC%, TLC%, DLCO%) and alveolar-arterial gradient values (A-aO2) were collected at the baseline and 1, 3, 6, 12, 18 months after the procedure. RESULTS: A statistically significant improvement of VC% (p = 0.013, 95%CI 3.49-30.19), FVC% (p = 0.016, 95%CI 3.37-32.09), TLC% (p = 0.001, 95%CI 7.38-30.34) was observed in the mini-WLL group in comparison with the standard WLL group, while no significant difference in DLCO% and A-aO2 mean values were reported. CONCLUSION: Mini-WLL has demonstrated higher efficacy in ameliorating lung volumes, suggesting that a lower infusion volume is sufficient to remove the surfactant accumulation and possibly allows a reduced mechanical insult of the bronchi walls and the alveoli. However, no statistically significant differences were found in terms of DLCO% and Aa-O2.

Lung injury induced by different negative suction pressure in patients with pneumoconiosis undergoing whole lung lavage.

BACKGROUND: Pneumoconiosis is a diffuse interstitial fibronodular lung disease, which is caused by the inhalation of crystalline silica. Whole lung lavage (WLL) is a therapeutic procedure used to treat pneumoconiosis. This study is to compare the effects of different negative pressure suction on lung injury in patients with pneumoconiosis undergoing WLL. MATERIALS AND METHODS: A prospective study was conducted with 24 consecutively pneumoconiosis patients who underwent WLL from March 2020 to July 2020 at Emergency General Hospital, China. The patients were divided into two groups: high negative suction pressure group (group H, n = 13, negative suction pressure of 300-400 mmHg) and low negative suction pressure group (group L, n = 11, negative suction pressure of 40-50 mmHg). The arterial blood gas, lung function, lavage data, oxidative stress, and inflammatory responses to access lung injury were monitored. RESULTS: Compared with those of group H, the right and left lung residual were significantly increased in the group L (P = 0.04, P = 0.01). Potential of hydrogen (pH), arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), lactic acid (LAC) and glucose (GLU) varied from point to point in time (P < 0.01, respectively). There was statistical difference in the trend of superoxide dismutase (SOD) and interleukin-10 (IL-10) over time between the two groups (P < 0.01, P = 0.02). In comparison with the group H, the levels of IL-10 (P = 0.01) and SOD (P < 0.01) in WLL fluid were significantly increased in the group L. There was no statistical difference in the trend of maximal volumtary ventilation (MVV), forced vital capacity (FVC), forced expiratory volume in one second (FEV1%), residual volume (RV), residual volume/total lung capacity (RV/TLC), carbon monoxide dispersion factor (DLCO%), forced expiratory volume in one second/ forced vital capacity (FEV1/FVC%) over time between the two groups (P > 0.05, respectively). CONCLUSION: Low negative suction pressure has the potential benefit to reduce lung injury in patients with pneumoconiosis undergoing WLL, although it can lead to increased residual lavage fluid. Despite differing suction strategies, pulmonary function parameters including FEV1%, RV and DLCO% became worse than before WLL. Trial Registration Chinese Clinical Trial registration number ChiCTR2000031024, 21/03/2020.

Whole-Lung Lavage-a Narrative Review of Anesthetic Management.

Pulmonary alveolar proteinosis is a rare disease characterized by progressive accumulation of lipoprotein material in the alveoli as a result of a dysfunction in surfactant clearance. The whole-lung lavage procedure is considered the current standard of care and consists of the sequential lavage of both lungs for mechanical removal of residual material in the alveoli. However, a lack of standardization has resulted in different procedural techniques among institutions. Even though whole-lung lavage is considered to be a safe procedure, unforeseen complications might occur, and proper knowledge of physiologic implications may allow clinicians to establish the appropriate therapy. This review provides an insight into the underlying physiology of the disease, the technical details of the procedure from an anesthesiologist's perspective, and discussion of potential intraoperative complications.

Bilateral Whole Lung Lavage in Hereditary Pulmonary Alveolar Proteinosis in a 4-year-old Child Using Extracorporeal Membrane Oxygenation.

The hereditary form of pulmonary alveolar proteinosis (PAP) is an uncommon entity. We report a case of PAP due to colony-stimulating factor 2 receptor alpha (CSF2RA) gene mutation. The standard of care includes whole lung lavage (WLL). We faced two challenges: Firstly, a severely hypoxemic patient, and secondly, the nonavailability of appropriate size of double-lumen endotracheal tube for pediatric patients for a WLL while permitting single-lung ventilation. Hence, we performed WLL using venovenous extracorporeal membrane oxygenation (VV ECMO) with a successful outcome. The patient has been discharged and is off oxygen support since more than a year. There are only a few case reports of children having hereditary PAP treated with WLL using ECMO in Indian and Western literature. HOW TO CITE THIS ARTICLE: Prabhudesai P, Khosla I, Kulkarni S, Arya MK, Pandey A, Yadav N. Bilateral Whole Lung Lavage in Hereditary Pulmonary Alveolar Proteinosis in a 4-year-old Child Using Extra corporeal Membrane Oxygenation. Indian J Crit Care Med 2021;25(9):1069-1072.

Pulmonary alveolar proteinosis.

PAP is an ultra-rare disease in which surfactant components, that impair gas exchange, accumulate in the alveolae. There are three types of PAP. The most frequent form, primary PAP, includes autoimmune PAP which accounts for over 90% of all PAP, defined by the presence of circulating anti-GM-CSF antibodies. Secondary PAP is mainly due to haematological disease, infections or inhaling toxic substances, while genetic PAP affects almost exclusively children. PAP is suspected if investigation for ILD reveals a crazy-paving pattern on chest CT scan, and is confirmed by a milky looking BAL that gives a positive PAS reaction indicating extracellular proteinaceous material. PAP is now rarely confirmed by surgical lung biopsy. WLL is still the first-line treatment, with an inhaled GM-CSF as second-line treatment. Inhalation has been found to be better than subcutaneous injections. Other treatments, such as rituximab or plasmapheresis, seem to be less efficient or ineffective. The main complications of PAP are due to infections by standard pathogens (Streptococcus, Haemophilus and Enterobacteria) or opportunistic pathogens such as mycobacteria, Nocardia, Actinomyces, Aspergillus or Cryptococcus. The clinical course of PAP is unpredictable and spontaneous improvement can occur. The 5-year actuarial survival rate is 95%.

Combined-modality therapy for pulmonary alveolar proteinosis in a remote setting: a case report.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of phospholipoproteinaceous material in the alveoli. The presentation is nonspecific but typically includes dyspnea; the spectrum of disease includes rapidly progressive hypoxic respiratory failure. Whole lung lavage (WLL) is the treatment of choice in symptomatic PAP, but transient worsening of oxygenation sometimes requires salvage modalities of support such as extracorporeal membrane oxygenation (ECMO). Granulocyte macrophage colony-stimulating factor (GM-CSF) plays a role in the pathophysiology of PAP. We highlight a case of severe PAP treated with exogenous GM-CSF and sequential lobar lavage due to the unavailability of salvage methods of oxygenation. CASE PRESENTATION: A 36 year old female was admitted with fevers, chills, and progressive dyspnea. On presentation she was tachypneic, tachycardic, and hypoxemic; labs revealed leukocytosis and lactic acidosis. Chest CT identified diffuse ground glass opacities in a 'crazy-paving' pattern. Following intubation due to impending respiratory failure, bronchoscopy with bronchoalveolar lavage was performed. The lavage return stained positive with Periodic Acid Schiff, confirming the diagnosis of PAP. Continued deterioration necessitated treatment; however, at this geographically remote center without ECMO services WLL was judged to carry significant risk. Nebulized GM-CSF was administered without significant improvement. Subcutaneous GM-CSF was administered and isolated subsegmental lavages of the bilateral upper lobes were performed, with rapid improvement in oxygenation. Additional sequential lobar lavage and continued GM-CSF therapy as an outpatient resulted in complete resolution of oxygen requirement and return to normal pulmonary physiology. CONCLUSIONS: The autoimmune form of PAP is the most common, indicating that therapy with GM-CSF may play an important role for many patients. Treatment with WLL may be impractical in some clinical settings due to the expertise and salvage modalities required. Sequential lobar lavage requires less specialized expertise and may incur less risk of refractory hypoxemia. We posit that this combined-modality therapy is ideally suited to geographically-remote centers such as our own.

Whole-lung Lavage and Pulmonary Alveolar Proteinosis: Review of Clinical and Patient-centered Outcomes.

OBJECTIVE: The objective of this retrospective review was to evaluate the perioperative and procedural management of patients with pulmonary alveolar proteinosis (PAP) who presented for whole-lung lavage (WLL). DESIGN: The records of all adult patients with PAP who underwent WLL between January 1, 1988 and August 20, 2017 were reviewed and pertinent demographic, preoperative, anesthetic, procedural, and postoperative data were recorded. SETTING: Large academic tertiary referral center. PARTICIPANTS: Forty patients with PAP underwent 79 WLL procedures. INTERVENTIONS: Patients with PAP undergoing WLL. MEASUREMENTS: Successful WLL, defined by visual clearing of lavage fluid, was completed in 91% of cases. Whole-lung lavage was terminated prematurely in 9% of cases (refractory hypoxia most common), while 8% of cases were found to have 30-day complications. There were no cases of intraoperative death, hemodynamic collapse, pneumothorax or hydrothorax, or need for emergent reintubation. Postoperative clinical follow-up at the authors' institution within 6 months of WLL showed 68% of patients reported improvement in symptoms and/or functional status. CONCLUSION: The authors here present a retrospective study describing the perioperative and procedural management of PAP patients undergoing WLL to help familiarize providers with the management of this population (Fig 1). The findings of this study outline a successful and consistent approach to WLL using a multidisciplinary team experienced in this procedure. Even in experienced hands, procedural complications and 30-day postoperative complications emphasize the risk in this complex patient population.

Rituximab for auto-immune alveolar proteinosis, a real life cohort study.

BACKGROUND: Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody. METHODS: We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed. RESULTS: Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naïve to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced. CONCLUSIONS: These data do not support rituximab as a second line therapy for patients with refractory aPAP.

Whole-lung lavage for severe pulmonary alveolar proteinosis assisted by veno-venous extracorporeal membrane oxygenation: a case report.

Pulmonary alveolar proteinosis (PAP) is a rare pathology characterized by accumulation of phospholipoproteinaceous material within the alveoli. The evolution of PAP is variable and treatment modalities are limited. Pharmacological therapeutic targets are being actively developed, but whole-lung lavage (WLL), first described in the 1960s, remains the cornerstone of therapy. The preferential treatment for PAP in our center is sequential WLL, where each lung is separately and sequentially perfused with warmed saline. However, some patients do not tolerate single lung ventilation (SLV), as there is a greater risk of severe hypoxemia with this method. Extracorporeal membrane oxygenation (ECMO), referring to an extracorporeal circuit that directly oxygenates and removes carbon dioxide from the blood, may be considered in highly selected patients with severe respiratory failure who otherwise would not be able to undergo WLL. In this context, veno-venous ECMO is most often utilized. We describe a case of a 44-year-old male diagnosed with silicosis five years earlier who presented with severe hypoxemic respiratory failure not amenable to WLL under general anesthesia with SLV, which was successfully managed with ECMO-assisted WLL.

Case series of rare Interstitial Lung Disease (ILD).

Pulmonary alveolar proteinosis (PAP) is a rare lung disease where periodic acid Schiff (PAS)-positive eosinophilic material accumulates in the alveoli of the lungs. Here we describe two cases of young males who presented with dynpnoea and weight loss. The HRCT scan of the chest in both cases showed the typical "crazy-paving" pattern and lung biopsies confirmed the diagnosis of PAP. They showed remarkable symptomatic improvement with therapeutic whole lung lavage.

[A retrospective study of the perioperative complications following whole lung lavage in the treatment of pulmonary alveolar proteinosis].

Objective: To evaluate the safety of the procedures of whole lung lavage(WLL) for pulmonary alveolar proteinosis(PAP) in perioperative period. Methods: In this retrospective study, we collected clinical data from 78 WLL procedures of PAP patients from January 2006 to June 2016 in Guangzhou Institute of Respiratory Disease. The causes of perioperative complications were analyzed. Results: Eighteen (23.07%) of the 78 procedures developed complications, including pleural effusion(n=4), pneumonia(n=4), cardiac failure(n=2), cardiac arrhythmia (n=2), pneumothorax(n=2), atelectasis(n=1), lung edema(n=1), laryngeal edema(n=1), pleural effusion and pneumonia(n=1). All complications were mild and easy to treat. Seventy-four procedures had successful extubation, but 4 procedures developed a prolonged time of extubation. Age, DSS, PaCO(2,)FEV(1,)lavage volume, lavage times and underlying diseases were not predictors for any complications(each P>0.05). High fluid recovering rate had a protective effect against the occurring of complications (Wald=7.672, OR<0.01, P<0.05). Conclusions: Whole lung lavage was a safe procedure in the treatment of PAP. Complications could recovery after proper therapy. The perioperative complications showed a correlation with low fluid recover rate. Operation under guideline was the key to avoid complications.

A mathematical model to predict protein wash out kinetics during whole-lung lavage in autoimmune pulmonary alveolar proteinosis.

Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5-2.0 l of saline aliquots for 10-30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and ß2-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of ß2-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.

Atypical image of pulmonary alveolar proteinosis - a case report.

Pulmonary alveolar proteinosis is a very rare interstitial lung disease caused by abnormal intra-alveolar surfactant accumulation. Usually, it appears as a "crazy-paving" pattern on high-resolution computed tomography. The image is so typical, that together with the characteristic bronchoalveolar lavage examination with presence of Periodic Acid Schiff positive substance is sufficient for establishing diagnosis, without histological confirmation. We present the case of the young woman with severe dyspnoea suspected of acute hypersensitivity pneumonia. The computed tomography showed numerous intralobular nodules uniformly distributed troughout the lungs. Treatment by corticosteroids had no clinical effect and next computed tomography showed progression. Despite the high risk of complications (patient had a respiratory failure), a surgical lung biopsy was performed and the histopathological diagnosis of pulmonary alveolar proteinosis was made. The whole lung lavage procedure performed twice caused regression of radiological lesions and respiratory failure.

CYFRA 21-1 as a disease severity marker for autoimmune pulmonary alveolar proteinosis.

BACKGROUND AND OBJECTIVE: Serum markers, including Krebs von den Lungen (KL-6), surfactant protein (SP)-D, SP-A and carcinoembryonic antigen (CEA), are reported to reflect autoimmune pulmonary alveolar proteinosis (APAP) disease severity. We evaluated serum CYFRA21-1 levels as a marker of APAP. METHODS: In addition to KL-6, SP-D and CEA, we prospectively measured serum CYFRA 21-1 levels in 48 patients with APAP, consecutively diagnosed between 2002 and 2010. Diagnostic usefulness of CYFRA 21-1 was determined from 68 patients with interstitial lung diseases by receiver operator characteristic curve analysis. We evaluated the association between these serum markers and other disease severity markers, including pulmonary function parameters, alveolar-arterial oxygen gradient, British Medical Research Council score reflecting shortness of breath, and disease severity score. CYFRA 21-1 localization in the lung was examined by immunohistochemistry. RESULTS: Receiver operator characteristic curve demonstrated that CYFRA 21-1 effectively identified APAP. Serum CYFRA 21-1 levels at diagnosis were significantly associated with the measured disease severity parameters. Following whole lung lavage (n = 10) and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation (n = 20), serum CYFRA 21-1 levels were significantly decreased. Responders (n = 11) to GM-CSF inhalation revealed significantly higher serum CYFRA 21-1 levels than non-responders (n = 9). Serum CYFRA 21-1 appeared to be a significant predictor of effectiveness of GM-CSF based on regression analysis. Immunohistochemistry showed that CYFRA 21-1 was localized on hyperplastic alveolar type II cells and lipoproteinaceous substances in alveoli. CONCLUSIONS: Serum CYFRA 21-1 is a sensitive and useful serum marker for diagnosis and evaluation of disease severity of APAP, and may predict the response to GM-CSF inhalation.

Pulmonary alveolar proteinosis: presentation, diagnostic challenges, and management.

Pulmonary alveolar proteinosis is a rare diffuse lung disease; diagnosis and treatment of which is often delayed. We present the case study of a 43-year-old male with a six-month history of worsening breathlessness and non-productive cough referred for specialist respiratory input. Rapid investigations, including high-resolution computed tomography (HRCT) and bronchoalveolar lavage, confirmed the diagnosis of pulmonary alveolar proteinosis. Treatment with whole lung lavage significantly improved pulmonary function and quality of life. We discuss the diagnosis and management of this condition and highlight the importance of early recognition and multidisciplinary teamwork in managing pulmonary alveolar proteinosis.