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Year : 2016  |  Volume : 33  |  Issue : 6  |  Page : 626-634  

Pulmonary alveolar proteinosis: Experience from a tertiary care center and systematic review of Indian literature

1 Department of Pulmonary Medicine and Sleep Disorders, All Institute of Medical Sciences, New Delhi, India
2 Department of Anaesthesiology, All Institute of Medical Sciences, New Delhi, India
3 Department of Pathology, All Institute of Medical Sciences, New Delhi, India

Date of Web Publication27-Oct-2016

Correspondence Address:
Vijay Hadda
Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-2113.192876

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Background: Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by deposition of lipoproteinaceous material within alveoli, with a variable clinical course. Here, we report an experience of management of PAP at our center. A systematic review of previously reported cases from India is also included in the article. Materials and Methods: This study included patients with primary PAP managed at our center from 2009 to 2015. Diagnosis of primary PAP was based on histopathologic diagnosis on bronchoalveolar lavage or transbronchial lung biopsy and absence of causes of secondary PAP. For systematic review of Indian publications, the literature search was performed using PubMed and EMBASE databases using the terms “pulmonary alveolar proteinosis'” or “alveolar proteinosis” and “India” or “Indian.” Results: During the above-specified period, five patients with diagnosis of PAP were admitted at our center. Median age of patients was 32 years (interquartile range [IQR] 30.5–59); 80% were female. Mean duration (± standard deviation) of symptoms was 6.2 (±1.79) months. Anti-granulocyte-macrophage colony stimulating factor (GM-CSF) antibodies were elevated in 4 out of 5 patients (80%). For management, whole lung lavage (WLL) was done for four patients with median volume of 32.5 (IQR 18–74) L per patient. All the patients showed significant symptomatic as well as improvement in physiological parameters. Subcutaneous GM-CSF and ambroxol were given to 3 patients and 1 patient, respectively. The median follow-up of all patients was 18 (IQR 5–44) months. A systematic review of all Indian studies of PAP revealed thirty publications. Conclusions: WLL is the most common, effective, and safe therapy in patients with PAP. GM-CSF administration is an efficacious treatment for patients with incomplete response after WLL.

Keywords: Granulocyte-macrophage colony stimulating factor, pulmonary alveolar proteinosis, whole lung lavage

How to cite this article:
Hadda V, Tiwari P, Madan K, Mohan A, Gupta N, Bharti SJ, Kumar V, Garg R, Trikha A, Jain D, Arava S, Khilnani GC, Guleria R. Pulmonary alveolar proteinosis: Experience from a tertiary care center and systematic review of Indian literature. Lung India 2016;33:626-34

How to cite this URL:
Hadda V, Tiwari P, Madan K, Mohan A, Gupta N, Bharti SJ, Kumar V, Garg R, Trikha A, Jain D, Arava S, Khilnani GC, Guleria R. Pulmonary alveolar proteinosis: Experience from a tertiary care center and systematic review of Indian literature. Lung India [serial online] 2016 [cited 2021 Jun 14];33:626-34. Available from: https://www.lungindia.com/text.asp?2016/33/6/626/192876

   Introduction Top

Pulmonary alveolar proteinosis (PAP) is a rare clinical syndrome associated with deposition of lipoproteinaceous material within alveoli, leading to varied clinical presentations ranging from being asymptomatic to respiratory failure. Exact incidence PAP is not known; estimated prevalence is approximately 1–2 per million people. It predominantly affects men, with male to female ratio 3:1, in the third and fourth decades of life.[1],[2]

Three forms of PAP are recognized – congenital, secondary, and acquired or primary. Among these, primary PAP remains the most common, constituting up to 90% of all reported cases. The most common clinical manifestation is progressive dyspnea (50–80%).[2],[3] Other symptoms of PAP include dry cough, fatigue, and low-grade fever.[2],[3] Due to macrophage and neutrophil dysfunction, there is increased risk of superinfection in PAP with organisms such as Nocardia, mycobacteria, and endemic or opportunistic fungi.[1],[2] Patients can have polycythemia, hypergammaglobulinemia, increased lactate dehydrogenase (LDH), and various tumor marker levels. Diagnosis is suspected based on the presence of homogeneous ground-glass opacities (GGOs), with thickened intralobular and interlobular septa in typical polygonal shapes, referred to as “crazy-paving” on high-resolution computed tomography (HRCT) of the chest.[4],[5] Fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) are diagnostics. Characteristic BAL findings of PAP include opaque or milky appearance, which settles on standing. Lung biopsy shows preserved alveolar architecture, slight thickening of alveolar septa, little or no inflammatory cell infiltration, and presence of PAS-positive proteinaceous material in a background of eosinophilic granules in terminal bronchioles and alveoli. Electron microscopy of BAL fluid or lung tissue shows concentrically laminated structures called lamellar bodies. These bodies are comprised phospholipids and are probably derived from the Type II alveolar epithelial cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) autoantibodies have been casually linked to autoimmune or primary PAP, and elevated levels are diagnostic, with almost 100% sensitivity and 98% specificity for primary PAP.[6]

Treatment options for PAP include observation and close follow-up, whole lung lavage (WLL), GM-CSF, and rituximab. Asymptomatic patients with little or no physiologic impairment are usually closely followed up with periodic symptom assessment, pulmonary functions tests, and imaging. Those with mild symptoms and mild hypoxemia on exertion can be treated symptomatically or with oxygen supplementation. Patients with severe symptoms and severe impairment on physiologic testing are treated with WLL. The patients with progressive disease despite WLL or those not tolerating WLL are treated with GM-CSF. Rituximab is used as the last resort.[7]

PAP being a rare disease, the experience of managing such patients in our country is limited only to case reports and small case series.[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33] It should also be noted that the facility and expertise for management of PAP may not be available at all centers. We hereby report the experience of treatment of PAP from our center. In addition, we performed a systematic review of all previously reported cases of PAP from India.

   Materials and Methods Top

This study includes all patients of PAP admitted at our center from January 2009 to July 2015. Patients with clinicoradiological features of PAP underwent BAL and TBLB to establish the diagnosis. All patients were evaluated for secondary causes of PAP, including BAL cultures to rule out infections and hematologic malignancies. Attempts to test serum GM-CSF autoantibody testing were made for all patients. GM-CSF autoantibody testing was done using enzyme-linked immunosorbent assay at Translational Pulmonary Science Center Laboratory, Cincinnati Ohio, USA (Courtesy: Dr. Bruce C. Trapnell; supported in part by National Heart, Lung and Blood Institute grant HL985453 to Dr. Bruce C Trapnell).

Selection of treatment modality

Treatment of all patients was based on symptoms which included dyspnea or cough related to PAP.[2] Symptoms were classified using dyspnea severity score (DSS) which ranges from 1 to 5. Patients who were asymptomatic with PaO2 ≥70 mmHg were classified as DSS 1; symptomatic patients with PaO2 ≥70 mmHg were classified as DSS 2; patients with PaO2 from 60 mmHg to ≤70 mmHg were classified as DSS 3; patients with PaO2 from 50 mmHg to ≤60 mmHg were classified as DSS 4; and patients with PaO2 <50 mmHg were classified as DSS 5.

Patients with no or mild symptoms were kept under close follow-up with every 6 monthly (earlier, if required) assessment of symptoms and physiological parameters. Patients with moderate to severe symptoms (DSS 3 or more), those with progressive symptoms, and those with alveolar–arterial oxygen ([A-a]O2) gradient >40 were offered WLL.

WLL was performed after putting double-lumen tracheal tube (DLT) under general anesthesia in operation theater or interventional bronchoscopy suite using the standard guidelines [34],[35] by a team of interventional pulmonologists, anesthetists, and physiotherapist. Extracorporeal membrane oxygenation (ECMO) backup was kept arranged. Following WLL, for evaluation of response DSS, arterial blood gas analysis, pulmonary function test (PFT), 6 min walk test, chest radiograph, and HRCT of the chest were performed and compared with the baseline. Patients with residual symptoms, elevated (A-a)O2 gradient, and residual GGOs on HRCT were treated with subcutaneous GM-CSF.

Systematic review of Indian studies

We performed a systematic review of all reported cases of PAP from India. For systematic review, the literature search was performed using PubMed and EMBASE databases using the terms “pulmonary alveolar proteinosis” or “alveolar proteinosis” and “India” or “Indian”.

   Results Top

During the above-specified period, five patients with PAP were admitted under our unit. Median age of patients included was 32 (interquartile range [IQR] 30.5–59) years. The youngest patient was 27 years of age at diagnosis and the oldest patient was 71 years of age. Mean duration (± standard deviation) of symptoms was 6.2 (±1.79) months. Dyspnea and cough were the presenting complaints. Four patients had symptoms and hypoxemia at admission while one patient was asymptomatic. Elevated LDH levels were present in 4 out of 5 patients (80%). Other baseline characteristics are shown in [Table 1].
Table 1: Baseline characteristics of the study participants

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All patients were diagnosed as primary PAP on the basis of clinicoradiological and histopathological findings and absence of causes of secondary PAP. Anti-GM-CSF antibodies were elevated in all four patients who were tested for it.

All four symptomatic and hypoxemic patients were treated with WLL. All patients required more than one session of WLL. Two patients required two sessions and two patients required three sessions. A median WLL volume of 32.5 (IQR 18–74) L was required per patient. The highest cumulative WLL volume lavage was 85 L in three sessions (Case 4). All the patients showed significant symptomatic improvement along with improvement in oxygenation and spirometric parameters, following WLL [Table 2]. Complications associated with WLL include hypoxemia or hypotension (n = 2); DLT displacement (n = 1); visible fluid in the ventilating side of WLL (n = 1); and ineffective ventilation with DLT (requiring DLT replacement/repositioning [n = 1]). There were no instances of pneumothorax, hemodynamic compromise, salvage requirement of ECMO, ventilator-associated pneumonia, or death.
Table 2: Comparison of important clinical and laboratory features before and after whole lung lavage

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Three patients were treated with subcutaneous GM-CSF therapy. One patient was treated initially with GM-CSF for 6 weeks, with partial improvement in symptoms and required WLL. Two patients were treated with GM-CSF after WLL [Table 2].

All patients were followed up for a median period of 18 (IQR 5–44) months. One patient developed leukocytosis with total leukocyte counts of 90,000/dl, following GM-CSF and required dose adjustment. Significant improvement was achieved in all the patients with therapeutic WLL and/or GM-CSF. All the patients have shown persistent response to treatment, without any evidence of symptomatic or radiologic worsening with stable spirometric and 6 min walk test variables on follow-up till date.

Case details

Case 1

A 27-year-old homemaker, resident of Delhi, presented with progressive dyspnea and dry cough for 8 months. There was no history of fever, other constitutional symptoms, exposure to dust or fumes, arthralgias, oral ulcers, photosensitivity, or recurrent lower respiratory tract infections. There was no history of hematologic malignancy, chemotherapy, or immunosuppressant drug intake. At presentation, she was hypoxemic (SpO2 81%) on room air. The examination of the chest revealed bilateral scattered crepitations. Her chest radiograph showed bilateral middle and lower zone interstitial infiltrates. HRCT of the chest showed bilateral GGOs, more in the left lung fields as compared to the right, with interlobular septal thickening (crazy-paving). TBLB showed PAS-positive diastase-resistant material suggestive of PAP. Workup for secondary PAP was negative. Spirometry (though poorly performed due to poor effort) revealed severe restriction (forced expiratory volume in one second/forced vital capacity [FEV1/FVC] 99; FEV1 29.5%; FVC 33.6%), and diffusion for carbon monoxide (DLCO) could not perform. Initial (A-a)O2 gradient was 125. She refused to undergo WLL; therefore, subcutaneous GM-CSF was started (5 µg/kg/day). There was partial symptomatic response, and (A-a)O2 gradient was still elevated (96) after 6 weeks of GM-CSF. Counseling of the patient and relatives was done again. This time, all agreed and patients underwent two sessions of therapeutic WLL augmented with chest physiotherapy under general anesthesia. There was significant improvement in symptoms as well as physiological and radiological parameters. She has been asymptomatic without any radiologic progression on follow-up for the last 5 years.

Case 2

A 32-year-old nonsmoker man, working in petrochemicals in Assam, was referred for evaluation of bilateral alveolar infiltrates on the chest radiograph done for routine yearly medical examination. He had no symptoms even on severe exertion. His history was unremarkable. Clinical examination did not reveal any abnormality. HRCT of the chest showed bilateral alveolar opacities, predominantly in bilateral lower lobes, with GGOs and septal thickening. BAL fluid was milky and cytology and TBLB both showed typical finding of PAP. Serum anti-GM-CSF antibody was positive (88.7 µg/ml). Workup for secondary PAP was negative. Spirometry revealed FEV1/FVC 78%; FEV1 74%; FVC 76%; and DLCO 64%. Room air saturation was 98% and (A-a)O2 gradient was 18. In view of the absence of symptoms and physiological abnormality, he was kept under close follow-up, with a plan for WLL or GM-CSF therapy in the event of progression of disease. However, he continues to be asymptomatic without any worsening in (A-a)O2 gradient, radiologic or spirometric variable on follow-up for the last 2 years.

Case 3

A 30-year-old homemaker, from Nepal, presented with productive cough and progressive dyspnea (modified Medical Research Council II to IV) for the last 8 months. Symptoms started during the third trimester of pregnancy. These symptoms were attributed to being pregnancy related and no further evaluation was done. She had relatively uneventful peripartum course and had full-term normal delivery 5 months back. However, her symptoms continued to progress; she developed Type I respiratory failure for the last 2 months before presentation. She had no history of fever, other constitutional symptoms, exposure to dust or fumes, arthralgias, oral ulcers, photosensitivity, or recurrent lower respiratory tract infections. Her history was unremarkable. On examination, she was tachypneic and bilateral scattered crepitations were present on auscultation of the chest. Her oxygen saturation and PaO2 while breathing at room air were 78% and 51 mmHg, respectively. The (A-a)O2 gradient was 187. She could not perform spirometry. Her chest radiograph showed bilateral middle and lower zone interstitial infiltrates. HRCT of the chest showed bilateral crazy-paving pattern. Workup for secondary PAP was negative. Diagnosis of PAP was confirmed on both BAL and TBLB. Serum GM-CSF antibody test was positive (271.3 µg/ml). She underwent three sessions of WLL under general anesthesia with significant improvement in symptoms, (A-a)O2 gradient, and radiology. She was able to perform PFT and 6 min walk test. She has been asymptomatic without any radiologic progression on follow-up for the last 18 months.

Case 4

A 65-year-old homemaker presented with complaints of dry cough and dyspnea started 4 months ago. The dyspnea was rapidly progressive, and at presentation, she was dyspneic even at rest. She had no fever, chest pain, or hemoptysis. She had diabetes mellitus, hypertension, and hypothyroidism diagnosed 5, 5, and 3 years back, respectively. On examination, she was tachypneic and chest examination revealed bilateral scattered inspiratory crepitations. Chest radiograph showed bilateral reticular and alveolar opacities in the bilateral middle and lower zones. HRCT of the chest showed bilateral middle and lower lobe predominant GGOs, with interlobar septal thickening. Arterial blood gas (ABG) showed pH 7.47 with pCO2 30 mmHg and PO2 72 (FiO2 35%), suggestive of respiratory alkalosis with hypoxemia, and (A-a)O2 gradient was 128. PFT showed FEV1/FVC 78%; FEV1 63%; FVC 69%; and DLCO 58%. BAL and TBLB revealed features of PAP. Workup for secondary PAP was negative. Serum GM-CSF antibody test was positive (62.9 µg/ml). She underwent three sessions of WLL. With WLL, she had partial relief in symptoms and still had elevated (A-a) O2 gradient. In view of this, we started subcutaneous GM-CSF (3 µg/kg/day; increased to 5 ug/kg/day). In view of neutrophilic leukocytosis, the dose of GM-CSF was adjusted and she received 300 µg on alternate days. With this, she showed improvement in symptoms, radiology, physiological parameters, and 6 min walk distance.

Case 5

A 71-year-old homemaker presented with productive cough and progressive dyspnea for the past 4 months. For the last 2 months, she had respiratory failure and requiring continuous supplemental oxygen to maintain saturation. She had no constitutional symptoms. She had systemic hypertension and hypothyroidism diagnosed 7 and 5 years ago, respectively. There was no other significant history. On examination, she was tachypneic, with bilateral inspiratory crepitations on chest examination. ABG was suggestive of respiratory alkalosis, with hypoxemia and elevated (A-a)O2 gradient. PFT showed moderate restriction (FEV1/FVC 84; FEV1 54%; FVC 60%; DLCO 54%). HRCT of the chest, BAL, and TBLB revealed features of PAP. Workup for secondary PAP was negative. Serum GM-CSF antibody test was positive (29.2 µg/ml). She underwent two sessions of WLL. First, WLL was performed on the right lung with 28 L of saline. Six days later, she underwent WLL with 13 L of saline on the left lung. With WLL, she had partial improvement in symptoms and borderline (A-a)O2 gradient. Therefore, she was initiated on GM-CSF therapy (3 µg/kg/day) along with ambroxol (45 mg/day). Currently, she is able to do all daily chores without difficulty, with improvement in (A-a)O2 gradient and 6 min walk distance.

Systematic review of Indian cases of pulmonary alveolar proteinosis

A total of 69 citations were identified (28 in PubMed and 41 on EMBASE). After initial screening, thirty studies were excluded either because of duplicate citations (n = 24) or not related to PAP (n = 6).[36],[37],[38],[39],[40],[41] Remaining 39 studies were selected for further analysis. Among these, 5 studies were not from India,[42],[43],[44],[45],[46] seven studies were review articles,[47] meta-analysis,[48] laboratory experiments,[49],[50] comments,[51] replies to previous comments,[52] or quiz [53] and they were excluded from the study. No abstract or full text was available for two citations [10],[54] and both were also excluded. Finally, 25 studies were selected for systematic review [Table 3].
Table 3: Summary of the case studies included for the systematic review

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The median age of patients was 34.5 (IQR 19–45) years at diagnosis. Among these, two were infants and three were adolescents. There were 23 (76.7%) men. Four patients were smokers. The common reported symptoms were dyspnea (83.3%), cough with or without expectoration (70%), fever (26.7%), loss of weight or appetite (16.67%), bilateral pneumothorax (6.6%), and pleuritic chest pain (3.3%). One-third of the patients (33.3%) presented to hospital with respiratory failure. Median duration of symptoms (reported by 25 studies) was 4 months (IQR 3-9). History of pulmonary tuberculosis was present in 3 (10%) patients.

Diagnosis of PAP was based on BAL cytology (23.3%), TBLB (26.6%), VATS-guided lung biopsy (3.3%), thoracoscopic lung biopsy (3.3%), open lung biopsy (33.3%), and postmortem lung biopsy (6.6%). Anti-GM-CSF antibody testing was done only in one case. One report did not mention the mode of diagnosis. Majority of patients, i.e., 24 (80%) had primary PAP. Remaining six patients were labeled as secondary PAP related to cyclosporine/mycophenolate (1), cotton dust exposure (2), sandstone exposure (1), glass cutting and fiber exposure (1), or Nocardia (1). Concomitant infections were seen in four (Mycobacterium tuberculosis [n = 2] and Pneumocystis jiroveci [n = 2]) patients.

Among these, two patients (6.67%) did not receive any treatment for PAP. WLL was performed for 17 (56.67%) patients. The details of WLL were reported in 14 studies. WLL was performed for both lungs (n = 5) during the same session (simultaneous WLL) or one lung followed by other (n = 9) after variable interval (sequential WLL). Complications reported with WLL include need for ECMO (n = 1)[12] and tension pneumothorax (n = 1).[12] Other procedures described for treatment of PAP include serial lobar lung lavage using flexible bronchoscopy for 3 (10%) patients [20],[22],[25] and large volume bronchoscopic [29] and nonbronchoscopic BAL [18] for one each (both for children).

Medical treatment including subcutaneous GM-CSF therapy was given to 9 (30%) patients. The dosage and duration were variable. Other medications which were used include n-acetylcysteine (n = 1) and intravascular immunoglobulin (n = 2, both infants).[18],[29] Five patients received specific antimicrobial therapy – anti-tubercular therapy (n = 2, both BAL showed acid-fast bacilli)[17],[22] and co-trimoxazole (2 for PCP [17],[22] and one for nocardiosis [12]). Long-term oxygen therapy (LTOT) was prescribed to two patients at discharge.[16],[29] Among all cases, 5 (16.7%) patients were given empirical anti-tubercular therapy before diagnosis.[15],[20],[31],[32]

All patients who were treated with either WLL or GM-CSF along with other treatment showed significant symptomatic and radiologic improvement at discharge. Two (6.6%) patients died during index admission.[9],[32] One patient died 1 week postdischarge on LTOT.[29] The reported follow-up duration is variable, ranging from 2 weeks to 3 years. No details regarding follow-up after discharge could be found for 9 studies.[11],[15],[19],[20],[26],[27],[30],[31] One study mentioned symptomatic improvement on follow-up (duration not mentioned).[20] One patient required two more sessions of WLL over during 2.5 years along with GM-CSF administration and was asymptomatic during additional 1 year of follow-up.[13]

   Discussion Top

In this study, we describe our experience of managing patients with PAP for the last 6 years. During this period, five patients got admitted with the diagnosis of PAP. Among these, 4 patients were treated by WLL. WLL has been described as early as in the 1960s. Since then, it has remained the most effective therapeutic option for treatment of PAP. WLL is an invasive procedure which is done under general anesthesia and quite labor intense procedure. The procedure requires a multidisciplinary team consisting pulmonologists, anesthetist, and respiratory therapist/physiotherapist and may take many hours to get the desired results. However, based on its efficacy, it is the “standard of care” for the treatment of PAP, especially for patients with respiratory failure. In this study also, all patients showed significant improvement in symptoms, oxygenation, and radiology. Notably, all these patients had respiratory failure. Our results are consistent with the previous case reports. WLL, although time-consuming, is a relatively safe procedure for these patients. As described in this study, complications associated with WLL include hypoxemia or hypotension, DLT displacement, visible fluid in the ventilating side of WLL, and ineffective ventilation with DLT. All these complications may be managed easily. Other major complications which may occur in these patients include pneumothorax, hemodynamic compromise, ventilator-associated pneumonia, or death.[34] While performing the WLL, one should be ready for salvage requirement of ECMO, in case severe compromise of ventilation.[55] During the study period, we did not come across any such complication; however, we had ECMO backup facility. Our systemic review of Indian studies also showed that among patients who required treatment, WLL was offered to 56.67% (17/30) and all of those showed improvement; one of the patients required ECMO during WLL.[12]

Some authors, especially for children, have used BAL instead of WLL as a therapeutic modality though results were variable. One child was managed with large volume (exact volume not mentioned) BAL every week and was discharged after 4 months from the hospital. However, this patient also received co-trimoxazole, steroids, and intravenous immunoglobulin (IVIG).[18] Other child who treated with BAL also stayed in hospital for more than 2 months and died after 1 week of discharge.[29] Both these reports suggest that BAL with or without other drugs (co-trimoxazole, steroids, IVIG) is not an optimum treatment for PAP.

Among medical management options, subcutaneous GM-CSF is the most commonly used drug.[48] Considering the fact that reduced GM-CSF effect (e.g. due to altered receptor function or antibodies) contributes to PAP pathophysiology, GM-CSF therapy should have a significant role. In this study, three patients received GM-CSF. One patient received it as the first-line treatment; however, despite treatment, the patient did not improve and WLL was done later. Other two patients received GM-CSF due to the suboptimal improvement following WLL. Indicating that response to GM-CSF may be variable. The factors which may be responsible for variable response include the neutralizing capability of endogenous GM-CSF antibodies and penetration of subcutaneous GM-CSF to reach the site of action, i.e., alveoli. Whatever may be the reason, however, it seems that GM-CSF alone is not an effective therapy for PAP. Therefore, it should be reserved for the patients where either WLL is not possible or there is suboptimal improvement following WLL. Other drugs which have been used for treatment of PAP include rituximab [56] and ambroxol.[57] A reasonable approach for treatment of PAP is patients with severe symptoms, and impairment on physiologic testing should be treated with WLL; patients with progressive disease or those not tolerating WLL should be treated with subcutaneous GM-CSF; and rituximab should be used as the last resort.[7]

Long-term prognosis is unclear. Significant spontaneous improvement has been described in 7.9% of patients.[2] No simple biochemical or clinical parameters are in routine use as prognostic variables. Only 10–15% patients may die directly from PAP-induced pulmonary failure. A recent study noted a PAP recurrence rate of <30% at 7 years after successful WLL; residual gas exchange abnormalities and exercise intolerance were common, even in the absence of recurrent PAP.[58] In our study, no patient required WLL during follow-up till date.

One of the important features of PAP is presence of macrophage and neutrophil dysfunction which predisposes these patients to increased risk of superinfection with organisms such as Nocardia, mycobacteria, and endemic or opportunistic fungi.[1],[2] In our systematic review of Indian studies also, 4 (13.33%) patients had concomitant infections (M. tuberculosis[17],[22] and P. jiroveci,[17],[22] two each). However, it should be noted that 5 (16.7%) patients were given empirical anti-tubercular therapy before diagnosis.[15],[20],[31],[32] Inappropriate use of ATT is associated with adverse effects and increased risk of multidrug-resistant mycobacteria. Although this is a rare condition, physicians treating such patients should be aware of this differential diagnosis so that appropriate management may be initiated and unnecessary medications may be avoided. Progressive respiratory failure and typical crazy-paving pattern on radiology may be a helpful clue. Such patients should be referred to higher centers with experience in treating such patients.

One of our patients (Case 3) had onset of symptoms in the third trimester of pregnancy. Although she did not have any peripartum complication, her symptoms progressed to Type I respiratory failure. The relationship between pregnancy and PAP is not known. There are only few case reports describing PAP during pregnancy.[59],[60],[61],[62] Its presence may lead to perinatal or postnatal complications.[59],[60],[61],[62] Whether physiologic changes in pregnancy or alteration in levels of various growth factors predispose to PAP is not known.[63]

This study reports one of the largest case series of PAP from India. Similar to this study, Khan et al. also published a case series from another tertiary care hospital.[12] Although the results of both studies are comparable, in this study we were able to demonstrate anti-GM-CSF antibodies in 4 out of 5 patients, therefore confirming the diagnosis of primary PAP. Being a rare disease, it is less likely that the number of patients in any study is going to be huge. This study has given a good overview of clinical profile and management issues of patients with PAP.

   Conclusions Top

Our study indicates that the PAP is rare disease entity with an incidence of approximately 5 per 1100 hospital admission in respiratory unit at a tertiary care center. The presentation may vary from progressive respiratory failure to totally asymptomatic radiological abnormality. Crazypaving pattern on the chest computed tomography scan is quite typical of PAP. Flexible bronchoscopy can make diagnosis in almost all patients. WLL is safe and the most effective treatment for patients with PAP. A few patients may require experimental therapy such as GM-CSF, rituximab, and ambroxol.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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  [Table 1], [Table 2], [Table 3]


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