Address for Correspondence: Dr C Ravindran, Professor and Head,Dept of Respiratory Medicine, Institute of Chest Diseases, Medical College, Calicut. E-mail nithya_87_5@yahoo.co.in

Abstract: Pulmonary alveolar proteinosis is a rare cause of diffuse infiltrative lung disease. Less than 400 cases were reported so far in world literature. Here we are presenting a case of alveolar proteinosis in a young male who had a rapidly progressing fulminant clinical course.

Key Words: Pulmonary Alveolar Proteinosis,Silicoproteinosis,Surfactant, Crazy Paving

Clinical Profile:

A 35 year old male, non-smoker doing casual job developed progressive breathlessness and dry cough for three months. He also had low grade fever for two months. There was no history of chest pain or palpitation. There is no significant loss of weight. There was no history of exposure to any organic or inorganic dust at work place or any drug intake. Promiscuous sex contact is also not reported. He was apparently normal before the development of these symptoms.

Clinical examination revealed a cyanosed, tachypnoec patient with fine end inspiratory crackles on both lung bases. His cardiovascular system and abdomen were essentially normal.

Investigation:
Blood routine examination: Hb: 12.7Gm%, Total WBC count 9000 cells/cmm, Differential Count: Polymorphs 84% and Lymphocytes 16%, ESR 15 mm fall in one hour.
Fasting Sugar 85 mg%, Blood Urea 35mg%
Sao2: 65% at time of admission and 78% with nasal oxygen of 4litre/minute.
Sputum AFB Negative, Tuberculin skin test: Nonreactive
Sputum and blood culture: No growth detected
HIV Elisa: Negative
HBs Ag: Negative
X- Ray chest: showed bilateral diffuse alveolar shadows more crowded in the midzones resembling Bat wing appearance.

Figure 1 X-Ray chest PA view showing Bat wing appearance

HRCT: Revealed areas of ground glass attenuation in almost all lung fields with fine linear pattern forming polygonal shapes(due to interlobular thickening) seen superimposed on the ground glass opacities - "Crazy Paving" pattern highly suggestive of pulmonary alveolar proteinosis.

Thoracoscopic Lung Biopsy was performed to get a histopathological confirmation. It revealed PAS positive material with few alveolar macrophages.

	Figure 3  Lung biopsy specimen showing PAS positive alveolar filling pattern
	Figure 4  BAL fluid showing PAS positive material
	Figure 5   Lung biopsy specimen showing PAS positive material & Inflammatory cells

Patient underwent bronchioalveolar lavage under unilateral ventilation, Lavage fluid was milky, opaque and it showed PAS positive material confirming the diagnosis.

Figure 6   Typical BAL fluid, milky & opalescent, showing three layers.

Patient showed initial improvement, but had sudden cardiac arrest on the third day of bronchoalveolar lavage and expired.

Discussion: 

Pulmonary alveolar proteinosis (PAP) is a rare disorder. In 1998 Goldstein et al[1] reviewed literature and reported a total of 332 cases till date. Rosen[2] first described PAP in 1958 in a case series consisting of 27 patients, two of whom are children. PAP is characterized by intra alveolar accumulation of lipid and proteinaceous material that is periodic acid schiff (PAS) positive, and is clinically associated with increased work of breathing and derangement of gas exchange.

Etiology:
Three types of PAP are being described 
1) Primary PAP,
2) Congenital PAP and 
3) Secondary PAP. 

Primary PAP is of unknown etiology. Congenital PAP is seen in neonates, due to gene defect leading on to deficient surfactant associated protein-B (SP-B) [3]. This is an autosomal recessive condition. It is also reported that GM-CSF gene is defective in PAP [4]. Secondary PAP occurs due to many causes like

1) Exposure to silica (Siliciproteinosis)[5], aluminium dust, titanium dioxide and other inorganic dust.
2) Haematological malignancies especially of myeloid series[6].
3) In HIV infection it has bees seen associated with Pnemocystis carinii pneumonia.
4) Lysinuric protein intolerance[7]
5) In infections due to mycobacterium avium complex, nocardia asteroids etc.
6) Associated with exposure to certain pesticides
7) Sometimes also seen in conditions like Fanconi syndrome[7], Renal tubular acidosis and exogenous lipoid pneumonia[8].

Pathophysiology:
It is considered to be due either to overproduction of surfactant or impaired surfactant reutilization or clearance. Alveolar proteinosis is a common manifestation of heterogonous factors that affect the type II pneumocytes (which are concerned with secretion and recycling of the surfactant) or alveolar macrophages (which are concerned with the catabolism of the surfactant) or both.

Clinical features:
This usually occurs between the age 20 -50 years with a male predominance of 2:1 to 4:1. No racial predilection is observed. Progressive dyspnoea is the main symptom. Up to 80% of males report with cough[2], which is usually dry, or with scanty sputum. Chest pain is uncommon, seen only in 10 -20% cases[2]. Fever is unusual and if present signifies secondary infection.
Physical signs include tachypnoea and cyanosis. Digital clubbing is a late sign. PAP has been termed as a silent pulmonary condition in that the auscultatory findings are usually less when compared to radiographic appearance. End inspiratory rales may be scattered through out the lung fields.

Radiographic Changes:
The chest radiographic changes in alveolar proteinosis are nonspecific. Bilateral symmetric airspace opacification is usually seen. Shadows are most pronounced in the central lung resembling a butterfly or bat wing appearance seen in pulmonary oedema, although cardiomegaly, kerley lines and pleural effusion are absent9.
Goldstein reported that 62% of patients have alveolar pattern of involvement, 12% an interstitial pattern and 12% a mixed pattern in the chest radiograph[1].
HRCT Thorax demonstrates " Crazy paving" pattern made up of a striking geographical distribution of ground glass opacification and thickened interlobular septa and intralobular septa[9]. Reticular interstitial opacity also may be noted. HRCT appearance is highly suggestive of PAP in appropriate clinical settings.

Pulmonary Function Tests:
PFT may show restrictive pattern with slightly diminished lung volumes and carbon monoxide diffusing capacity[9].

Bronchioalveolar Lavage (BAL):
Classic finding in diagnostic BAL is the milky or opalescent aspirate which shows PAS positive staining. Cell counts and differential counts are not helpful in diagnosis. However elevated level of inflammatory cells may suggest infection either a primary or secondary event.. SP-A and SP-D levels are elevated in BAL fluid[2].

Lung Biopsy:
Open lung biopsy or thoracoscopic biopsy is preferable. Histological findings are of eosinophilic fluid filled alveolar spaces, which stain strongly with PAS. Cholesterol crystals are sometimes being observed. Alveolar structure is generally well preserved with some thickening of interlobular septa. No airway involvement is seen. Electron microscopy may demonstrate lamellar bodies and tubular myelin within the alveolar space in PAP. In congenital alveolar proteinosis usually no tubular myelin is present[2].

Management:
Any precipitating conditions (eg: Malignancy, Infections) should be properly treated as resolution of the primary condition may lead on to remission of PAP. The mainstay of treatment of PAP is whole lung lavage[10]. Lung lavage reduces both symptoms and risk of opportunistic infections. Other modes of therapy include extra corporeal membrane oxygenation and lung transplantation. There are reports of PAP recurring in transplanted lung in adults11. Recently GM-CSF is being tried in patients with PAP[4].

Prognosis:
In congenital PAP mortality is as high as 100% if transplantation is not done[7]. Some patients with primary PAP may undergo spontaneous remission[12]. Mortality in adult patients is between 1 to 8%. The prognosis of secondary PAP is related to its cause. Analysis of cases documented in the literature before the introduction of therapeutic BAL shows that the disease is fatal in about one third of cases, death resulting either from respiratory failure caused by proteinosis or by super infection[1].

Conclusion:

A case of primary alveolar proteinosis in an adult male is reported here due to its rarity. This patient had a short disease span of three months from onset of symptoms to death.

References:
1) Goldstein LS, Kavuru MS, Curtis-McCarthy P et al: Pulmonary alveolar proteinosis, Clinical features and outcome. Chest; 114(5): 1357-62, 1998.
2) Claypool WD, Rogus RM, Mataschak GM: Update on the clinical diagnosis, Management and pathogenesis of Alveolar Proteinosis. Chest; 85(4): 550-8,1984.
3) Ballard PL, Nogee LM, Beers MF: partial deficiency of Surfactant Protein B in an infant with chronic lung disease. Paediatrics; 96(6): 1046-52,1995.
4) Baraclough RM, Gillet AJ: Pulmonary alveolar proteinosis, complete response to GM-CSF therapy. Thorax; 56(8): 664-5,2001.
5) Gough J: Silicosis and alveolar proteinosis. Br Med J 1(540): 629,1967.
6) Habermann TM, Tazelaar HD: Pulmonary complication of Leukemia. Chest; 98(5): 1233-9,1990.
7) Parto K, Kallojoki M, Aho H, Simell O: Pulmonary alveolar proteinosis and glomerulonephritis in Lysinuric protein intolerance, case report and autopsy finding of four paediatric patients. Hum Path; 25(4): 400-7,1994.
8) Fisher M, Riggli V, Merten D et al: Co existing endogenous lipoid pneumonia, Cholesterol granuloma and pulmonary alveolar proteinosis in a paediatric population - A clinical, radiographic, pathologic correlation. Paed Pathol; 12(3): 369-83,1992
9) Lee KN, Levin DL, Webb WR et al: Pulmonary alveolar proteinosis- High resolution CT, Chest radiograph and functional correlation. Chest; 116(4): 989-95,1997.
10) Jasen HM, Zuurmond WW, Roos CM et al: Whole lung lavage under hyperbaric oxygen conditions for alveolar proteinosis with respiratory failure. Chest; 91(6): 829-32,1987.
11) Parker LA, Novotny DB: Recurrent alveolar proteinosis following double lung transplantation. Chest; 111(5): 1457-8,1997.
12) Martinez-Lopez MA, Gomez Cerizo G, Villasante C et al: Pulmonary alveolar proteinosis prolonged spontaneous remission in two patients. Eur Respir J; 4(3): 377-9.1991.

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