Alveolar proteinosis – disease with unpredictable evolution (series of clinical cases)

Anti-GM-CSF antibodies >19 μg/mL are specific to auto-immune PAP; levels <10 mg/mL have a good negative predictive value (28,29). These autoantibodies may be detected at low concentrations in healthy subjects or in patients with acute myeloid leukaemia (30,31). Serum LDH is elevated in half of the cases. KL-6 (Krebs von den Lungen 6), a mucin-like glycoprotein, correlates well with the disease severity, and high levels predict severe evolution and need for repeated whole lung lavage (WLL) (32).

Pulmonary function tests are important for therapeutical decision and disease monitoring. The most frequent pattern is the restrictive one (although smokers can show an obstructive or mixed ventilatory dysfunction), with low diffusing capacity for carbon monoxide (DLco) (20).

In more advanced cases, blood-gas analysis shows arterial hypoxaemia with increased alveolar-arterial gradient. 6-min walking test (6MWT) shows desaturation on effort and is useful in the follow-up of patients.

A 35-year-old male was admitted for fever, sweats, malaise and frequent cough with purulent sputum, starting 5 days ago. He was an active smoker of 13 pack-year. No previous dyspnoea on exertion was noted. Antibiotic treatment with oral cefuroxime was started 2 days before, with only a slight improvement of symptoms.

Physical examination was quite common, except the anterior part of the right hemithorax; end-inspiratory crackles could be heard. Saturation in oxygen in room air was in the normal range.

Chest X-ray showed bilateral perihilar opacities with predominance of lower lobes, more expressed on the right side (Figure 1).

Figure 1

Laboratory investigations from blood revealed leukocytosis (19.300/mm³) with neutrophilia (86.2%), elevated ESR and C reactive protein, negative HIV test, normal liver and kidney parameters.

Sputum examination was negative for acid-fast bacilli, Gram stain showed neutrophils, macrophages, Gram-positive cocci and Gram-negative coccobacilli; the aerobic cultures were negative.

CT scan showed alveolar consolidation in medium lobe with air bronchogram, together with “crazy-paving” areas alternating with normal ones (Figure 2A,B).

Figures 2

Bronchoalveolar lavage from lingula showed rare PAS-positive intra- and extra-cellular corpuscles.

Pulmonary function tests were in a normal range except DLco (51.5% from predicted), with Kco 74.9%.

The diagnosis was “Middle lobe community-acquired pneumonia; a mild form of alveolar proteinosis”.

A broad-spectrum antibiotic treatment was started (cefoperazone + sulbactam), with rapid improvement in general status and remission of fever and cough. A chest X-ray after 3 weeks showed marked remission (Figure 3). No indication for WLL was found, so follow-up without any treatment was the medical decision.

Figure 3

After 6 months, he was evaluated again: he quit smoking, he had no respiratory symptoms, the physical examination was normal, chest X-ray and thoracic CT scan showed complete remission of crazy-paving areas with linear sequellae in median lobe (Figures 4 and 5A,B).

Figure 4

Figure 5

Conclusion in Case 1:mild PAP in infectious context, with spontaneous remission and good prognosis.

A 34-year-old male patient, admitted for severe dyspnoea even at rest, frequent dry cough, night sweats, significant weight loss (≈15 kg in 12 months). The symptoms started 4 months ago, with progressive worsening. He was an active smoker of 20 pack-year and had important professional exposure to silica dust (48).

His general status was severely altered, he had cachexia (BMI = 17 kg/m²), cyanosis, saturation in room air was 72%, with 6 L of oxygen reached 90%, respiratory rate was 30/min. The chest murmur was diminished on the left thorax, and bilateral inspiratory crackles were audible.

Blood tests showed polycythaemia (Hb = 18.56 g/dL; Ht = 56.44%), leukocytosis (16.030/mm³).

Arterial blood gases were severely altered: PaO₂ = 54.8 mmHg, PaCO₂ = 69.7 mmHg, pH = 7.26, SaO₂ = 87% (with 5 L/min O₂).

The chest X-ray (Figure 6) showed “white lungs” and a partial left pneumothorax. A CT scan performed a few days before admission (Figure 7) revealed widespread “crazy-paving” with almost no normal areas, no pneumothorax.

Figure 6

Figure 7

A bronchoalveolar lavage was done despite severe hypoxaemia and showed abundant PAS-positive material, supporting the diagnosis of PAP, probably secondary to silica dust exposure.

Because of the left pneumothorax, the WLL at the moment of diagnosis was impossible. A sequential therapeutic approach was started, with surgical tube drainage of the pneumothorax as the first step. Unfortunately, the lung failed to re-expand after 30 days, with the presence of a large broncho-pleural fistula.

The next step was the surgical intervention for the suture of fistula, with very risky anaesthetic and surgical conditions (the quality of lung tissue was not known and possible risk of dehiscent sutures). The postoperative evolution was good, with re-expansion of the left lung (Figure 8).

Figure 8

Then both lungs were consecutively washed by WLL 3 weeks apart, with excellent immediate evolution, both clinical and radiological.

Chest film showed great improvement after 3 months (Figure 9). Further exposure to silica was avoided, and no relapse occurred after years.

Figure 9

Conclusion in Case 2:extremely severe form of secondary PAP probably related to professional exposure to silica dust; difficult therapeutic approach due to severity of the respiratory failure and left spontaneous pneumothorax; excellent results after only one WLL on each lung; good prognosis because of cessation of exposure.

A 31-year-old non-smoker woman, with no professional exposure, who was diagnosed with an interstitial lung disease in 2011 which proved to be PAP after surgical lung biopsy from lingula.

She had multiple WLL on both the lungs because she had symptoms (dyspnoea on minimal efforts and cough), a reduction in lung volumes (vital capacity at 54% from predicted, FEV1 at 55% from predicted), desaturation on 6MWT (from 94% to 70% after 6 min), LDH was >1,000 U/L.

Despite good immediate results after each WLL, her symptoms and X-ray worsened every 3–6 months, demanding a new WLL (Figures 10,11,12,13).

Figure 10

Figure 11

Figure 12

Figure 13

Conclusion in Case 3: A recurrent form of PAP (probably autoimmune form), demanding repeated WLL every 3–6 months; poor prognosis due to frequent relapses in the last 7 years.

A 52-year-old non-smoker male with no professional exposure who was addressed to the pneumology department for dry cough and mild dyspnoea on exertion.

Chest X-ray showed bilateral alveolar opacities in both the lungs with lower lobe predominance (Figure 14).

Figure 14

Blood tests showed polycythaemia (Hb = 18.50 g/dL; Ht = 54.2%), elevated LDH (880 U/L), no inflammatory syndrome, number of leucocytes in a normal range.

Pulmonary function tests showed normal volumes and capacities, but low DLco (65% from predicted).

The 6MWT showed desaturation on effort (from 95% to 84%). Thoracic CT scan revealed widespread “crazy-paving” together with normal areas, giving to clinician a high suspicion of PAP (Figure 15A–D).

Figure 15

Bronchoalveolar lavage was done showing a milky fluid with abundant PAS-positive material, supporting the diagnosis of PAP.

A first WLL was done on the left lung with 15 L of saline, with good results.

After discharge from our hospital, the patient was evaluated in other services and haematologic diseases or other solid organ tumours were excluded.

In the next 10 months, the patient’s respiratory condition worsened, so after 6 months from diagnosis he already had signs of chronic respiratory failure; he had a second and a third WLL with a slight improvement and was discharged from hospital with oxygen at home.

In 4 months, he was admitted again, with severe hypoxemic respiratory failure (SaO₂ = 75% in room air), frequent cough, orthopnoea, with bilateral inspiratory crackles. Chest X-ray (Figure 16) and CT scan (Figure 17A–D) showed impressive worsening, both the lungs are being occupied by a “crazy-paving” pattern, with almost no normal areas. He needed supplemental oxygen at high flow (reservoir-mask, high flow nasal cannula) to maintain SaO₂ around 90%. His PaO₂ was <50 mmHg in room air, with an elevated alveolar-arterial difference.

Figure 16

Figure 17

The autoantibodies against GM-CSF were positive (26 mg/mL), which proved the autoimmune nature of PAP.

He had several successive WLL on both lungs, but the patient’s condition was not much better despite its apparent usage (Figure 18 shows the fluid at the beginning and the end of WLL, much improved). He became bed-ridden and needed someone else to take care of him.

Figure 18

In front of this dramatic situation, we addressed other therapies, suitable for autoimmune PAP non-responsive to WLL: he had 5 days of plasmapheresis, followed by therapy with inhaled GM-CSF (Sargramostim 250 mg/day) for 15 days. A slight improvement was noted (better oxygenation), which allowed the patient to be discharged from the hospital, with oxygen at home. There, he continued to feel better, he obtained SaO₂ >90% with only 5–6 L/min of oxygen and he could walk a short distance around the bed. This encouraged us to have a second session of plasmapheresis, followed by inhaled Sargramostim 250 mg/day for another 15 days. With this therapy, his condition continued to become better, and the last evaluation showed marked clinical improvement (SaO₂ = 95% with 3 L/min O₂ through a nasal cannula) and also a radiological one (Figure 19).

Figure 19

Conclusion in Case 4: extremely severe form of autoimmune PAP, refractory to repeated WLL; good response to alternative therapies (plasmapheresis, inhaled GM-CSF). Future concerns: how stable is this improvement? where to get from GM-CSF on a long-term basis, as it is an off-label prescription?