Presentation and treatment of four children with autoimmune pulmonary alveolar proteinosis (PAP)

Patient 1Patient 2Patient 3Patient 4
Age at presentation14 years14 years10 years15 years
Age at last follow-up14 years, 8 months16 years10 years, 6 months17 years
Previous historyProgressive dyspnoea on exertion for 7 months, two episodes of presumptive “community-acquired pneumonia” with fever, parenchymal lung infiltrates and dyspnoea during the past 18 monthsProgressive dyspnoea with exercise for 1.5 years, weight loss, no appetiteNo previous respiratory complaints. For 1 year, progressive dyspnoea on exertion, dry cough starting with a lower respiratory tract infection with fever over 2 weeks. Weight loss (3–4 kg). For 6 months, inhaled steroids, long-acting β-agonistsNo previous relevant respiratory or other symptoms
3 months of progressive asthenia (very low weight: body mass index 15 kg·m−2; <3rd percentile), dry cough and dyspnoea
Initial presentation37.9°C, progressive dyspnoea, SpO2 89% in ambient air at rest, 94% on 4 L·min−1 oxygen, 25 breaths·min−1, expiratory cracklesNo fever, no infections, pale, acrocyanosis, SpO2 at rest 88%, with slight movements <85%No fever, no infections, pale, tachydyspnoea, SpO2 89% in ambient air at rest, inspiratory cracklesNo fever, significant retractions, tachypnoea, inspiratory crackles
SpO2 <89%
CT scan with crazy-paving patternYesYesYesYes
BAL with milky appearance and cytology with acellular debris, no pathogenic organismsYesYesYesYes
Anti-GM-CSF antibody level (µg·mL−1) (reference <3µg·mL−1)25.521.2Positive (Berlin and Hannover, Germany; not quantified)Highly positive (Cambridge, UK; not quantified)
LDH (U·mL−1) at diagnosis (fold upper limit)
FVC (% pred) initial/last50/6035/3216.5/3532/28
DLCO (% pred)31Not doneNot done (55.3 after first WLL)20.4
SARS-CoV-2 PCR testNegativeSevere COVID-19 at age 15.3 years; 6 days hospitalisation, dexamethasone, 5 days NIV, increased oxygen needNegativeNot done
SARS-CoV-2 serum antibody level (U·mL−1)Not done228 (ref. <0.8)Not doneNot done
WLL number (time period)None13 (within 1 year)3 (within 5 months)6 (within 8 months) prior to rituximab/plasmapheresis over 1 month, followed by 1 WLL after 8 months
Inhaled GM-CSF (dose, duration)Sargramostim (Leukine) 250 μg daily via an LC-STAR nebuliser with a manual interrupter valve connected to a PARI Turbo BOY compressorLimited approval by insurance after 1 year of application and a court hearingSargramostim (Leukine) 250 μg daily via an e-flow nebuliserNot available
Plasmapheresis-scheme, rituximabNot doneNot doneNot done10 sessions of plasmapheresis followed by two doses of rituximab 375 mg·m−2 per dose; clinical improvement with less dyspnoea and need of oxygen
Overall outcome of PAPGradual improvement, complete remission of respiratory failure at rest at the end of the first month of treatment. Treatment was tapered to 4 days on, 1 day off at 3 months of further improvement. At 4 months after treatment initiation, CT of the chest demonstrated amelioration of the radiological findings and PFTs showed an increase of FVC to 58% predicted and DLCO to 49% predictedWith monthly WLL, just stable; deterioration to baseline before next WLLImproved after first lung lavage (no oxygen dependency since then) and initiation of GM-CSF inhalation. No dyspnoea at rest or low physical activity, but no reconstitution of lung function since first WLLWLL insufficiently treating respiratory failure; invasive off-label plasmapheresis and rituximab resulted in less dyspnoea, need of oxygen and WLL. CT and lung function improved, but did not normalise

CT: computed tomography; BAL: bronchoalveolar lavage; GM-CSF: granulocyte–macrophage colony-stimulating factor; LDH: lactate dehydrogenase; FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; WLL: whole-lung lavage; SpO2: peripheral oxygen saturation; COVID-19: coronavirus disease 2019; NIV: noninvasive ventilation; PFT: pulmonary function test.