ABSTRACT
Pulmonary alveolar proteinosis (PAP) is a rare syndrome due to increased
production or decreased clearance of surfactant in alveoli and terminal
bronchi that cause hypoxemic respiratory insufficiency. Here we present
a patient with past medical history of PAP whose disease was exacerbated
by superimposed COVID-19 pneumonia. He underwent whole pulmonary lavage
(WPL). Evaluation of the viral count of the first and the last lavage of
the left lung showed viral load in the alveolar space dropped by
approximately 10-folds, however the magnitude of the viral load was
substantial in both lavage samples. Whole pulmonary lavage may be used
as a treatment option on patients with COVID pneumonia superimposed on a
pulmonary alveolar proteinosis (PAP) exacerbation.
Background
PAP is a rare syndrome characterized by abnormal accumulation of
surfactant in alveoli and terminal airways resulting in hypoxemic
respiratory insufficiency [1,2], and defects in alveolar macrophage-
and neutrophil-mediated host defense [3]. It is divided into
disorders of surfactant production or surfactant clearance [4].
Disorders of production include pulmonary surfactant metabolic
dysfunction disorders caused by mutations in genes encoding surfactant
proteins or genes encoding proteins involved in production of
surfactant. Disorders in clearance can be further divided into primary
PAP caused by disruption of granulocyte/macrophage colony-stimulating
factor (GM-CSF) signaling and secondary PAP caused by another condition
that disrupts alveolar macrophage surfactant clearance.
Case presentation
The patient is a 29-year-old man with a past medical history of PAP
diagnosed in 2018. He had no other medical problems and endorsed working
in construction for 12 years, mainly brick work with some exposure to
cement and dust.
In 2018, he presented with complain of 15-days of lip/ear cyanosis,
shortness of breath (SOB), cough productive of yellow sputum, and
maculopapular rash on his back and neck. He was found to be hypoxic to
72% on room air and admitted to the medical intensive care unit. CT
scan on admission was concerning for PAP with grand glass opacities with
inter-septal thickening. Two months prior to his admission, he had been
hospitalized at another hospital and underwent a lung biopsy that
confirmed PAP. There, he received a right lung lavage with 18L normal
saline, which was aborted as he developed hypoxemia.
Extensive work up was negative for HIV, acid fast bacilli (AFB) and
various fungal infections. His ANA, P-ANCA, C-ANCA were negative. GM-CSF
autoantibody was positive and STAT5 phosphorylation index test was
abnormal.
During his stay, he underwent a left lung lavage with 24L of saline,
followed by a right lung lavage with 25L of saline 7 days later. He was
discharged on room air, with inhaled GM-CSF for 12 weeks. He was
instructed to return to pulmonary clinic for serial pulmonary function
tests (PFT), as well as genetics and rheumatology to assess for familial
autoimmune PAP.
He was lost to follow up until March 2020. In March, he presented to the
emergency department (ED) with SOB, cough with green phlegm, myalgias,
and fever. His chest x-ray showed patchy infiltrates consistent with
pneumonia and CT chest showed diffuse ground glass opacities and
consolidation with interlobular thickening. He was found to be COVID
negative and discharged with a course of doxycycline.
He then presented to the ED in December 2020 with complains of SOB,
headache, and fever for one week. He was found to be hypoxic as low as
55% and admitted to MICU on 40mL/min high nasal flow cannula (HFNC) at
60% inspired oxygen fraction (FiO2). He was found to be COVID+ and
started on Remdesivir and Dexamethasone with cefepime and azithromycin
to cover for superimposed bacterial pneumonia. Due to his history of
PAP, he was started on GM-CSF nebulizers twice a day.
Expectorated sputum was sent for culture, periodic acid Schiff (PAS)
stain, and acid fast bacilli (AFB) and bronchoscopy was deferred due to
COVID positivity and severe hypoxia. Sputum showed granular PAS+, fungal
hyphae suggestive of candida, and rare alveolar macrophages. AFB
cultures were negative x3.
Over the next 4 days his oxygen requirement decreased to 15mL/min HFNC
on 100% FiO2 and he was transferred to the intensive medical unit. Six
days into his admission, the patient reported clinically feeling better
but chest imaging was stable and oxygen requirements remained the same.
Ten days into his admission, his oxygen requirements were unchanged and
CT chest showed crazy paving consistent with PAP (Figure 1).
Due to his inability to wean from HFNC, ongoing sputum production, and
completion of a full course of Remdesivir and Dexamethasone concern was
that his underlying pathology was more likely due to a PAP flare than
his known COVID infection. The patient remained persistently positive
for COVID on PCR throughout his entire admission so a decision was made
to use another course of Remdesivir to hopefully lower his viral load in
anticipation of a bronchoscopy and possible WLL. Unfortunately, his
oxygen saturations worsened and his O2 requirements increased. He was
transferred back to the MICU on HFNC to 40L on 100% FiO2 with worsening
chest x-ray findings.
After a discussion in consensus conference compose of physicians from
infectious disease, pulmonology, critical care, surgery and pathology
regarding this atypical course of COVID pneumonia, the cause of his
ongoing symptoms and worsening oxygen requirements was thought to be
much more likely from a PAP flare. Thus, the decision was made to
undergo a bronchoscopy and perform a WLL with cardiothoracic surgery for
extracorporeal membrane oxygenation backup. Sixteen days into his
admission, we performed a WLL on the patients left lung with 18L NS
(Figure 2). The following day, WLL was performed on the right lung with
18L NS. The patient was successfully extubated the following day and was
discharged 3 days later on 3L NC O2 at rest and 4L with exertion. He was
started one nebulized GM-CSF for a total of 24 weeks, 1 week on and 1
week off.
The first and last specimens from the left WLL were tested (details can
be provided upon request). The viral load in first BAL specimen with the
highest concentration of proteinosis had a high viral load of 8.6
log10 copies/mL of N1. The viral load reduced to 7.7
log10 copies/mL of N1 in the last lavage specimen
obtained, which was also reflected by a decrease in the level of
proteinosis. This suggested that between the lavage samples the viral
load in the alveolar space dropped by approximately 10-folds, however
the magnitude of the viral load was substantial in both lavage samples.
As of 3/15/21, the patient reports he is clinically improving and fully
compliant with his inhaled GM-CSF. He is off the oxygen and saturation
remains >95% during exertion.