174 AJTCCM VOL. 29 NO. 4 2023
TO THE EDITOR: Tuberculosis (TB) is a common cause of chronic
cough in South Africa (SA). Empirical anti-TB therapy is often
initiated in the absence of a microbiological diagnosis. We report on
a patient who initially commenced treatment for TB despite negative
sputum results and on re-evaluation was diagnosed with pulmonary
alveolar proteinosis (PAP), which is a rare cause of chronic cough.
is case report emphasises the need for microbiological diagnosis
of pulmonary TB to justify the long-term use of potentially toxic
medications, and also shows that rare diseases may present with
common TB-like symptoms.
A 29-year-old black African woman had a 12-month history of dry
cough, weight loss, intermittent wheezing and progressive dyspnoea.
She was HIV negative and had no constitutional symptoms such as
anorexia, fever or night sweats, and no joint pains or stiness. She had
never smoked, and had no exposure to organic or inorganic dust. She
had been commenced on empirical treatment for TB at a peripheral
hospital before transfer to Nelson Mandela Academic Hospital,
Mthatha, for re-evaluation because she continued to deteriorate
clinically despite 4 months of TB treatment, which had been started
based on ndings on the chest radiograph of bilateral diuse inltrates
not responding to antibiotics.
Physical examination revealed grade 4 digital clubbing with
peripheral and central cyanosis. She had tachypnoea (32 breaths per
minute) with oxygen saturation of 70% in room air and 88 - 90% on a
non-rebreather oxygen mask at 15 L/min. Chest examination revealed
Velcro-like crepitation most pronounced in the lung bases. e rest of
the clinical examination was unremarkable.
Laboratory results revealed a normal white cell count of 10.9× 109/L
(normal range 3.9 - 12.6), polycythaemia (haemoglobin concentration
15.6 g/dL, normal range 12.0 - 15.0), and a normal platelet count of
358× 109/L (normal range 186 - 454). Connective tissue screening
including antinuclear antibodies, antineutrophil cytoplasmic antibodies
and the serum angiotensin-converting enzyme level was negative. e
results of renal and liver function tests were normal, and the erythrocyte
sedimentation rate was slightly elevated at 38 mm/h. Sputum GeneXpert
MTB/RIF Ultra was negative for Mycobacterium tuberculosis, and
microscopy showed normal ora. Apolymerase chain reaction test
for COVID-19 was also negative. Achest radiograph revealed bilateral
diuse alveolar inltrates. A high-resolution computed tomography
(HRCT) scan of the chest showed a bilateral ground-glass appearance
with septal thickening consistent with a crazy-paving pattern.
e patient went on to have bronchoscopy, which revealed copious
amounts of milky fluid (Fig.1), and a small-volume lavage was
done. Specimens were sent for periodic acid-Schi (PAS) staining,
GeneXpert MTB/RIF Ultra, and cytological, bacterial and fungal
studies. Unfortunately, our laboratory could not perform PAS staining
on the sample, but GeneXpert MTB/RIF Ultra was negative for TB.
A clinical diagnosis of PAP was made and TB treatment was
discontinued. e patient was referred to Groote Schuur Hospital
in Cape Town, where whole-lung lavage was performed with
marked improvement in her clinical state. She no longer required
supplemental oxygen and had an oxygen saturation of 99% in room
air. She is being followed up at the pulmonology clinic at Nelson
Mandela Academic Hospital.
PAP is a rare cause of interstitial lung disease caused by alveolar
accumulation of lipoproteinaceous material in the alveoli due to
disordered surfactant homeostasis.[1] The rarity of the disease is
underscored by the ndings in an Israeli study in which only 15 cases
were identied in the entire country over the 22-year period from 1976
to 1998.[2] China, with a population of more than billion, reported only
241 cases of PAP over four decades from 1965 to 2006.[3] PAP has also
rarely been reported in SA, and we found only 2 reports.[4,5]
There are three types of PAP: primary PAP due to autoimmune
and hereditary disease, secondary PAP and congenital PAP.[6] Our
patient probably has the autoimmune type, which constitutes 90% of
all cases. Although we were unable to perform PAS staining on the
bronchoalveolar lavage (BAL) uid or to measure serum granulocyte
macrophage-colony stimulating factor (GM-CSF) antibody, the
diagnosis of PAP was made on the basis of clinical ndings and imaging.
e characteristic milky uid noted on BAL further strengthened the
likelihood of the diagnosis. Although there is a high prevalence of
TB in our environment,[7] this case highlights the need for restraint
in initiating TB therapy without microbiological evidence of TB. An
alternative diagnosis was considered in our patient because she did
not improve on empirical TB therapy and was profoundly hypoxic,
which is unusual in TB. e dierential diagnosis of PAP includes
pulmonary infections such as COVID-19, TB and Pneumocystis
jirovecii pneumonia, interstitial lung disease from connective tissue
disease, sarcoidosis, pulmonary oedema, bronchoalveolar carcinoma,
hypersensitivity pneumonitis and cryptogenic organising pneumonia.
Pulmonary alveolar proteinosis diagnosis aer
re‑evaluation forchronic cough unresponsive to empirical
Fig.1. Milky uid from bronchoalveolar lavage in 50 mL specimen
AJTCCM VOL. 29 NO. 4 2023 175
e National Department of Health in SA provides algorithms for TB
diagnosis that advise additional investigations when initial sputum
smear microscopy or GeneXpert MTB/RIF Ultra for TB are negative
and individuals under investigation are co-infected with HIV. ese
algorithms recommend that clinicians commence TB treatment for
HIV-positive individuals when two sputum smear microscopy tests
or a single sputum GeneXpert are negative forM. tuberculosis, chest
radiographic ndings are compatible with TB, and symptoms do not
respond to broad-spectrum antibiotics.
In our case, the recognition of a crazy-paving pattern on the HRCT
scan that was suggestive of PAP prompted bronchoscopy and alveolar
lavage, which revealed the characteristically milky uid associated
with this diagnosis. Whole-lung lavage at Groote Schuur Hospital was
then oered to our patient, with dramatic resolution in her symptoms.
Treatment for PAP is not required for patients with mild symptoms.
In patients with troubling dyspnoea, whole-lung lavage is done under
general anaesthesia with a double-lumen endotracheal tube. Lavage
of one lung is done up to 15 times with 1 - 2 L saline while the other
lung is ventilated. e process is then reversed.
Systemic corticosteroids play no role in the management of
PAP and may increase the risk of secondary infection. e role of
GM-CSF (inhalation or subcutaneous) in management remains
to be determined. Lung transplantationis not oen done, because
the disorder may recur in the transplanted lung. PAP may remit
spontaneously in up to 10% of patients. When patients are treated
with whole-lung lavage, the 5-year survival rate is 95%. Secondary
bacterial pulmonary infections occasionally develop because of
impaired macrophage function, and require treatment.
Our case report is limited by our inability to perform PAS staining
of the alveolar uid or measurement of serum alveolar macrophage
colony-stimulating factor antibody. Spirometry was not done because
the patient was severely hypoxaemic at presentation. We do not
have facilities to measure diusion capacity of the lung for carbon
monoxide (DLCO) in our institution. Pulmonary function testing is
of limited usefulness in diagnosing the severity of PAP. An increased
alveolar-arterial oxygen gradient correlates better with disease
severity. Forced vital capacity (FVC) and forced expiratory volume in
1 second are generally within normal limits, although some patients
show decreased FVC consistent with restrictive physiology. DLCO is
frequently reduced and correlates with disease severity.
is study extends the reports of PAP in SA, in this case a 29-year-
old HIV-negative black African woman with no history of smoking.
Patients with respiratory symptoms who are microbiologically negative
for TB should be carefully evaluated for an alternative diagnosis.
H Ghammo, FCP (SA), CertPulmonology (SA); M Tau, FCP (SA);
B omas MD
Department of Medicine, Faculty of Health Sciences, Walter Sisulu University
and Nelson Mandela Academic Hospital, Mthatha, South Africa
T Fathuse, MBBS
Department of Medicine, Nelson Mandela Academic Hospital, Mthatha,
C Ekpebegh, FMCP
Department of Medicine, Faculty of Health Sciences, Walter Sisulu University
and Nelson Mandela Academic Hospital, Mthatha, South Africa
T Dubula, FCP (SA); N Ndlovu, PhD
Cardiometabolic Research Niche, Walter Sisulu University, Mthatha,
Corresponding author: C Ekpebegh (chuksekpebegh@yahoo.com)
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Submitted 20 June 2023. Accepted 10 September 2023. Published 27 November 2023.
Afr J Thoracic Crit Care Med 2023;29(4):e1186. https://doi.