144 AJTCCM VOL. 28 NO. 4 2022
EDITORIAL
e advent of antibrotic drugs such as nintedanib and pirfenidone
has heralded a new and exciting era in the eld of the interstitial lung
diseases (ILDs), many of which progress to end-stage brosis despite
immunomodulatory treatment. Until recently, the management of
patients who develop lung brosis has essentially been palliative. e
initial trials of antibrotic drugs for idiopathic pulmonary brosis
(IPF)[1,2] were met with great enthusiasm and optimism, as clinicians
now had pharmacological tools to alter the trajectory of this dismal
disease. ese ndings were extended to other progressive brosing
ILDs in the subsequent SENSCIS[3] and INBUILD[4] trials.
In this issue of AJTCCM, Seixas et al.[5] report the ndings of a
cross-sectional retrospective study of outpatients with chronic brotic
hypersensitivity pneumonitis (f-HP) attending a district ILD clinic in
Portugal. All patients were assessed by a multidisciplinary team and
were followed up for a minimum of 1 year.
Of their 83 patients with hypersensitivity pneumonitis (HP), 63
(75.9%) had evidence of f-HP. In analysing the subjects with f-HP
and a behaviour pattern of progressive brosis, the authors used the
same criteria as the INBUILD study, viz. at least one of the following
within the past 24 months in antifibrotic drug-naive patients:
(i)arelative decline in forced vital capacity (FVC) ≥10% of predicted
value; (ii)arelative decline in FVC of 5 - 9% of predicted value +
worsening of respiratory symptoms or increased extent of brosis
on a high-resolution computed tomography scan (HRCT); and
(iii)worsening of respiratory symptoms + increased extent of brosis.
Of the 63f-HP patients, 21 (33.3%) fullled criteria for progressive
brosing hypersensitivity pneumonitis (PF-HP). Compared with the
f-HP patients without evidence of progressive brosis, the PF-HP
group was more likely to demonstrate a pattern of usual interstitial
pneumonia (UIP) or a UIP-like pattern on HRCT (61.9% v. 38.1%)
and was more likely to experience acute exacerbations (26.2% v.
14.3%). e most common inciting agents for HP were avian proteins
(57.1%) and moulds (25.4%).
The American Thoracic Society (ATS), European Respiratory
Society (ERS), Japanese Respiratory Society (JRS) and Asociación
Latinoamericana de Tórax (ALAT) have since published an updated
clinical practice guideline in 2022[6] in which the lung function
criteria for progressive pulmonary brosis (PPF), the preferred term
for PF-ILD, have been changed to: (i) absolute decline in FVC ≥5%
predicted within 1 year of follow-up; or (ii) absolute decline in DLCO
(diusing capacity of the lung for carbon monoxide) (corrected for
haemoglobin) ≥10% predicted within 1 year of follow-up. Patients with
PPF must demonstrate deterioration in at least two of the following
three domains: symptoms, lung function, and HRCT changes.
The formalisation of a definition for PPF raises the question
whether antibrotic drugs should be prescribed in this category of
patients irrespective of the underlying cause. So far, only the INBUILD
study[4] has explored this. In the active arm of this multicentre double-
blind, placebo-controlled phase 3 trial, 663 patients with non-IPF PF-
ILD were given nintedanib for 52 weeks. Patients with HP comprised
26.1% of the study population. While nintedanib showed a statistically
signicant lower decline in FVC over the 52-week study period in
the overall population and in the subset with a UIP-like fibrotic
pattern on HRCT scan (dierence in decline 107.0 mL and 128.2 mL,
respectively, compared with the placebo group), subgroup analysis of
the 84/173 subjects with chronic HP showed a less impressive benet
of 72.9 mL/year.[7] However, the study was not designed or powered to
analyse the eect of nintedanib on specic ILD subgroups. It should
also be noted that when analysing the data stratied by HRCT features
(UIP-like v. other brotic patterns), statistically signicant benet was
shown only in the UIP-like group.
Although nintedanib is promising as an antibrotic agent in non-IPF
PPF-ILD, clinicians should be cautiously optimistic, as the INBUILD
trial is the only published trial in this eld so far. Other considerations
include whether there are dierences in response between dierent
subgroups of non-IPF ILD and whether the concurrent use of
immunosuppressive agents, e.g. in connective tissue disease-related
ILD, should be advocated. In the INBUILD trial, patients who
were receiving azathioprine, cyclosporine, mycophenolate mofetil,
tacrolimus, rituximab, cyclophosphamide or oral glucocorticoids
>20 mg/day were excluded. However, at the discretion of the
investigator, the addition of these drugs was permitted 6 months into
the trial if there was signicant clinical deterioration in the ILD or
connective tissue disease.
While both pirfenidone and nintedanib, antibrotic drugs with
dierent mechanisms of action, showed similar benet in IPF,[2,8] it is a
great pity that the RELIEF study, a double-blind, randomised, placebo-
controlled phase 2b trial of pirfenidone in patients with PF-ILD, was
prematurely terminated owing to slow recruitment.[9]
There is probably no other disease that demands a sleuth-like
diagnostic approach more than HP. Antigens causing HP may be found
in the home, in the workplace and in recreational environments. ese
antigens may be categorised into three groups: microbes (bacteria,
fungi, mycobacteria), proteins (animal proteins, plant proteins) and
chemical agents. Chronic HP may easily be misdiagnosed as IPF, not
only by clinicians but also by radiologists and pathologists.[10-13] In a
study by Fernández Pérez et al.,[14] of 142 cases of surgical lung biopsy-
proven HP, 53% had no identiable inciting antigen. Aer adjusting
for age, lung brosis and smoking, the median survival was 8.0 years
where the antigen was identied, but only 2.9 years where the antigen
remained elusive. e median survival was 16.9 years in those without
lung brosis, but only 4.9 years in those with brosis.
e global prevalence of HP appears to vary widely,[15] but it is rarely
reported from Africa. A literature search for case series of African
patients with HP (including the old term ‘extrinsic allergic alveolitis’),
and also a search for reports on the two most common causes, avian
antigens and moulds, yielded only four articles. e largest series
(40cases) was that of bird fancier’s disease in Western Cape Province,
South Africa.[16] Other reports comprised 5 cases of summer-type HP
in Eastern Cape Province[17] (now recognised as hypersensitivity to
inhalation of Trichosporon cutaneum, a fungus that grows in mouldy,
decaying organic matter in hot and humid environments, and the
Hypersensitivity pneumonitis: An infrequent cause of chronic lung
brosis in Africa?
AJTCCM VOL. 28 NO. 4 2022 145
EDITORIAL
commonest cause of HP in Japan),[18] a single case of bird fancier’s lung
in a 12-year-old boy in the Western Cape,[19] and a single case (antigen
not stated) in a series of 42 children in KwaZulu-Natal Province with
chronic lung disease.[20]
What makes chronic HP a particularly challenging diagnosis is
that it is not always preceded by acute disease, which is more easily
recognisable; standardised and validated antigen preparations and
immunoassays for diagnosis are not available; cut-off values for
quantitative immunoglobulin G assays have not been validated; and
lymphocytosis on bronchoalveolar lavage is not always present.[21] e
clinical practice guideline on the diagnosis of HP endorsed by the
ATS, JRS and ALAT[22] has replaced the categories of acute, subacute
and chronic HP with two categories, non-brotic and brotic HP. e
rationale for this change is that the evolution of the disease is not
always clear. In addition, the presence or absence of brosis provides
a more practical approach to management.
Are we misdiagnosing patients with chronic HP in Africa, or is it
a rare disease on our continent? is is a call to clinicians not only to
actively interrogate patients regarding exposure to possible antigens,
but also to increase local awareness by publishing conrmed cases.
M L Wong, MB BCh, FCP (SA), FCCP, FRCP (Lond) ORCID
Division of Pulmonology, Department of Medicine, Chris Hani Baragwanath
Academic Hospital and School of Clinical Medicine, Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg, South Africa
michelle.wong@wits.ac.za
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