Keywords
Cyclophosphamide - pleuroparenchymal fibroelastosis - upper-lobe fibrosis
Introduction
Cyclophosphamide is a commonly used alkylating agent in chemotherapy as well as an
immunosuppressant. Cyclophosphamide is activated primarily in the liver to the toxic
metabolites acrolein, 4-hydroxycyclophosphamide and phosphoramide mustard. Lung injury
in the form of pneumonitis is due to increased transforming growth factor-β production
and enhanced collagen synthesis.[1] Few reports describe the development of pleuroparenchymal fibroelastosis (PPFE)
over 18–72 months after the initiation of cyclophosphamide therapy which usually progresses
gradually.[2]
An interesting case of early-onset and rapidly progressive PPFE induced by cyclophosphamide
is described below.
Case Report
A 16-year-old boy diagnosed with primitive neuroectodermal tumor (PNET) of the chest
wall (right second rib) treated with surgery (local excision), focal radiotherapy,
and systemic chemotherapy (vincristine, doxorubicin, ifosfamide, etoposide, cyclophosphamide,
and dactinomycin) in 2012. After a disease-free interval of 4 years, he had disease
recurrence in the form of solitary right upper-lobe pulmonary nodule which was excised.
This was followed by concurrent chemotherapy(consisting of topotecan, cyclophosphamide,
temozolomide and irinotecan) and radiotherapy (consisting of bilateral lung irradiation
of 11.2 Gray in 7 fractions). After completion of 8 months of above-mentioned salvage
chemotherapy, he was started on oral maintenance chemotherapy (cyclophosphamide, etoposide,
celecoxib, and tamoxifen). Six months later, on this oral chemotherapy regimen, the
patient developed mild exertional breathlessness, dry cough, and fatigue. High-resolution
computed tomography (HRCT) of the chest revealed the presence of bronchocentric and
diffuse ground-glass opacities predominantly in bilateral upper lobes [Figure 1]. The patient was afebrile. Respiratory rate was 16 breaths/min with a saturation
of 97% on room air. Normal vesicular breath sounds were present on auscultation. He
had a normal hemogram and bronchoscopy with bronchoalveolar lavage was negative for
Pneumocystis jirovecii, bacterial and tuberculous infection. The patient was initiated on therapy with oral
corticosteroids; however, he had no symptomatic relief and developed worsening of
breathlessness over the next 4 months. His resting respiratory rate increased to 26/min,
and few fine end-inspiratory crackles were noted in bilateral infraclavicular areas
on auscultation. Six-minute walk test (6MWT) at this assessment showed desaturation
from 95% to 86%. Bilateral upper-lobe pleural thickening with subpleural fibrosis
was noted in repeat HRCT chest [Figure 2] in the same areas which previously had ground glass opacities. In addition, bilateral
loculated apical pneumothoraces with minimal fibrosis in lower lobes were noted suggestive
of PPFE.
Figure 1: (a and b) High-resolution computed tomography chest showing centrilobular
ground glass opacities in bilateral upper lobes and superior basal segments
Figure 2: (a and b) High-resolution computed tomography chest showing bilateral upper-lobe
interseptal thickening with pleural thickening and pneumothorax
Discussion
The entity of idiopathic upper-lobe pulmonary fibrosis was first described in 13 patients
by Amitani et al. in 1992. Frankel et al. are credited with coining the term “pleuropulmonary fibroelastosis” in 2004.[3] Idiopathic PPFE has subsequently been classified as a separate entity under rare
idiopathic interstitial pneumonias.[4]
PPFE is a rare progressive interstitial lung disease manifesting with predominantly
upper-lobe pleural thickening and subpleural fibrosis. Patients may remain asymptomatic
for a while; however, those that progress are often complicated by the presence of
pneumothorax. Most cases are idiopathic with bimodal age distribution at 20–30 years
and 50–60 years, with a slender flat chest cage and usually minimal findings on clinical
examination.[3] Histologically, evolution of PPFE has been described as initially presenting with
either interstitial inflammation with fibrosis or as organizing pneumonia pattern
which progresses to subpleural intraalveolar fibrosis with elastosis of the walls
and patchy lymphoplasmacytic infiltrates. In addition, the presence of upper zone
fibrosis of visceral pleura and small numbers of fibroblastic foci help to achieve
a definitive diagnosis on histology.[5]
Secondary causes of PPFE described in literature include systemic chemotherapeutic
agents such as carmustine and cyclophosphamide, radiation therapy (more than 20 Gray),
and bone marrow transplant.[2],[6],[7]
Clinically, patients of PPFE develop progressive exertional breathlessness with restrictive
defect and impaired diffusion capacity on lung functions along with exercise-induced
desaturation. Our patient was too breathless to test for lung functions; however,
his desaturation at 6MWT was suggestive of ventilatory impairment.
In PPFE, subpleural nodular and reticular opacities in the upper lobes with minimal
involvement of the other lobes are noted in initial stages of HRCT of the lung. Later
in progressive disease, pleuroparenchymal thickening of 4–15 mm with fibrosis and
volume loss, traction bronchiectasis with bullae and occasionally large cysts in upper
lobes with pneumothorax are described.[8]
Reddy et al.[8] have put forth definitive and consistent criteria for the diagnosis of PPFE on the
basis of imaging as follows:
Definitive pleuroparenchymal fibroelastosis
Presence of upper-lobe pleural thickening with subpleural fibrosis with absent or
minimal fibrosis in lower lobes.
Diagnosis consistent with pleuroparenchymal fibroelastosis
Presence of upper-lobe pleural thickening and subpleural fibrosis that are not concentrated
in the upper lobe or presence of coexistent disease elsewhere.
In the presented case, the initial radiological features of ground glass opacities
predominantly in upper lobes with subsequent development of bilateral upper-lobe fibrosis
and pleural thickening fulfill the criteria for definitive diagnosis of PPFE.
Systemic cyclophosphamide-induced lung toxicity is classified into early and late
pneumonitis as described by Malik et al. Early-onset pneumonitis develops within 6 months of initiation of therapy and may
be reversible with withdrawal of offending agent and treatment with steroids. It is
characterized by the presence of interlobular septal thickening and ground glass appearance
showing no lobar predilection on HRCT. Late-onset pneumonitis has been reported to
occur over 18 months–12 years after initiation of therapy with cyclophosphamide and
is generally not responsive to steroids.[9]
The causality of PPFE due to cyclophosphamide in this case has been established due
to the onset of symptoms 14 months after initiation of chemotherapy with cyclophosphamide
which includes 8 months of salvage and 6 months of oral maintenance chemotherapy.
It is unlikely that the initial radiological manifestation is radiation-induced since
radiation-induced pneumonitis occurs usually within 2–3 months of radiation, with
a radiation dose of more than 20 Gray and high V20 (volume of lung receiving 20 Gray
or more). Our patient received only a low dose 11.2 Gray of radiation 9 months before
the development of disease. Normal lung imaging, barring the right upper-lobe PNET
at disease recurrence, obviates the contribution of prior chemoradiotherapy toward
the development of current PPFE.
The time interval between the onset of interstitial inflammation to progression to
pulmonary fibrosis described in literature is between 31 months and 12 years.[5] Despite treatment with steroids, in this case, there was a rapid progression to
the fibrotic phase of PPFE from pneumonitis within 4 months.
Conclusion
PPFE with pneumothorax has a poor prognosis with poor response to steroids. A single
case of successful living donor lung transplant for PPFE is described in literature.[10] Due to its relentless progressive nature causing crippling respiratory disability,
physicians need to be aware of the occurrence of this disease in patients on cyclophosphamide
therapy. While the restrictive versus liberal fluid therapy for major abdominal surgery
trial is ongoing for the role of antifibrotics in conditions other than idiopathic
pulmonary fibrosis, perhaps the role of antifibrotics such as pirfenidone in PPFE
is a subject for future research.[11]
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
Acknowledgment
We would like to thank Dr. Pavan Biraris, Consultant, Department of Pulmonary Medicine,
Tata Memorial Hospital.
