Paclitaxel-Induced Acute Fibrinous and Organizing Pneumonitis in Early Breast Cancer: A Case Report

Abstract

Background: Paclitaxel is a chemotherapeutic drug widely used in breast cancer treatment. While common side effects are possible, paclitaxel-induced pneumonitis is rare, with an estimated incidence of 1%–5% and a high mortality rate.
Case presentation: A 57-year-old Thai woman was diagnosed with stage II right breast cancer. She received adjuvant chemotherapy comprising doxorubicin and cyclophosphamide, followed by weekly paclitaxel. After the ninth paclitaxel cycle, she developed progressive dyspnea and acute respiratory failure. Empirical antibiotic therapy with meropenem, levofloxacin, oseltamivir, and trimethoprim-sulfamethoxazole was initiated to address potential bacterial/viral pneumonias and Pneumocystis carinii pneumonia. Transbronchial biopsies revealed acute fibrinous and organizing pneumonitis. The patient was placed in the prone position, and a muscle relaxant was administered. Following the administration of dexamethasone, her symptoms improved. However, while reducing the dexamethasone dosage, she developed new-onset dyspnea as well as tachy-brady arrhythmia and hypotension. Echocardiography revealed Takotsubo cardiomyopathy (stress-induced cardiomyopathy). Intravenous methylprednisolone 500 mg/day was administered for 3 days followed by transition to intravenous dexamethasone and slow tapering to prednisolone. Prednisolone was gradually tapered and eventually discontinued after 3 months.
Discussion and Conclusions: Paclitaxel-induced pneumonitis is a rare complication. The diagnosis should be considered in any patient who develops respiratory symptoms while receiving paclitaxel. Acute fibrinous and organizing pneumonitis is a rare type of interstitial pneumonitis with high recurrence and mortality rates. High-dose steroids are needed to treat this type of pneumonitis.

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Paclitaxel-Induced Acute Fibrinous and Organizing
Pneumonitis in Early Breast Cancer: A Case Report
Piyarat Limpawittayakul (  piyarat.lim@cra.ac.th )
Chulabhorn Hospital, Chulabhorn Royal Academy
Supinda Petchjorm
Chulabhorn Hospital, Chulabhorn Royal Academy
Worawong Chueansuwan
Phramongkutklao Hospital
Wanvisa Boonfueang
Ramkhamhaeng Hospital
Case Report
Keywords: Paclitaxel, Pneumonitis, Interstitial Lung Disease
Posted Date: October 4th, 2023
DOI: https://doi.org/10.21203/rs.3.rs-3388091/v1
License:   This work is licensed under a Creative Commons Attribution 4.0 International License. 
Read Full License

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Abstract
Background: Paclitaxel is a chemotherapeutic drug widely used in breast cancer treatment. While
common side effects are possible, paclitaxel-induced pneumonitis is rare, with an estimated incidence of
1%–5% and a high mortality rate.
Case presentation: A 57-year-old Thai woman was diagnosed with stage II right breast cancer. She
received adjuvant chemotherapy comprising doxorubicin and cyclophosphamide, followed by weekly
paclitaxel. After the ninth paclitaxel cycle, she developed progressive dyspnea and acute respiratory
failure. Empirical antibiotic therapy with meropenem, levooxacin, oseltamivir, and trimethoprim-
sulfamethoxazole was initiated to address potential bacterial/viral pneumonias and
Pneumocystis carinii
pneumonia. Transbronchial biopsies revealed acute brinous and organizing pneumonitis. The patient
was placed in the prone position, and a muscle relaxant was administered. Following the administration
of dexamethasone, her symptoms improved. However, while reducing the dexamethasone dosage, she
developed new-onset dyspnea as well as tachy-brady arrhythmia and hypotension. Echocardiography
revealed Takotsubo cardiomyopathy (stress-induced cardiomyopathy). Intravenous methylprednisolone
500 mg/day was administered for 3 days followed by transition to intravenous dexamethasone and slow
tapering to prednisolone. Prednisolone was gradually tapered and eventually discontinued after 3
months.
Discussion and Conclusions: Paclitaxel-induced pneumonitis is a rare complication. The diagnosis
should be considered in any patient who develops respiratory symptoms while receiving paclitaxel. Acute
brinous and organizing pneumonitis is a rare type of interstitial pneumonitis with high recurrence and
mortality rates. High-dose steroids are needed to treat this type of pneumonitis.
Background
Paclitaxel, a chemotherapeutic agent originally derived from the bark of the North American yew tree,
Taxus brevifolia
, has been used primarily in ovarian and breast cancer treatment [1]. Notably, paclitaxel
has demonstrated signicant activity in various other cancers, including small-cell and non-small-cell
lung cancer, head and neck cancers, and gastric cancer [1]. The cellular mechanism of paclitaxel involves
inducing mitotic block by stabilizing microtubules, thereby reducing the dynamic nature of these
cytoskeletal structures [2].
Common adverse effects of paclitaxel comprise neutropenia, alopecia, peripheral neuropathy, nausea
with vomiting, arthralgia, myalgia, and hypersensitivity reactions [3, 4]. The latter is triggered by its
diluent, polyoxyethylated castor oil, known as Cremophor EL, and the adverse effects can be mitigated
through premedication with steroids and histamine receptor antagonists [3, 4]. While common side
effects are well-known, paclitaxel-induced pneumonitis is rare, cautiously estimated to occur at a rate of
1–5% [5].

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To the best of our knowledge, our case is the rst reported instance of paclitaxel-induced acute brinous
and organizing pneumonitis (AFOP). In this report, we describe the patient’s clinical symptoms,
radiographic and computed tomography (CT) ndings, and biopsy-conrmed AFOP resulting from
paclitaxel administration. This unique case involves a patient who developed acute respiratory failure
after the ninth cycle of weekly paclitaxel. The patient provided informed consent.
Case presentation
A 57-year-old Thai woman was diagnosed with early-stage right breast cancer in February 2021. Her
medical history included hypertension, and she was a non-smoker. On 3 May 2021, she underwent right
total mastectomy with sentinel lymph node dissection. Pathology results revealed grade III invasive
ductal carcinoma, with the mass measuring 3.1 cm in diameter. Immunohistochemical analysis indicated
negative expression of estrogen receptor, progesterone receptor, and human epidermal growth factor
receptor 2, with a Ki67 index of 50%. Sentinel lymph node dissection showed no metastasis in the four
dissected lymph nodes. This resulted in a nal pathologic stage of pT2N0M0, classied as stage II.
Following the surgery, the patient underwent four cycles of adjuvant chemotherapy with doxorubicin and
cyclophosphamide, administered at 3-week intervals. Subsequently, a regimen of weekly paclitaxel at 80
mg/m² over 1 hour was planned for 12 cycles. A standard premedication protocol comprising
dexamethasone, chlorpheniramine, and ondansetron was administered prior to the paclitaxel infusion,
followed by a 3-day course of dexamethasone at 8 mg per day post-infusion. The patient completed nine
cycles of weekly paclitaxel, which was generally well-tolerated, except for the development of grade II
peripheral neuropathy after the fourth cycle.
Approximately 1 week after completing the ninth cycle, the patient experienced exertional dyspnea that
persisted for 2 weeks with no cough or fever. Her symptoms worsened progressively, prompting her
referral to the emergency room on the day scheduled for her tenth cycle of paclitaxel. At this point, her
oxygen saturation was 75–82% on room air, necessitating intubation. Physical examination revealed
rhonchi in the right lung. A complete blood count revealed a white blood cell count of 4.7 × 10³/mL, with
85% neutrophils and no peripheral eosinophilia.
Empirical antibiotic therapy comprising meropenem, levooxacin, oseltamivir, and trimethoprim-
sulfamethoxazole was initiated to address potential bacterial/viral pneumonias and
Pneumocystis carinii
pneumonia. Enoxaparin treatment was also initiated for the acute pulmonary embolism. The patient was
placed on a ventilator with the fraction of inspired oxygen set at 1.0. Arterial blood gas analysis indicated
a pH of 7.319, partial pressure of carbon dioxide of 36, partial pressure of oxygen of 60.6, and an arterial
pO2(P) from arterial blood gas divided by FIO2(F) or P/F Ratio was 60.6.
Throughout her hospital stay, the patient remained afebrile, and the scant sputum was clear in color. To
ascertain the cause of the pneumonitis, bronchoscopy with bronchoalveolar lavage and transbronchial
biopsies were performed the following day. Notably, the results of throat swab real-time polymerase chain
reaction (RT-PCR) testing for a panel of 33 viruses, including inuenza and severe acute respiratory

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syndrome coronavirus 2, were negative. Microscopic examination of the bronchoalveolar lavage using
Wright’s, acid-fast bacilli, and modied acid-fast bacilli stains revealed no identiable pathogens.
Additionally, aerobic bacterial and fungal cultures from the lavage were negative. Further testing, namely
PCR for mycobacteria and
Aspergillus
(galactomannan) antigen, with an immunouorescence assay and
PCR for
Pneumocystis
, yielded negative results. Hemoculture results were also negative for all
specimens.
Transbronchial biopsies revealed alveolar septal thickening, which was attributed to increased
broblastic stroma and mononuclear inammatory cells. Notably, frequent interalveolar brin leakage
was observed, with a varying admixture primarily composed of macrophages, a smaller number of
lymphocytes, and occasional neutrophils. Pneumocyte hyperplasia with reactive changes was also
evident. Bronchial tissue exhibited mild lymphocyte inltration with no neutrophil inltration. No
granulomas, foamy material, fungi, or viral inclusions were detected. These pathological observations
consistently aligned with moderate subacute lung injury, morphologically congruent with AFOP (Fig. 2).
Following the bronchoscopy, the patient’s symptoms worsened, leading to a diagnosis of paclitaxel-
induced pneumonitis accompanied by severe acute respiratory distress syndrome. To address the
patient’s deteriorating condition, the muscle relaxant cisatracurium and the sedative drugs fentanyl and
midazolam were administered, and she was placed in the prone position. Intravenous dexamethasone at
a dosage of 10 mg every 12 hours was initiated, resulting in observable symptom improvement, as
evidenced by a chest X-ray that revealed reduced lung inltrations compared with the earlier images (Fig.
3A). However, upon reducing the dexamethasone dosage to 8 mg every 12 hours on the 10th day of
admission, the patient experienced new-onset dyspnea. A subsequent chest X-ray indicated progression
of multifocal reticulonodular patchy inltrations (Fig. 3B). Concomitantly, she developed tachy-brady
arrhythmia and hypotension. The concentrations of the cardiac biomarkers creatine kinase-MB, troponin-
T, and N-terminal pro-brain natriuretic peptide were elevated. Echocardiography revealed a left ventricular
ejection fraction of 10–15%, leading to a diagnosis of Takotsubo cardiomyopathy (stress-induced
cardiomyopathy). High-dose inotropic drugs, specically norepinephrine, were introduced to stabilize the
hemodynamics. The patient also received a temporary pacemaker to manage the arrhythmia. Intravenous
methylprednisolone 500 mg was administered for 3 days, followed by transition to intravenous
dexamethasone. Dexamethasone was continued for 30 days, after which dexamethasone was changed
to prednisolone. A tracheostomy was performed owing to the prolonged need for intubation. After 41
days of admission, the patient was successfully weaned from the ventilator.
Considering the severity of the adverse effects, the decision was made not to discontinue the paclitaxel.
Upon discharge, the patient received prednisolone 0.5 mg/kg/day. Subsequent chest X-ray showed
improvement in the previous ndings. Follow-up echocardiography before discharge demonstrated an
improved left ventricular ejection fraction of 60%. Prednisolone was gradually tapered and eventually
discontinued 3 months after discharge. Initially requiring oxygen supplementation at home for 2 months,
the patient eventually regained the ability to ambulate without the need for supplemental oxygen. A chest
X-ray obtained 4 months after discontinuing prednisolone revealed near-normal lung ndings (Fig. 3C).

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Discussion and Conclusions
Paclitaxel-induced pneumonitis represents a rare yet potentially fatal complication, underscoring the
importance of prompt recognition and management. Any patient undergoing paclitaxel treatment who
presents with dyspnea and/or fever warrants consideration for this complication, and early investigation
through chest imaging is paramount.
The proposed risk factors for paclitaxel-induced pneumonitis are pre-existing pulmonary brosis, prior
emphysematous changes, concurrent radiation therapy, and combination therapy with other
chemotherapy agents [6, 7]. Intriguingly, factors such as smoking status, age, and performance status
have not demonstrated signicant associations with the risk of pneumonitis [6, 7]. Notably, the risk of
pneumonitis with paclitaxel appears to be linked to dosing schedules rather than the total dose
administered. The CALGB 9840 randomized phase III trial comparing weekly and every-3-weeks paclitaxel
for metastatic breast cancer revealed that the weekly schedule resulted in a higher occurrence of grade ≥
3 dyspnea during therapy (7% for weekly vs. 4% for every 3 weeks) [8].
Anoop et al. performed a prospective study in India and reported that among patients who received
weekly paclitaxel, 10% developed acute interstitial pneumonitis after one cycle, 5% after two cycles, 3%
after three cycles, 8% after ve cycles, 3% after seven cycles, 3% after eight cycles, and 3% after twelve
cycles [9]. The median number of cycles required to induce interstitial lung disease was ve [9].
The precise mechanism underlying paclitaxel-induced pneumonitis remains incompletely understood.
Two hypotheses have been postulated: an allergic type (type I hypersensitivity reaction) and a cell-
mediated cytotoxic type (type IV hypersensitivity reaction). Type I hypersensitivity reactions involve
immunoglobulin E-mediated immune responses and histamine or vasoactive substance release from
basophils and mast cells. This hypersensitivity reaction is characterized by acute dyspnea,
bronchospasm, hypotension, and an erythematous rash (typically developing shortly after drug
administration). This type is observed in up to 30% of cases of paclitaxel-associated adverse reactions,
and the rate decreases to 1–3% with steroid premedication. In contrast, type IV hypersensitivity reactions,
also known as delayed-type hypersensitivity, result from T-cell-mediated reactions. Cytokine release
activates T-cells or macrophages, leading to tissue damage. Typically, this type manifests as an acute-
subacute clinical course over a few hours to 2 weeks and is characterized by bilateral pulmonary
inltrates, resembling the presentation in our case [10, 11].
Notably, our case lacked peripheral eosinophilia. Peripheral eosinophilia or neutrophilia is not commonly
noted, the presence of hypereosinophilia may indicate a favorable prognosis [12].
The characteristic features observed in our case's chest CT images mirrored those of similar cases,
featuring diffuse ground-glass opacities, reticular opacities, thickened septal lines, and irregular airspace
consolidations. The ndings from the transbronchial biopsy, which revealed interstitial pneumonitis
predominantly inltrated by mononuclear inammatory cells, lend further support to the proposed

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hypothesis of a type IV hypersensitivity reaction as the mechanism behind the paclitaxel-induced
pneumonitis in our patient.
Of particular interest, the pathological pattern indicated AFOP, which is an infrequent histological
presentation of interstitial pneumonitis characterized by intra-alveolar brin deposits and widespread
organizing pneumonia within alveolar ducts and bronchioles. While this pattern was initially described by
Travis in 2002, its etiological spectrum includes connective tissue disorders, drug reactions, occupational
exposures, and infections [14]. Clinically, this type of interstitial lung disease presents in two patterns: an
acute and fulminant course with rapid progression to respiratory failure and death, or a subacute, less
fulminating course with eventual recovery. The prognosis is generally grim, marked by a high mortality
rate ranging between 50% and 60% [15]. A retrospective study from Japan by Onishi et al. found that
AFOP has a high recurrence rate following steroid treatment, ranging between 60% and 76% and
necessitating higher corticosteroid doses during recurrences compared with the rst episode [16, 17].
Diagnosing paclitaxel-induced pneumonitis entails combining clinical and radiological patterns and
exposure history, and excluding other causes of diffuse pulmonary inltration. In our case, the presence
of typical clinical, radiological, and pathological ndings with the absence of evidence for other
infectious agents, led to the diagnosis of paclitaxel-induced pneumonitis.
Corticosteroids remain the cornerstone of paclitaxel-induced pneumonitis treatment. In our case, prompt
initiation of dexamethasone led to brief symptom improvement. However, attempting to reduce the
steroid dose triggered symptom progression and exacerbation. A similar case has been reported wherein
lung oxygenation improved temporarily upon steroid administration but deteriorated again upon tapering
[4]. Given the histopathological conrmation of AFOP in our case, and the associated high recurrence
rate, we transitioned the patient to pulse methylprednisolone, administering 500 mg/day for 3 days after
symptoms worsened. Recommendations for grade 4 (very severe, life-threatening, or disabling) drug-
induced interstitial pneumonitis advise pulse methylprednisolone, followed by high-dose steroids
(prednisolone 1–2 mg/kg/day) for 2–4 weeks with gradual tapering thereafter [18]. The severity of
pulmonary injury dictates the duration of corticosteroid therapy, with our case necessitating a total course
of approximately 5 months.
In conclusion, paclitaxel-induced pneumonitis remains a rare complication of paclitaxel therapy. Any
patient receiving paclitaxel therapy who exhibits respiratory symptoms accompanied by a diffuse
bilateral interstitial pattern on chest radiography warrants consideration for this diagnosis. Prompt
administration of steroids is essential upon diagnosis. AFOP represents an uncommon subtype of
interstitial pneumonitis with high recurrence and mortality rates. High-dose steroids are imperative to
effectively manage this variant of pneumonitis.
Abbreviations
CT Computed tomography

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RT-PCR
Real-time polymerase chain reaction
AFOP Acute brinous and organizing pneumonitis
Declarations
Ethics approval and consent to participate
This study was meticulously conducted with strict adherence to the ethical principles outlined in the
Declaration of Helsinki guidelines governing research involving human subjects. The study protocol
underwent thorough review and received approval from the Ethics Committee for Human Research at the
Chulabhorn Research Institute (Certicate No.085/2566).Informed consent was provided by the patient.
Consent for publication
Consent for publication was provided by the patient.
Availability of data and materials
Not applicable
Competing interests
The authors hereby declare that they have no known competing nancial interests or personal
relationships that could potentially inuence the work presented in this manuscript.
Funding
We are pleased to acknowledge the support extended by the Chulabhorn Royal Academy, Thailand, which
provided funding for the completion of this study.
Authors’ contributions
Conceptualization, P.L. (Piyarat Limpawittayakul); Pathologist, S.P.; Supervision, W.C. and W.B. All authors
have read and agreed to the published version of the manuscript.
Acknowledgements
We extend our heartfelt gratitude to the patient and her family for their invaluable participation in this
research endeavor. We would also like to acknowledge the editing assistance provided by Jane
Charbonneau, DVM, from Edanz (www.edanz.com/ac) in rening the draft of this manuscript.
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Figures
Figure 1
A: Chest X-ray showing multifocal reticulonodular patchy opacities in both lungs. B: Chest CT chest
showing newly developed multifocal consolidations and ground glass opacities involving both lungs,
with a peribronchovascular distribution CT, computed tomography

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Figure 2
A and B show the range of alveolar septal thickening from mild to moderate due to increased broblastic
stroma (red arrow) and mononuclear inammatory cell inltration. C shows multiple areas of intra-
alveolar brin leakage with mononuclear inltration (blue arrows) and pneumocyte type II hyperplasia
with reactive atypia (red arrows)

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Figure 3
A: Chest X-ray after dexamethasone administration showing some improvement in the inltrations. B:
Chest X-ray after tapering the dose of dexamethasone showing increased inltration in both lungs. C:
Chest X-ray after slowly tapering the dexamethasone and eventually stopping prednisolone for 4 months
showing near-normal ndings