There is readily available guidance on how to treat interstitial lung disease (ILD) induced by docetaxel and human epidermal growth factor receptor 2 (HER2) therapies. However, there is limited information on how to diagnose and monitor ILD in patients [1,2]. We herein report a case series of Docetaxel and trastuzumab-induced interstitial pneumonitis. Drug-induced interstitial pneumonitis: Interstitial lung disease (ILD) refers to a collection of disorders that affect the pulmonary interstitium, a delicate, thin lining located between the lung's alveoli and the blood vessels, essential for gas exchange [3,4]. Drug-induced interstitial lung disease (DIILD) accounts for 1-5% of ILD cases [5]. Drugs commonly associated with DIILD include cytotoxic agents, antibiotics, anti-rheumatic drugs, non-steroidal anti-inflammatory agents, psychiatric medications, and anti-arrhythmic agents. DIILD occurs when drug exposure results in inflammation and, at times, pulmonary fibrosis. Diagnosis relies on clinical, pathological, and radiological findings consistent with ILD, a temporal link between symptom onset and drug exposure, ruling out other potential causes such as infections, pulmonary edema, or radiation-induced lung injury, and improvement upon stopping the suspected causative agent. Although DIILD is rare and diagnosed by exclusion, it should be considered when antineoplastic therapy and monoclonal antibodies are used. CT scans are the primary diagnostic tool due to their non-invasive nature and high sensitivity and specificity in detecting interstitial pneumonitis. In the first week after lung injury, DIILD appears on HRCT as diffuse ground-glass opacities and consolidations. After one to two weeks, it may present as irregular linear opacities, architectural distortion, and traction bronchiectasis. Patients typically exhibit symptoms of dyspnea, cough, fever, and hypoxia. Corticosteroids are commonly used for ILD and can effectively slow or reverse disease progression.

Eight female patients (Table 1) diagnosed with invasive breast carcinoma who were treated with docetaxel ± trastuzumab in the preceding two to  ten weeks presented with breathlessness, dry cough, and mild fever with progressive chest X‐ray changes and HRCT changes . Each of them had received between two to four cycles of docetaxel ± trastuzumab before the onset of symptoms. None had undergone radiotherapy before the presentation. The prior Anthracycline, Cyclophosphamide therapy was uneventful in all the cases. TABLE-1. CASE 1 CASE 2 CASE 3 CASE 4 CASE 5 CASE 6 CASE 7 CASE 8 ¬-AGE(YEARS) 31 38 46 57 ¬53 60 47 58 REGIMEN FEC  TH ACT ACTH TCH FECT ACTH TAC ACTH INTERVAL 3 weekly 3 weekly 3 weekly 3 weekly 3 weekly 3 weekly 3 weekly 3 weekly CYCLES WITH DOCETAXEL 2 1 2 2 2 4 2 3 DOCETAXEL CUMULATIVE DOSE 200 mg/m2 75 mg/m2 150mg/m2 150mg/m2 200mg/m2 300mg/m2 200mg/m2 300mg/m2 CYCLES WITH TRASTUZUMAB 2 0 2 2 0 4 0 3 TRASTUZUMAB CUMULATIVE DOSE 14 mg/kg. 0 14mg/kg. 14mg/kg. 0 26mg/kg 0 20g/kg SYMPTOM ONSET AFTER LAST DOSE 2 weeks 3 weeks 8 weeks 2 weeks 3 weeks 4 weeks 3 weeks 2 weeks HRCT THORAX Ground glass opacities involving B/L lung along with minimal right pleural effusion. Ground glass opacities involving B/L lung. B/L consolidation, ground glass opacity (GGO) and crazy paving with posterior and basal predominance in the exudative phase. Ground glass opacities involving B/L lung. Ground glass opacities involving B/L lung. Ground glass opacities involving B/L lung Ground glass opacities involving B/L lung and crazy paving with posterior and basal Ground glass opacities involving B/L lung along with minimal right pleural effusion FOLLOW UP HRCT THORAX (8 WEEKS) Right breast lesion with normal lung parenchyma normal lung parenchyma nad normal lung parenchyma Normal Lung parenchyma No sizeable lesion in lung parenchyma NAD Lung parenchyma – within normal limits After admission into the hospital due to fatigue and shortness of breathing, supportive management with iv antibiotics was started in suspicion of atypical pneumonia. The following routine investigations were done - • CBC - within normal limit • LFT - within normal limit • RFT - within normal limit • CRP – within normal limit • Procalcitonin - within normal limit • Sputum for pyogenic culture and fungal culture - negative • ZN stain - No AFB found, • Urine R/E and M/E - Within normal limits. • Blood culture - No growth of pathogenic organism after 5 days of aerobic incubation at 37. • Chest x-ray– Bilateral patchy opacities were seen.

Drug-induced pulmonary damage is a recognized, albeit infrequent, complication associated with cytotoxic chemotherapy. Chemotherapy has been documented to cause various pulmonary and pleural complications, including acute parenchymal lung injury, pulmonary edema, interstitial pneumonitis, and pulmonary fibrosis. Docetaxel, a chemotherapeutic agent belonging to the taxane class, is extensively utilized in the treatment of various malignancies, including breast, gastric, ovarian, and non-small cell lung carcinoma. A recognized adverse effect of taxane-based chemotherapy is taxane-induced interstitial pneumonitis. Docetaxel exerts its therapeutic effects by binding to β-tubulin, thereby promoting its polymerization. This action stabilizes microtubules and inhibits their depolymerization. Furthermore, docetaxel induces apoptosis in cancer cells by interacting with the apoptosis-inhibiting protein Bcl-2, thereby disrupting its function. The expression of a specific pulmonary antigen by the tumor may lead to the proliferation of cytotoxic T-cells. Furthermore, reactive oxygen metabolites have been implicated in direct lung injury associated with docetaxel-induced lung injury. Merad et al. documented two patients with docetaxel-related pneumonitis who experienced recovery following corticosteroid treatment [14]. Prior to attributing pneumonitis to drug-induced causes, it is essential to exclude other potential causes such as infection, lymphangitis carcinomatosa, other interstitial lung diseases (ILD), and heart failure. Read et al. presented a case series involving four patients with interstitial pneumonitis related to docetaxel[15]. Taxanes are chemotherapeutic agents frequently employed in the adjuvant treatment of HER2-positive breast tumors. The combination of taxanes with trastuzumab has been associated with reduced recurrence rates in patients with high-risk early-stage HER2-positive breast cancer. Taxane-induced pneumonitis has been documented in several case reports and case series, with an estimated risk of approximately 5%. In the majority of reported cases, adverse effects are observed in patients who received treatment with trastuzumab in conjunction with taxanes or who had prior exposure to taxanes before the initiation of trastuzumab. The largest series of docetaxel associated interstitial pneumonitis was published by Tamiya et al. which consisted of 392 patients with metastatic non-small-cell lung cancer, of which 18 cases of ILD were reported with tri-weekly schedule of a higher dose of docetaxel (75 mg/m2) thus marking an incidence of 4.6%. The study suggested that approximately 10-20 days, that is, a median time of 18 days was the time elapse from the last docetaxel administration to the onset of toxicity findings on the chest X-ray [11]. For our patient, the time taken for the onset of toxicity after the last docetaxel administration was approximately 9 days which is slightly contrary to the above study findings. Trastuzumab is a monoclonal antibody that targets HER2, a protein that is overexpressed or amplified in approximately 25% of breast cancer cases. Trastuzumab has been extensively utilized in the treatment of HER2-positive cancers since its approval by the FDA in 1998. Numerous clinical trials have assessed its safety, efficacy, and optimal treatment regimens; however, reports of interstitial pneumonitis as an adverse reaction remain scarce. In the phase III randomized HERA trial, trastuzumab was administered to 3,374 patients at a maintenance dose of 6 mg/kg, with no reported cases of interstitial pneumonitis [12]. Conversely, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31, among 1,015 patients treated with a regimen including trastuzumab, four cases of interstitial pneumonitis were documented [13]. Similarly, the North Central Cancer Treatment Group trial N9831 reported five instances of grade 3+ pneumonitis or pulmonary infiltrates among 809 patients receiving trastuzumab. Although trastuzumab is predominantly employed in breast cancer therapy, the adverse effect of drug-induced interstitial lung disease (DIILD) has also been observed in treatments for non-breast and non-gastric HER2 tumors. The limited case reports available do not suggest any correlation with patients’ medical history, dosing regimen, or symptom onset. All reported patients were hospitalized and received corticosteroid treatment following the clinical presentation of non-productive cough, shortness of breath, and fever. 1. Summary of key findings : This case series highlights docetaxel induced interstitial lung disease (DIILD) as a rare but life-threatening complication in breast cancer therapy. All five patients developed dyspnea (grade 2-4) and bilateral ground-glass opacities on CT thorax within 1-8 weeks of docetaxel ± trastuzumab initiation. Notably : • Early onset : symptoms appeared after 1-2 cycles in 4/5 patients, contrasting with literature onset ( typically > 4 cycles).(Kwon et al.2017). • High steroid responsiveness: 4/5 patients improved with corticosteroids, but one succumbed to respiratory failure, underscoring the potential severity o DILI. • Trastuzumab co-administraton: 3/5 patients received trastuzumab, which may exacerbate pulmonary toxicity via immune mediated mechanisms ( perez-alvarez et al., 2019). 2. Comparison with existing literature : Our findings align with prior studies reporting 2-5% incidence of docetaxel-associated pneumonitis ( lin et al., 2020), but diverge in two key aspects : • Dose-dependence: two patients developed DILI at docetaxel doses ≤100 mg/m2 , challenging the assumption that toxicity is exclusively dose-related. • Imaging patterns: Rapid progression to crazy-paving (case 3) suggests broader radiological phenotypes than classic ground-glass opacities. 3. Mechanistic hypothesis : The Pathophysiology may involve: • Direct alveolar injury from polysorbate 80 (docetaxel’s solvent), supported by histopathological similarities to other solvent-driven ILDs (Barnias et al.,2016). • Immune activation: trastuzumab’s role in antibody dependent cellular cytotoxicity (ADCC) could amplify cytokine release (e.g., IL-6,TNF-α), as seen in case 3’s fatal progression. 4. Efficacy of Dexamethasone-based steroid regimen : Our case series demonstrates that intravenous dexamethasone followed by oral prednisolone represents an effective, accessible approach for managing docetaxel-induced interstitial lung disease (DILI). This regimen achieved clinical and radiological improvement in 80% of patients (4/5 cases), comparable to outcomes reported with methylprednisolone in literature. Key advantage of this approach: • Rapid response: symptomatic improvement occurred within 48-72 hours of IV dexamethasone initiation (8-12 mg/day). • Practical transition: oral prednisolone (1mg/kg) maintained therapeutic effects post-discharge without rebound pneumonitis. • Resource-conscious: Dexamethasone is 10-20x more cost-effective than methylprednisolone in many healthcare setting. Critical comparison: Parameter Our dexamethasone regimen Literature MPSS regimen Time to improvement 2.5 ± 0.8 days 2.1±1.2 days Hospital stay 7.3 ± 2.1 days 6.8 ± 3.4 days 30 day survival 80% 82-85% Cost per treatment Comparatively low Comparatively high 5. Limitations : • Retrospective design: potential symptom bias in symptom documentation. • Small sample size: Reflects DILI’s rarity but limits generalizabilty. • Lack of rechallange data: casuality could not be definitively proven. The present study was conducted at Department

Chemotherapy induced ILD, though rare, demands vigilance due to its unpredictable onset and potential morbidity. Our series underscores: 1. Early recognition of dyspnea/post-chemotherapy hypoxia as a red flag. 2. Dexamethasone to prednisolone an effective cost-efficient alternative to methylprednisolone. 3. HER2 / trastuzumab co-administration may lower toxicity thresholds. 4. Multidisciplinary collaboration to exclude mimics (infection, progression). These insights warrants guideline updates, particularly for resource-limited settings. Future studies should explore biomarkers and steroid sparing for risk predictions and steroid prophylaxis in high risk cohorts. It is important that this complication is identified and differentiated from other causes of lung infiltrates in malignancy such as infection and managed early so as to reduce the morbidity and mortality due to cancer chemotherapy. 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. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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