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A 69-year-old woman with breast cancer presents to hospital in Beirut to receive her first post-mastectomy chemotherapy session. She notes that in the past 6 months, she has received neoadjuvant chemotherapy, had a partial mastectomy of the left breast, and been treated with adjuvant radiotherapy. During admission, however, she reports sudden severe pain in her lower back.

Examination finds that her blood pressure has dropped to 80 mm Hg systolic and her pulse oxygen saturation has fallen to 85%. She is not feverish. Further examination is significant only for end-inspiratory bi-basilar crackles.

An electrocardiogram shows normal sinus rhythm with no ST segment changes, and chest x-ray reveals bilateral infiltrates with a left upper lobe predominance. Clinicians administer 3 L of normal saline in three divided boluses; the patient's blood pressure, however, remains low.

Clinicians start treatment with 0.2 μg/kg/min of intra­venous (IV) norepinephrine, and 15 L O₂ via a face mask, but the patient's oxygen saturation (SpO₂) fails to improve. She is transferred to the intensive care unit (ICU), where she is electively intubated and sedated with midazolam (5 mg/hour, IV) and fentanyl (100 μg/hour, IV). The patient receives ventilation via a volume-controlled mode.

Assessment shows:

• Tidal volume: 400 mL/min

• Respiratory rate: 15 breaths/min

• Fraction of inspired oxygen (FiO₂): 100%

• Positive end-expiratory pressure (PEEP): 10 cm H₂O

This stabilizes the SpO₂ at approximately 90%-92%; arterial partial oxygen pressure (PaO₂) is 66 mm Hg with a PaO₂/FiO₂ ratio of 66.

Patient's Oncologic History

Early 2018: The patient is diagnosed with grade III, estrogen receptor-negative, progesterone receptor-negative, HER2-positive invasive ductal carcinoma of the left breast. Treatment includes six sessions of neoadjuvant chemotherapy with dexamethasone (Decadron), docetaxel (Taxotere), and trastuzumab (Herceptin).

March 2018: The patient undergoes a partial mastectomy of the left breast with dissection of the axillary lymph nodes. Pathology reports show negative tumor margins; five of the 14 harvested lymph nodes are positive for stage IIIA breast cancer.

June 2018: Adjuvant radiotherapy is initiated, with a 16-session protocol of whole-breast irradiation with inclusion of the lower axilla. Each session involves 42.5 Gy delivered to the irradiated breast; the organs at risk are the ipsilateral lung and heart. The volume of lung receiving at least 20 Gy is estimated to be less than 25% of the total volume. The patient receives her last radiotherapy session 1 week prior to beginning chemotherapy.

August 2018: Given that her oxygen desaturation is not responding to high flow oxygen, clinicians perform an urgent thoracic-abdominal-pelvic angio-computed tomography (CT) scan to rule out pulmonary embolism or aortic dissection. The scan reveals bilateral pulmonary alveolar in­filtrates predominantly in the left upper lobe; there is no evidence of pulmonary embolism or aortic dissection. The affected area of the lung corresponds to the main area affected by her radiotherapy beams.

To assess for possible myocardial dysfunction related to the patient's Herceptin therapy, clinicians order trans-thoracic cardiac echocardiography, which shows a normal ejection fraction (56%) with no major signs of systolic or diastolic dysfunction. Her systolic pulmonary artery pressure is estimated to be 30 mm Hg.

Based on these findings, clinicians diagnose the patient with an atypical severe form of acute respiratory distress syndrome (ARDS) secondary to radiotherapy ().

Lab tests are ordered, showing:

• C-reactive protein (CRP): 69 mg/dL

• Procalcitonin: 0.214 ng/mL

• White blood cells: 14,000 cell/mm³ with 88% segmented neutrophils

• Creatinine: 1.4 mg/dL

Given the patient's elevated CRP, borderline procalcitonin, and elevated white blood cell count, clinicians suspect healthcare-associated pneumonia. Empirical treatment is initiated with IV piperacillin-tazobactam 2.25 g every 8 hours. The dose is adjusted to her creatinine level based on the likelihood that she is suffering from acute kidney injury secondary to renal hypoperfusion. The team also starts treatment with IV linezolid 600 mg every 12 hours, based on the patient's immunocompromised state and hemodynamic instability and the prevalence of methicillin-resistant Staphylococcus aureus in Lebanese hospitals.

Bronchoscopy is performed to eliminate any endobronchial lesions, and a broncho-alveolar lavage (BAL) from her left upper lobe is cultured. The patient is then ventilated using the same low tidal volume/high PEEP strategy.

Assessment the following day finds that her PaO₂ has increased to 81 mm Hg with a decrease in FiO₂ to 40% and a PaO₂/FiO₂ ratio of 202.5. Treatment is started with IV hydrocortisone 50 mg every 6 hours.

August 9, 2018: Follow-up chest x-ray finds the infiltrates in the left upper lobe markedly diminished, and the patient's oxygen requirement has decreased to 30% of FiO₂ and 5 cm of H₂O. Treatment with midazolam and fentanyl is discontinued, and she is started on low-dose dexmedetomidine with a Richmond Agitation-Sedation Scale of 0. Norepinephrine is gradually tapered, and the antibiotic treatment is stopped when the BAL culture results are negative and results of CRP, creatinine, and white blood cell tests are normal.

August 10, 2018: The patient is successfully extubated and transferred to the regular ward in the evening. Her treatment is switched from hydrocortisone to IV methylprednisolone 40 mg twice daily.

August 16, 2018: Clinicians order a chest x-ray, which returns nor­mal results. The patient is discharged to home.

September 2018: The patient undergoes a thoracic CT following hospitalization for an infected mammary epidermal cyst, which shows a marked reduction in the alveolar opacities from the previous month.

Discussion

Clinicians reporting this of a woman who developed ARDS following surgery and radiotherapy for breast cancer note that ARDS is an extremely rare complication of thoracic radiotherapy, and as such, requires a high level of clinical suspicion to allow prompt diagnosis and treatment.

After surgical resection of the primary tumor, breast cancer is often treated with adjuvant radiotherapy, which is associated with various respiratory side effects, among which ARDS represents a rare complication.

The study of epidemiology, patterns of care, and survival and mortality rates of ARDS in ICUs in 50 countries reported that clinical recognition of ARDS ranged from 51.3% (95% CI 47.5%-55.0%) in cases of mild ARDS to 78.5% (95% CI 74.8%-81.8%) in severe ARDS.

Less than two-thirds of patients with ARDS in that study received a tidal volume of 8 mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% of patients (95% CI 38.2%-42.1%), whereas 82.6% (95% CI 81.0%-84.1%) received a PEEP of less than 12 cm H₂O. Prone positioning was used in 16.3% (95% CI 13.7%-19.2%) of patients with severe ARDS.

"Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning," the LUNG SAFE authors wrote.

The case report authors note that radiotherapy is known to sometimes cause mild/moderate pulmonary toxicity, with the probability and severity of effects on the lungs determined by the total dose of radiation, the fraction per dose, and the incidentally irradiated lung volume.

For example, one study found that 28% of patients developed pneumonitis categorized as x-ray pneumonitis, CT pneumonitis, or clinical x-ray pneumonitis. Longer-term complications generally involve pulmonary fibrosis, which develops 6 to 24 months following radiation. The risk of secondary lung cancer is also increased in smokers who receive radiotherapy for breast cancer.

According to the most recent Berlin definition, ARDS is an acute-onset hypoxemia with bilateral pulmonary infiltrates on chest imaging within 1 week of a known clinical insult that is not fully explained by an underlying cardiac failure or volume overload. ARDS is further subdivided into three mutually exclusive categories based on the degree of hypoxemia:

• Mild: 200 mm Hg > PaO₂/FiO₂<300 mm Hg

• Moderate: 100 mm Hg > PaO₂/FiO₂<200 mm Hg

• Severe: PaO₂/FiO₂ <100 mm Hg

Mechanical ventilation, with a goal to minimize ventilator-induced lung injury (VILI), remains the key aspect of managing ARDS. The authors of a of advances in diagnosis and treatment of ARDS noted that adjunctive interventions to further minimize VILI, such as prone positioning in patients with a PaO₂/FiO₂ ratio less than 150 mm Hg, were associated with a significant mortality benefit, whereas others such as extracorporeal carbon dioxide removal remain experimental.

In addition, pharmacologic therapies such as β2 agonists, statins, and keratinocyte growth factor, which target pathophysiologic alterations in ARDS, were not beneficial and demonstrated possible harm.

The stages of mild, moderate, and severe ARDS were associated with the following increases in mortality and median duration of mechanical ventilation in survivors (P<0.001 for all):

• Mild: 27% (95% CI 24%-30%) 5 days; interquartile range (IQR) 2-11 days

• Moderate: 32% (95% CI 29%-34%) 7 days; IQR 4-14 days

• Severe: 45% (95% CI 42%-48%) 9 days; IQR 5-17 days

Acute radiation pneumonitis is not an uncommon complication of radiotherapy, and generally becomes symptomatic 6 to 12 weeks after the last radiation session with a non-productive cough, mild to moderate dyspnea, low-grade fever, and a subtle change in the patient's general status. The problem, however, the case authors note, is only rarely associated with ARDS -- of the few reported cases, most occurred in patients receiving thoracic irradiation for lung cancer and to a lesser extent, Hodgkin lymphoma.

One study of cancer patients who develop ARDS suggested a lower mortality in patients with solid tumors, including breast cancer, com­pared with patients with hematologic malignancies and ARDS.

Similarly, patients with good performance status and non-progressive disease (especially locoregional solid tumors, with no direct involvement of the respiratory tract by tumor) have been reported to have a hospital survival rate of 53% -- the highest among patients with malignancy.

The case authors state that they believe theirs is the first reported case of ARDS secondary to radiation therapy for breast cancer. There are also several other aspects that make this patient's case notable, they note:

• The absence of any predisposing respiratory comorbidities that might explain the occurrence of ARDS

• The 1-week interval between the last radiation session and the onset of ARDS, which is relatively shorter than the normal radiation pneumonitis latency

• The smaller irradiated lung volume in radiation therapy for breast cancer compared with radiation therapy for lung cancer

• That the lesions in the left upper lobe delineated the irradiated lung field

Furthermore, the patient's rapid clinical and radiological improvement after 48 hours was remarkable, the case authors state. In addition, the complete resolution of the infiltrates 1 month after the event makes the diagnosis of simple acute pneumonitis less likely. However, this component may have been present and simply responded to the steroids, the team add.

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