Oxaliplatin-induced diffuse alveolar hemorrhage: A case report

Abstract

BACKGROUND

Drug-induced lung injury is a common adverse effect of chemotherapeutic agents. Diffuse alveolar hemorrhage (DAH) is a fatal complication associated with drug-induced lung injury. Early diagnosis and treatment of DAH is critical, as delayed management can lead to respiratory failure and poor outcomes. However, the diagnosis of DAH is difficult because of the nonspecific clinical manifestations; as such, bronchoscopy is necessary to establish a diagnosis.

CASE SUMMARY

The patient presented with fever and dry cough. He had been receiving fluoropyrimidine and oxaliplatin therapy for esophageal squamous cell carcinoma. Chest imaging revealed diffuse ground-glass opacities. Bronchoscopy with bronchoalveolar lavage was performed, which confirmed the diagnosis of DAH. Although the patient’s respiratory status rapidly worsened, high-dose corticosteroid therapy with respiratory support gradually improved the patient’s condition and he was successfully extubated.

CONCLUSION

Prompt DAH diagnosis and bronchoscopy in patients receiving oxaliplatin-containing chemotherapy presenting with acute respiratory failure are critical for improving outcomes.

Key Words: Diffuse alveolar hemorrhage; Oxaliplatin; Esophageal neoplasms; Lung injury; Drug therapy; Case report

Core Tip: This report describes a case of a serious complication of oxaliplatin-induced diffuse alveolar hemorrhage. The diagnosis of diffuse alveolar hemorrhage (DAH) is challenging because the clinical manifestations and radiographic findings of DAH, such as diffuse bilateral opacities, are non-specific, necessitating bronchoscopy with bronchoalveolar lavage fluid analysis to establish the diagnosis of DAH. As early diagnosis by bronchoscopy and prompt initiation of corticosteroid treatment were essential for saving the patient, clinicians should be aware that diffuse alveolar hemorrhage is a potential cause of respiratory failure in patients receiving oxaliplatin.

INTRODUCTION

Drug-induced lung injury is commonly associated with chemotherapeutic agents. Diffuse alveolar hemorrhage (DAH) is one of the most severe complications of drug-induced lung injury, with a mortality rate reaching over 50%[1]. Oxaliplatin is a platinum-derived agent that is widely applied to treat gastrointestinal cancers. Oxaliplatin-induced pulmonary toxicity is relatively uncommon but can be life-threatening. Early recognition of oxaliplatin-induced pulmonary toxicity is critical, as prompt intervention can improve survival and prevent respiratory failure[2]. In addition, older patients may be at an increased risk of infection due to age-related changes in immune function. This vulnerability may be of particular concern during the treatment of DAH using corticosteroids and other immunosuppressive agents. Herein, we present a case of oxaliplatin-induced DAH, which rapidly deteriorated necessitating the use of mechanical respiratory support. Early diagnosis with bronchoscopy and prompt initiation of high-dose corticosteroids improved the symptoms and saved the patient.

CASE PRESENTATION

Chief complaints

A 72-year-old man presented with fever and dry cough.

History of present illness

The patient completed eight cycles of treatment with folinic acid, fluorouracil, and oxaliplatin (modified FOLFOX-6 therapy) 1 month before presentation and then started oral fluoropyrimidine monotherapy for recurrent esophageal squamous cell carcinoma. Plain chest radiography showed opacification in the right lower lung, and computed tomography demonstrated bilateral ground-glass opacities (GGOs) (Figure 1A). Treatment with oral amoxicillin-clavulanate was empirically started. After 3 days, the patient developed a persistent fever. His dry cough progressively worsened, and he experienced moderate respiratory distress on exertion.

Figure 1 Computed tomography scan of the lungs. A: At the initial presentation. Ground glass opacity was seen in a limited area of both lungs; B: On admission. The ground glass opacity expanded and involved about 20% of the total lung volume; C: On day 3 of admission. Almost all lung fields are opacified; D: On day 12 of admission. The opacities are dramatically improved.

History of past illness

The patient had a history of advanced atrioventricular block and hypertrophic cardiomyopathy.

Personal and family history

The patient had quit smoking, but had a smoking history of two packs a day lasting 25 years.

Physical examination

His oxygen saturation was 97% at rest, but decreased to < 93% with mild exertion. Fine crackles were heard in both the lower lung fields.

Laboratory examinations

Leukocytosis (11900/μL) and elevated C-reactive protein (8.9 mg/dL) was noted. Arterial blood gas analysis showed mild hypoxemia (partial pressure of oxygen was 49 mmHg on room air).

Imaging examinations

Computed tomography revealed rapid worsening of diffuse bilateral GGOs involving approximately 20% of the total lung volume (Figure 1B).

MULTIDISCIPLINARY EXPERT CONSULTATION

We consulted a pulmonologist and bronchoscopy was performed on the day of admission. The bronchoalveolar lavage fluid became progressively more hemorrhagic. An extensive workup did not reveal any infectious etiology, autoimmune disease, heart failure or coagulopathy to cause DAH.

FINAL DIAGNOSIS

A diagnosis of DAH was made, with oxaliplatin suspected as the causative agent.

TREATMENT

High-dose methylprednisolone (1000 mg/day) was administered immediately after diagnosis. However, his respiratory status suddenly deteriorated on day 3 of the hospitalization. Computed tomography revealed marked enlargement of the GGO area without pulmonary embolism (Figure 1C). The patient was transferred to the intensive care unit and intubated. After the administration of the second dose of high-dose methylprednisolone, his respiratory status gradually improved, and he was eventually successfully extubated.

OUTCOME AND FOLLOW-UP

The patient was discharged home with full activities of daily living after the corticosteroids were tapered to 30 mg. The pulmonary opacities were markedly improved (Figure 1D). The clinical course during hospitalization was summarized in Figure 2. Corticosteroids were tapered to 5 mg over 6 months without any relapse; the patient was alive at the time of writing.

Figure 2 Clinical course following admission. Bronchoscopy was performed on day 0, which confirmed the diagnosis of alveolar hemorrhage. High-dose methylprednisolone was initiated on the same day; however, the patient’s respiratory status suddenly deteriorated on day 3. High-dose methylprednisolone was repeated, and he was extubated on day 10. Corticosteroids were tapered into 30 mg, and the patient was discharged on day 25. In the line chart, the black points signify the P/F ratio and the gray squares signify the C-reactive protein level. BAL: Bronchoalveolar lavage; CRP: C-reactive protein; mPSL: Methylprednisolone; P/F ratio: Partial pressure of oxygen/fraction of inspired oxygen ratio; PSL: Prednisolone.

DISCUSSION

Herein, we present a case of oxaliplatin-induced DAH. This case highlights the importance of an early diagnosis using bronchoscopy and corticosteroid therapy. Oxaliplatin is an antineoplastic platinum derivative and widely used in gastrointestinal cancers including esophageal, gastric, pancreatic, and colorectal cancers. Interstitial lung disease (ILD) is a relatively uncommon, but serious adverse event of oxaliplatin. Although the incidence of oxaliplatin-induced ILD has been reported to be < 1%, the overall mortality rate is reportedly 30%[2,3]. Moreover, a review of previous literature showed that the mortality rate can reach up to 44.4% in patients requiring corticosteroids and 76.9% in patients requiring invasive respiratory support, respectively[4]. DAH is the most severe consequence of drug-induced lung injury. To date, several cases of oxaliplatin-induced DAH have been reported (Table 1)[2,5,6]. FOLFOX regimen was administered in two cases and oxaliplatin monotherapy in one case. In all of the three cases, invasive mechanical ventilation was applied, and corticosteroids were administered. Corticosteroids are the gold standard for treating DAH and they suppress inflammatory and immune responses, reducing lung damage[7,8]. Although information regarding the timing of corticosteroid therapy initiation was missing in two patients, corticosteroid treatment was delayed for 3 days after the diagnosis of DAH in one patient, who died without improvement. Several literature reviews on oxaliplatin-induced ILD suggested that steroid therapy should be immediately initiated because the time from symptom onset to steroid initiation has been correlated with treatment success[2,9]. However, diagnosing DAH is particularly challenging. Hemoptysis is a hallmark sign of DAH but may be absent in one-third of patients[10]. In addition, radiographic findings of DAH such as diffuse bilateral opacities are nonspecific[11]. Bronchoscopy with bronchoalveolar lavage fluid analysis is the gold standard for diagnosing DAH. As DAH can rapidly deteriorate within a few days, prompt bronchoscopy should be considered in patients at risk of DAH, such as those receiving potentially pulmotoxic chemotherapy including oxaliplatin. In this case, bronchoscopy could be performed on the day of admission, which confirmed the diagnosis of DAH soon after symptom onset. The early initiation of high-dose corticosteroid therapy may have improved the symptoms. However, older patients receiving corticosteroid therapy are at an increased risk of infections due to immunosuppression[12-14]. Given the vulnerability of this population, careful decision-making and close monitoring are essential for management of DAH.

Table 1 Previously reported cases of oxaliplatin-induced diffuse alveolar hemorrhage.

Characteristics	Kumaran et al[6]	Lou et al[5]	Watkins et al[2]	Present case
Types of cancer	Unknown primary	Esophageal	Colorectal	Esophageal
Regimen	Oxaliplatin	FOLFOX	FOLFOX	FOLFOX and S-1
Chemotherapy before onset	1 cycle	1 cycle	11 cycles	8 cycles
Mechanical ventilation	Yes	Yes	Yes	Yes
Treatment	Corticosteroids	mPSL 1 mg/kg	mPSL 125 mg q6h	mPSL 1000 mg
Timing of corticosteroids	Not addressed	Not addressed	After 3 days of hospitalization	On the day of hospitalization
Outcome	Extubation	Extubation	Death	Extubation

FOLFOX: Folinic acid, fluorouracil, and oxaliplatin; mPSL: Methylprednisolone; S-1: Started oral fluoropyrimidine; q6h: Every 6 hours.

CONCLUSION

Oxaliplatin can cause DAH, a serious pulmonary adverse effect. Oncologists should suspect the possibility of DAH and perform bronchoscopy immediately when patients receiving chemotherapy containing oxaliplatin present with acute respiratory failure.

ACKNOWLEDGEMENTS

We thank the patient and the patient’s family for granting permission to share the patient’s clinical information.