Case Presentation – July 2024

Iron Pill Aspiration

Written by: Roberta Trader, student, Cleveland Clinic School of Cytotechnology, Cleveland, Ohio

Patient Age: 75-year-old male

Specimen Type:  Right Lower Lobe Lung Brush, Thin Prep® Non-GYN, modified Romanowsky smear, and Cellient® cell block.

Patient History: History of Prostate Cancer, presents with Right Lower Lobe lung infiltrate, bronchial stenosis, and mediastinal lymphadenopathy.

Cytologic Diagnosis: Negative for malignant cells, acute inflammation, multinucleated giant cells, few poorly formed granulomas, iron pill fragments.

Biopsy/Pathology Diagnosis: Iron Pill Bronchitis

Case provided by: Cleveland Clinic Anatomical Pathology Lab, Cleveland, OH

Iron Pill Aspiration

Etiology:  

Iron Pill Aspiration (IPA) is the result of an accidental aspiration of an iron pill supplement that is taken orally. Oral iron supplements, which commonly consist of ferrous sulfate, are the standard treatment for and prevention of iron-deficiency anemia.¹    On aspiration, ferrous sulfate can begin to disintegrate in the respiratory environment and result in deep mucosal injury from chemical burns and an inflammatory response. If left untreated, the respiratory response may result in life-threatening airway damage including fibrosis and airway stenosis.²   The degree of damage can depend on the amount of active iron in the medication and on the length of time that it remains in direct contact with the bronchial mucosa.³  Approximately 7% of foreign body aspirations are the result of a medicine aspiration.⁴  In 2004, the National Safety Council reported that more than 4,000 patients died of foreign body aspiration.⁵  Iron Pill Aspiration was first reported in the French literature in 1975 by Milillo et al and in the English literature in 1988 by Tarkka et al.⁶  Even with the utilization of clinical background, radiologic imaging and bronchoscopy, the diagnosis of IPA remains difficult due to the rapid dissolution of the pill, the non-specific finding and the rarity of occurrence.⁶  In the current case, the patient had been prescribed iron supplements to treat anemia.

Clinical Features:

Iron pill supplements are prescribed to a wide age range of patients. Most iron pill aspiration occurs in older patients and those who have decreased swallow reflex. Patients who have experienced an aspiration event may not be immediately aware of the occurrence. In a study conducted by Xing et al in 2023, the most common presenting symptoms included persistent cough, shortness of breath and hemoptysis. It was noted in the study that few patients had reported an aspiration event.⁶    If the aspiration event is not known at the time of clinical presentation, a case of non-asphyxiating foreign body aspiration can often be misdiagnosed. Common misdiagnoses have included bronchial asthma, pneumonia, or bronchiolitis.⁷   Radiologic images early in the aspiration event may appear normal while later imaging may indicate bronchial mucus build-up, ulceration, or atelectasis. Common sites for the findings are the central bronchi and right lower lobe.⁶  The patient in the current case was incidentally found by radiology to have right lower lobe lung infiltrates, bronchial stenosis, and mediastinal lymphadenopathy.

Treatment and Prognosis:

Bronchoscopy can be used to diagnosis and treat iron pill aspiration. Due to the non-specific symptoms and often unreported aspiration, clinical teams may request bronchoscopy to determine the cause by visualizing the affected tissue. Brush and FNA sample collection and biopsy can be performed to assist with diagnosis. It was reported in a study by Xing, et al in 2023 that common bronchoscopy findings in cases where IPA was the final diagnosis included “mucosal discoloration and bronchial narrowing, stenosis, or obstruction”.⁶    Bronchoscopy findings in the acute phase of IPA can include a golden-yellow, hemorrhagic, necrotic mucosa while the chronic phase may present with bronchial stenosis.¹   The use of bronchoscopy for treatment of IPA after diagnosis includes the use of bronchial balloon dilation to provide patency, or opening, of the stenotic airway.  Also, during bronchoscopy, therapy such as methylprednisolone injection or topical mitomycin C application and removal can be administered. Topical mitomycin C is an antitumor antibiotic isolated from Streptomyces caespitosus. It has an inhibitory effect on fibroblast proliferation but allows for epithelial growth.⁸

The prognosis of IPA is dependent on the duration of exposure. The amount of free radicals generated by iron oxidation and the duration from the initial aspiration of an iron pill to its removal may contribute to the severity of the airway injury.⁷   Early diagnosis and removal of the aspirated iron pill has been linked with good prognosis. Long duration of iron exposure can lead to vessel ulceration and may be fatal.³

The diagnostic bronchoscopy performed in the current case revealed a discolored mucosa at the main bronchus of the right lower lobe. A biopsy and bronchial brush sample were collected. Following cytology and histology reports, the patient underwent a bronchoscopy with balloon dilation and steroid injection to treat stenosis and alleviate dyspnea. The patient was treated for pneumonia and is still prescribed oral iron supplements.

Cytology:

Initial diagnosis of IPA is not always readily distinguishable on cytology examination of slides. There may be a presence of a small amount of yellow-brown material on modified Romanowsky and Papanicolaou stains which without the clinical history of aspiration could easily be interpreted as non-specific artifact or other types of pigmented particles such as hemosiderin or carbonaceous particles.⁶   Histological examination of biopsy material is typically the gold standard for diagnosis, wherein iron pill injury is characterized by the presence of crystalline iron fibrils in the presence of necrosis or in an ulcer base.¹  An iron stain such as Perls’ Prussian Blue can aid in determining the iron composition of the yellow-brown material by staining iron as a bright blue color.⁹   Microscopic features of the biological response to the aspiration exposure may include the presence of multinucleated giant cells, hemosiderin-laden macrophages, granulomas, and reactive atypia of squamous metaplasia.  Care should be taken when assessing the Prussian Blue stain results as the hemosiderin in macrophages will also stain positively.⁹

Differential Diagnosis: 

Iron Pill Aspiration presents in a nonspecific way related to the amount of time elapsed since the aspiration event. When the findings are detected early, a differential diagnosis may be a fungal or bacterial infection or bronchial asthma. Later, differential diagnoses may include sarcoidosis or squamous cell carcinoma.

Respiratory Infection – Cytology can play an important role in diagnosing infections.¹⁰   The respiratory response to a bacterial or fungal infection can include acute and chronic inflammatory cells.  A neutrophilic exudate is often present in bacterial infections while respiratory fungal infections should be suspected whenever there is a granulomatous inflammation and/or necrosis.¹⁰

Bronchial Asthma – One of the most common chronic diseases in the world is bronchial asthma.¹¹   Asthma is an inflammatory response to environmental stimuli that results in irreversible remodeling of the bronchial wall. The increased thickness of the bronchial wall results from submucosal fibrosis. Cytology and histology samples of the fibrosis contain fibroblasts, myofibroblasts and inflammatory cells.¹¹

Sarcoidosis – Pulmonary sarcoidosis presents in a wide variety of clinical conditions from an asymptomatic state to a severe pulmonary disorder which can lead to respiratory failure. The symptoms of pulmonary sarcoidosis are nonspecific and typically include dyspnea and cough. Bilateral hilar adenopathy is observed in 50 – 85% and parenchymal opacities in 20 – 65% of cases.¹²   Since there is no known cause and no definitive biomarkers, diagnosis of pulmonary sarcoidosis relies on the presence of non-necrotizing granulomatous inflammation in the involved tissue with the exclusion of alternative granulomatous diseases.¹²   The non-necrotizing granulomas of pulmonary sarcoidosis appear histologically as discrete, well-circumscribed aggregates of epithelial cells, macrophages, multinucleated giant cells and CD4+ T lymphocytes.¹²

Squamous Cell Carcinoma – Many primary pulmonary squamous cell carcinomas are centrally located lesions of the respiratory system. It is the subtype of respiratory cancer most often associated with the initial symptom of hemoptysis.¹⁰   Imaging reports for these tumors can include post-obstructive pneumonia and cavitation of the tumor.¹⁰ Moderate to poorly differentiated squamous cell carcinoma may present in clusters of spindle shaped cells with little to no keratin in the cytoplasm.¹⁰

References:

1.Henriques V, Santos DC, Lerias G, Monteiro LC. Iron pill aspiration: cytologic and histologic findings of a potential life-threatening airway injury. A case report and literature review. Diagn Cytopathol. 2018;46:532-539. doi:10.1002/dc.23886.

2.Sedhai YR, Bhat P, Spalitto D, et al. Iron pill aspiration syndrome: a case report and literature review. Respir Med Case Rep. 2023;45:101908. doi:10.1016/j.rmcr.2023.101908.

3.Caterino U, Battistoni P, Batzella S, Iacono RD, Lucentoni G, Galluccio G. Syndrome of iron pill inhalation in four patients with accidental tablet aspiration: severe airway complications are described. Respir Med Case Rep. 2015;15:33-35. doi:10.1016/j.rmcr.2015.02.002.

4.Mehta AC, Khemasuwan D. A foreign body of a different kind: pill aspiration. 2014;9(1): 1-2. Ann Thorac Med. doi:10.4103/1817-1737.124404.

5.Narula T, Jaber W, Machuzak M, Gildea TR. Acute central airway obstruction: an occupational hazard: aspiration of crack cocaine. J Bronchology Interv Pulmonol. 2012; 19(2): 126 – 128. doi:10/1097/LBR.0b013e31824fd03.

6.Xing J, Yadav R, Ntiamoah P, et al. Airway injury caused by aspiration of iron sulfate pills: a series of 11 cases. Mod Pathol. 2023;36. doi:10/1016/j.modpat.2023.100347.

7.Okamoto S, Takamori M, Yamamoto M, Murata K, Wada A. Pleural effusion as a rare presentation of foreign body aspiration. Respir Med Case Rep. 2021;33:101416. doi:10.1016/j.rmcr.2021.101416.

8.Lee P, Culver DA, Farver C, Mehta AC. Syndrome of iron pill aspiration. Chest. 2002;121:1355-1357. doi:10.1378/chest.121.4.1355.

9.Ghio,AJ,  Roggli, VL. Perls’ Prussian blue stains of lung tissue, bronchoalveolar lavage, and sputum. J Environ Pathol Toxicol Oncol. 2021; 40(1): 1-15. doi:10.1615/JEnvironPatholToxicolOncol.2020036292.

10.Cibas ES and Ducatman BS. Cytology: Diagnostic Principles and Clinical Correlates: Fifth Edition. 2021. Elsevier Inc. 58 – 105. ISBN: 978-0-323-63636-0.

11.Michalik M, Wojcik-Pszczola K, Paw M, et al. Fibroblast-to-myofibroblast transition in bronchial asthma. Cell Mol Life Sci. 2018; 75(21): 3943-3961. doi:10.1007/s00018-018-2899-4.

12.Trivieri MG, Spagnolo P, Birnie D, et al. Challenges in cardiac and pulmonary sarcoidosis: a JACC state-of-the-art review. J Am Coll Cardiol. 2020; 76(16):1878-1901. doi:10/1016/j.jacc.2020.08.042.