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“Pills” and the Air Passages A Continuum Elif Kupeli, MD, FCCP; Danai Khemasuwan, MD, MBA; Pichapong Tunsupon, MD; and Atul C. Mehta, MD, FCCP
Recently, we reported a number of key, common medications that affect the air passages in a variety of fashions. The purpose of this article is to provide a comprehensive review of the literature on the subject, including supportive articles published in languages other than English. The presented information was gathered by a review of the English literature, by cross referencing, and by communication with other interventional pulmonologists. We identified several additional medications causing either direct or systemic effects on the air passages. In this review, we update the clinical presentation, mechanism of injury, diagnosis, and management of the airway complications related to these medications. CHEST 2015; 147(1):242-250 ABBREVIATIONS: BSG 5 bismuth subgallate; ICS 5 inhaled corticosteroid; SPS 5 sodium polystyrene sulfonate; TEF 5 tracheoesophageal fistula
Aspiration of a pill in the air passages can occur even among adults with an intact swallowing mechanism. It is often difficult to establish the diagnosis, especially in the absence of a reliable history. Some pills may remain intact in the endobronchial tree for a number of years without causing much harm, whereas others may dissolve, making recognition of the foreign body aspiration difficult (Fig 1A). The clinical consequences may also vary, from an asymptomatic granuloma formation to a severe, life-threatening airway necrosis, depending upon the chemical characteristics of the “pill.” Thus, if the diagnosis is delayed, severe airway damage can occur. A high degree of suspicion is required to establish
Manuscript received March 4, 2014; revision accepted July 19, 2014. AFFILIATIONS: From the Pulmonary Diseases Department (Dr Kupeli), Baskent University School of Medicine, Ankara, Turkey; Pulmonary and Critical Care Medicine (Dr Khemasuwan), Respiratory Institute, Cleveland Clinic, Cleveland, OH; Internal Medicine (Dr Tunsupon), Medicine Institute, Cleveland Clinic, Cleveland, OH; and Lerner College of Medicine (Dr Mehta) Respiratory Institute, Cleveland Clinic, Cleveland, OH.
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the diagnosis, especially if the pill has dissolved. Our previous review delineated the local and systemic reactions on the airways of some common medications, their diagnosis, and the management of the most common complications.1 Since that publication, we have discussed with many experts their experiences with “pill aspiration,” prompting further review of the literature since the 1920s, including cross referencing for the articles that were published in languages other than English.1 The following discussion deals with additional medications affecting the airways (Table 1). Moreover, we have compiled an appendix containing all the supportive articles related to “pill”-induced airway injury
CORRESPONDENCE TO: Atul C. Mehta, MD, FCCP, Respiratory Institute, 9500 Euclid Ave, A-90, Cleveland Clinic, Cleveland, OH; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0531
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Figure 1 – A (left), An enteric-coated intact vitamin pill embedded in the trunchus intermedius for . 2 y. A (right), Minimal granulation at the site of the foreign body after its removal. B, A whitish adherent pseudomembrane over the left mainstem bronchus (arrow) and right mainstem bronchus (arrowhead). (Reprinted with permission from Sundar et al.4) C, Numerous foci of intra-alveolar large purple polygonal crystals (arrows) consistent with sodium polystyrene sulfonate aspiration (hematoxylin and eosin, original magnification 3 400). D, BAL fluid in a patient with lipoid pneumonia. Note oil particles floating at the top. E, Microscopic examination with Oil Red O stating of BAL revealing lipid-laden macrophages (arrow) (Reprinted with permission from Majori et al.40)
that we could gather from the published literature but were unable to include in the main article (e-Appendix 1). As stated earlier, pills can affect the airways via their local inflammatory, obstructive, or systemic effects.
Inflammation Aspirin
Aspirin is often prescribed as an analgesic or an antipyretic and also for antiplatelet aggregation. An uncoated journal.publications.chestnet.org
aspirin pill can adhere firmly to the mucous membrane. Upon contact with moisture, aspirin hydrolyzes into salicylic and acetic acids, which are irritants to the mucous membrane. There are four confirmed case reports of aspirin aspiration among toddlers, based strictly on the histories.2 It was hypothesized that the mucosal irritation resulted in laryngeal spasm, which led to cardiopulmonary arrest in these cases. Two toddlers did survive; however, they had permanent anoxic 243
TABLE 1
] Updated List of Medications Involving the Airways and Their Mechanism of Action
Inflammation Aspirin
a
Obstruction
Systemic Effects
Alendronate sodium
Iatrogenic Administration
Calcium carbonate
Amiodarone
Epinephrine
Ciprofloxacina
Bevacizumaba
Inhaled corticosteroida
a
Cocaine bag
Clopidogrel
Insulin
Endoscopic capsule
Cocaine
Mineral oil productsa
Diatrizoic acid
Lanthanum carbonatea
Inhaled corticosteroida
N-acetylcysteine
Ferrous sulfate
Sevelamer hydrochloridea
Heroin
Pentamidine
Sucralfate
Mercury
Bismuth subgallatea Charcoal
Mercury
a
Tetracyclinea
a
Sirolimus
Sodium polystyrene sulfonatea Meprobamate and quinine sulfate preparationa Metformin Mineral oil productsa Nortriptyline Pomegranate supplement Potassium chloride Propyliodone 3,5-Diiodo-4-pyridine Additional medications from previous article.1
a
brain injury. In one of the two fatal cases, postmortem examination revealed pulmonary congestion, hemorrhage, and consolidation of the lungs. Microscopic examination revealed diffuse pulmonary hemorrhage with a collection of acute inflammatory cells. However, no evidence of aspirin was found on either the gross or the microscopic examination of the respiratory system.3 There are no reports of bronchoscopic intervention among these patients. The diagnosis was based solely on the history. Tetracycline
Tetracycline is a commonly prescribed broad-spectrum polypeptide antibiotic. There is one case report of tetracycline aspiration in a patient with a swallowing difficulty.4 The patient developed intense airway inflammation and parenchymal consolidation a few days after the “choking” incident. Bronchoscopy revealed an intense inflammation, mucosal edema, and a whitish adherent pseudomembrane involving the vocal cords, trachea, and left main bronchus (Fig 1B). Incidentally, there was no mention of any bronchoscopic intervention in this case. It is very likely that the highly acidic nature of the tetracycline was responsible for the airway injury. The patient was treated conservatively with empirical antibiotic therapy. A follow-up bronchoscopy confirmed residual, albeit clinically insignificant, 244 Special Features
mucosal scarring without significant airway stenosis. In this case, the diagnosis of tetracycline aspiration was established by the history of aspiration but in the absence of the actual foreign body on bronchoscopic examination. Sodium Polystyrene Sulfonate
Sodium polystyrene sulfonate (SPS) (Kayexalate) is a cation-binding resin indicated for the treatment of hyperkalemia. Case reports of pneumonitis following SPS aspiration involving all age groups have been found in the literature since 1978. The first case of SPS aspiration was reported in a postterm hyperkalemic female infant with meconium ileus. She developed neonatal asphyxia and succumbed.5 Since then, nine other cases of SPS aspiration have been cited in various journals. All patients developed cardiopulmonary compromise as a consequence and subsequently died without bronchoscopic intervention. All cases were diagnosed from postmortem examination because there was an unclear history of SPS aspiration. The examination revealed multifocal pulmonary consolidation and severe pulmonary congestion.6 The characteristic histologic finding of SPS is deposition of parallel, laminated, purple polygonal amorphous crystals in the lung tissue.7 These crystals were confirmed as SPS by Fourier transform infrared microspectrophotometry.8 However, the latter
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is seldom required because of the unique characteristic of the SPS crystal.9 Duggal et al10 reported a case of SPS aspiration-associated refractory ARDS. The pathology from the postmortem examination revealed numerous foci of intraalveolar large purple polygonal crystals consistent with SPS aspiration from all the lobes (Fig 1C).11 In a rat model, Haupt and Hutchins12 demonstrated an acute inflammation and SPS particle deposition in the alveoli after direct injection of the solution in the trachea and concluded that gastric content was not the sole cause of aspiration pneumonitis in the fatal cases of SPS aspiration. Physicians should use oral SPS judiciously in patients with altered mental status and/or multiple chronic debilitating diseases. Rectal administration of SPS is an alternative route with similar efficacy in this population. Nevertheless, one should be aware of ischemic colitis and colonic necrosis as common GI adverse effects of rectally administered SPS.13 The role of bronchoscopy in SPS aspiration remains to be established. Meprobamate and Quinine Sulfate Preparation
The preparation of meprobamate and quinine sulfate is used for the treatment of nocturnal muscle cramps of the lower limbs. There is a case report of airway injury from the aspiration of a capsule containing meprobamate and quinine sulfate. This patient presented to the emergency room with fever, dyspnea, oropharyngeal pain, and drooling. A chest radiograph was unremarkable. Flexible bronchoscopy revealed evidence of caustic damage to the larynx, trachea, and main bronchi with a psesudomembrane formation, without any evidence of a foreign body. Otherwise, the mainstem bronchi were patent. Microscopic examination from an endobronchial specimen revealed a fibrin-leukocyte membrane containing a few clusters of dystrophic cells. No therapeutic bronchoscopic intervention was required. The patient was treated with broad-spectrum antibiotics and systemic corticosteroids. There was a minimal area of mucosal injury on follow-up bronchoscopic examination after the 12th day.14 Bismuth Subgallate
Bismuth subgallate (BSG) is a heavy metal compound used as a hemostatic substance to reduce the incidence of bleeding after tonsillectomy and adenoidectomy. It works by initiating a clotting pathway through the activation of factor XII. In an experimental rat model, intratracheal administration of BSG resulted in a subacute pneumonia, with clusters of neutrophils surrounding journal.publications.chestnet.org
the intraparenchymal particles of the drug. The pneumonia resolved spontaneously within 30 days of the observation period.15 There are two case reports of BSG aspiration pneumonitis following tonsillectomy and adenoidectomy among children. Chest radiography demonstrated radio-opaque material of bismuth throughout the lung fields, oropharynx, and nasopharynx.16 The patients were treated conservatively with supplemental oxygen, aggressive chest physiotherapy, and frequent aerosolized bronchodilators without significant long-term complication. BSG should be used cautiously to avoid inadvertent aspiration, especially in children in whom uncuffed endotracheal tubes are used frequently during the upper-airway procedures. Mercury
Two major forms of mercury are used for medical purposes: organic and inorganic. The side effects of organic mercury usually include neurologic symptoms, whereas inorganic mercury causes GI and renal symptoms. It is the elemental form of mercury that causes the pulmonary symptoms.17 Several forms of pulmonary toxicity from elemental mercury have been reported in the literature. In the past, the use of a GI Miller-Abbott tube caused an accidental ingestion and aspiration of mercury in the endobronchial tree. The aspiration of elemental mercury can cause acute pneumonitis and is associated with high mortality.18,19 However, there is one case report of spontaneous absorption of intrabronchial mercury without systemic toxicity.20 Interestingly, remnants of mercury can persist as radiopaque particles in the lungs and may lead to granuloma formation and extensive pulmonary fibrosis decades later.21 Histologically, metallic mercury globules can be found in the lung parenchyma surrounded by a dense fibrous tissue, epithelioid cells, and fibroblasts.22 A medical thermometer contains approximately 600 mg of elemental mercury, which can occasionally lead to toxicity because of high vapor pressure.23 There are two reported cases of dislodged metallic mercury in the airways after biting on a glass mercury thermometer (Fig 2) In one case, globules of mercury were seen on a chest radiograph. The patient was observed overnight and was discharged because he developed no complications.24 Acute inhalation of mercury vapor leads to the development of nonspecific symptoms such as fever, nausea, vomiting, shortness of breath, cough, and chest tightness within a few hours of inhalation. In addition, approximately 80% of the inhaled elemental mercury 245
TABLE 2
] Mineral Oil Products Associated With Lipoid Pneumonia Reported in the Literature
Products Combined cod liver oil and liquid petroleum Laxatives containing mineral oil Oil mists Liquid paraffin Paraffin Lip balm Baby oil Mineral oil enema Animal fat (Ghee) Domestic insecticides Petroleum jelly for nasal application Vaseline for nasogastric tube insertion Olive oil self-injection Cod liver oil
Figure 2 – Broken piece of a mercury thermometer in the left main bronchus of a young patient. (Reprinted with permission from Moxham and Lee.23)
Mexican folk remedies Squalene Facial petroleum for erythrodermic psoriasis
vapor is absorbed into the bloodstream and it crosses the blood-brain barrier, causing systemic toxicity.22 Intoxication with mercury can be confirmed with a urine mercury level . 200 mg/L. The first step in the management of acute mercury inhalation is to eliminate the source of exposure, for instance, using bronchoscopic suction to remove the remaining quantity of mercury from the aspirated broken thermometer.19 In the case of systemic toxicity or elevated serum or urine mercury level, the chelating agents of choice include penicillamine, N-acetyl-dl-penicillamine, 2,3-dimercaptopropanol, meso-2,3-dimercaptosuccinic acid, and 2,3-dimercapto1-propane sulfonic acid.24 Mineral Oil
Mineral oil products are used for different purposes and are commercially available in multiple forms in the market. Repeated aspiration or inhalation of these products can potentially lead to lipoid pneumonias, which are reported in both adult and pediatric populations.25 The first case of lipoid pneumonia was described in 1925.26 Since then, there have been many case reports of different forms of mineral oil-related lipoid pneumonias (Table 2). Among adults, the most common cause of lipoid pneumonia is the improper use of mineral oil for the treatment of constipation and the frequent use of oily nose drops for chronic rhinitis, mainly at bedtime.27 The oily particles once introduced into the nostrils can 246 Special Features
White spirit Gas oil Lorenzo oil
easily reach the bronchial tree and can impair the mucociliary function, subsequently inhibiting the protective cough reflex.27 Once in the alveolar spaces, oily substances are emulsified by the lung lipase, resulting in a foreign-body reaction. Lipoid pneumonia is categorized as exogenous, endogenous, or idiopathic.28 Exogenous lipoid pneumonia is associated with chronic aspiration of mineral oil, not only in the elderly, but also in children with neuromuscular disorders. Endogenous lipoid pneumonia is usually associated with lipid storage disease or with a proximal obstructive lesion such as carcinoma.29 Idiopathic lipoid pneumonia is rare; however, it has been described in male smokers who are otherwise healthy.30 Patients typically present with nonspecific symptoms such as fever, productive cough, and gradual onset of dyspnea, similar to bacterial pneumonia or other chronic lung diseases. Less commonly described clinical features include chest pain and hemoptysis.31 The clinical manifestations of lipoid pneumonia vary widely. It may present as an asymptomatic, incidentally discovered pulmonary infiltrate,32-34 acute pneumonitis,34 chronic respiratory failure,35 a localized granuloma, or even an ARDS.36
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The history of inhalation or ingestion of mineral oil products is essential to establish the diagnosis. The chest radiography could reveal a pulmonary mass, diffuse airspace infiltration, or a localized consolidation similar to a malignancy.37 CT scanning is the best imaging modality for the evaluation of the lipoid pneumonia and usually provides the first clue to the diagnosis of this disease (Fig 3).27 The CT scan findings usually show foci of fat attenuation surrounded by parenchymal consolidation.38 MRI does not produce images specific to this condition because of high signal intensity on T1-weighted images caused by blood and/or fat contents.39 A BAL or a transbronchial biopsy is necessary to support the diagnosis of lipoid pneumonia (Figs 1D, 1E40). The typical findings are numerous lipid-laden macrophages and a deposition of inflammatory cells, as well as evidence of fibrosis in the lung parenchyma and the interstitium on histologic examination.40-42 The management of lipoid pneumonia is not clearly defined. The mineral oil products must be discontinued, and early diagnosis, supportive therapy, and treatment with corticosteroids have been shown to have positive outcomes.36,43 Multiple therapeutic BALs have produced rapid clinical recovery in children.44,45
Airway Obstruction Calcium Carbonate
Calcium carbonate is used as a supplemental source of elemental calcium. It may be used as a phosphatebinding agent in the management of hyperphosphatemia in patients with chronic renal failure. Aspiration of a calcium tablet has been reported in three cases in the literature.46,47 These patients presented with nonresolving pneumonia. The calcium pills could be visualized
Figure 3 – Right upper-lobe alveolar process in a patient receiving a laxative containing mineral oil. (Reprinted with permission from Bandla et al.32)
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on both a plain chest radiograph and a noncontrast CT scan of the chest (Fig 4). In one case, the pill was removed with a rigid bronchoscope, revealing a granulation tissue around the embedded foreign body. Pneumonia resolved after the removal and with a course of antibiotics. A follow-up chest radiograph revealed residual bronchiectatic changes in the right lower lobe.47 Phosphate Binders
Sevelamer hydrochloride (Renegel), a noncalcium phosphate binder, is used in the management of hypophosphatemia and is also indicated for the control of serum phosphorus levels in patients with end-stage renal disease.48 There is one case report of sevelamer aspiration in the literature. The patient presented with an obstructive pneumonia and a pleural effusion. Because the pill was radiolucent, the chest radiograph was unrevealing. Bronchoscopic examination revealed remnants of a white tablet in the left lower-lobe bronchus. Following endoscopic removal of the pill, oxygenation improved significantly.49 On the other hand, lanthanum carbonate, also a phosphate binder (Fosrenal) is a radio-opaque substance. Aspiration of this medication can be detected easily on a plain chest radiograph.50 However, bronchoscopic examination was not performed in a case of lanthanum carbonate aspiration because of an unclear history of aspiration. The patient developed worsening respiratory distress and expired, most likely as a consequence of postobstructive pneumonia.
Figure 4 – Chest radiograph revealing calcium carbonate pill (arrow) in the trunchus intermedius several weeks after the choking incident. (Reprinted with permission from Micallef et al.47).
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Ciprofloxacin
Ciprofloxacin is an antibiotic in the quinolone group. There is one case report of ciprofloxacin aspiration in the endobronchial tree. The patient presented with hypoxemic respiratory distress. A plain chest radiograph revealed total opacification of the left hemithorax and ipsilateral volume loss. A CT scan of the chest confirmed complete obstruction of the left mainstem bronchus and lung collapse. There was an appearance of a “pill-like” object in the left mainstem bronchus (Fig 5). Bronchoscopic examination showed a white object obstructing the left main bronchus. There was no sign of granulation tissue formation or local inflammation in the airway. The foreign object was removed with a rigid bronchoscope, and the follow-up chest radiograph revealed a fully expanded left lung.51
Systemic Effects Bevacizumab
Bevacizumab is a humanized monoclonal antibody that binds to the vascular endothelial growth factor A, inhibiting angiogenesis. It was approved by the US Food and Drug Administration for several metastatic malignancies such as colon, lung, and breast. Spigel et al52 reported case series of patients with a new diagnosis of tracheoesophageal fistula (TEF) with concurrent exposure to bevacizumab and radiation to the mediastinum. The mechanism of injury was delayed wound healing from antiangiogenesis property and mucosal injury from radiation exposure. The time to onset of TEF after exposure to bevacizumab can vary; however, it can occur as early as within 3 weeks of the therapy53 or with a remote or even no history of radiation to the medias-
Figure 5 – CT scan of the chest revealing an enteric-coated ciprofloxacin tablet (arrow) obstructing the left lower lobe, leading to collapse. (Reprinted with permission from Karakan et al.51).
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tinum.53,54 The outcome of bevacizumab-associated TEF is usually unfavorable and is associated with high mortality and morbidity. A majority of these patients die despite bronchoscopic intervention. A high index of suspicion, CT scanning of the chest, and a bronchoscopy are required to establish the diagnosis (Fig 6).
Iatrogenic Administration Inhaled Corticosteroids
Inhaled corticosteroids (ICSs) have been widely used as antiinflammatory agents in patients with asthma and COPD. Small particles of corticosteroids can be delivered to the alveoli with minimal systemic side effects. However, there are several side effects of ICSs on the airways. Long-term use of ICSs may result in the reduction of smooth muscle thickness in the trachea and mainstem bronchi. (These patients have usually been using ICSs for more than a decade.) In terms of systemic side effects, approximately 10% to 20% of a dose of ICS from a metered-dose inhaler is delivered to the respiratory tract, whereas 80% to 90% can be swallowed and get absorbed through the GI tract. Although systemic side effects are infrequent, they have been reported occasionally.55 In addition, the possibility of an increased risk of TB and nontuberculous mycobacterial infections, as well as community-acquired pneumonia related to ICS use, have been reported in patients with asthma as
Figure 6 – Bronchoscopic view of RMSB, esophagus (arrow). The figure demonstrates a severe inflammatory response and the presence of tracheoesophageal fistula. RMSB 5 right mainstem bronchus. (Image courtesy of R. Wesley Shepherd, MD.)
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well as COPD.56-59 These complications are related to the systemic as well as the local effects of ICSs on the bronchial mucosa.56-59 These studies raise the possibility of an adverse effect of ICSs and suggest that the dose of ICS should be reduced at the earliest opportunity. In addition, spacers should be used with metered dose inhalers to optimize delivery to the lung, especially in adults receiving a high dose of ICS. Among ICSs, the pharmacokinetics of ciclesonide are different from those of other ICSs because it is delivered to the airway as an inactive compound; it is subsequently converted to the active metabolite, potentially lowering the systemic side effects.59
Conclusions The severity and consequences of a foreign-body aspiration depend on factors such as the location and size of the obstruction, the chemical composition of the object, and its physical characteristics. From our literature review, it is apparent that aspiration of a medicinal pill is common and may be underrecognized. Clinical consequences certainly depend on the chemical composition of the pill and/or that of its coating. The spectrum of symptoms ranges from an asymptomatic status to fatal airway obstruction or inflammation. Gelatin coating of the pills does dissolve in the endobronchial tree. Plastic- or enteric-coated capsules cause fewer complications because of the lack of proteolytic enzymes in the airways to dissolve the outer layer. Thus, the capsule can cause symptoms only of airway obstruction, and inflammation is rare. On the contrary, medications such as sucralfate expand in the presence of bronchial secretions and may even cause life-threatening airway obstruction. To reduce the risk of aspiration, patients who are on multiple medications should be instructed to swallow one pill at a time and to avoid sedative medication prior to taking other medications. Preferably, patients who are at a high risk of aspiration should be prescribed liquid or granules instead of tablet formulas. All forms of pills should be avoided in infants and toddlers. In addition, it is important for physicians to warn parents about the risks of accidental pill aspiration. A detailed history is a key to establishing the diagnosis of pill aspiration. All foreign-body aspirations should be treated as medical emergencies. A high degree of suspicion is required to make the diagnosis of pill aspiration when it has dissolved in the tracheobronchial tree. Under such circumstances BAL, endobronchial biopsy, and transbronchial biopsy may help in establishing the
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diagnosis. Systemic steroids may be helpful in palliating the consequences of the pill aspiration. Rigid bronchoscopy can be used in severe cases to manage the complications of initial airway injury. Subsequent surveillance bronchoscopy is needed to assess any ongoing airway obstruction from edema, stenosis, or granulation tissue formation.60
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article.
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20. Wallach L. Aspiration of elemental mercury—evidence of absorption without toxicity. N Engl J Med. 1972;287(4):178-179. 21. Schulze W. Roentgenologische Studien nach Aspiration von mettalischen Quecksilber. Fortschr Röntgenstr. 1958;89(7):24-30. 22. Dzau VJ, Szabo S, Chang YC: Aspiration of metallic mercury: a 22-year follow-up. JAMA. 1977;238(14):1531-1532. 23. Moxham JP, Lee PK. Broken glass mercury thermometer: a difficult airway foreign body. Otolaryngol Head Neck Surg. 2002;127(4): 339-341. 24. Saxena R, Kumar A, Satkurunathan M. Mercury aspiration from a broken thermometer. BMJ Case Rep. 2009;pii:bcr04.2009.1741. 25. Załeska J, Ptaszek B, Malong P, et al. Lipoid pneumonia in patients after laryngectomy [in Polish]. Otolaryngol Pol. 2007;61(6):1004-1010. 26. Laughlen GF. Studies on pneumonia following naso-pharyngeal injections of oil. Am J Pathol. 1925;1(4):407-414.1. 27. Gondouin A, Manzoni P, Ranfaing E, et al. Exogenous lipid pneumonia: a retrospective multicentre study of 44 cases in France. Eur Respir J. 1996;9(7):1463-1469. 28. Crofton J, Douglas J. Chemical pneumonia. In: Crofton J, ed. Respiratory Diseases. 3rd ed. Boston, MA: Blackwell Scientific; 1981: 194-196. 29. Kennedy JD, Costello P, Balikian JP, Herman PG. Exogenous lipoid pneumonia. AJR Am J Roentgenol. 1981;136(6):1145-1149. 30. Chin NK, Hui KP, Sinniah R, Chan TB. Idiopathic lipoid pneumonia in an adult treated with prednisolone. Chest. 1994;105(3):956-957. 31. Fournier P, Aerts J, Damade R, Pasquier P. A rare cause of inflammatory syndrome: lipoid pneumonia [in French]. Presse Med. 1990; 19(38):1768-1769. 32. Bandla HP, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics. 1999;103(2):E19. 33. Ciravegna B, Sacco O, Moroni C, et al. Mineral oil lipoid pneumonia in a child with anoxic encephalopathy: treatment by whole lung lavage. Pediatr Pulmonol. 1997;23(3):233-237. 34. Ferguson GT, Miller YE. Occult mineral oil pneumonitis in anorexia nervosa. West J Med. 1988;148(2):211-213. 35. Weinstein M. First do no harm: the dangers of mineral oil. Paediatr Child Health (Oxford). 2001;6(3):129-131. 36. Hadda V, Khilnani GC, Bhalla AS, Mathur S. Lipoid pneumonia presenting as non resolving community acquired pneumonia: a case report. Cases J. 2009;2:9332. 37. Dawson JK, Abernethy VE, Graham DR, Lynch MP. A woman who took cod-liver oil and smoked. Lancet. 1996;347(9018):1804. 38. Marchiori E, Zanetti G, Mano CM, Irion KL, Daltro PA, Hochhegger B. Lipoid pneumonia in 53 patients after aspiration of mineral oil: comparison of high-resolution computed tomography findings in adults and children. J Comput Assist Tomogr. 2010; 34(1):9-12. 39. Bréchot JM, Buy JN, Laaban JP, Rochemaure J. Computed tomography and magnetic resonance findings in lipoid pneumonia. Thorax. 1991;46(10):738-739. 40. Majori M, Scarascia A, Anghinolfi M, et al. Lipoid pneumonia as a complications of Lorenzo’s oil therapy in a patient with adrenoleukodystrophy. J Bronchology Interv Pulmonol. 2014;21(3):271-273.
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41. Franquet T, Giménez A, Rosón N, Torrubia S, Sabaté JM, Pérez C. Aspiration diseases: findings, pitfalls, and differential diagnosis. Radiographics. 2000;20(3):673-685. 42. Zurrow HB, Sergay H. Lipoid pneumonia in a geriatric patient. J Am Geriatr Soc. 1966;14(3):240-243. 43. Ayvazian LF, Steward DS, Merkel CG, Frederick WW. Diffuse lipoid pneumonitis successfully treated with prednisone. Am J Med. 1967;43(6):930-934. 44. Khilnani GC, Hadda V. Lipoid pneumonia: an uncommon entity. Indian J Med Sci. 2009;63(10):474-480. 45. Sias SM, Daltro PA, Marchiori E, et al. Clinic and radiological improvement of lipoid pneumonia with multiple bronchoalveolar lavages. Pediatr Pulmonol. 2009;44(4):309-315. 46. Lovell B. Calcichew tablet causing oesophageal obstruction and aspiration pneumonia. Emerg Med J. 2014;31(3):260. 47. Micallef J, Montefort S, Mallia Azzopardi C, Galea J. Two cases of aspiration of calcium tablets. Lung India. 2011;28(4):312-314. 48. Goldsmith DR, Scott LJ, Cvetković RS, Plosker GL. Sevelamer hydrochloride: a review of its use for hyperphosphataemia in patients with end-stage renal disease on haemodialysis. Drugs. 2008;68(1):85-104. 49. David S, Merscher S, Schmidt-Guertler H, Kielstein JT, Kirchhoff T, Meier M. A bitter pill to swallow. Clin Nephrol. 2009;72(4):319-321. 50. Sánchez RR, Azancot MA, Bartolomé J. Hyperamylasaemia and broncoaspiration associated with lanthanum carbonate [in Spanish]. Nefrologia. 2009;29(6):613. 51. Karakan Y, Akpinar A, Yildiz H, Aksoy H, Dikensoy O. A case of ciprofloxacin tablet aspiration. Tuberk Toraks. 2010;58(1):97-99. 52. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol. 2010;28(1):43-48. 53. Schreiber J, Waldburg N. Bronchoesophageal fistula and fatal hemoptysis after bevacizumab-containing chemotherapy without radiation in lung cancer. J Clin Oncol. 2012;30(32):e324. 54. Gore E, Currey A, Choong N. Tracheoesophageal fistula associated with bevacizumab 21 months after completion of radiation therapy. J Thorac Oncol. 2009;4(12):1590-1591. 55. Johnson M. Pharmacodynamics and pharmacokinetics of inhaled glucocorticoids. J Allergy Clin Immunol. 1996;97(1 pt 2):169-176. 56. Kim JH, Park JS, Kim KH, Jeong HC, Kim EK, Lee JH. Inhaled corticosteroid is associated with an increased risk of TB in patients with COPD. Chest. 2013;143(4):1018-1024. 57. Andréjak C, Nielsen R, Thomsen VØ, Duhaut P, Sørensen HT, Thomsen RW. Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax. 2013;68(3):256-262. 58. O’Byrne PM, Pedersen S, Carlsson LG, et al. Risks of pneumonia in patients with asthma taking inhaled corticosteroids. Am J Respir Crit Care Med. 2011;183(5):589-595. 59. Nave R. Clinical pharmacokinetic and pharmacodynamic profile of inhaled ciclesonide. Clin Pharmacokinet. 2009;48(4):243-252. 60. Kinsey CM, Folch E, Majid A, Channick CL. Evaluation and management of pill aspiration: case discussion and review of the literature. Chest. 2013;143(6):1791-1795.
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“Pills” and the Air Passages A Continuum Elif Kupeli, MD, FCCP; Danai Khemasuwan, MD, MBA; Pichapong Tunsupon, MD; and Atul C. Mehta, MD, FCCP
Recently, we reported a number of key, common medications that affect the air passages in a variety of fashions. The purpose of this article is to provide a comprehensive review of the literature on the subject, including supportive articles published in languages other than English. The presented information was gathered by a review of the English literature, by cross referencing, and by communication with other interventional pulmonologists. We identified several additional medications causing either direct or systemic effects on the air passages. In this review, we update the clinical presentation, mechanism of injury, diagnosis, and management of the airway complications related to these medications. CHEST 2015; 147(1):242-250 ABBREVIATIONS: BSG 5 bismuth subgallate; ICS 5 inhaled corticosteroid; SPS 5 sodium polystyrene sulfonate; TEF 5 tracheoesophageal fistula
Aspiration of a pill in the air passages can occur even among adults with an intact swallowing mechanism. It is often difficult to establish the diagnosis, especially in the absence of a reliable history. Some pills may remain intact in the endobronchial tree for a number of years without causing much harm, whereas others may dissolve, making recognition of the foreign body aspiration difficult (Fig 1A). The clinical consequences may also vary, from an asymptomatic granuloma formation to a severe, life-threatening airway necrosis, depending upon the chemical characteristics of the “pill.” Thus, if the diagnosis is delayed, severe airway damage can occur. A high degree of suspicion is required to establish
Manuscript received March 4, 2014; revision accepted July 19, 2014. AFFILIATIONS: From the Pulmonary Diseases Department (Dr Kupeli), Baskent University School of Medicine, Ankara, Turkey; Pulmonary and Critical Care Medicine (Dr Khemasuwan), Respiratory Institute, Cleveland Clinic, Cleveland, OH; Internal Medicine (Dr Tunsupon), Medicine Institute, Cleveland Clinic, Cleveland, OH; and Lerner College of Medicine (Dr Mehta) Respiratory Institute, Cleveland Clinic, Cleveland, OH.
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the diagnosis, especially if the pill has dissolved. Our previous review delineated the local and systemic reactions on the airways of some common medications, their diagnosis, and the management of the most common complications.1 Since that publication, we have discussed with many experts their experiences with “pill aspiration,” prompting further review of the literature since the 1920s, including cross referencing for the articles that were published in languages other than English.1 The following discussion deals with additional medications affecting the airways (Table 1). Moreover, we have compiled an appendix containing all the supportive articles related to “pill”-induced airway injury
CORRESPONDENCE TO: Atul C. Mehta, MD, FCCP, Respiratory Institute, 9500 Euclid Ave, A-90, Cleveland Clinic, Cleveland, OH; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0531
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Figure 1 – A (left), An enteric-coated intact vitamin pill embedded in the trunchus intermedius for . 2 y. A (right), Minimal granulation at the site of the foreign body after its removal. B, A whitish adherent pseudomembrane over the left mainstem bronchus (arrow) and right mainstem bronchus (arrowhead). (Reprinted with permission from Sundar et al.4) C, Numerous foci of intra-alveolar large purple polygonal crystals (arrows) consistent with sodium polystyrene sulfonate aspiration (hematoxylin and eosin, original magnification 3 400). D, BAL fluid in a patient with lipoid pneumonia. Note oil particles floating at the top. E, Microscopic examination with Oil Red O stating of BAL revealing lipid-laden macrophages (arrow) (Reprinted with permission from Majori et al.40)
that we could gather from the published literature but were unable to include in the main article (e-Appendix 1). As stated earlier, pills can affect the airways via their local inflammatory, obstructive, or systemic effects.
Inflammation Aspirin
Aspirin is often prescribed as an analgesic or an antipyretic and also for antiplatelet aggregation. An uncoated journal.publications.chestnet.org
aspirin pill can adhere firmly to the mucous membrane. Upon contact with moisture, aspirin hydrolyzes into salicylic and acetic acids, which are irritants to the mucous membrane. There are four confirmed case reports of aspirin aspiration among toddlers, based strictly on the histories.2 It was hypothesized that the mucosal irritation resulted in laryngeal spasm, which led to cardiopulmonary arrest in these cases. Two toddlers did survive; however, they had permanent anoxic 243
TABLE 1
] Updated List of Medications Involving the Airways and Their Mechanism of Action
Inflammation Aspirin
a
Obstruction
Systemic Effects
Alendronate sodium
Iatrogenic Administration
Calcium carbonate
Amiodarone
Epinephrine
Ciprofloxacina
Bevacizumaba
Inhaled corticosteroida
a
Cocaine bag
Clopidogrel
Insulin
Endoscopic capsule
Cocaine
Mineral oil productsa
Diatrizoic acid
Lanthanum carbonatea
Inhaled corticosteroida
N-acetylcysteine
Ferrous sulfate
Sevelamer hydrochloridea
Heroin
Pentamidine
Sucralfate
Mercury
Bismuth subgallatea Charcoal
Mercury
a
Tetracyclinea
a
Sirolimus
Sodium polystyrene sulfonatea Meprobamate and quinine sulfate preparationa Metformin Mineral oil productsa Nortriptyline Pomegranate supplement Potassium chloride Propyliodone 3,5-Diiodo-4-pyridine Additional medications from previous article.1
a
brain injury. In one of the two fatal cases, postmortem examination revealed pulmonary congestion, hemorrhage, and consolidation of the lungs. Microscopic examination revealed diffuse pulmonary hemorrhage with a collection of acute inflammatory cells. However, no evidence of aspirin was found on either the gross or the microscopic examination of the respiratory system.3 There are no reports of bronchoscopic intervention among these patients. The diagnosis was based solely on the history. Tetracycline
Tetracycline is a commonly prescribed broad-spectrum polypeptide antibiotic. There is one case report of tetracycline aspiration in a patient with a swallowing difficulty.4 The patient developed intense airway inflammation and parenchymal consolidation a few days after the “choking” incident. Bronchoscopy revealed an intense inflammation, mucosal edema, and a whitish adherent pseudomembrane involving the vocal cords, trachea, and left main bronchus (Fig 1B). Incidentally, there was no mention of any bronchoscopic intervention in this case. It is very likely that the highly acidic nature of the tetracycline was responsible for the airway injury. The patient was treated conservatively with empirical antibiotic therapy. A follow-up bronchoscopy confirmed residual, albeit clinically insignificant, 244 Special Features
mucosal scarring without significant airway stenosis. In this case, the diagnosis of tetracycline aspiration was established by the history of aspiration but in the absence of the actual foreign body on bronchoscopic examination. Sodium Polystyrene Sulfonate
Sodium polystyrene sulfonate (SPS) (Kayexalate) is a cation-binding resin indicated for the treatment of hyperkalemia. Case reports of pneumonitis following SPS aspiration involving all age groups have been found in the literature since 1978. The first case of SPS aspiration was reported in a postterm hyperkalemic female infant with meconium ileus. She developed neonatal asphyxia and succumbed.5 Since then, nine other cases of SPS aspiration have been cited in various journals. All patients developed cardiopulmonary compromise as a consequence and subsequently died without bronchoscopic intervention. All cases were diagnosed from postmortem examination because there was an unclear history of SPS aspiration. The examination revealed multifocal pulmonary consolidation and severe pulmonary congestion.6 The characteristic histologic finding of SPS is deposition of parallel, laminated, purple polygonal amorphous crystals in the lung tissue.7 These crystals were confirmed as SPS by Fourier transform infrared microspectrophotometry.8 However, the latter
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is seldom required because of the unique characteristic of the SPS crystal.9 Duggal et al10 reported a case of SPS aspiration-associated refractory ARDS. The pathology from the postmortem examination revealed numerous foci of intraalveolar large purple polygonal crystals consistent with SPS aspiration from all the lobes (Fig 1C).11 In a rat model, Haupt and Hutchins12 demonstrated an acute inflammation and SPS particle deposition in the alveoli after direct injection of the solution in the trachea and concluded that gastric content was not the sole cause of aspiration pneumonitis in the fatal cases of SPS aspiration. Physicians should use oral SPS judiciously in patients with altered mental status and/or multiple chronic debilitating diseases. Rectal administration of SPS is an alternative route with similar efficacy in this population. Nevertheless, one should be aware of ischemic colitis and colonic necrosis as common GI adverse effects of rectally administered SPS.13 The role of bronchoscopy in SPS aspiration remains to be established. Meprobamate and Quinine Sulfate Preparation
The preparation of meprobamate and quinine sulfate is used for the treatment of nocturnal muscle cramps of the lower limbs. There is a case report of airway injury from the aspiration of a capsule containing meprobamate and quinine sulfate. This patient presented to the emergency room with fever, dyspnea, oropharyngeal pain, and drooling. A chest radiograph was unremarkable. Flexible bronchoscopy revealed evidence of caustic damage to the larynx, trachea, and main bronchi with a psesudomembrane formation, without any evidence of a foreign body. Otherwise, the mainstem bronchi were patent. Microscopic examination from an endobronchial specimen revealed a fibrin-leukocyte membrane containing a few clusters of dystrophic cells. No therapeutic bronchoscopic intervention was required. The patient was treated with broad-spectrum antibiotics and systemic corticosteroids. There was a minimal area of mucosal injury on follow-up bronchoscopic examination after the 12th day.14 Bismuth Subgallate
Bismuth subgallate (BSG) is a heavy metal compound used as a hemostatic substance to reduce the incidence of bleeding after tonsillectomy and adenoidectomy. It works by initiating a clotting pathway through the activation of factor XII. In an experimental rat model, intratracheal administration of BSG resulted in a subacute pneumonia, with clusters of neutrophils surrounding journal.publications.chestnet.org
the intraparenchymal particles of the drug. The pneumonia resolved spontaneously within 30 days of the observation period.15 There are two case reports of BSG aspiration pneumonitis following tonsillectomy and adenoidectomy among children. Chest radiography demonstrated radio-opaque material of bismuth throughout the lung fields, oropharynx, and nasopharynx.16 The patients were treated conservatively with supplemental oxygen, aggressive chest physiotherapy, and frequent aerosolized bronchodilators without significant long-term complication. BSG should be used cautiously to avoid inadvertent aspiration, especially in children in whom uncuffed endotracheal tubes are used frequently during the upper-airway procedures. Mercury
Two major forms of mercury are used for medical purposes: organic and inorganic. The side effects of organic mercury usually include neurologic symptoms, whereas inorganic mercury causes GI and renal symptoms. It is the elemental form of mercury that causes the pulmonary symptoms.17 Several forms of pulmonary toxicity from elemental mercury have been reported in the literature. In the past, the use of a GI Miller-Abbott tube caused an accidental ingestion and aspiration of mercury in the endobronchial tree. The aspiration of elemental mercury can cause acute pneumonitis and is associated with high mortality.18,19 However, there is one case report of spontaneous absorption of intrabronchial mercury without systemic toxicity.20 Interestingly, remnants of mercury can persist as radiopaque particles in the lungs and may lead to granuloma formation and extensive pulmonary fibrosis decades later.21 Histologically, metallic mercury globules can be found in the lung parenchyma surrounded by a dense fibrous tissue, epithelioid cells, and fibroblasts.22 A medical thermometer contains approximately 600 mg of elemental mercury, which can occasionally lead to toxicity because of high vapor pressure.23 There are two reported cases of dislodged metallic mercury in the airways after biting on a glass mercury thermometer (Fig 2) In one case, globules of mercury were seen on a chest radiograph. The patient was observed overnight and was discharged because he developed no complications.24 Acute inhalation of mercury vapor leads to the development of nonspecific symptoms such as fever, nausea, vomiting, shortness of breath, cough, and chest tightness within a few hours of inhalation. In addition, approximately 80% of the inhaled elemental mercury 245
TABLE 2
] Mineral Oil Products Associated With Lipoid Pneumonia Reported in the Literature
Products Combined cod liver oil and liquid petroleum Laxatives containing mineral oil Oil mists Liquid paraffin Paraffin Lip balm Baby oil Mineral oil enema Animal fat (Ghee) Domestic insecticides Petroleum jelly for nasal application Vaseline for nasogastric tube insertion Olive oil self-injection Cod liver oil
Figure 2 – Broken piece of a mercury thermometer in the left main bronchus of a young patient. (Reprinted with permission from Moxham and Lee.23)
Mexican folk remedies Squalene Facial petroleum for erythrodermic psoriasis
vapor is absorbed into the bloodstream and it crosses the blood-brain barrier, causing systemic toxicity.22 Intoxication with mercury can be confirmed with a urine mercury level . 200 mg/L. The first step in the management of acute mercury inhalation is to eliminate the source of exposure, for instance, using bronchoscopic suction to remove the remaining quantity of mercury from the aspirated broken thermometer.19 In the case of systemic toxicity or elevated serum or urine mercury level, the chelating agents of choice include penicillamine, N-acetyl-dl-penicillamine, 2,3-dimercaptopropanol, meso-2,3-dimercaptosuccinic acid, and 2,3-dimercapto1-propane sulfonic acid.24 Mineral Oil
Mineral oil products are used for different purposes and are commercially available in multiple forms in the market. Repeated aspiration or inhalation of these products can potentially lead to lipoid pneumonias, which are reported in both adult and pediatric populations.25 The first case of lipoid pneumonia was described in 1925.26 Since then, there have been many case reports of different forms of mineral oil-related lipoid pneumonias (Table 2). Among adults, the most common cause of lipoid pneumonia is the improper use of mineral oil for the treatment of constipation and the frequent use of oily nose drops for chronic rhinitis, mainly at bedtime.27 The oily particles once introduced into the nostrils can 246 Special Features
White spirit Gas oil Lorenzo oil
easily reach the bronchial tree and can impair the mucociliary function, subsequently inhibiting the protective cough reflex.27 Once in the alveolar spaces, oily substances are emulsified by the lung lipase, resulting in a foreign-body reaction. Lipoid pneumonia is categorized as exogenous, endogenous, or idiopathic.28 Exogenous lipoid pneumonia is associated with chronic aspiration of mineral oil, not only in the elderly, but also in children with neuromuscular disorders. Endogenous lipoid pneumonia is usually associated with lipid storage disease or with a proximal obstructive lesion such as carcinoma.29 Idiopathic lipoid pneumonia is rare; however, it has been described in male smokers who are otherwise healthy.30 Patients typically present with nonspecific symptoms such as fever, productive cough, and gradual onset of dyspnea, similar to bacterial pneumonia or other chronic lung diseases. Less commonly described clinical features include chest pain and hemoptysis.31 The clinical manifestations of lipoid pneumonia vary widely. It may present as an asymptomatic, incidentally discovered pulmonary infiltrate,32-34 acute pneumonitis,34 chronic respiratory failure,35 a localized granuloma, or even an ARDS.36
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The history of inhalation or ingestion of mineral oil products is essential to establish the diagnosis. The chest radiography could reveal a pulmonary mass, diffuse airspace infiltration, or a localized consolidation similar to a malignancy.37 CT scanning is the best imaging modality for the evaluation of the lipoid pneumonia and usually provides the first clue to the diagnosis of this disease (Fig 3).27 The CT scan findings usually show foci of fat attenuation surrounded by parenchymal consolidation.38 MRI does not produce images specific to this condition because of high signal intensity on T1-weighted images caused by blood and/or fat contents.39 A BAL or a transbronchial biopsy is necessary to support the diagnosis of lipoid pneumonia (Figs 1D, 1E40). The typical findings are numerous lipid-laden macrophages and a deposition of inflammatory cells, as well as evidence of fibrosis in the lung parenchyma and the interstitium on histologic examination.40-42 The management of lipoid pneumonia is not clearly defined. The mineral oil products must be discontinued, and early diagnosis, supportive therapy, and treatment with corticosteroids have been shown to have positive outcomes.36,43 Multiple therapeutic BALs have produced rapid clinical recovery in children.44,45
Airway Obstruction Calcium Carbonate
Calcium carbonate is used as a supplemental source of elemental calcium. It may be used as a phosphatebinding agent in the management of hyperphosphatemia in patients with chronic renal failure. Aspiration of a calcium tablet has been reported in three cases in the literature.46,47 These patients presented with nonresolving pneumonia. The calcium pills could be visualized
Figure 3 – Right upper-lobe alveolar process in a patient receiving a laxative containing mineral oil. (Reprinted with permission from Bandla et al.32)
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on both a plain chest radiograph and a noncontrast CT scan of the chest (Fig 4). In one case, the pill was removed with a rigid bronchoscope, revealing a granulation tissue around the embedded foreign body. Pneumonia resolved after the removal and with a course of antibiotics. A follow-up chest radiograph revealed residual bronchiectatic changes in the right lower lobe.47 Phosphate Binders
Sevelamer hydrochloride (Renegel), a noncalcium phosphate binder, is used in the management of hypophosphatemia and is also indicated for the control of serum phosphorus levels in patients with end-stage renal disease.48 There is one case report of sevelamer aspiration in the literature. The patient presented with an obstructive pneumonia and a pleural effusion. Because the pill was radiolucent, the chest radiograph was unrevealing. Bronchoscopic examination revealed remnants of a white tablet in the left lower-lobe bronchus. Following endoscopic removal of the pill, oxygenation improved significantly.49 On the other hand, lanthanum carbonate, also a phosphate binder (Fosrenal) is a radio-opaque substance. Aspiration of this medication can be detected easily on a plain chest radiograph.50 However, bronchoscopic examination was not performed in a case of lanthanum carbonate aspiration because of an unclear history of aspiration. The patient developed worsening respiratory distress and expired, most likely as a consequence of postobstructive pneumonia.
Figure 4 – Chest radiograph revealing calcium carbonate pill (arrow) in the trunchus intermedius several weeks after the choking incident. (Reprinted with permission from Micallef et al.47).
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Ciprofloxacin
Ciprofloxacin is an antibiotic in the quinolone group. There is one case report of ciprofloxacin aspiration in the endobronchial tree. The patient presented with hypoxemic respiratory distress. A plain chest radiograph revealed total opacification of the left hemithorax and ipsilateral volume loss. A CT scan of the chest confirmed complete obstruction of the left mainstem bronchus and lung collapse. There was an appearance of a “pill-like” object in the left mainstem bronchus (Fig 5). Bronchoscopic examination showed a white object obstructing the left main bronchus. There was no sign of granulation tissue formation or local inflammation in the airway. The foreign object was removed with a rigid bronchoscope, and the follow-up chest radiograph revealed a fully expanded left lung.51
Systemic Effects Bevacizumab
Bevacizumab is a humanized monoclonal antibody that binds to the vascular endothelial growth factor A, inhibiting angiogenesis. It was approved by the US Food and Drug Administration for several metastatic malignancies such as colon, lung, and breast. Spigel et al52 reported case series of patients with a new diagnosis of tracheoesophageal fistula (TEF) with concurrent exposure to bevacizumab and radiation to the mediastinum. The mechanism of injury was delayed wound healing from antiangiogenesis property and mucosal injury from radiation exposure. The time to onset of TEF after exposure to bevacizumab can vary; however, it can occur as early as within 3 weeks of the therapy53 or with a remote or even no history of radiation to the medias-
Figure 5 – CT scan of the chest revealing an enteric-coated ciprofloxacin tablet (arrow) obstructing the left lower lobe, leading to collapse. (Reprinted with permission from Karakan et al.51).
248 Special Features
tinum.53,54 The outcome of bevacizumab-associated TEF is usually unfavorable and is associated with high mortality and morbidity. A majority of these patients die despite bronchoscopic intervention. A high index of suspicion, CT scanning of the chest, and a bronchoscopy are required to establish the diagnosis (Fig 6).
Iatrogenic Administration Inhaled Corticosteroids
Inhaled corticosteroids (ICSs) have been widely used as antiinflammatory agents in patients with asthma and COPD. Small particles of corticosteroids can be delivered to the alveoli with minimal systemic side effects. However, there are several side effects of ICSs on the airways. Long-term use of ICSs may result in the reduction of smooth muscle thickness in the trachea and mainstem bronchi. (These patients have usually been using ICSs for more than a decade.) In terms of systemic side effects, approximately 10% to 20% of a dose of ICS from a metered-dose inhaler is delivered to the respiratory tract, whereas 80% to 90% can be swallowed and get absorbed through the GI tract. Although systemic side effects are infrequent, they have been reported occasionally.55 In addition, the possibility of an increased risk of TB and nontuberculous mycobacterial infections, as well as community-acquired pneumonia related to ICS use, have been reported in patients with asthma as
Figure 6 – Bronchoscopic view of RMSB, esophagus (arrow). The figure demonstrates a severe inflammatory response and the presence of tracheoesophageal fistula. RMSB 5 right mainstem bronchus. (Image courtesy of R. Wesley Shepherd, MD.)
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well as COPD.56-59 These complications are related to the systemic as well as the local effects of ICSs on the bronchial mucosa.56-59 These studies raise the possibility of an adverse effect of ICSs and suggest that the dose of ICS should be reduced at the earliest opportunity. In addition, spacers should be used with metered dose inhalers to optimize delivery to the lung, especially in adults receiving a high dose of ICS. Among ICSs, the pharmacokinetics of ciclesonide are different from those of other ICSs because it is delivered to the airway as an inactive compound; it is subsequently converted to the active metabolite, potentially lowering the systemic side effects.59
Conclusions The severity and consequences of a foreign-body aspiration depend on factors such as the location and size of the obstruction, the chemical composition of the object, and its physical characteristics. From our literature review, it is apparent that aspiration of a medicinal pill is common and may be underrecognized. Clinical consequences certainly depend on the chemical composition of the pill and/or that of its coating. The spectrum of symptoms ranges from an asymptomatic status to fatal airway obstruction or inflammation. Gelatin coating of the pills does dissolve in the endobronchial tree. Plastic- or enteric-coated capsules cause fewer complications because of the lack of proteolytic enzymes in the airways to dissolve the outer layer. Thus, the capsule can cause symptoms only of airway obstruction, and inflammation is rare. On the contrary, medications such as sucralfate expand in the presence of bronchial secretions and may even cause life-threatening airway obstruction. To reduce the risk of aspiration, patients who are on multiple medications should be instructed to swallow one pill at a time and to avoid sedative medication prior to taking other medications. Preferably, patients who are at a high risk of aspiration should be prescribed liquid or granules instead of tablet formulas. All forms of pills should be avoided in infants and toddlers. In addition, it is important for physicians to warn parents about the risks of accidental pill aspiration. A detailed history is a key to establishing the diagnosis of pill aspiration. All foreign-body aspirations should be treated as medical emergencies. A high degree of suspicion is required to make the diagnosis of pill aspiration when it has dissolved in the tracheobronchial tree. Under such circumstances BAL, endobronchial biopsy, and transbronchial biopsy may help in establishing the
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diagnosis. Systemic steroids may be helpful in palliating the consequences of the pill aspiration. Rigid bronchoscopy can be used in severe cases to manage the complications of initial airway injury. Subsequent surveillance bronchoscopy is needed to assess any ongoing airway obstruction from edema, stenosis, or granulation tissue formation.60
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article.
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