Pulmonary toxicity

Pulmonary toxicity is the medical name for side effects on the lungs.

Although most cases of pulmonary toxicity in medicine are due to side effects of medicinal drugs, many cases can be due to side effects of radiation (radiotherapy). Other (non-medical) causes of pulmonary toxicity can be chemical compounds and airborne particulate matter.

Presentation

Side effects on the lungs can be very varied, and can include signs and symptoms that are either clinical, or radiological (i.e., seen on chest X-ray or CT), or both. They can include lung inflammation (pneumonitis), secondary (in this context, indirectly caused) lung infection (pneumonia), lung fibrosis, organising pneumonia (bronchiolitis obliterans organising pneumonia, BOOP), ARDS (acute respiratory distress syndrome), solitary pulmonary mass (even including lung cancer in some cases, mainly in cases of asbestos-related lung disease, but today this is very rare, because asbestos is now completely prohibited by law in most countries), or lung nodule. The diagnosis should be made by a specialist, if possible.

Cause

Pulmonary toxicity due to medicinal drugs

Within all classes of medicinal drugs that possibly can lead to pulmonary toxicity as a side effect, most pulmonary toxicity is due to chemotherapy for cancer.[1][2]

Many medicinal drugs can lead to pulmonary toxicity. A few medicinal drugs can lead to pulmonary toxicity frequently (in medicine defined by international regulatory authorities such as the U.S. Food and Drug Administration and the EMEA [European Union] as > 1% and < 10%) or very frequently (defined as > 10%). These medicinal drugs can include gold and nitrofurantoin, as well as the following drugs used in chemotherapy for cancer: Methotrexate, the taxanes (paclitaxel and docetaxel), gemcitabine, bleomycin, mitomycin C, busulfan, cyclophosphamide, chlorambucil, and nitrosourea (e.g., carmustine).

Also, some medicinal drugs used in cardiovascular medicine can lead to pulmonary toxicity frequently or very frequently. These include above all amiodarone, as well as beta blockers, ACE inhibitors (however, pulmonary toxicity of ACE inhibitors usually lasts only 3–4 months and then usually disappears by itself), procainamide, quinidine, tocainide, and minoxidil.

Both oncologists and cardiologists are well aware of possible pulmonary toxicity.

Pros and cons of medicinal drugs

The "medical benefit-cost ratio" for the patient should be kept in mind. Medicinal drugs should not be ruled out completely right from the start just because they possibly could cause pulmonary toxicity. A number of medicinal drugs that could cause pulmonary toxicity can be life-saving for certain patients with specific diseases. For example, amiodarone falls into this category. Ideally, the pros and cons should be weighed at the start of therapy and in regular intervals thereafter, based on the available scientific/medical evidence, by an expert physician, together with an informed patient.[3]

Pulmonary toxicity due to radiation (radiotherapy)

Radiation (radiotherapy) is frequently used for the treatment of many cancer types, and can be highly effective. Unfortunately, it also can lead to pulmonary toxicity as a side effect.[4][5]

Radiotherapists are well aware of possible pulmonary toxicity, and take a number of precautions to minimise the incidence of this side effect. There are research efforts to possibly eliminate this side effect in the future.[6]

Pulmonary toxicity due to chemical compounds

Pulmonary toxicity is possible due to many chemical compounds. However, the most famous (infamous) example is pulmonary toxicity due to asbestos.[7] Asbestos can lead to a highly dangerous (i.e., highly malignant) lung cancer called malignant pleural mesothelioma, sometimes also simply called mesothelioma. As a consequence, the use of asbestos is now completely prohibited by law in most countries.

Particulate matter leading to pulmonary toxicity

Atmospheric particulate matter is part of air pollution. Particulate matter is produced mainly by car traffic, overland traffic (trucks), industrial production facilities, and cigarette smoking. More and more data were gathered in recent years. The data showed that particulate matter can be a major cause of cardiovascular disease, and can also cause pulmonary toxicity.[8][9][10][11] As a consequence, laws, by-laws and guidelines that regulate the amount of particulate matter that can be emitted in a given time period were issued in the European Union.[12][13]

Diagnosis

Lung symptoms in a patient who is taking a medicinal drug that can cause pulmonary toxicity should not automatically lead to a diagnosis of "pulmonary toxicity due to the medicinal drug", because some patients can have another (i.e., simultaneous) lung disease, e.g. an infection of the lungs not related to the medicinal drugs the patient is taking. But if the patient is taking such a medicinal drug, this should not be overlooked. Diagnostic care should be executed. The correct diagnosis is an exclusion diagnosis and can require some tests.[14]

Treatment

The treatment of pulmonary toxicity due to medicinal drugs is to discontinue (= to stop taking) the medicinal drug in question. A dose reduction (instead of discontinuation) can be attempted in selected cases only, only under the guidance of an expert physician. Discontinuation (or, if possible, dose reduction under the guidance of an expert physician) should be done in all cases. This approach has been published for many individual medicinal drugs, but it is principally valid for all cases pulmonary toxicity due to medicinal drugs.[15][16]

As an example to illustrate what can be done, the use of the medicinal drug amiodarone: a) Prescribing the lowest possible dose of amiodarone leads to a lower incidence of pulmonary toxicity.[17] b) Regular monitoring, in order to diagnose any possible pulmonary toxicity early.[18][19] c) Discontinuation as soon as pulmonary toxicity is detected.

One publication summarises the most important points about amiodarone-induced pulmonary toxicity (AIPT) as follows: "The most serious adverse reaction of amiodarone is pulmonary toxicity (AIPT). AIPT may manifest as chronic interstitial pneumonitis, organising pneumonia, acute respiratory distress syndrome, pulmonary mass, or nodules. On radiological imaging, pulmonary infiltrates induced by amiodarone are usually high in attenuation. On biopsy, the presence of foamy macrophages confirms exposure to amiodarone but not necessarily proves that amiodarone is the responsible cause. Most patients with AIPT respond well to the withdrawal of amiodarone and to the addition of corticosteroid treatment, which is usually given for two to six months." [20]

References
  1. Meadors M, Floyd J, Perry MC. Pulmonary toxicity of chemotherapy. Semin Oncol. 2006 Feb;33(1):98-105. Review.
  2. Abid SH, Malhotra V, Perry MC. Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol. 2001 Jul;13(4):242-8. Review.
  3. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA. 2007 Sep 19;298(11):1312-22. Review.
  4. Kong FM, Ten Haken R, Eisbruch A, Lawrence TS. Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Semin Oncol. 2005 Apr;32(2 Suppl 3):S42-54. Review.
  5. Movsas B, Raffin TA, Epstein AH, Link CJ Jr. Pulmonary radiation injury. Chest. 1997 Apr;111(4):1061-76. Review.
  6. Tsoutsou PG, Koukourakis MI. Radiation pneumonitis and fibrosis: mechanisms underlying its pathogenesis and implications for future research. Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1281-93. Review.
  7. O'Reilly KM, Mclaughlin AM, Beckett WS, Sime PJ. Asbestos-related lung disease. Am Fam Physician. 2007 Mar 1;75(5):683-8. Review.Fulltext
  8. Miller KA, Siscovick DS, Sheppard L, Shepherd K, Sullivan JH, Anderson GL, Kaufman JD. Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med. 2007 Feb 1;356(5):447-58. Fulltext
  9. Mills NL, Törnqvist H, Gonzalez MC, Vink E, Robinson SD, Söderberg S, Boon NA, Donaldson K, Sandström T, Blomberg A, Newby DE. Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease. N Engl J Med. 2007 Sep 13;357(11):1075-82.
  10. Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Lipsett M, Luepker R, Mittleman M, Samet J, Smith SC Jr, Tager I; Expert Panel on Population and Prevention Science of the American Heart Association. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation. 2004 Jun 1;109(21):2655-71. Review.
  11. Girod CE, King TE Jr. COPD: a dust-induced disease? Chest. 2005 Oct;128(4):3055-64. Review.
  12. Ambient air pollution by particulate matter: position paper. European Union. Fulltext
  13. Second position paper on particulate matter. European Union. Fulltext
  14. Malhotra A, Muse VV, Mark EJ. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 12-2003. An 82-year-old man with dyspnea and pulmonary abnormalities. N Engl J Med. 2003 Apr 17;348(16):1574-85.
  15. Camus P, Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Clin Chest Med. 2004 Mar;25(1):65-75. Review.
  16. Sunderji R, Kanji Z, Gin K. Pulmonary effects of low dose amiodarone: a review of the risks and recommendations for surveillance. Can J Cardiol. 2000 Nov;16(11):1435-40. Review.
  17. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997 Sep;30(3):791-8.
  18. Goldschlager N, Epstein AE, Naccarelli G, Olshansky B, Singh B. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med. 2000 Jun 26;160(12):1741-8.
  19. Goldschlager N, Epstein AE, Naccarelli GV, Olshansky B, Singh B, Collard HR, Murphy E; Practice Guidelines Sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm. 2007 Sep;4(9):1250-9.
  20. Azzam I, Tov N, Elias N, Naschitz JE. Amiodarone toxicity presenting as pulmonary mass and peripheral neuropathy: the continuing diagnostic challenge. Postgrad Med J. 2006 Jan;82(963):73-5.
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