Tobacco Worker's Lung


Practice Essentials

Tobacco worker's lung (TWL) is one disease in the group of parenchymal lung diseases categorized as hypersensitivity pneumonitis (United States) or extrinsic allergic alveolitis (Britain). [1This disease entity is caused by inhalation of tobacco molds and is encountered in persons who work in tobacco fields and cigarette manufacturing plants. Increased humidity plays a major role in favoring mold growth. [2The clinical features and natural history are akin to hypersensitivity pneumonitis of other causes. [345]

TWL usually involves inhalation of an antigen, particularly organic ones. This leads to an exaggerated immune response, which produces a complex clinical presentation within the pulmonary parenchyma. Immune mediation plays a major pathogenetic role in tobacco worker’s lung. Serum antibodies are present in most patients with tobacco worker’s lung, but a lack of correlation between the presence of serum antibodies and pulmonary symptoms has been noted.

In tobacco worker’s lung, the culprit antigen is the Aspergillus species, with a source in tobacco molds. The antigens induce injury by causing macrophages and polymorphonuclear leukocytes to produce substances such as proteolytic enzymes and reactive oxygen compounds. These further lead to synthesis and release of interleukin (IL)-1, tumor necrosis factor (TNF)-alpha, and IL-6 from macrophages and lymphokines from lymphocytes, which result in pulmonary inflammation. Lung biopsies in patients with long-term exposure usually demonstrate chronic interstitial inflammation and poorly formed nonnecrotizing granulomas. [6]

In addition, smoking can potentiate the effects of tobacco dust. [7]

Studies have shown that there may be a genetic predisposition to hypersensitivity pneumonitis, postulated to play a major role in determining an individual's risk of disease. It is likely that the immunologic abnormalities that underlie hypersensitivity pneumonitis reflect the interplay of multiple genes involved in the immune response. Genetic involvement can be extrapolated to apply to risk for tobacco worker's lung. [8]

Major causative antigens include the following:

  • Aspergillus species

  • Scopulariopsis brevicaulis

  • Rhizopus nigricans [9]

Lung biopsies are rarely required to confirm diagnosis, because diagnosis is primarily derived from a thorough occupational history, clinical features, and radiography. Both transbronchial and video-assisted thoracoscopic lung biopsy are used to provide adequate specimens for histopathological examination. [10]

The major treatment strategy is elimination of exposure to tobacco molds or leaves. Preventing further exposure to the offending agents usually leads to symptom resolution.

Avoidance of exposure to tobacco leaves is the best prevention. Curwin et al report that washing hands in the field while harvesting significantly reduces the amount of nicotine absorbed through the skin. [11]

Devices that limit inhalation of inciting antigens is recommended for those who must continue to work on tobacco farms. Installing controls that reduce moisture and humidity in occupied buildings will prevent excessively moldy tobacco leaves.

CLINICAL PRESENTATION

History

A comprehensive history of exposure to tobacco mold and leaves should be obtained. Workers who do not use masks during their working period are 5 times more likely to develop this disease, [12and longer duration of work is associated with an increased risk of disease. In one study, those working with tobacco for more than 10 years were twice as likely to develop the disease than those who worked in the field for less than 5 years. [12]

Tobacco worker’s lung, as with most hypersensitivity pneumonitis syndromes, has acute, subacute, and chronic presentations. In acute presentations, patients develop abrupt onset of fever, cough, chills, myalgias, headache, and malaise about 4-6 hours after exposure to tobacco plants and molds. These symptoms are self-limited, resolving in 12 hours to several days once the patient avoids the inciting agent. The symptoms may recur with reexposure.

Patients who have had long-term exposure to tobacco plantations usually have insidious onset of cough, exertional dyspnea, fatigue, and weight loss. Disabling and irreversible respiratory findings due to pulmonary fibrosis may occur late in the course of the disease. Removing patients from tobacco exposure results in only partial improvement.

Physical

Physical examination reveals the following:

  • Tachypnea

  • Diffuse fine rales

  • Wheezing

  • Weight loss

  • Digital clubbing

  • Fever

  • Evidence of cor pulmonale

Ddx

Differential Diagnoses

Medical Care

Most patients (>75%) require only symptomatic therapy with NSAIDs. Approximately 10% of patients need treatment for extrapulmonary disease, while 15% of patients require treatment for persistent pulmonary disease.

Steroid treatment

Corticosteroids are the mainstay of therapy.

Generally, prednisone given daily and then tapered over a 6-month course is adequate for pulmonary disease. Earlier recommendations suggested an initial dose of 1 mg/kg/d of prednisone; however, more recent expert opinions endorse a lower dose (eg, 40 mg/d), which is tapered to every-other-day long-term therapy over several weeks. In one study, treatment of acute exacerbations of pulmonary sarcoidosis with steroid doses as low as 20 mg of prednisone for a median of 21 days improved spirometry back to baseline and improved clinical symptoms. [58] Most patients who require long-term steroids can be treated using 10-15 mg of prednisone every other day.

Some data suggest that corticosteroid use may be associated with increased relapse rates. However, data suggest early treatment of stage II sarcoidosis with oral prednisolone for 3 months followed by inhaled budesonide for 15 months improves 5-year pulmonary function and reduces the need for future steroid treatment. [59]

High-dose inhaled corticosteroids may be an option, but conclusive data are lacking. Inhaled corticosteroids, in particular, can be used in patients with endobronchial disease.

Although corticosteroids are used for symptom relief and remain the mainstay of therapy, their efficacy in this disease is unclear. Since many patients' conditions improve spontaneously, showing a true benefit to therapy requires a careful control arm.

The best study addressing corticosteroids was the multicenter trial from Britain sponsored by the British Thoracic Society. In this nonrandomized study, 55 patients were selectively observed or treated with corticosteroids. Additionally, patients who were thought to have an immediate indication for steroids were treated. The trial required a 6-month run-in period to exclude patients who improved spontaneously. At the end of the trial, the groups treated with long-term steroids fared better on some measures than did the patients who were observed and treated with short bursts of steroids (see Table 1 below for detail).

Table 2. Results of Multicenter Trial Sponsored by the British Thoracic Society (Open Table in a new window)

Characteristics

Group La

Group Sb

P

Dyspnea score (range 1-4)

0.24

0.47

NS

Fibrosis score (range 0-16)

0.83

1.47

NS

FEV1c (% predicted)

95.9

86.9

0.05

VCd (% predicted)

99.8

90.8

0.02

DLCOe (% predicted)

84.3

77.7

NS

Weight gain (kg)

+3.26

+0.99

0.02

a Long-term steroids.

b Short bursts of steroids.

c Forced expiratory volume in 1 second.

d Ventilatory capacity.

e Diffusing capacity of lung for carbon monoxide.

Acthar gel (repository corticotropin injection) was used to treat pulmonary sarcoidosis in the 1950s. It was abandoned because of cost and toxicity compared with prednisone. More recently, it has been suggested as an alternative in patients who are on high-dose prednisone. [60, 61]

Nonsteroid treatment

Noncorticosteroid agents are being increasingly tried. Common indications for the initiation of such agents include steroid-resistant disease, intolerable adverse effects, or patient desire not to take corticosteroids.

Methotrexate (MTX) has been a successful alternative to prednisone and is a steroid-sparing agent. [62]

Chloroquine and hydroxychloroquine are antimalarial drugs with immunomodulating properties, which have been used for cutaneous lesions, hypercalcemia, neurological sarcoidosis, and bone lesions. Chloroquine has also been shown to be efficacious for the treatment and maintenance of chronic pulmonary sarcoidosis. [3, 4]

Cyclophosphamide has been rarely used with modest success as a steroid-sparing treatment in patients with refractory sarcoidosis. [5, 6]

Azathioprine is another second-line therapy, which is best used as a steroid-sparing agent rather than as a single-drug treatment for sarcoidosis. [7]

Chlorambucil is an alkylating agent that may be beneficial in patients with progressive disease unresponsive to corticosteroids. [8]

Cyclosporine is a fungal cyclic polypeptide with lymphocyte-suppressive properties and may be of limited benefit in skin sarcoidosis or in progressive sarcoidosis resistant to conventional therapy. [9]

Infliximab [10, 11] and thalidomide [12, 13] have also been used for refractory sarcoidosis, particularly for cutaneous disease. Infliximab appears to be an effective treatment for patients with systemic manifestations such as lupus pernio, uveitis, hepatic sarcoidosis, and neurosarcoidosis.

In addition, long-term treatment with infliximab can be effective for extrapulmonary sarcoidosis, according to a retrospective study of 26 patients with biopsy-proven sarcoidosis. [14] In the study, sustained resolution or improvement occurred in 58.5% of organs, but disease activity progressed in 5.7% despite treatment. In 57.7% of patients, there were adverse events during an average duration of therapy of 46.2 months. [14] Improvement in pulmonary imaging findings was observed in patients with pulmonary sarcoid after initiation of infliximab treatment, but results at post-treatment were inconclusive. Infliximab treatment was well tolerated. [14]

Callejas-Rubio et al reported inconsistent results with tumor necrosis factor (TNF)–inhibitor therapy. [63] However, at least one study has shown treatment with adalimumab can reduce disease activity, as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. [64] Adalimumab has also been used successfully in sarcoidosis patients with refractory chronic noninfectious uveitis. [65]

Nontreatment and other issues

For pulmonary disease, asymptomatic pulmonary function testing and/or chest radiography abnormalities are not an indication for treatment. In patients with minimal symptoms, serial reevaluation is prudent. Significant respiratory symptoms associated with pulmonary function test and chest radiograph abnormalities likely require therapy. For such patients, treatment is indicated if objective evidence of recent deterioration in lung function exists. As mentioned above, corticosteroids can result in improvements in the functional vital capacity and in the radiographic appearance in patients with more severe stage II and III disease.

One study demonstrated an approach that may minimize the use of corticosteroids without harming the patient. This is accomplished by withholding therapy unless the patient shows at least a 15% decline in one spirometric measure associated with increasing symptoms or, if asymptomatic, withholding therapy unless the patient shows worsening pulmonary function test results and a change in the chest radiograph.

For extrapulmonary sarcoidosis involving such critical organs as the heart, liver, eyes, kidneys, or central nervous system, medical intervention is indicated.

Topical corticosteroids are effective for ocular disease.

Surgical Care

Lung transplantation is a viable option for patients with stage IV sarcoidosis. Transplantation in such patients should be strongly considered when the forced vital capacity falls below 50% predicted and/or the forced expiratory volume in 1 second falls below 40% predicted. [15Patients with advanced sarcoidosis awaiting lung transplantation have a high mortality rate with a median survival of less than 2 years. Mortality is most closely linked to elevated right atrial pressure. In one retrospective cohort study, survival after transplantation determined by the Kaplan-Meier method was 62% at both 1 and 2 years, and a mere 50% at 3 years. [66]

Long-Term Monitoring

Monitor pulmonary function and chest radiography every 6-12 months.

Assess for progression or resolution.

Determine if previously uninvolved organs have become affected.

Annual slit-lamp eye examination and ECG are recommended.


MEDICATION


Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Class Summary

NSAIDs are indicated for arthralgias and other rheumatic complaints and not for significant pulmonary disease. Patients with stage I sarcoidosis require only occasional treatment with NSAIDs.

Naproxen (Aleve, Anaprox, Naprelan, Naprosyn)

Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Flurbiprofen

Flurbiprofen may inhibit cyclo-oxygenase, which, in turn, inhibits prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.

Ibuprofen (Motrin, Ibuprin, Advil, Addaprin, Neoprofen)

Ibuprofen and other NSAIDs are useful in the management of joint complaints. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Ketoprofen

Ketoprofen is indicated for relief of mild to moderate pain and inflammation. Small initial dosages are indicated in small and elderly patients and in those with renal or liver disease. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Indomethacin (Indocin)

Indomethacin inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis. It is rapidly absorbed and metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation.

Corticosteroids

Class Summary

Corticosteroids are the cornerstone of therapy. They have potent immunologic effects that ameliorate many signs and symptoms.

Prednisone (Rayos)

Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. The response may be rapid but often is seen over 12-16 weeks.

Antimetabolites

Class Summary

Given the adverse effect profile of corticosteroids, methotrexate has recently received significant attention as either a corticosteroid alternative or a corticosteroid-sparing agent.

Methotrexate (Folex PFS, Rheumatrex, Otrexup)

Methotrexate is an antimetabolite that interferes with folate metabolism. It is cell cycle specific. Actively proliferating cells are more susceptible to its effects.

Antimalarial agents

Class Summary

Antimalarial agents have previously been used for the treatment of rheumatoid arthritis. Literature supporting its use in sarcoidosis is limited to case series. They have a relatively benign adverse effect profile.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine may be most useful in the management of osseous involvement. It inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions.

Immunosuppressants

Class Summary

These agents may be of benefit in patients whose conditions have not responded to steroids or in patients unable to tolerate prednisone.

Chlorambucil (Leukeran)

Chlorambucil is a bifunctional slow-acting aromatic nitrogen mustard derivative that interferes with DNA replication, transcription, and nucleic acid function by alkylation. It alkylates and cross-links strands of DNA. Alkylation takes place through the formation of a highly reactive ethylenimonium radical. The probable mode of action involves cross-linkage of the ethylenimonium derivative between two strands of helical DNA and subsequent interference with replication. Chlorambucil is known chemically as 4-[bis(2chlorethyl)amino]benzene butanoic acid.

The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as an abrupt fall in the white blood cell count occurs.

Azathioprine (Azasan, Imuran)

Azathioprine is an imidazolyl derivative of 6-mercaptopurine. Many of its biological effects are similar to those of the parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and the liver. No azathioprine or mercaptopurine is detectable in urine 8 hours after it is taken.

Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. The mechanism whereby azathioprine affects autoimmune diseases is unknown. It works primarily on T cells. It suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. It works very slowly; it may require 6-12 months of trial prior to effect. Up to 10% of patients may have idiosyncratic reactions disallowing use. Do not allow the WBC count to drop below 3000/μL or the lymphocyte count to drop below 1000/μL.

Azathioprine is available in a tablet form for oral administration or in 100-mg vials for intravenous injection.

Cyclophosphamide

Cyclophosphamide is a cyclic polypeptide that suppresses some humoral activity. It is chemically related to nitrogen mustards. It is activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Cyclophosphamide is biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. The interaction of phosphoramide mustard with DNA is considered cytotoxic.

When used in autoimmune diseases, the mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, it affects B cells by inhibiting clonal expansion and suppression of the production of immunoglobulins. With long-term low-dose therapy, it affects T-cell functions.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Cyclosporine is an 11-amino acid cyclic peptide and natural product of fungi. It acts on T-cell replication and activity.

It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle is suggested.

Cyclosporine binds to cyclophilin, an intracellular protein, which, in turn, prevents the formation of interleukin 2 and the subsequent recruitment of activated T cells.

It has about 30% bioavailability, but there is marked interindividual variability. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during the first 24 hours of antigenic exposure.

Cyclosporine suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.

Infliximab (Remicade)

Infliximab neutralizes cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. Mix it in 250 mL of normal saline for infusion over 2 hours. It must be used with a low-protein-binding filter (1.2 micron or less). Infliximab is indicated to reduce the signs and symptoms of active ankylosing spondylitis

Thalidomide (Thalomid)

Thalidomide is an immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration

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