Hazards of the ‘ hard cash ’ : Hypersensitivity pneumonitis

1 Department of Pulmonary Diseases, Baskent University School of Medicine; 2School of Medicine, Department of Chest Diseases, Ankara University; 3Department of Pathology, Baskent University School of Medicine, Ankara, Turkey Correspondence: Dr Elif Kupeli, Baskent University School of Medicine, Chest Diseases Department, Maresal Fevzi Cak Cad, 5.sokak, No:5, 06490 Besevler, Ankara, Turkey. Telephone 90-312-212-2912, fax 90-312-215-2631, e-mail elifkupeli@yahoo.com Patients with hypersensitivity pneumonitis (HP) may present with a wide variety of clinical findings depending on the nature of the inhaled dust, the immunological response of the host, and concomitant bacterial or viral infections. HP can be categorized into acute, subacute and chronic forms according to clinical presentation and radiological findings (1-4). We present a case involving a 45-year-old woman, who worked as a money counter and was diagnosed with subacute HP due to exposure to freshly minted banknotes – an occupation that has not been previously linked with HP.


CASE prESEntAtion
A 45-year-old woman who was a lifelong nonsmoker was admitted with a six-month history of recurrent bouts of productive cough and dyspnea.She had been working as a money counter for 20 years at a central bank.She complained of strong odour and dust, especially while counting freshly minted banknotes, that was often followed by dry cough and chest tightness.She denied any other occupational exposure, contact with birds or animals, or having peculiar hobbies.
The bank notes she handled were delivered directly from the mint, stored in the vault and were never in the general circulation.However, details regarding the exact date of printing of the notes were not available.The vault maintained a constant temperature, with humidity at 38%.In earlier years, she counted all notes manually; for the past five to six years, the notes were being counted by a machine and manually.Her workplace was centrally air conditioned, with a humidifier in close proximity to her desk.Her job was unique in nature and no other coworker reported similar symptoms.
Her physical examination was normal except for bibasilar fine crackles on auscultation of her lungs.On laboratory analysis, her C-reactive protein (CRP) and immunoglobulin (Ig) G levels were high (77 mg/L and 236 g/L, respectively).A chest x-ray (CXR) showed bilateral reticulonodular infiltration predominantly involving the middle and lower zones of the lung.High-resolution computed tomography (HRCT) demonstrated ground-glass opacities involving bilateral upper lobe apical and apicoposterior segments (Figure 1); lower lobe basilar segments were involved and demonstrated a mosaic pattern.
Pulmonary function tests (PFTs) revealed mild restriction (forced expiratory volume in 1 s of 75% predicted, forced vital capacity of 78% and a forced expiratory volume in 1 s/forced vital capacity ratio of 81) and a normal diffusion capacity.She had mild hypoxemia (PO 2 = 68 mmHg) while breathing ambient air.
Diagnostic bronchoscopy exhibited edematous bronchial mucosa involving both endobronchial trees.Bronchoalveolar lavage (BAL) fluid analysis revealed lymphocytosis (80%) with a predominance of CD4-positive (CD4 + ) T cells.Transbronchial lung biopsy revealed a very small fragment of lung tissue with lymphoctes bundled in the interstitial septae, without any granuloma formation, along with a small fibrotic area.Hypersensitivity pneumonitis (HP) is a nonimmunoglobulin E-related immune-mediated parenchymal lung disease.A 45-year-old woman who was a lifelong nonsmoker with a six-month history of frequent episodes of cough and dyspnea was admitted to hospital.She had been working as a money counter for 20 years at a central bank.Bibasilar crackles on lung auscultation, ground-glass opacities and a mosaic pattern on high-resolution computed tomography, restrictive abnormality on pulmonary function tests and mild hypoxemia were the prominent findings.Bronchoalveolar lavage fluid analysis revealed a predominance of CD4-positive T cells, and she tested positive on her natural challenge test.She was diagnosed with subacute HP based on established criteria.She was advised to discontinue counting fresh banknotes.Prednisolone was commenced, then tapered to discontinue in the ensuing six months.Clinical and radiological improvement was achieved within two months.To the authors' knowledge, the present report is the first to describe 'hard cash HP', possibly caused by chipping dust or printing dye.
Can Respir J Vol 17 No 5 September/October 2010 e103 Because the antigen that caused HP was unknown in the present case, a natural challenge test was performed by re-exposing the patient to a suspected antigen in her natural environment.Her peak expiratory flow rates (PEFRs) were checked at the beginning (morning) and at the end of the work day (evening) for one week.The values were best in the early mornings (75% of predicted), became worse as the day progressed and were worst at the end of the week (60% of predicted), thus confirming the relationship between her occupation and her symptoms (Figure 2).
A diagnosis of subacute HP was verified according to the established major and minor criteria (Table 1).She was prescribed prednisolone 1 mg/kg/day to be tapered to discontinue within the following six months.She was also advised to avoid exposure to freshly minted banknotes.HRCT performed after two months of therapy revealed total resolution of the lung infiltrates (Figure 1B).After three months of therapy, she retired and her PEFRs have remained optimal over the duration of her follow-up.

DiSCUSSion
HP represents a heterogeneous group of diseases resulting from repeated inhalation of and sensitization to various dispersed antigens (1-5).Patients with HP may present with a variety of clinical abnormalities (5).Clinically, HP can be categorized into three different forms (1,4,(6)(7)(8).
Acute HP typically occurs after a high-level, intermittent exposure to the offending antigen over a short period of time.Subacute HP is characterized by the gradual development of symptoms that occur during weeks to months after repeated low-level exposure.Chronic HP may develop in different settings -either chronic insidious or chronic recurrent HP.The former involves continuous long-term, low-level antigen exposure leading to irreversible pulmonary damage without major acute attacks.There may be a delay in seeking medical care for several months or years after illness onset (1,4,(8)(9)(10).Physical examination often reveals fine crackles; clubbing can be seen in 20% to 50% of patients.Pulmonary hypertension or cor pulmonale develops in only advanced stages of chronic HP (1,8-11).Our patient worked at a bank as a money counter for many years, with low-level antigen (printing dye or typesetting water) exposure.Over the years, she was hospitalized on several occasions with respiratory symptoms, and received subjective treatment.With low-dose antigen exposure over many years, we suspected she developed subacute HP.An environmental exposure challenge test and cessation of exposure to the suspected offending agent further supported our diagnosis.
Combinations of several subjective and objective parameters are essential in most patients to establish a conclusive diagnosis.The recommended criteria for the diagnosis are listed in Table 1 (1,7,8).There is usually a marked blood neutrophilia and lymphopenia in acute HP.Elevation of CRP, erythrocyte sedimentation rate and serum lactate dehydrogenase may be present.Elevated rheumatoid factor may be detected in more than 50% of patients.Increased serum IgA, IgG and IgM levels have been reported in HP patients (1,2,4).Our patient consistently matched these criteria and also had elevated levels of CRP and IgG.
Specific serum precipitating antibodies are found in many patients with HP (7,9).The presence of these antibodies indicates exposure and sensitization to respective antigens, but not necessarily the presence of the disease.It should be noted that 40% to 50% of asymptomatic individuals exposed to the same antigens will also have serum IgG antibodies.For the diagnosis of HP, the precipitin test is reasonably sensitive, but it is nonspecific and should be ordered selectively (7,9,10,12).Because the actual antigen was unknown, we were unable to detect precipitating antibodies.Instead, a natural challenge test was performed by exposing the patient to the offending environment, which led to the diagnosis of hard cash HP.
Restrictive patterns with a decrease in diffusion capacity, hypoxemia and bronchial hyper-reactivity due to bronchiolitis can be encountered in patients with HP.Early diagnosis and avoidance of antigen exposure are the mainstays of treatment (1-4,7,10,13).Our patient showed a mild restriction, with unaffected diffusion capacity along with hypoxemia at rest due to impaired gas exchange compatible with the findings seen in patients with HP.Avoidance of exposure to the antigen resulted in improvement in her symptoms and PEFR.There has been no recurrence of her symptoms since her retirement.
Radiographic findings in HP correlate with the stage of the disease.In subacute form, fine linear or reticulonodular infiltrates can be found on CXR; however, normal CXR findings can also be seen in the acute form of HP (1)(2)(3)(4).HRCT features include centilobular nodules associated with larger areas of ground-glass opacity as well as air trapping and mosaic pattern.Occasionally, thin-walled cysts can be noticed in patients with subacute HP.The sensitivity of HRCT for the diagnosis of HP is greater than that of CXR (14)(15)(16)(17).The present case demonstrated ground-glass attenuation in a mosaic pattern and centrilobular nodules on HRCT.
Analysis of BAL fluid reveals lymphocytosis of predominantly CD8 + T cells with a decrease in the CD4 + /CD8 + ratio.
However, BAL findings may vary depending on clinical presentation, the timing of the most recent antigen exposure and the attainment of BAL fluid.A predominant accumulation of CD8 + T cells seems to be a feature in acute or subacute HP, whereas a prevalent elevation of CD4 + T cells is found in the chronic form of the disease (1)(2)(3)(4)(8)(9).The present patient demonstrated lymphocytic BAL fluid with CD4 + T cell predominance, suggesting chronic exposure to the antigen over many years.She may have been demonstrating a transition from the subacute form, slowly converting to the chronic phase based on her BAL findings.
The characteristic histopathological findings of subacute HP are diffuse interstitial infiltrates with lymphocytes, macrophages, mast and plasma cells, scattered noncaseating granulomas and cellular inflammation of bronchioles -findings seen in 50% to 75% of patients.Other typical histopathological findings in the subacute form of HP are plasma cells, mast cells and foamy alveolar machrophages.Fifteen per cent to 25% of patients may exhibit bronchiolitis obliterans with organizing pneumonia on biopsy (1)(2)(3)(4).Surgical biopsy may be misleading if considered in isolation and without the integration of clinical and radiological information.In HP, it is now known that the typical histological appearances are absent only in a minority of cases (18).In the present case, although we could not capture the granulomas in the transbronchial lung biopsy, clinical and radiological findings helped us to establish the diagnosis.
Parenteral steroids are indicated for patients with abnormal PFTs and radiographs, or with hypoxemia.They have been shown to improve symptoms and hypoxemia, and not to affect long-term prognosis (1-4,7,10).In our patient, oral prednisolone 1 mg/kg/day was started and tapered within six months.In the second month of treatment, her improvement both clinically and radiographically was dramatic.

ConCLUSion
The present case fulfills the diagnostic criteria for HP according to medical history, evidence of exposure to the antigen, physical findings, PFTs, hypoxemia on blood gases, demonstration of BAL fluid lymphocytosis, and compatible histological changes as well as a positive natural challenge test.To our knowledge, HP from an exposure to freshly minted banknotes (hard cash HP) has not been previously reported.In the literature we found a condition similar to that of the present case -'Bible printer's lung' (19,20) -in which the offending antigen was mouldy typesetting water/printing dye.We believe that either the printing dye or the paper dust could have been the culprit in the development of 'hard cash HP' the present case.

Figure 1 )Figure 2 )
Figure 1) High-resolution computed tomography scan of the patient before treatment (A).Ground-glass opacities involving bilateral upper lobe apical and apicoposterior segments, lower lobe basilar segments showed a mosaic pattern.Total resolution of the infiltrates were seen after treatment (B)

TABLE 1 Diagnostic criteria for hypersensitivity pneumonitis (HP) Major criteria (four major criteria should be presented)
History of symptoms compatible with HP Evidence of exposure to the offending antigen by history or through detection in serum or bronchoalveolar lavage fluid antibody Changes characteristic of HP on chest radiograph (reticulonodular infiltrates, linear opacities) or high-resolution computed tomography of the chest (ground-glass opacities, micronodules, honeycombing, linear opacities, airtrapping) Demonstration of bronchoalveolar lavage fluid lymphocytosis, if bronchoalveolar lavage analysis is performed Demonstration of histological changes consistent with HP, if lung biopsy is performed, such as alveolitis, noncaseating granulomas, giant cells, foamy alveolar machrophages or fibrosis Positive 'natural challange' that produces symptoms and objective abnormalities either through controlled inhalational challange or after re-exposure to the offending environment