Inhaled Steroid (A Case Report)
Demet KARNAK*, Oya KAYACAN*, Sumru BEDER*, Serpil DİZBAY SAK**
* Department of Chest Diseases and Tuberculosis Medical Faculty of Ankara University,
** Department of Pathology Medical Faculty of Ankara University, ANKARA
SUMMARY
It is known that inhaled steroids can be used for the treatment of interstitial lung diseases such as sarcoidosis to avoid syste- mic side effects of oral or intravenous forms. However there is no information about the role of inhaled steroids in the treat- ment of hypersensitivity pneumonitis (HP). Here in, a 38 year-old male patient with chronic HP treated by 16 months of high dose inhaled steroid is presented. Inspite of avoiding antigen exposure as much as possible, persisting radiological ab- normalities necessitated histopathological confirmation of the diagnosis even if early-good clinical response. All findings were resolved after therapy and no pathology has been detected in a 1.5 year of follow-up. The authors recommend that high dose inhaled steroids should be considered in the treatment of HP. This observation needs to be supported by studies in large series.
Key Words: Hypersensitivity pneumonitis, interstitial lung disease, inhaled steroid.
ÖZET
Hipersensitivite Pnömonisi ve İnhaler Steroid (Olgu Sunumu)
İnterstisyel akciğer hastalıklarında, örneğin sarkoidozda, özellikle sistemik steroidlerin yan etkilerinden kaçınmak için in- haler steroidlerin kullanıldığı bilinmektedir. Ancak hipersensitivite pnömonisi (HP) tedavisinde inhaler steroidlerin rolü ko- nusunda kesin bir bilgi yoktur. Burada, 16 ay boyunca yüksek doz inhaler steroid tedavi verilen, kronik HP tanılı 38 ya- şındaki bir erkek olgu sunulmaktadır. Antijen ekspozisyonundan olabildiğince kaçınılmasına rağmen, radyolojik bozuk- lukların kalıcı olması, erken ve iyi klinik yanıt gözlense bile, tanının histopatolojik açıdan doğrulanması gerekliliğini orta- ya çıkarmıştır. Olgunun tedavi sonrası tüm bulguları tamamen gerilemiş ve 1.5 yıllık izlemde olguda bir patoloji tespit edi- lememiştir. Yazarlar, yüksek doz inhaler steroidlerin HP tedavisinde akılda tutulması gerektiğini ve bu gözlemin geniş seri- lerde yapılan çalışmalarla kanıtlanması gerektiğini ileri sürmektedirler.
Anahtar Kelimeler: Hipersensitivite pnömonisi, interstisyel akciğer hastalığı, inhaler steroid.
In recent years, inhaled steroid therapy for in- terstitial lung disease has been used especially in pulmonary sarcoidosis without extrapulmo- nary involvement, bronchiolitis obliterans and organizing pneumonia (1-5). Hypersensitivity pneumonitis (HP) is an immunologically medi- ated pulmonary disease induced by the inhalati- on of any of a wide variety of antigens. Studies suggest that an initial immune-complex medi- ated lung injury is followed by cell-mediated pulmonary damage (6-8). Although systemic steroids are known to be used in the treatment of chronic HP, there is no previous report con- cerning on the role of inhaled steroids in the tre- atment of this disease. Therefore we present a case of chronic HP treated successfully with long term high dose inhaled steroid administration.
CASE REPORT
A 38 year-old male was admitted to the clinic with the complaints of dyspnea, wheezing, co- ugh, night sweats and chest-pain of three months duration. These complaints had begun since he had started to work. We learn that he had close contact with file archives which was a dusty medium at work. He had smoked 30 pack-years of cigarette which he had omitted for four months. There was no history of respiratory illness and not any relevant family history.
On admission, his body temperature was 36.7OC. Auscultation of his chest revealed basal crackling sounds and sibilant rhonchi in both lung fields. There was no other pathology in his physical examination. Plain chest roentgenog- ram (CX-R) demonstrated diffuse fine reticulo- nodular pattern (Figure 1A). Computed tomog- ram (CT) of the chest showed a ground-glass li- ke appearance and interstitial shadows throug- hout both lungs (Figure 1B). 67Galium pulmo- nary perfusion scintigraphy (67Ga scan) has al- so demonstrated diffuse increased uptake.
Pulmonary function tests (PFT) showed the for- ced vital capacity (FVC) to be 3.46 L (87% of predicted), forced expiratory volume in 1s (FEV1) of 3.11 L (88% of predicted), forced mi- dexpiratory airflow (FEF25-75) of 4.32 L (100%
of predicted), diffusion capacity (DLCO) of 29.6 mL min-1 mmHg-1 (101% of predicted) and
transfer factor (DLCO/VA) of 4.64 mL min-1 mmHg-1(96.3% of predicted). Arterial blood gas measurements were as follows, pH 7.42, PaO2 81 mmHg, PaCO2 37 mmHg and HCO3- 24 mEq/L. However, after a 6 minutes of treadmill exercise these measurements were pH 7.37, Pa- O267.2, PaCO239 mmHg, HCO3- 22.5 mEq/L.
The erythrocyte sedimentation rate was 18 mmh-1, leukocyte count was 8900 µL-1. Bioche- mical parameters were in normal limits.
Skin tests against common allergens and serum precipitins against Thermophilic actinomyces and Micropolyspora faeni were negative. Bronc- hial provocation test was positive; a 20% of dec- rease in FEV1 at concentration of 12.2 mg/mL was established. FEV1 value was increased by 27% after an inhalation of salbutamol (100 µg) this was commented as positive for reversibility.
Figure 1A. CX-R of the patient on admission.
Figure 1B. Interstitial involvement and ground-glass like appearance on CT of the chest.
He had mild eosinophilia of 300 mm-3 and total IgE level of 10.20 kU/mL (laboratory normal range: 1-100 kU/mL). On protein electrophore- sis a polyclonal gammopathy was detected.
Fiberoptic broncoscopy was normal. No asido- resistant basil was found in bronchial lavage or sputum. Bronchoalveolar lavage (BAL) de- monstrated the total cell count to be 21 x 106 with a 43.4% lymphocyte predominance (CD4 27%, CD8 64%, CD4/CD8< 1). Macrophages were found in normal range (53.2%) and most of them had foamy degeneration and 3.4% of cells were granulocytes. Histopathological examinati- on of the transbronchial lung biopsy (TBLB) re- vealed lymphocytic infiltration and fibrosis of the interstitial spaces.
A diagnosis of chronic type of HP was establis- hed through clinical, radiological, BAL and TBLB findings which met the major and minor criteria of the diagnosis (Table 1). The patient notified that it could not be possible to change his job but he would try to avoid of antigen ex- posure and he was on clinic follow-up. Theoph- yilline derivatives and antibiotics were adminis- tered for fifteen days and he was started on high- dose inhaled dry powder steroid therapy (fluti- casone propionate-2000 µg/day-flixotide dis- kus®), in the hospital. This therapy was initiated knowing that functional capacities and blood ga- ses were not so much impared and expecting complete removal from exposure in hospitaliza- tion period (four week). The clinical symptoms and 67Ga scan findings improved in three months time after commencing the therapy in spite of starting to work at previous job. Because
of persisting CT findings, the patient underwent an open lung biopsy after five months of the- rapy. Histopathological examination of biopsy specimen showed a nonspesific type of chronic inflammation distributed around bronchioles le- aving the intervening areas of parenchyma unin- volved. Lymphocytes comprised the majority of infiltrating cells with some plasma cells. Eosi- nophils and neutrophils were not prominent and fibrosis was minimal (Figure 2).
On follow-up, the patient continued the same therapy for 16 months. Now, he has no respira- tory complaint, and his PFT and DLCO are still normal and his exertional hypoxemia has disap- peared (pH 7.41, PaO2 88.3 mmHg, PaCO2 34 mmHg and HCO3- 21.6 mEq/L) although has been working at the same job. CX-R and CT fin- dings are nearly normal with resolution of gro- und-glass like appearance (Figure 3). Galium scan changed to normal.
Figure 2. (HE x 50) open lung biopsy specimen; chro- nic inflammation around bronchioles.
Table 1. Major and minor criteria used to substantiate a diagnosis of HP (6).
Major Minor
Evidence of exposure to appropriate antigen Bibasilar rales from history or detection of serum antibody
Symptoms compatible with HP Decreased diffusing capacity
Findings compatible with HP on chest Arterial hypoxemia, either at rest or during exercise radiographs or high-resolution CT scan
Pulmonary histologic changes compatible with HP BAL fluid lymphocytosis
Positive “natural challenge”
DISCUSSION
The outcome of the HP is variable depending upon several factors, such as the duration of an- tigen exposure, the concentration and chemical composition of the inhaled antigens, and the age and genetic background of the patient. It is cla- imed that lung immunoregulatory T cells may play a major role in the development of pulmo- nary fibrosis in HP (6-8).
There is two different clinical presentation of HP;
acute and chronic. Chronic HP presents with progressive and more severe dyspnea, nonpro- ductive cough, weight loss, and often anorexia in a patient exposed to recognized cause of the disease. Symptoms are usually present for months to years. Tachypnea and bibasilar dry rales are usually present. Plain chest radiograms are notable for diffuse linear and nodular opaci- ties, with upper lobe predominance. The diagno- sis of HP is confirmed in a patient who fulfills all of the major or at least four of the minor criteria, after ruling out all other diseases with similar symptoms (Table 1) (6).
In the present case, clinical and radiological fin- dings were compatible with all major criteria and some of the minor criteria of the disease and he was diagnosed to have chronic type of HP. A ca- reful differential diagnosis was made among the other causes of pulmonary fibrosis. The patient denied exposure to any chemotherapeutic agent, radiation or toxins, which could cause a lung injury. Because of the lack of suggestive ra-
diological and laboratory findings, sarcoidosis was also excluded. Pneumoconiosis was not a possible diagnosis either, because of the absen- ce of history suggesting inorganic dust exposu- re (6,9-11).
Chronic HP may be indistinguishable from idi- opathic pulmonary fibrosis (IPF). For IPF, a pre- dominance of lymphocytes and neutrophils is found in BAL, and a rapid progression and poor prognosis even accompanied by cor pulmonale can be seen. The present case showed a good response to therapy, which diverted us from the diagnosis of IPF (6,12).
In the treatment of HP, the patient was recom- mended to change his environment in order to avoid possible antigen exposure. We know that avoidance of exposure usually is followed by re- solution of signs and symptoms, but it could not be possible for the patient except hospitalization period. We also know that complete removal from antigen exposure may not always lead cli- nical and radiological improvement, and pati- ents with chronic form of HP may manifest prog- ressive pulmonary impairment even after avo- idance (13).
Systemic steroids have been suggested to be ef- fective in the medical treatment of HP (6-8). To our best knowledge of literature, inhaled steroids were not used in the treatment of HP. Standard or high doses of inhaled steroids (budesonide, fluti- casone, triamcinolone) can be used in patients with bronchiolitis obliterans (BO) which develops after lung transplantation, BO with organizing pneumonia (BOOP) and pulmonary sarcoidosis without extrapulmonary involvement (1,3-5,14).
We preferred to initiate inhaled steroid knowing that steroid-sparing capacity was also documen- ted if it would be needed (15-17). This drugs (i.e.
inhaled budesonide) has also been found to re- duce the number and proportion of T-lymphocy- tes in BAL and to normalize the increased CD4/CD8 ratio and may reduce the concentrati- on of hyaluronan in the BAL fluid, which can be a marker of early fibroblast activation. Finally, a normalization of BAL macrophage subpopulati- ons with a decrease in antigen-presenting mac- rophages has been reported (15-19). As our pa- tient had normal values of pulmonary function Figure 3. Control chest CT of the case demonstrates
remarkable resolution.
tests and DLCO, and a stable clinic condition with mild symptoms, he was followed-up on in- haled steroid therapy. We surprisingly observed gradually a successful recovery. Sixteen months later, this is documented by the disappearance of the ground glass like appearance on CT and exertional hypoxemia. We think that systemic ef- fects of 2000 µg/day fluticasone may cause this result. As fluticasone at dose of 2000 µg/day has systemic effects, which has been recently de- monstrated in the treatment of chronic asthma when compared with prednisolone 30 mg daily, this may not be topical effect alone (20). We be- lieve that, this is the first documented case of cli- nical and histopathologically confirmed HP tre- ated with inhaled steroids. A satisfactory respon- se gained after long-term high dose inhaled ste- roid therapy suggested that inhaled steroid the- rapy could be a safe, effective and satisfactory alternative to systemic steroid administration even if it may have systemic effects at high the- rapeutic doses in the treatment of HP. We recom- mend high dose inhaled steroids should be con- sidered in the treatment of HP and the efficacy of this modality of treatment needs to be determi- ned in large series.
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Address for Correspondence:
Demet KARNAK, MD
Department of Chest Diseases and Tuberculosis Ankara University Medical Faculty
06100, Cebeci, ANKARA
