Streptomyces albus: a new cause of hypersensitivity pneumonitis

Streptomyces albus: a new cause of hypersensitivity pneumonitis Steven L. Kagen, M.D., Jordan N. Fink, M.D., Donald Viswanath P. Kurup, Ph.D., and Robert B. Fruchtman,

P. Schlueter, M.D.,. M.D. Mi/w(iukrr, uy-‘:

Hywwnsiri~ity

to lx> indurwl

pneat~~oniri.s

is un immunologic

lung

disease

known

Ity thr

inhalarion of‘ either organic or inorganic, antigens, und ir muy thus be associuwd wilh a \‘~~tx .: ot’ ocwpariorts and microorgunism.s. To idenr$y an inciting allrrgen, cv~~ironmet~tal. htrc,trriolr,~ic,, immunologk, and bronchial challengr studies n7usr he employed Thcw iwhttiyrws ~t’cre used fo demonsrrute that a bacterium utfjtbrm/y pwscnt in proc’c.s.scyi dit t, Streptomycex albus, IIYIS re.spotr.sihle jtir- u hiop.s~-pro\vtt UI.W of’ /t!prtv~tt,sitrl,it~ pnctttn~~rtirr ( l.i

ALLERGY

C‘LIN

iMMWOL

68:295.

/WI .)

HP is an immunologic lung disease caused by the inhalation of and sensitization to any of a wide variety of organic dusts or chemicals.” p The syndrome usually occurs 4 to 6 hr after the inhalation of an offending antigen, with both acute respiratory and systemic symptoms.:’ Prolonged exposure may produce irreversible pulmonary parenchymal damage, and complete avoidance of exposure may bring about reversal of all abnormalities. 4-ti Although the immune mechanisms involved in the pathogenesis of HP are not completely understood, several effector processes have been implicated. These include the classic and alternative complement pathways, immune complexes, cytotoxic antibody, and cellular immune mechanisms.7’-1z More recently, an imbalance in immunoregulation has been suggested as a primary defect leading to the development of HP, as demonstrated by inadequate suppressor T-cell function in symptomatic individuals. I3 The most commonly cited sources of antigen asso-

Fr>m the Allergy-Immunology and Medical Chest Sections, Department of Medicine, The Medical College of Wisconsin and the Wood Veterans Administration Medical Center, Milwaukee, Wise. Supported by Special Center of Research grant HL 15389 from the National Institutes of Health, the Veterans Administration, and Clinical Research Center grant RR88. Received for publication April 6, 1981. Axepted for publication July 1, 1981. Reprint requests to: Jordan N. Fink, M.D., Research Service/ 15 1, Wood Veterans Administration Medical Center, Milwaukee, WI 53193.

ciated with HP are the thermophilic Actinomycetes.’ These organisms, which are found in compost of farm crops, sugar cane, and mushroom farms, may be inhaled as the worker disturbs the moldy substrate. Thermophilic Actinomycetes may also be inhaled by and cause disease in individuals exposed to working or living environments contaminated by colonized ventilation systems. ‘I However. recent studies suggest that these systems are contaminated with a variety of organisms, any of which may serve as the offending antigen. I5 A wide variety of fungi may also cause HP.’ The fungal antigens are contacted in environments such as cheese factories, paper-related industries. and grainharvesting areas. There is, however, no known common feature of the fungi that explains their ability to induce the disorder other than their heavy concentrations within the offending environments. Other sources of organic materials capable of causing HP have recently been reviewed and include a number of avian proteins, bat droppings, insect and vegetable materials, and several amoebae. Ifi Smaller molecules such as the hapten toluene diisocyanate are by no means excluded from this diverse gallery of HP-inducing substances. l7 This article describes the first case of HP in which environmental, immunologic, and bronchial challenge studies documented the etiologic agent to be a common inhabitant of the soil. Srrrprctmyces ulbus. CASE REPORT The patient. a 31-yr-old nance for 5 yr at a company

white man. specializing Vol.

worked in rnaintein the production of

68, No

4, pp.

295-299

r OCTOBER 1981

AhbrPviatiof~s LfSCOl HP: Hypersensitivity pneumonitis Forced expiratory volume in one second FEV,: FVC: Forced vital capacity ANA: Antinuclear antibodies SGA: Sabouraud’s glucose agar TSA: Trypticase soy agar FEF25--75: Forced expiratory flow in middle half of FVC

fertilizer used to inoculate plant dirt and peat moss. He was in good health until December 1979, when symptoms of cough, shortness of breath, and sharp pleuritic anterior chest pains began. By March 1980 he was forced to take sick leave because of progressive cough, shortness of breath, intermittent fevers of 38” to 39” C, chills, myalgias, and fatigue. These symptoms began several hours after leaving his work area each day, and were notably absent on weekends. After 1 wk of sick leave he felt much improved, but after returning to work his symptoms recurred so severely that hospitalization was required. Physical findings at that time revealed a blood pressure of 110/70, a pulse rate of 88, a respiratory rate of 18, and a temperature of 37” C. Crepitant inspiratory rales were heard in both lung fields. A chest film revealed bilateral fine interstitial markings, with some hilar node enlargement (Fig. 1). Arterial blood gases documented a resting hypoxemia with the pH 7.43, Pco, 34, and PO, 74 on room air. Pulmonary function studies showed a mild restrictive pattern with a FEV,/FVC ratio of 86% and an FVC of 75% of predicted. FEV, was 3.5 L or 82% of predicted. Clinical evaluation, including hematologic and biochemical studies, serum protein electrophoresis, sputum cultures for bacteria and fungi, ANA, electrocardiogram, ventilation/perfusion lung scan, and echocardiogram, were normal. The rheumatoid factor titer was 1:40. A transbronchial biopsy demonstrated focal fibrosis, but brushings for cytologic study and cultures for bacteria and fungi were not diagnostic. An open-lung biopsy revealed scattered interstitial plasma cells and lymphocytes, with focal sarcoidlike granulomas characteristic of HP (Fig. 2). The patient avoided his work area from April to July of 1980, during which time he was entirely asymptomatic. He was then admitted to the Clinical Research Center of The Medical College of Wisconsin for further evaluation. Physical findings at that time were unremarkable except for a right-sided thoracotomy scar from his open-lung biopsy. Laboratory studies included normal quantitative immunoglobulins, multiphasic biochemical screening studies, and urinalysis. His hemoglobin was 14.7 gm/lOO ml, the hematocrit 43%, a white cell count of 4.7/mti’ with a normal differential, a sedimentation rate of 1 mm/hr, a negative ANA, an unreactive VDRL, and a rheumatoid factor titer of 1: 160. The chest X-ray was normal except for postthoracotomy changes.

FIG. 1. Chest X-ray revealing hilar node enlargement interstitial markings bilaterally.

LABORATORY Environmental

and

DATA assessment

Three dirt materials to which the patient was exposed while on the job were plated directly onto SGA, SGA with antibiotics, TSA, and TSA with novobiocin. SGA plates were incubated at room temperature and 37” C, and TSA plates were incubated at 55”

C. Plates were observed daily for growth of organisms, which were then subcultured, isolated, and identified according to standard methods. l8 Three organisms were isolated from one sample and included Bacillus subtilis, Bacillus polymyxa, and S. albus. No fungi

or thermophilic

organisms

were

found.

The

other two dirt samples were sterile. Environmental sampling from the patient’s work area and home areas is presented in Table I. Dust samples were collected from air conditioner filters and an air return tunnel in the ventilating system at the factory and were cultured on both Rhizobium medium and starch-casein agar with selective actinomycete medium after passage through a loo-mesh screen. Samples from rugs in the patient’s home were similarly processed. Organisms isolated were grouped into three classes (actinomycetes, bacteria, and fungi) and are expressed as colony counts per gram of dust. Respirable dust densities were determined according to chapter 1090.1000 of the Federal Occupational Safety and Health Regulations (O.S.H.A.)lg by using a Mine Safety Appliances air sampling pump. Immunologic

evaluation

Precipitating antibodies were detected to 10% w/v sterile extracts of the cultured S. albus, B. subtilis, and B. polymyxa by agar gel immunodiffusion as previously described. 2o No precipitating antibodies were detected to raw dirt. Serum samples from four individuals not knowingly exposed to the same envi-

VOLUME 66 NUMEER 4

3repromyce.s

FIG. 2. Biopsy loma formation

TABLE ---

I. Environmental

displaying scattered and multinucleated

sampling

interstitial lymphocytes giant cells.

a/bus

and

Home I ivinp room Bedroom f stimated respirable

Actinomycetes

organisms/8

hr*

area tunnel respirable

focal

organisms/8

ventilation

297

granrl

and 100%

of dust Bacteria

1.9 8.7 3.8 1.8

x IO” x IO5 x IO”+ x 10”’ I

1.6

x

__.__ .._ l_l--.__-

Fungi

Respirable dust (gmlm3)

lti

1.7 x IO6 6.9 x lO’$ 5.4 x lO”jj

hr

-*A!summg 6 IJmin tI.iving room. iBedroom. SPr xluction l/Air return

with

^--I

Location

Air return Mimated

cells

pneur*:opitis

data Organismslgm

Factory Production

plasma

hypersensitivity

aerosolization

of dust.

area. tunnel.

ronment did not have demonstrable precipitins to these organisms or dirt samples. Skin testing by cutaneous and intracutaneous techniques with common inhalant antigens revealed immediate wheal and flare reactions to grass pollen and house dust extracts (Hollister-Stier Laboratories, Spokane, Wash.). Cutaneous testing with sterile 10% w/v buffered saline extracts of the cultured organisms revealed an imme-

diate reaction with 10 mm of wheal and 40 mm of flare to all cultured organisms. There was no detectable late reaction (4 to 6 hr) demonstrable by this technique. Serial tenfold dilutions of the extracts were used for intracutaneous testing to gauge the sensitivity of the patient for inhalation challenge. A 1% w/v dilution of each of the three extracted cultured organisms caused an immediate reaction to 8 mm of

298

Kagen

et al.

hmm of flare. These reactions were followed in 4 hr by erythema and induration measuring 20 by 20 mm, which resolved by 24 hr. Inhalation

challenge

With techniques previously described,” pulmonary function tests were carried out prior to inhalation challenges while the patient was asymptomatic. Spirometry, flow-volume curves, static lung volumes, diffusing capacity, and arterial blood gases at rest were normal. With exercise, however, there was a significant fall in arterial PO, from 87 to 75 mm Hg. A methacholine challenge was negative. Inhalation challenges were performed with each of the isolated organisms in 2-ml aliquots of 10% w/v sterile extracts. The raw dirts were also tested by having the patient inhale dust created by shaking the dirts in a paper bag. Challenges with B. subtilis and B. polymyxa extracts and with raw dirts failed to produce any changes in symptoms, white blood count, temperature, or pulmonary functiotns. Seven hours after inhalation exposure to S. albus extract, however, the patient developed chills, rigors, muscle aches, headache, fever to 39” C, crepitant wet rales in both lung fields, and an elevated white blood cell count. Pulmonary function studies documented decreases of 18% in FVC, 21% in FEV,, 34% in FEF,,+,, and 30% in the carbon monoxide transfer factor. The arterial PO, fell from 78 to 58 mm Hg (26%). These symptoms and pulmonary function abnormalities resolved over 5 days with prednisone therapy (30 mg/day). Nonexposed controls were not tested because of the risk of sensitization to the antigens. Exposed and asymptomatic individuals were not available for evaluation and challenge testing. The patient has since remained asymptomatic while avoiding his work environment. DISCUSSION Since the initial descriptions of HP in grain workers and farmers, a wide variety of agents have been proven to cause the disease.**, 22 The spectrum includes bacterial, fungal, avian, insect, and vegetable proteins, various hapten molecules, amoebae, and most commonly thermophilic bacteria of the order Actinomycetales. The current case represents the first instance of S. albus-induced HP. The S. albusinduced pulmonary and systemic response could be considered specific because the patient acted as his own control; that is, there were no responses to other environmental antigens to which he was skin reactive. Although the nature of the offending antigen is still unclear, much is known of its source. Streptomyces are sporulating, antibiotic-producing bacteria from

J. ALLERGY CLIN. IMMUNOL. OCTOBER 1981

the same order as Actinomycetes, Nocardia, and mycobacteria. 23The organisms are uniformly present in soil and it was therefore not too surprising to find organisms of that order in high densities within the environment of the soil fertilizer factory in which the patient worked. The number of organisms found in his home may thus represent its ubiquitous nature. Initial interest in Streptomyces began with the work of Waksman in the 1940s; from this bacterial group alone over 500 antibiotics have been discovered, including streptomycin, chloramphenicol, tetracycline, erythromycin, nystatin, and amphotericin. 24 Although ubiquitous in soil, Streptomyces spp. have rarely been associated with human disease. In both Africa and India, however, mycetomas of the lower extremities are known to occur.2”* 26 Additionally, one case of constrictive pericarditis has occurred due to a Streptomyces organism acquired in Zaire, Africa by a Peace Corps worker.27 To our knowledge there are no prior documented episodes of human pulmonary hypersensitivity to Streptomyces sp., although it has been demonstrated that extracts of S. olivaceus cultured from roof thatch can induce an experimental interstitial lung disorder suggestive of a human nontuberculous lung disease found in New Guinea natives when immunized guinea pigs are aerosol challenged with the organism. 28 As a group, temperature bacteria are an uncommon cause of HP. B. subtilis, however, has been a suggested etiologic agent in cases of nonasthmatic respiratory disease among workers employed in the enzyme detergent industry. *’ This same organism has recently been proven to cause a familial outbreak of HP in individuals remodeling their homes.30 It is of interest that our patient was exposed to B. subtilis and found to be sensitized to it with regard to serum precipitins and skin testing, and yet his bronchial challenge with B. subtilis extract was negative. This most clearly demonstrates the importance of reviewing together the environmental, immunologic, and bronchial challenge studies in attempting to identify potential HP-inducing antigens. As demonstrated in our environmental studies, the dust levels within the fertilizer factory were within the OSHA guidelines,ig yet the workers were exposed to large numbers of potentially respirable organisms. Even though the filters in the air purification system did decrease the density of Actinomycetes lOOO-fold, substantial quantities of viable organisms remained in the air returning to the work environment (Table I). The true meaning and importance of these findings, however, is unclear, since there is to date no known means of detecting (prior to exposure) which workers

VOLLME68 NUMXR 4

ma) develop HP when exposed to an offending antigen For this reason the process of trying to determine maximal allowable concentrations of microorganisms within industrial environments remains a complicated one A.lthough the spectrum of antigens capable of inducing HP is varied, the clinical course, immunologic features. and inhalation challenge studies are nearly uni arm. Therefore, careful historical inquiry, toge rher with environmental, immunologic, and bronchl;d challenge studies are the best means of diagnosis. Until more specific immunoregulatory agents are available, avoidance of the antigen with early judicious use of corticosteroids remains the therapy of chc ice. \hje thank Dr. Gerard T. Scanlon for his radiographic mterpretations, and Anita Balistreri and Catherine Walther for their typing and editorial assistance in the preparation of this. manuscript. REFERENCES

1 Fink JN: Hypersensitivity pneumonitis, in Middleton

2 i 3. S,

f,.

7

8

,j

IO. 1I

E, Reed Ellis EF, editors: Allergy principles and practice. St. 1978, The C. V. Mosby Co., p. 855. J: Hypersensitivity diseases of the lungs due to fungi and organic dusts. Monogr Allergy 469, 1969. JN: Hypersensitivity pneumonitis. J ALLERGY CLIN IMMUNOI. 52:309, 1973. Edwards C, Luntz G: Budgerigar-fancier’s lung: a report of a fatal case. Br J Dis Chest 68:57, 1974. Fink JN, Sosman AJ. Barboriak JJ, Schlueter DP, Holmes RA: Pigeon breeder’s disease: a clinical study of a hypersensitivity pneumonitis. Ann Intern Med 68:1205, 1968. Schlueter DP, Fink IN, Sosman AJ: Pulmonary function in pigeon breeder’s disease. A hypersensitivity pneumonitis. Ann intern Med 70:457, 1969. Olenchock SA, Burrell R: The role of precipitins and complement activation in the etiology of allergic lung disease. J ALLERGY CLIN IMMUNOI. 58:76, 1976. Berrens L. Guikers CLH, Van Dijk A: The antigens in pigeon breeder’s disease and their interaction with human complement. Ann NY Acad Sci 221:153, 1974. Edwards JH: A quantitative study on the activation of the alternate pathway of complement by moldy hay dust and thermophilic actinomyces. Clin Allergy 6:19, 1976. Spector WG, Heesom W: The production of granulomata by antigen-antibody complexes. J Pathol 98:3 1, 1969. Wenzel FJ, Emanuel DA, Gray RL: Immunofluorescent studies in patients with farmer’s lung. J ALLERGY CLIN IMMUNOI. 48~224, 1971.

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{JIWl~!~~'7O:lltis

299

12. Moore VL, Fink JN, Barborlak JJ. Kuf< I %h!ucrer 1%’ Immunologic events in pigeon breeders I AI ! i HI%! (‘i :h Iz+ MtiNOl 53:319. 1974. 13. Keller RH, Fink JN, Lyman St., Pererscn (; Aitcred immunoregulation in hypersensitivity pneum~mm> i‘!in I?,.\ 28: 102. 1980. (Abst.) 14. Fink JN, Resnlck AJ. Salvaggio JE: Pre\cn,e <>I thermophllrc actmomycetes in residual heating \?stemc ippl M~cr~~birrl 22:7X). 1971. JJ, Hcnsle? *,;I. kurup VP, 15. Fink JN. Banaszak EF. Barborlak Scanlon GT. Schlueter DP, Sosman AJ Thlcdc WH. Ynger GF: lnterstitial lung disease due to cctntarninJt!s *II bl! for; cd ‘in systems. Ann Intern Med 84:406, 197b. 16. Salvagglo JE: Diagnosis and management t,~t ~~)[~rseni~!l~!ty pneumonitis. Hosp Pratt 15:93. 1980. Lund: dn unusual 17 Fink JN, Schlueter DP: Bathtub retimsher’s response to tolucnc dii\ocyanate 4m Kc-, Rt:>\~r ii!\ 118~955. 1978 18 Kurup VP, Barbonak JJ. Fink JN. Lechevairer Mf’: 17w!.ttrocrc~rlrrotn~c YS rudiciu.s, a new spccre< o!. thennophilic actinomyces. Int J Syst Bacterial 25:150. l9Y.i 19 OSHA Safety and Health Standards ;XCf R i 9lli liH)O) General Industry Standards, Washington. D.( ‘\ici\cmher 7. 197x. p. 545. 20 Fink JN, Tebo T. Barboriak JJ: C’hara&r;ratiorr ot human precipitating antibody to inhaled antigens .t lmmunoi 103; 244, 1969. 21 RamaLzim B: De Morbus Artihcium Diatribe. ! 7 j .: (‘h~cago. 1940, L’niversity of Chicago Press follnw~ng work wrth hay. Br 22 Campbell JM: Acute symptoms Med J 2:1143. 1932. Manual of 23 Lennette EM, Spaulding EM, Truant JP (ediriw), climcal microbiology, ed. 7. W&mghm i).C . 1974. American Society for Microbiology 24 Camroc JM: Pay dirt: the story of streptomy~ ;n 4m Rzv Kcspir Dis 117:773, 197X. VV. Pankajalakshmi L’V. Kamaiakdnnan R, An25 Taralakshmi namalai R, Shetty BMV, Subramanian S. Shanmugasundaram T. Mycetomas caused by Srreptom~~c [JC,//~ IIC~: 111 Madras, India. Arch Dermatol 114:204, 1978 26 Abbot P: Mycetomas in the Sudan. Tranr R SKY Tmp Mcd Hyg 50:1 I. 1956. 27 Shanley JD. Snyder K, Child JS: Chronic perrcarditis due to a Strq~<~~~~c<,s species. Am J Clin Pathol 72: 107, I979 CRB, Green WF: Experimental extrmsic ailergic 28 Blackburn alveolitis induced in the guinea pig u,tth Strq~