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Allergic bronchopulmonary aspergillosis with low serum immunoglobulin E
Allergic bronchopulmonary aspergillosis with low serum immunoglobulin E Robert
H. Schwartz,
M.D. and Gary E. Hollick,
Ph.D. Rochester,
N.Y.
Elevated total serum IgE is helpful in making the diagnosis of ABPA and in monitoring the onset of exacerbations and response to therapy. ABPA occurs frequently in patients with CF, and in these instances a high total serum IgE is seen. This is the first case report of ABPA without an elevated total serum IgE level. At no time prior to this patient’sjrst episode of ABPA, at the time of the illness, or at monthly intervals during follow-up did her total serum IgE level exceed 29 Wlml. (J ALLERGY CLIN ~MUNOL 68:290, 1981.)
ABPA was first described by Hinson et al.’ in 1952. It occurs especially in young adult subjects with atopic asthma.* An association between CF and ABPA also has been known since the original report by Mearns et al.3 in 1965. Several other case reports have appeared in the literature since then.4-* In 1980, Brueton et a1.s described seven additional cases of ABPA in CF and stressed extensive pulmonary collapse and consolidation as ABPA complications of CF. They also stressed the young age at which ABPA can complicate CF. The incidence of ABPA is difficult to estimate because of variations in environmental mold spore exposure in different geographic areas and sporadic case-finding efforts among clinics. In 1979 Nelson et a1.4 reported their experience with Aspergillus and CF in Rochester, N. Y. They studied 46 patients during a 2-year period between 1976 and 1978. The respiratory tracts of 57% of these patients were colonized with Aspergillus fumigatus; 37% had serum precipitins to antigenic extracts of this fungus; 39% had positive immediate skin tests; and 22% had elevated total serum IgE levels. Five of the 46 patients From the Departments of Pediatrics, Division of Allergy and Clinical Immunology (R. H. S.) and Microbiology (G. E. H.), University of Rochester School of Medicine and Dentistry and Strong Memorial Hospital. This work was supported in part by a Care, Teaching and Resource Center grant from the Cystic Fibrosis Foundation. Received for publication April 6, 1981. Accepted for publication July 1, 1981. Reprint requests to: Robert H. Schwartz, M.D., Box 667, Strong Memorial Hospital, 601 Elmwood Ave., Rochester, N. Y. 14642.
Vol.
68, No.
4, pp.
290-294
develped ABPA. Between 1978 and 1980 two more of the original 46 patients developed ABPA, a cumulative incidence of 15% for this group. Schwartz et al. lo had previously shown that 30% of CF patient groups from Rochester, N.Y., Boston, Mass., and Los Angeles, Calif., had serum precipitins to antigens of A. fumigatus, a prevalence very much similar to that found in London by Meams et al.” This indicated a ubiquitous significant exposure to this fungus and suggested that ABPA might be anticipated as a frequent complication of CF. There are now good clinical criteria for suspecting and confirming the diagnosis of ABPA. I2 Major criteria are the following: (1) episodic or chronic bronchial obstruction, (2) transient of fixed pulmonary infiltrates, (3) peripheral blood and sputum eosinophilia, (4) immediate skin reactivity to Aspergillus antigen, (5) elevated serum IgE concentration, (6) serum precipitating antibodies (IgG) against Aspergillus antigens, and (7) central (proximal) bronchiectasis. Other clinical features that are helpful in making the diagnosis include (1) history of expectoration of brown mucus plugs or flecks, (2) sputum culture positive for A. fumigatus, (3) Aspergillus hyphae in bronchial secretions, (4) Arthus-type skin reactivity to Aspergillus antigens, and (5) immediate and delayed bronchoconstrictive reactions to Aspergillus antigens by inhalation challenge. ABPA is thought to be the result of type I (specific IgE-mast cell-histamine release) and type III (local IgG-immune complex-complement activation-Arthus reaction) immune reactions. Aspergillus-specific IgG and IgE antibodies are required to experimentally induce the disease in monkeys.13 0091-6749181/100290+05$00.5010
0 1981
The
C.
V. Mosby
Co.
1i,ht-iJ1,itrtioir.s
ABPA: CF: SSA: RAST: PRIST: P-K:
ic.std
Allergic bronchopulmonary Cystic fibrosis Skin-sensitizing antibody Radioallergosorbent test Paper radioimmunosorbent Prausnitz-Kiistner reaction
aspergillosis
test
IL’ untreated, these ABPA inflammatory processes ma:: have as their end result significant proximal bronchiectasis, pulmonary fibrosis, and pulmonary retraction. Since the acute process can be rapidly controlled with glucocorticosteroids,14 early diagnosis of ,\BPA and its recurrences is desirable. The ability to easily measure total serum IgE has made early diagnosis possible. Serum IgE levels are considerably ele.iated in ABPA. Total serum IgE levels may rise as high as 30.000 IU/ml (1 IU = 2.4 ng). Patterson and colieagues’“. I6 have stressed an elevated IgE level as an aid in diagnosis. Wang et al. I7 have shown that the total serum IgE level mirrors the activity of ABPA ant its response to therapy. A rising total serum IgE (two to six times baseline) may precede pulmonary infiltrations by several months. With adequate therap) . levels fall within 1 to 2 months. These observations seem to apply whether ABPA complicates asthma or CF. ‘. ” ‘This the first case report of a patient who developed ABPA ~~ith~~ltthe elevated total serum IgE level that is thought to be so characteristic of this entity. CASE REPORT This 20-year-old woman first came to medical attention at the age of 10 years with a history, since early infancy, of large. foul-smelling, bulky, floating greasy stools and frequent passage of foul flatus. Although her growth was at the lift eth percentile for age and she had not experienced signifcant respiratory infections, a diagnosis of CF was made on the basis of steatorrhea, decreased pancreatic enzymes, am! a positive sweat test (chloride = 104 mEq/L). Her first respiratory symptoms developed at about age 12 years, with na>al stuffiness on the basis of bilateral nasal polyps and bil.lteral maxillary sinusitis. In the fall of her thirteenth year sbc developed symptoms of sneezing, rhinorrhea, and conjunctivitis typical of ragweed hayfever. Complete allergy was done. skin testing with antigens, including Aspergilfus, Oriy ragweed was positive. Her first lower respiratory symptoms began in the late winter of her fifteenth year, with cough and sputum production during and after a docuaureus was minted in~urn:a A infection. Sraphylococcus Gtured from her sputum. The process involved the lingular segment of her left upper lobe. 4t age 16 she volunteered to be part of the Rochester
FIG. 1. Chest x-ray (6-9-80) showing left linguiar with otherwise very mild changes of CF
infiltrate
Cystic Fibrosis Aspergillus Study and had a completely negative workup. Sputum culture, \kln tcs!. RAS’I’. precipitins and peripheral eosinophil i‘ount. and sputum eosinophil evaluation were negative The smoking of marijuana and hashish became part of her late adolescent adjustment, which began at about age 17. During late March of her twentieth year sht: developed an episode of fever, chills, left-side plcuritic I:~IW pain. and increased sputum production. A lingular mfiitrate wax seen on chest X-ray. Sputum grew S. UUV~~~Sand 4. \~rnt,~c~tr,s intradermal immediate skin test became The Asprrgillus positive ( I : 10,000 w/v). However. A.s/;l,er-~i!ilc.tprecipitins could not be demonstrated, and her serum IgE! Levi was only 9 1Uiml. She was treated with odium diclou;icilim. Her symptoms and infiltrate resolved Three months later a similar episode OCCLIIred wtth a new lingular infiltrate (Fig. I ). The A.s~~r~~iilrc.5 prccipitin test became positive. but her total serum IgE le\si was only 16 lU/ml. The diagnosis of ABP?1, nab considered but not made because of the low 1gE level She ti.1~ rreattd a\ a staphylococcal infection patient without improbemcnt. After IO days of sodium nafcillin therapy ,.hc coughed up some brown sputum flecks. Fiberoptic brcincboscctpy revealed an inflamed narrowed left upper iohe bronchus. A mucus bpecimen from that segment c.s)ntained SW eosinophils. an inAammatory cytolog? Branched septate hyphae with preserved cytoplasm were seen. mdtcating that a fungus was actively growing in the respiraior)i tract Fun-
292
J. ALLERGY CLIN. IMMUNOL. OCTOBER 1981
Schwartz and Hollick
TABLE
I. ABPA
in CF without
Period
elevated
Date
Study Illness I Illness II On prednisone
Off prednisone
IgE Skin
test*
RASTt
-
-
<5
+
-
+
-
9
+ N.D. N.D. N.D. N.D. + N.D. N.D.
-
+ + + + -
+ + + + -
16 29 16 6 6 13 10 21
fumigutus
culture; Prcip. = precipitins
ASPERGILLOSIS DATA Total serum IgE Serum IgE levels were determined by the PRIST Diagnostic,
Inc.,
Piscataway,
IgES
-
gal cultures grew A. jiumigut~s. She had a peripheral eosinophil count of 1540imm”. Despite a total serum IgE level that had risen only to 29 llJ/ml over a period of IO days, a diagnosis of ABPA was made. The other serum immunoglobulins at that time were as follows: IgG 1136 mgidl, IgA 173 mg/dl, and IgM 251 mg/dl. She was treated with daily prednisone (1 mg/kg) for 2 weeks and everyother-day prednisone (0.5 mg/kg) for another 4 weeks. Her symptoms resolved in 4 days, and her infiltrate had cleared by the end of 6 weeks of therapy.
(Pharmacia
Prcip.
-
8/l l/76 Age 16 3/20/80 Age 20 6/9/80 6/20/80 7/2&O 70 l/80 8/19/80 9/ 12/80 10/12/80 12/8/80
N.D. = not done; Af cult. = A. *A. fumigatus (Hollister-Stier). TPharmacia. SPharmacia.
Af cult.
N.
J.)
method. They were verified by similar values found by Pharmacia, Inc., and the Mayo Medical Laboratories, Rochester, Minn. Aspergillus precipitin testing was performed as previously described,4 using the following Aspergillus antigens: Hollister-Stier Aspergillus mixture 1 : 10 (lot no. 19L8901; HollisterStier Laboratories, Spokane, Wash.), Aspergillus fumigatus 40,000 pnu/ml (lot no. 229303; Hollister), and Greer A. fimigatus, 20 mg/ml, strains 1, 2, and 3 (Greer Laboratories, Inc., Lenoir, N. C.). When found, precipitin lines formed with each antigen preparation except Greer strain 2. Table I summarizes the aspergillosis-related data. The patient had a negative workup when she enlisted in the study at age 16 yr. The first illness, at age 20, was characterized by a conversion of her A. fumigates immediate skin test to positive at a time when A. fumigatus was present in her sputum. However, her serum precipitin tests were negative and her serum IgE level was low (9 IU/ml). The second illness, 3
months later, was accompanied by the appearance of Aspergillus serum precipitins. The total serum IgE level was low (16 IU/ml), with a slight rise (29 IU/ml) during the IO-day period when the diagnosis of ABPA was considered but the condition was not treated. With prednisone therapy, sputum fungal cultures became negative, total serum IgE level decreased, and the serum precipitins eventually disappeared. At no time during the acute illness while the patient was receiving prednisone therapy or for close to 4 months after prednisone had been discontinued did the total serum IgE rise to the high levels usually associated with ABPA in general or with CF complicated by ABPA. Wang et al. I7 have used a total serum IgE concentration of more than 2500 rig/ml (1 IU = 2.4 ng) as one of the diagnostic criteria for ABPA. The mean total serum IgE levels for the remaining six CF patients in the Rochester series was 4545 IU/ml (range 570 to 8600). The mean serum level for the CF patients reported by Brueton et a1.g was 2715 IU/ml (range 500 to 8000). Aspergillus-specific
SSA
The A. fumigatus RAST (Phadebas RAST; Pharmacia) results were negative and remained negative throughout all the periods of observation. This was so despite the regularly positive RASTs in our other CF patients with ABPA4 and despite this patient’s positive prick and intradermal immediate type I skin tests to A. fumigatus extracts from three different sources including Hollister-Stier, an extract (strain 6) supplied by Greer, and The American Type Culture Collection, ATCC 1022 extract (strain 2) also supplied by Greer.
VOL;I’VIE 68 NlhlBER 4
Several studies were done to reconcile the negative ilspcrgil1u.s RASTs in the face of a positive skin test. The immediate skin test was positive at a dilute concentration of I : 10,000 (w/v), indicating that the patient had mast cell-fixed SSA. The negative RAST suggested that her serum did not contain large or measureable amounts of Aspergillus-specific IgE antihotly. Passive transfer P-K testing with the patient’s serum (0. I ml) was done with a suitable recipient (skin test-negative and able to accept P-K test). When individual donor sites were tested at 4 and 48 hr, negative reactions were observed. This indicated that the patient’s serum did not contain “short-term” Ig(; skin-sensitizing antibody.lx, I!’ It also again showed the absence of circulating “long-term” IgE shin-sensitizing antibody. Another possible explanation of a negative RAST in the face of a positive skin test is the presence of “interfering factors” such as A.,,wrgillrts IgG antibodies, which can tie up antigenic determinants on the solid-phase RAST discs and thus prevent measurement of IgE antibodies. This type of interference has been described for Aspergillus IgE anribodies by Vervloet et al.“’ in 1974 and for IgE honeybee venom antibodies by Zimmermann et al.” in i 980. The patient’s serum did not inhibit Aspergil/us RAST counts of a known positive serum when te+ted according to the method of Zimmermann et al., ?’ indicating the absence of interfering factors that might have given a falsely negative IgE-RAST. The only other positive immediate skin test that this patient had was to ragweed. She had seasonal raguied hayfever. Ragweed RAST was also negative. Tt-is finding. coupled with the Aspergillus data, suggests that the patient produces small amounts of SSA thilt fixes to mast cells and is clinically significant. DISCUSSION How did this young lady acquire respiratory tract colonization with A. jumigatus? Patients with CF pr lbably are predisposed to colonization because their respiratory mucus traps and encourages the germinaticIn ofilspcrgillus spores, which are ubiquitous under most atmospheric conditions.4. I3 In one case report, Cl’ mucus was shown to act as a nutritive substance for A. ,fi~ni~atus.“~ In addition, various species of .A.rper,c$llu.s,including A. fumigafus, are known contaminants of marijuana. 23 There have been case repc.lrtsof invasive pulmonary aspergillosis and ABPA associated with smoking moldy marijuana.*“. 25 The patient in the present report had been smoking marijuana for at least 3 years prior to the onset of ABPA. She allowed us to culture one small sample of her marijuana and a sample of her hashish. AspergilI;AStc~rwus was isolated. Although A. fumigatus was
ABPA
wiry
*cx\?~ lgi
293
not isolated from these samples. the> represent only a small proportion of the marijuana smokl*d over 3 pcriod of 3 years. A. terreus has recenti! been implicated as a cause of ABPA.“” However. ~:ulture filtrate antigens derived from the A. terrc’rt: vit*lded ncpativc skin tests. This 20-year-old woman with mild (‘I’ bad h\,c of’ the seven major criteria for making tbts diagnosis 01‘ ABPA. including bronchial obstruction, pulmonary intiltrates, blood and sputum eoiinophliia. ~I.~,~r;lillus immediate skin reactivity, and .3.v~~~~~ii/rl.c \erum precipitins. Her serum IgE level was icry low and was not helpful in making the diagnosi:, (lr in monitoring treatment. Central bronchiectasis ot:curs late in ABPA, and central and peripheral bmnchiecrasis is the rule in CF. Therefore its presence .idds little to help establish an early diagnosis of ABI%. especially in a CF patient. However. she had other jindinps helpful in making the diagnosis, including ,,:xpcctoration of brown plugs or flecks, sputum culturvh positive for A. fkmigatus, and branched septate ht. phae 111her brdnchial secretions. There are two possible explanation:, 10; this patient’s low total serum IgE level. The f~rsr is that she is genetically programmed to product iou levels of total serum IgE and small amounts ot’ *,pecific SSA. These antibodies have strong avidity for maht cells, thus permitting a positive skin test ;md one of the immunologic reactions (type I: IgE. .rn,kslceils histamine release) required for the dcl ciopmcnt of ABPA. The possibility of a genettc. :wY~\ \n ill hc difficult to prove, since she was adupreil and her biologic family is unknown. The scconci ~~\planatron is that this may be the tirst documented instance >)i’an initial ABPA episode. The observatii’n \~a\, made possible by the prospective study 01’ ;I group of patients in anticipation of their develr~pm.:nt c~fARPA. Elevated total serum IgE may onI> OLYUI-it‘ the process becomes recurrent or chronic. Folic>w-up ot’ this patient and recognition of similar CN:‘X ma! help determine whether the low total sc”rum I@; level ix unique to this patient’s irnrnunorespc,nsl~‘cn~,~~. is characteristic of very early ABPA. or 11.J!,~nlc i‘~s/c, that has been escaping diagnosi, REFERENCES 1. Hinson
KFW.
Moon
aspergilloslsThorax 1.
Pepy!, J: ~mtWWpathdogy
AJ. 7:317.
Plummcr 1%2. of allerplL
\4’\. lung
tjiir:iihnpuliliorlar~ :I*wase
Ierg) 3: I. I973 3. Mearns M. Young W, Batten J: Tranxwnr ~wimonar~ tions In cystic fibrosis due to allcrg~c acptcpiiloh~\ 20:385, 1965. 4. Nelson LA. Callerame ML, Schwartz RH. Iqq$lna~r atopy in cystic fibrosis. Am Rev Respi! DI- 120:86\1.
Chin Al mtiltraThorax and lV7Y.
294
Schwartz
and
J ALLERGY CLIN. IMMUNOL. OCTOBER 1981
Hollick
5. Ores CN, Neu HC, Denning CF: Allergic bronchopulmonary aspergillosis. CF Club Abstracts, 1975, p. 20. 6. Batten JC: Allergic aspergillosis in cystic fibrosis. Fourth International Congress on Cystic Fibrosis of the Pancreas (Mucoviscidosis), part I. Mod Probl Pediatr 10:227, 1975. 7. Mitchell-Heggs P, Mearns M, Batten JC: Cystic fibrosis in adolescents and adults. Q J Med 45:479, 1976. 8. Lewiston NJ, Biedermann AA, Harvey B: Allergic bronchopulmonary aspergillosis plus C.F. CF Club Abstracts, 1973, p. 47. 9. Brueton MJ, Ormerod LP, Shah KJ, Anderson CM: Allergic bronchopulmonary aspergillosis complicating cystic fibrosis in childhood. Arch Dis Child 55:348, 1980. IO. Schwartz RH, Johnstone DE, Holsclaw DS, Dooley RR: Serum precipitins to Aspergillus fumigatus in cystic fibrosis. Am J Dis Child 120:432, 1970. 11. Mearns M, Longbottom J, Batten JC: Precipitating antibodies toAspergillusfumigir?us in cystic fibrosis. Lancet 1:538, 1967. 12. Rosenberg M, Patterson R, Mintzer R, Cooper BJ, Roberts M, Harris K: Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 86:405, 1977. 13. Slavin RG: Allergic bronchopulmonary aspergillosis, in Middleton E, Reed CE, Ellis EF, editors: Allergy: principles and practice. St. Louis, 1978, The C. V. Mosby Co., pp. 843-854. 14. Rosenberg M, Patterson R, Roberts M, Wang J: The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergilIosis. Am J Med 64:599, 1978. 15. Patterson R, Fink J, Pruzansky JJ, Reed C, Roberts M, Slavin R, Zeiss CR: Serum immunoglobulin levels in pulmonary allergic aspergillosis and certain other lung disease with special reference to immunoglobulin-E. Am J Med 54:16, 1973. 16. Rosenberg M, Patterson R, Roberts M: Immunologic re-
17.
18. 19.
20.
21.
22.
23.
24.
25.
26.
sponses to therapy in allergic bronchopuimonary aspergillosis: serum IgE value as an indicator and predictor of disease activity. J Pediatr 91:914, 1977. Wang JLF, Patterson R, Roberts M, Ghory AC: The management of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 120:87, 1979. Parish WE: Short term anaphylactic IgG antibodies in human serum. Lancet 2:591, 1970. Assem ESK, Turner-Warwick M: Cytophilic antibodies in bronchopulmonary aspergilloma and cryptogenic pulmonary eosinophilia. Clin Exp Immunol 26:67, 1976. Vervloet D, Fujita Y, Wypych JI, Reisman RE, Arbesman CE: The inhibitory effect of serum factors on measurement of IgE Aspergillus antibodies by RAST. Clin Allergy 4:359, 1974. Zimmermann EM, Yunginger JW, Gleich GJ: Interference in ragweed pollen and honeybee venom radioallergosorbent tests. J ALLERGYCLIN IMMUNOL 66:386, 1980. Staib F, Abel T, Mishra SK, Miiller JA: Aspergillusfumigarus-Infektion der Lunge bei Mucoviscidose. Dtsch Med Wochenschr 105:442, 1980. Kagen S, Sohnle P, Kurup V, Fink J: Marijuana smoking as a source of Aspergillus exposure, in Proceedings of the 37th Annual Meeting of the American Academy of Allergy, March 1981, San Francisco, Calif., p. 63. Llamas R, Hart DR, Schneider NS: Allergic bronchopulmonary aspergillosis associated with smoking moldy marihuana. Chest 73:871, 1978. Chusid MJ, Gelfand JA, Nutter C, Fauci AS: Pulmonary aspergillosis, inhalation of contaminated marihuana smoke, chronic granulomatous disease. Ann Intern Med 82:682, 1975. Laham MN, Allen RC, Greene JC: Allergic bronchopulmonary aspergillosis (ABPA) caused by Aspergillus terreus: specific lymphocyte sensitization and antigen-directed serum opsonic activity. Ann Allergy 46:74, 1981.
H. Schwartz,
M.D. and Gary E. Hollick,
Ph.D. Rochester,
N.Y.
Elevated total serum IgE is helpful in making the diagnosis of ABPA and in monitoring the onset of exacerbations and response to therapy. ABPA occurs frequently in patients with CF, and in these instances a high total serum IgE is seen. This is the first case report of ABPA without an elevated total serum IgE level. At no time prior to this patient’sjrst episode of ABPA, at the time of the illness, or at monthly intervals during follow-up did her total serum IgE level exceed 29 Wlml. (J ALLERGY CLIN ~MUNOL 68:290, 1981.)
ABPA was first described by Hinson et al.’ in 1952. It occurs especially in young adult subjects with atopic asthma.* An association between CF and ABPA also has been known since the original report by Mearns et al.3 in 1965. Several other case reports have appeared in the literature since then.4-* In 1980, Brueton et a1.s described seven additional cases of ABPA in CF and stressed extensive pulmonary collapse and consolidation as ABPA complications of CF. They also stressed the young age at which ABPA can complicate CF. The incidence of ABPA is difficult to estimate because of variations in environmental mold spore exposure in different geographic areas and sporadic case-finding efforts among clinics. In 1979 Nelson et a1.4 reported their experience with Aspergillus and CF in Rochester, N. Y. They studied 46 patients during a 2-year period between 1976 and 1978. The respiratory tracts of 57% of these patients were colonized with Aspergillus fumigatus; 37% had serum precipitins to antigenic extracts of this fungus; 39% had positive immediate skin tests; and 22% had elevated total serum IgE levels. Five of the 46 patients From the Departments of Pediatrics, Division of Allergy and Clinical Immunology (R. H. S.) and Microbiology (G. E. H.), University of Rochester School of Medicine and Dentistry and Strong Memorial Hospital. This work was supported in part by a Care, Teaching and Resource Center grant from the Cystic Fibrosis Foundation. Received for publication April 6, 1981. Accepted for publication July 1, 1981. Reprint requests to: Robert H. Schwartz, M.D., Box 667, Strong Memorial Hospital, 601 Elmwood Ave., Rochester, N. Y. 14642.
Vol.
68, No.
4, pp.
290-294
develped ABPA. Between 1978 and 1980 two more of the original 46 patients developed ABPA, a cumulative incidence of 15% for this group. Schwartz et al. lo had previously shown that 30% of CF patient groups from Rochester, N.Y., Boston, Mass., and Los Angeles, Calif., had serum precipitins to antigens of A. fumigatus, a prevalence very much similar to that found in London by Meams et al.” This indicated a ubiquitous significant exposure to this fungus and suggested that ABPA might be anticipated as a frequent complication of CF. There are now good clinical criteria for suspecting and confirming the diagnosis of ABPA. I2 Major criteria are the following: (1) episodic or chronic bronchial obstruction, (2) transient of fixed pulmonary infiltrates, (3) peripheral blood and sputum eosinophilia, (4) immediate skin reactivity to Aspergillus antigen, (5) elevated serum IgE concentration, (6) serum precipitating antibodies (IgG) against Aspergillus antigens, and (7) central (proximal) bronchiectasis. Other clinical features that are helpful in making the diagnosis include (1) history of expectoration of brown mucus plugs or flecks, (2) sputum culture positive for A. fumigatus, (3) Aspergillus hyphae in bronchial secretions, (4) Arthus-type skin reactivity to Aspergillus antigens, and (5) immediate and delayed bronchoconstrictive reactions to Aspergillus antigens by inhalation challenge. ABPA is thought to be the result of type I (specific IgE-mast cell-histamine release) and type III (local IgG-immune complex-complement activation-Arthus reaction) immune reactions. Aspergillus-specific IgG and IgE antibodies are required to experimentally induce the disease in monkeys.13 0091-6749181/100290+05$00.5010
0 1981
The
C.
V. Mosby
Co.
1i,ht-iJ1,itrtioir.s
ABPA: CF: SSA: RAST: PRIST: P-K:
ic.std
Allergic bronchopulmonary Cystic fibrosis Skin-sensitizing antibody Radioallergosorbent test Paper radioimmunosorbent Prausnitz-Kiistner reaction
aspergillosis
test
IL’ untreated, these ABPA inflammatory processes ma:: have as their end result significant proximal bronchiectasis, pulmonary fibrosis, and pulmonary retraction. Since the acute process can be rapidly controlled with glucocorticosteroids,14 early diagnosis of ,\BPA and its recurrences is desirable. The ability to easily measure total serum IgE has made early diagnosis possible. Serum IgE levels are considerably ele.iated in ABPA. Total serum IgE levels may rise as high as 30.000 IU/ml (1 IU = 2.4 ng). Patterson and colieagues’“. I6 have stressed an elevated IgE level as an aid in diagnosis. Wang et al. I7 have shown that the total serum IgE level mirrors the activity of ABPA ant its response to therapy. A rising total serum IgE (two to six times baseline) may precede pulmonary infiltrations by several months. With adequate therap) . levels fall within 1 to 2 months. These observations seem to apply whether ABPA complicates asthma or CF. ‘. ” ‘This the first case report of a patient who developed ABPA ~~ith~~ltthe elevated total serum IgE level that is thought to be so characteristic of this entity. CASE REPORT This 20-year-old woman first came to medical attention at the age of 10 years with a history, since early infancy, of large. foul-smelling, bulky, floating greasy stools and frequent passage of foul flatus. Although her growth was at the lift eth percentile for age and she had not experienced signifcant respiratory infections, a diagnosis of CF was made on the basis of steatorrhea, decreased pancreatic enzymes, am! a positive sweat test (chloride = 104 mEq/L). Her first respiratory symptoms developed at about age 12 years, with na>al stuffiness on the basis of bilateral nasal polyps and bil.lteral maxillary sinusitis. In the fall of her thirteenth year sbc developed symptoms of sneezing, rhinorrhea, and conjunctivitis typical of ragweed hayfever. Complete allergy was done. skin testing with antigens, including Aspergilfus, Oriy ragweed was positive. Her first lower respiratory symptoms began in the late winter of her fifteenth year, with cough and sputum production during and after a docuaureus was minted in~urn:a A infection. Sraphylococcus Gtured from her sputum. The process involved the lingular segment of her left upper lobe. 4t age 16 she volunteered to be part of the Rochester
FIG. 1. Chest x-ray (6-9-80) showing left linguiar with otherwise very mild changes of CF
infiltrate
Cystic Fibrosis Aspergillus Study and had a completely negative workup. Sputum culture, \kln tcs!. RAS’I’. precipitins and peripheral eosinophil i‘ount. and sputum eosinophil evaluation were negative The smoking of marijuana and hashish became part of her late adolescent adjustment, which began at about age 17. During late March of her twentieth year sht: developed an episode of fever, chills, left-side plcuritic I:~IW pain. and increased sputum production. A lingular mfiitrate wax seen on chest X-ray. Sputum grew S. UUV~~~Sand 4. \~rnt,~c~tr,s intradermal immediate skin test became The Asprrgillus positive ( I : 10,000 w/v). However. A.s/;l,er-~i!ilc.tprecipitins could not be demonstrated, and her serum IgE! Levi was only 9 1Uiml. She was treated with odium diclou;icilim. Her symptoms and infiltrate resolved Three months later a similar episode OCCLIIred wtth a new lingular infiltrate (Fig. I ). The A.s~~r~~iilrc.5 prccipitin test became positive. but her total serum IgE le\si was only 16 lU/ml. The diagnosis of ABP?1, nab considered but not made because of the low 1gE level She ti.1~ rreattd a\ a staphylococcal infection patient without improbemcnt. After IO days of sodium nafcillin therapy ,.hc coughed up some brown sputum flecks. Fiberoptic brcincboscctpy revealed an inflamed narrowed left upper iohe bronchus. A mucus bpecimen from that segment c.s)ntained SW eosinophils. an inAammatory cytolog? Branched septate hyphae with preserved cytoplasm were seen. mdtcating that a fungus was actively growing in the respiraior)i tract Fun-
292
J. ALLERGY CLIN. IMMUNOL. OCTOBER 1981
Schwartz and Hollick
TABLE
I. ABPA
in CF without
Period
elevated
Date
Study Illness I Illness II On prednisone
Off prednisone
IgE Skin
test*
RASTt
-
-
<5
+
-
+
-
9
+ N.D. N.D. N.D. N.D. + N.D. N.D.
-
+ + + + -
+ + + + -
16 29 16 6 6 13 10 21
fumigutus
culture; Prcip. = precipitins
ASPERGILLOSIS DATA Total serum IgE Serum IgE levels were determined by the PRIST Diagnostic,
Inc.,
Piscataway,
IgES
-
gal cultures grew A. jiumigut~s. She had a peripheral eosinophil count of 1540imm”. Despite a total serum IgE level that had risen only to 29 llJ/ml over a period of IO days, a diagnosis of ABPA was made. The other serum immunoglobulins at that time were as follows: IgG 1136 mgidl, IgA 173 mg/dl, and IgM 251 mg/dl. She was treated with daily prednisone (1 mg/kg) for 2 weeks and everyother-day prednisone (0.5 mg/kg) for another 4 weeks. Her symptoms resolved in 4 days, and her infiltrate had cleared by the end of 6 weeks of therapy.
(Pharmacia
Prcip.
-
8/l l/76 Age 16 3/20/80 Age 20 6/9/80 6/20/80 7/2&O 70 l/80 8/19/80 9/ 12/80 10/12/80 12/8/80
N.D. = not done; Af cult. = A. *A. fumigatus (Hollister-Stier). TPharmacia. SPharmacia.
Af cult.
N.
J.)
method. They were verified by similar values found by Pharmacia, Inc., and the Mayo Medical Laboratories, Rochester, Minn. Aspergillus precipitin testing was performed as previously described,4 using the following Aspergillus antigens: Hollister-Stier Aspergillus mixture 1 : 10 (lot no. 19L8901; HollisterStier Laboratories, Spokane, Wash.), Aspergillus fumigatus 40,000 pnu/ml (lot no. 229303; Hollister), and Greer A. fimigatus, 20 mg/ml, strains 1, 2, and 3 (Greer Laboratories, Inc., Lenoir, N. C.). When found, precipitin lines formed with each antigen preparation except Greer strain 2. Table I summarizes the aspergillosis-related data. The patient had a negative workup when she enlisted in the study at age 16 yr. The first illness, at age 20, was characterized by a conversion of her A. fumigates immediate skin test to positive at a time when A. fumigatus was present in her sputum. However, her serum precipitin tests were negative and her serum IgE level was low (9 IU/ml). The second illness, 3
months later, was accompanied by the appearance of Aspergillus serum precipitins. The total serum IgE level was low (16 IU/ml), with a slight rise (29 IU/ml) during the IO-day period when the diagnosis of ABPA was considered but the condition was not treated. With prednisone therapy, sputum fungal cultures became negative, total serum IgE level decreased, and the serum precipitins eventually disappeared. At no time during the acute illness while the patient was receiving prednisone therapy or for close to 4 months after prednisone had been discontinued did the total serum IgE rise to the high levels usually associated with ABPA in general or with CF complicated by ABPA. Wang et al. I7 have used a total serum IgE concentration of more than 2500 rig/ml (1 IU = 2.4 ng) as one of the diagnostic criteria for ABPA. The mean total serum IgE levels for the remaining six CF patients in the Rochester series was 4545 IU/ml (range 570 to 8600). The mean serum level for the CF patients reported by Brueton et a1.g was 2715 IU/ml (range 500 to 8000). Aspergillus-specific
SSA
The A. fumigatus RAST (Phadebas RAST; Pharmacia) results were negative and remained negative throughout all the periods of observation. This was so despite the regularly positive RASTs in our other CF patients with ABPA4 and despite this patient’s positive prick and intradermal immediate type I skin tests to A. fumigatus extracts from three different sources including Hollister-Stier, an extract (strain 6) supplied by Greer, and The American Type Culture Collection, ATCC 1022 extract (strain 2) also supplied by Greer.
VOL;I’VIE 68 NlhlBER 4
Several studies were done to reconcile the negative ilspcrgil1u.s RASTs in the face of a positive skin test. The immediate skin test was positive at a dilute concentration of I : 10,000 (w/v), indicating that the patient had mast cell-fixed SSA. The negative RAST suggested that her serum did not contain large or measureable amounts of Aspergillus-specific IgE antihotly. Passive transfer P-K testing with the patient’s serum (0. I ml) was done with a suitable recipient (skin test-negative and able to accept P-K test). When individual donor sites were tested at 4 and 48 hr, negative reactions were observed. This indicated that the patient’s serum did not contain “short-term” Ig(; skin-sensitizing antibody.lx, I!’ It also again showed the absence of circulating “long-term” IgE shin-sensitizing antibody. Another possible explanation of a negative RAST in the face of a positive skin test is the presence of “interfering factors” such as A.,,wrgillrts IgG antibodies, which can tie up antigenic determinants on the solid-phase RAST discs and thus prevent measurement of IgE antibodies. This type of interference has been described for Aspergillus IgE anribodies by Vervloet et al.“’ in 1974 and for IgE honeybee venom antibodies by Zimmermann et al.” in i 980. The patient’s serum did not inhibit Aspergil/us RAST counts of a known positive serum when te+ted according to the method of Zimmermann et al., ?’ indicating the absence of interfering factors that might have given a falsely negative IgE-RAST. The only other positive immediate skin test that this patient had was to ragweed. She had seasonal raguied hayfever. Ragweed RAST was also negative. Tt-is finding. coupled with the Aspergillus data, suggests that the patient produces small amounts of SSA thilt fixes to mast cells and is clinically significant. DISCUSSION How did this young lady acquire respiratory tract colonization with A. jumigatus? Patients with CF pr lbably are predisposed to colonization because their respiratory mucus traps and encourages the germinaticIn ofilspcrgillus spores, which are ubiquitous under most atmospheric conditions.4. I3 In one case report, Cl’ mucus was shown to act as a nutritive substance for A. ,fi~ni~atus.“~ In addition, various species of .A.rper,c$llu.s,including A. fumigafus, are known contaminants of marijuana. 23 There have been case repc.lrtsof invasive pulmonary aspergillosis and ABPA associated with smoking moldy marijuana.*“. 25 The patient in the present report had been smoking marijuana for at least 3 years prior to the onset of ABPA. She allowed us to culture one small sample of her marijuana and a sample of her hashish. AspergilI;AStc~rwus was isolated. Although A. fumigatus was
ABPA
wiry
*cx\?~ lgi
293
not isolated from these samples. the> represent only a small proportion of the marijuana smokl*d over 3 pcriod of 3 years. A. terreus has recenti! been implicated as a cause of ABPA.“” However. ~:ulture filtrate antigens derived from the A. terrc’rt: vit*lded ncpativc skin tests. This 20-year-old woman with mild (‘I’ bad h\,c of’ the seven major criteria for making tbts diagnosis 01‘ ABPA. including bronchial obstruction, pulmonary intiltrates, blood and sputum eoiinophliia. ~I.~,~r;lillus immediate skin reactivity, and .3.v~~~~~ii/rl.c \erum precipitins. Her serum IgE level was icry low and was not helpful in making the diagnosi:, (lr in monitoring treatment. Central bronchiectasis ot:curs late in ABPA, and central and peripheral bmnchiecrasis is the rule in CF. Therefore its presence .idds little to help establish an early diagnosis of ABI%. especially in a CF patient. However. she had other jindinps helpful in making the diagnosis, including ,,:xpcctoration of brown plugs or flecks, sputum culturvh positive for A. fkmigatus, and branched septate ht. phae 111her brdnchial secretions. There are two possible explanation:, 10; this patient’s low total serum IgE level. The f~rsr is that she is genetically programmed to product iou levels of total serum IgE and small amounts ot’ *,pecific SSA. These antibodies have strong avidity for maht cells, thus permitting a positive skin test ;md one of the immunologic reactions (type I: IgE. .rn,kslceils histamine release) required for the dcl ciopmcnt of ABPA. The possibility of a genettc. :wY~\ \n ill hc difficult to prove, since she was adupreil and her biologic family is unknown. The scconci ~~\planatron is that this may be the tirst documented instance >)i’an initial ABPA episode. The observatii’n \~a\, made possible by the prospective study 01’ ;I group of patients in anticipation of their develr~pm.:nt c~fARPA. Elevated total serum IgE may onI> OLYUI-it‘ the process becomes recurrent or chronic. Folic>w-up ot’ this patient and recognition of similar CN:‘X ma! help determine whether the low total sc”rum I@; level ix unique to this patient’s irnrnunorespc,nsl~‘cn~,~~. is characteristic of very early ABPA. or 11.J!,~nlc i‘~s/c, that has been escaping diagnosi, REFERENCES 1. Hinson
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tjiir:iihnpuliliorlar~ :I*wase
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