Serum lmmunoglobulin Levels in Pulmonary Allergic Aspergillosis and Certain Other Lung Diseases, with Special Reference to lmmunoglobulin E ROY PATTERSON, M.D. Chicago, Illinois J. N. FINK, M.D. Milwaukee, Wisconsin J. J. PRUZANSKY, Ph.D. Chicago, lllinois C. REED, M.D. Madison, Wisconsin M. ROBERTS Chicago, Illinois R. SLAVIN, M.D. St. Louis, Missouri C. R. ZEISS, M.D. Chicago, Illinois From the Sections of Allergy-Immunology, Departments of Medicine of Northwestern University-McGaw Medical Center, Chicago, Illinois; the Medical College of Wisconsin, Milwaukee, Wisconsin: the University of Wis- consin Medical Center, Madison, Wisconsin; and the St. Louis University School of Medi- cine, St. Louis, Missouri. This study was sup- ported by U.S. Public Health Service Train- ing Grant 5TOl Al-00057 and the Ernest S. Bazley Asthma Research Fund to Chicago Wesley Memorial Hospital and Northwestern University, Chicago, Illinois. Requests for reprints should be addressed to Dr. Roy Pat- terson, Section of Allergy-Immunology, Northwestern University-McGaw Medical Center, 303 East Chicago Avenue, Chicago, Illinois 60611. Manuscript received Novem- ber 22,197l. A study of serum immunoglobulin concentrations was made with serum obtained from patients with hypersensitivity lung diseases and from other patients with pulmonary disease of various types. Serum immunoglobulin E (IgE) was measured by a radioimmunoassay technic and demonstrated marked ele- vations in patients with the clinical and laboratory findings of pulmonary allergic aspergillosis, especially during the acute phase of pulmonary infiltration. In contrast, serum IgE levels were not elevated in patients with pigeon breeders’ disease, farmer’s lung or with pulmonary infiltrates and eosinophilia as- sociated with polyarteritis nodosum. The serum IgE level in the acute cases of pulmonary allergic. aspergillosis was sufficiently high to detect by routine gel double diffusion analysis using anti-IgE. This may constitute a useful diagnostic aid in recog- nizing the disease. The respiratory disease termed pulmonary allergic aspergillosis (PAA) has received increasing attention [I]. The description of the disease [2] was followed by identification of a number of cases in Great Britain [3]. Reports of the disease in the United States [4-61 have resulted in increasing recognition as de- scribed in the current series. The clinical entity of PAA has sev- eral components [l]. PAA occurs in patients with extrinsic asthma, generally of long duration. Fluctuating pulmonary infil- trates are seen by radiography and are associated with eosino- philia in the sputum and peripheral blood. Cough and fever may be present. Aspergillus fumigatus may be cultured repeatedly from the sputum and fungal mycelium found in sputum plugs by direct microscopic examination. Studies of serum from these patients show precipitating antibodies against A. fumigatus. Skin testing with antigen prepared from this fungus shows a dual type of reaction consisting of an immediate type wheal and erythema reaction and a late Arthus type of reaction. In certain cases, bronchiectasis and fibrosis have occurred, but the fluctuating infiltrates resolve with adrenal corticosteroid treat- ment. The identification of immunoglobulin E (IgE) as the major immunoglobulin to which human reaginic antibody is localized [7] and development of sensitive assays for serum IgE led to the current study of serum IgE levels in patients with PAA. The 16 January 1973 The American Journal of Medicine Volume 54
Transcript
Serum lmmunoglobulin Levels in Pulmonary Allergic Aspergillosis and Certain Other Lung Diseases, with Special Reference to lmmunoglobulin E
ROY PATTERSON, M.D.
Chicago, Illinois
J. N. FINK, M.D.
Milwaukee, Wisconsin
J. J. PRUZANSKY, Ph.D.
Chicago, lllinois
C. REED, M.D.
Madison, Wisconsin
M. ROBERTS
Chicago, Illinois
R. SLAVIN, M.D.
St. Louis, Missouri
C. R. ZEISS, M.D.
Chicago, Illinois
From the Sections of Allergy-Immunology, Departments of Medicine of Northwestern University-McGaw Medical Center, Chicago, Illinois; the Medical College of Wisconsin, Milwaukee, Wisconsin: the University of Wis- consin Medical Center, Madison, Wisconsin; and the St. Louis University School of Medi- cine, St. Louis, Missouri. This study was sup- ported by U.S. Public Health Service Train- ing Grant 5TOl Al-00057 and the Ernest S. Bazley Asthma Research Fund to Chicago Wesley Memorial Hospital and Northwestern University, Chicago, Illinois. Requests for reprints should be addressed to Dr. Roy Pat- terson, Section of Allergy-Immunology, Northwestern University-McGaw Medical Center, 303 East Chicago Avenue, Chicago, Illinois 60611. Manuscript received Novem- ber 22,197l.
A study of serum immunoglobulin concentrations was made with serum obtained from patients with hypersensitivity lung diseases and from other patients with pulmonary disease of various types. Serum immunoglobulin E (IgE) was measured by a radioimmunoassay technic and demonstrated marked ele- vations in patients with the clinical and laboratory findings of pulmonary allergic aspergillosis, especially during the acute phase of pulmonary infiltration. In contrast, serum IgE levels were not elevated in patients with pigeon breeders’ disease, farmer’s lung or with pulmonary infiltrates and eosinophilia as- sociated with polyarteritis nodosum. The serum IgE level in the acute cases of pulmonary allergic. aspergillosis was sufficiently high to detect by routine gel double diffusion analysis using anti-IgE. This may constitute a useful diagnostic aid in recog- nizing the disease.
The respiratory disease termed pulmonary allergic aspergillosis (PAA) has received increasing attention [I]. The description of the disease [2] was followed by identification of a number of cases in Great Britain [3]. Reports of the disease in the United States [4-61 have resulted in increasing recognition as de- scribed in the current series. The clinical entity of PAA has sev- eral components [l]. PAA occurs in patients with extrinsic asthma, generally of long duration. Fluctuating pulmonary infil- trates are seen by radiography and are associated with eosino- philia in the sputum and peripheral blood. Cough and fever may be present. Aspergillus fumigatus may be cultured repeatedly from the sputum and fungal mycelium found in sputum plugs by direct microscopic examination. Studies of serum from these patients show precipitating antibodies against A. fumigatus. Skin testing with antigen prepared from this fungus shows a dual type of reaction consisting of an immediate type wheal and erythema reaction and a late Arthus type of reaction. In certain cases, bronchiectasis and fibrosis have occurred, but the fluctuating infiltrates resolve with adrenal corticosteroid treat- ment.
The identification of immunoglobulin E (IgE) as the major immunoglobulin to which human reaginic antibody is localized [7] and development of sensitive assays for serum IgE led to the current study of serum IgE levels in patients with PAA. The
16 January 1973 The American Journal of Medicine Volume 54
SERUM IMMUNOGLOSULIN LEVELS IN LUNG DISEASES-PATTERSON ET AL.
TABLE I Patients with Pulmonary Allergic Aspergillosis (PAA) Who Had Fluctuating Pulmonary Infiltrates on Roentgenograms, Positive Sputum Cultures for Asperglllus fumigatus and Serum Precipitins Against
Aspergillus Antigen
Reaction to Serum lmmunoglobulins Skin Tests for
Blood IgG &A IgM A. fumigatus
Case Sex and Eosinophils IgE (mg (mg (mg Imme- No. Age(yr) (percu mm) (units/ml) %) %) %) diate Late
Bronchiectasis Bronchiectasis Bronchiectasis, lobectomy in 1963
showed granulomatous pneumonitis . . .
Lung biopsy, interstitial granulomatous
pneumonitis with eosinophils and giant cells
EA ..1 EA Bronchiectasis
500 92 + + 500 102 + +
After Acute Phase
180 112 + + 500 170 + +
EA,AR Bronchiectasis EA,AR Bronchiectasis
*EA = extrinsic asthma; AR = allergic rhinitis; A = asthma, etiology unknown. 1 Four years later, there was no clinical evidence of allergic aspergillosis and his serum IgE level was 3,000 units/ml. $ ND = not determined.
resulting studies demonstrated significant eleva- tions of serum IgE levels in patients in whom the clinical and laboratory findings were consistent with this diagnosis. Other patients with hyper- sensitivity lung disease due to inhaled organic dusts and patients with pulmonary disease of var- ied types, with or without serum precipitating anti- bodies against Aspergillus or with Aspergillus species cultured from the sputum, were studied. No consistent pattern of immunoglobulin abnor- malities including serum IgE levels was found. These studies demonstrate that determination of serum IgE is of diagnostic significance during the acute phase of hypersensitivity lung disease and permit further consideration of the role of IgE im- munologic mechanisms responsible for PAA.
METHODS AND MATERIALS
requested from patients in whom a diagnosis of pigeon breeders’ disease or farmer’s lung disease had been made. The third group of serum samples were from patients with a variety of lung diseases and were in- cluded for study if they contained precipitating anti- bodies against Aspergillus antigens as demonstrated by gel double diffusion reactions. All serum was stored at -20°C prior to use. Clinical and laboratory data on each serum donor were supplied by the respective clinician from each institution. Quantiiation of Immunoglobulins. Serum IgE was measured by inhibition of double antibody coprecipita- tion using rabbit antiserums specific for the Fc piece of IgE and 1251 labelled IgE from myeloma patient PS [8]. The concentration of IgE in serum from normal subjects using this method varies between 1 and 2,700 ng/ml [8]. The mean and median were 179 and 80 ng/ml, respectively [8], and the normal range was from 6 to 780 ng/ml at the 94 per cent confidence level [8].
Sources of Human Serum. Serum samples were re- The serum IgE concentrations in the current studies quested from investigators at four medical centers for are expressed as units/ml as suggested by the World study. These samples were to be obtained from pa- Health Organization [9]. Bazaral et al. [lo] have found tients with the clinical and laboratory findings of PAA the concentration of IgE in purified PS IgE to be 0.45 as described in the introduction. Other samples were units/ng protein. Multiplying the IgE units as used in
January 1973 The American Journal of Medicine Volume 54 17
t
TAB
LE
II P
atie
nts
w
ith
A
sth
ma
and
P
reci
pit
ins
to A
sper
gill
us
fum
igat
us
Wh
o
Lac
k O
ne
or
Mo
re
of
the
Fea
ture
s o
f A
llerg
ic
Asp
erg
illo
sis
Reac
tion
to
F
Skin
Te
sts
for
E I
Bloo
d Se
rum
lm
mun
oglo
bulin
s A.
fum
igat
us
Pul-
Case
Se
x an
d Eo
sinop
hils
JgE
JgG
Ig
A Ig
M
Im-
mon
ary
Ato
pic
$ C
NO
. A
ge (y
r)
(per
cu
mm
) (u
nits
/ml)
(m8
%)
(m8
%)
(m8
%)
med
iate
La
te
Spu
tum
Cul
ture
In
filtr
ates
D
isea
se
Com
men
ts
Z
D
15
M,2
6 2,
400
2,50
0 72
0 70
92
-t
- +
-
+
EA
,AR
N
o pn
eum
oniti
s fo
r se
vera
l ye
ars;
6
very
se
vere
st
eroi
d de
pend
ent
E
asth
ma,
cu
lture
s ne
gativ
e r
16
F,2
4 3,
000
250
1,10
0 18
0 17
0 +
+
A
sper
gillu
s fia
vus
+
EA
,AR
O
nly
one
epis
ode
of
pneu
mon
itis,
z
Asp
ergi
llus
fum
igat
us
seve
re
ster
oid
depe
nden
t as
thm
a 5
17
M.1
7 90
0 34
0 3,
000
220
102
-t-
+
- +
E
A,A
R
Onl
y on
e ep
isod
e of
pn
eum
oniti
s,
m
cultu
res
nega
tive
G;
18
M,6
9 1,
500
4,00
0 2,
000
235
170
+
+
Asp
ergi
llus
fum
igat
us
0 E
A
Pre
cipi
tins
dem
onst
rabl
e on
ly
in
f
conc
entr
ated
se
rum
E
19
F,2
0 18
0 60
1,
300
470
83
+
+
Asp
ergi
llus
fum
igat
us
+
EA
,AR
R
ecur
rent
R
ML
pneu
mon
itis,
$
RM
L lo
bect
omy
1966
for
br
onch
iec-
ta
sis
show
ed
gran
ulom
atou
s le
- %
sion
w
ith
hyph
ae
of
A.
fum
igat
us,
no
F
recu
rren
ce
of
pneu
mon
itis
sinc
e fi
lobe
ctom
y,
asth
ma
very
m
ild
;
NO
TE
: R
ML
=
mid
dle
lobe
of
rig
ht
lung
, f
=
posi
tive
or
pres
ent;
othe
r ab
brev
iatio
ns
as i
n T
able
I.
-!
G
P, 6 Z
TAB
LE
Ill
Pat
ien
ts
wit
h
Lu
ng
D
isea
se
of
Var
iou
s T
ypes
n
ot
Co
nsi
der
ed
to b
e P
AA
b
ut
wit
h
Str
on
gly
P
osi
tive
P
reci
pit
in
Tes
ts
to A
sper
gill
us
An
tig
en
Reac
tion
to
Bloo
d E
osin
- S
kin
Tes
ts fo
r
ophi
ls
Ser
um lm
mun
oglo
bulin
s A
.fum
igat
us
Pul
- C
ase
Sex
and
(p
er c
u l8
E
l8C
l8
A
l8M
Im
- m
onar
y A
topi
c N
o.
Age
(yr)
m
m)
(uni
ts/m
l) (m
g %
) (m
g%)
(mg
%)
med
iate
La
te
Spu
tum
Cul
ture
In
filtr
ates
D
isea
se
Clin
rcal
Dia
gnos
is
Com
men
ts
20
F,7
6 70
0 1,
450
1,30
0 47
0 11
2 +
+
A
sper
gillu
s fu
mig
atus
0.
N
one
CO
PD
21
M,5
7 11
6 58
0 3,
000
535
67
ND
N
D
- +
N
one
Bro
nchi
ecta
sis,
C
OP
D
22
F,2
9 31
0 20
0 1,
300
180
92
ND
N
D
-
23
F,4
6 30
0 50
0 1,
650
700
230
f N
D
Asp
ergi
llus
fum
igat
us
24
M,5
6 15
0 18
,000
60
0 25
5 15
5 N
D
ND
A
sper
gillu
s fu
mig
atus
25
M&
O
120
100
. . .
. . .
. . .
f +
A
sper
gillu
s fu
mig
atus
NO
TE
: C
OP
D
=
chro
nic
obst
ruct
ive
pulm
onar
y di
seas
e;
othe
r ab
brev
iatio
ns
as
in T
able
I.
+
+ 0 +
A
Sar
coid
w
ith
cavi
ty
and
aspe
rgill
oma
Non
e R
heum
atoi
d lu
ng
dise
ase
Non
e B
ronc
hoge
nic
carc
inom
a N
one
Sar
coid
w
ith
A.
empy
ema
_.
Lung
ab
cess
co
loni
zed
by
A.
fum
igat
us
Rep
eate
d pn
eum
onia
,
colo
niza
tion
of
bron
- ch
iect
atic
ca
vity
by
A
.
fum
igat
us
Ast
hma
Fun
gus
ball
Asp
ergi
llus
empy
ema
. . .
TAB
LE
IV
Pat
ien
ts
wit
h
Po
lyar
teri
tis
Nod
osa
____
Rea
ctio
n to
B
lood
S
erum
lmm
unog
lobu
lins
Ski
n T
ests
for
Eos
in-
~
ophi
ls
l8E
-
A. f
umig
atus
P
ul-
Cas
e S
ex a
nd
(per
cu
(uni
ts/
I@
l8A
lg
M
Im-
Spu
tum
m
onar
y A
topi
c
No.
A
ge (y
r)
mm
) m
l)
(mg
%)
(mg
%)
(mg
%)
med
iate
La
te
Cul
ture
In
filtr
ates
S
erum
Pre
cipi
tins
Dis
ease
C
linic
al D
iagn
osis
__
__
~~
_.~
.~
~__
_ 26
M
,60
1,14
0 50
0 2,
000
180
140
- N
D
- +
-
EA
P
olya
rter
itis
with
Lo
efle
r’s
pneu
mon
itis
27
M,5
8 63
0 38
0 72
0 50
0 14
0 N
D
ND
-
0 A
sper
gillu
s fu
mig
atus
N
one
Pol
yart
eriti
s no
dosa
28
M
,18
3,00
0 35
0 72
0 18
0 12
5 -
ND
-
+
- E
A,A
R
Pol
yart
eriti
s no
dosa
w
ith
Loef
ler’s
pn
eum
oniti
s
NO
TE
: A
bbre
viat
ions
as
in
Tab
le
I.
TAB
LE
V
Pat
ien
ts
wit
h
Hyp
erse
nsi
tivi
ty
Lu
ng
D
isea
se
Du
e to
in
hal
ed
Org
anic
D
ust
s
Ser
um lm
mun
oglo
bulin
s
Cas
e S
ex a
nd
f8E
N
o.
Age
(YO
29
M,5
4
(uni
ts/m
l) .._
_ 1,35
0
30
M,5
2
31
F,5
3
32
M,6
4
33
M,4
8
34
M,3
8
35
M,3
3
36
M,4
9
I&
(mg %
)
400
450
2,00
0
10
. .
10
. . .
280
1,65
0
100
1,85
0
100
900
3,00
0
1.30
0
NO
TE
: A
bbre
viat
ions
as
in
Tab
le
I.
. . .
. . .
180
255
80
210
. . .
. . . 61
61
50
155
Ser
um
Pre
cipi
tins
Asp
ergi
llus
fum
igat
us
Asp
ergi
llus
flavu
s
Mic
ropo
lysp
ora
faen
i
Asp
ergi
llus
fum
igat
us
Asp
ergi
llus
flavu
s M
icro
poly
spor
a fa
eni
Asp
ergi
llus
fum
igat
us
Mic
ropo
lysp
ora
faen
i
Asp
ergi
llus
fum
igat
us
Pig
eon
antig
ens
Pig
eon
antig
ens
Pig
eon
antig
ens
Pig
eon
antig
ens
Org
anic
Dus
t
Exp
osur
e
Mol
dy
corn
Che
st R
oent
geno
gram
Infil
trat
es
at
lung
ba
ses
Gra
in
dust
D
iffus
e fib
rosi
s
and
infil
trat
es
Sila
ge,
mol
dy
hay
Mol
dy
oats
Pig
eon
drop
ping
s
Pig
eon
drop
ping
s
Diff
use
infil
trat
es,
perib
ronc
hial
fibro
sis
Inte
rstit
ial
infil
trat
es
Nod
ules
an
d
coar
se
mar
king
s
Nor
mal
Pig
eon
drop
ping
s
Nor
mal
A
R
Pig
eon
drop
ping
s
Nor
mal
N
one
Ato
pic
Dis
ease
Non
e
Clin
ical
Dia
gnos
is
Far
mer
’s
lung
Non
e F
arm
er’s
lu
ng
Non
e F
arm
er’s
lu
ng
Non
e F
arm
er’s
lu
ng
AR
Non
e
Pig
eon
bree
ders
’ di
seas
e
Pig
eon
bree
ders
’
dise
ase
Pig
eon
bree
ders
’ di
seas
e
Pig
eon
bree
ders
’
dise
ase
-
Com
men
ts
~~
Pol
yart
eriti
s no
dosu
m
on
biop
sy,
mon
oneu
ritis
mul
tiple
x
Die
d P
olya
rter
itis
nodo
sum
on
biop
sy,
mon
oneu
ritis
mul
tiple
x _ _
Lung
bi
opsy
, br
onch
iolit
is
oblit
eran
s
Insi
diou
s on
set
Insi
diou
s on
set
of
inte
rstit
ial
pneu
mon
itis
Insi
diou
s on
set
of
dysp
nea
Acu
te
onse
t 4
hour
s
afte
r co
ntac
t w
ith
antig
en
Acu
te
onse
t 4
hour
s af
ter
cont
act
with
antig
en
Acu
te
onse
t 4
hour
s af
ter
cont
act
with
antig
en
Acu
te
onse
t 4
hour
s
afte
r co
ntac
t w
ith
antig
en
this report by 2 would give the approximate concentra- tion of IgE as ng/ml. lmmunoglobulins G (IgG), A (IgA) and M (IgM) were estimated quantitatively by radial diffusion immunoassay using I mmunoplates (Hyland Laboratories, Costa Mesa, Calif.). Gel Double Diffusion Analysis for IgE. This was done by standard technics using rabbit antihuman IgE spe- cific for the Fc piece.
RESULTS
Patients with PAA. Table I includes the results of studies of patients who had fluctuating pulmonary infiltrates, positive sputum cultures for A. fumi- gatus and serum precipitating antibodies against A. fumigatus antigen. All these patients were con- sidered to have PAA. A second serum sample was obtained from one patient (Case 1) after a four year remission. Two patients were not seen during episodes of pneumonic infiltrates but were studied several months after the most recent epi- sode (Cases 13 and 14, Table I). Six of the four- teen patients were female. Peripheral blood eosinophilia was present in all patients, and there were over 2,000 cells/cu mm in six. All patients were atopic and had the diagnosis of extrinsic asthma with or without a diagnosis of allergic rhi- nitis. Of the thirteen patients tested, all had imme- diate type skin reactivity to Aspergillus antigen and eleven had a late skin reaction. This late or Arthus type of reaction was considered to be present if an erythematous, indurated skin reaction occurred about three hours after skin testing with a maximal reaction at approximately eight hours. Serum IgE levels were elevated in all patients ex- amined during or shortly after an episode of pneu- monitis. The serum IgE level was above 10,000 units/ml in ten and above 19,000 units/ml in six serum samples.
Serum from patients shown in Table I was test- ed by Ouchterlony double gel precipitin analysis using rabbit antihuman IgE. All serum from pa- tients with acute cases demonstrated IgE by the formation of a precipitating band with antiserum specific for human IgE (Figure 1). Serum concen- trations of other immunoglobulins varied in the de- gree of elevation, and there appears to be no con- sistent pattern to these changes.
Lung tissue from three patients showed intersti- tial granulomatous pneumonitis with eosinophils and giant cells (Table I). Patients with Asthma and Precipitins to A. fumi- gatus, but in Whom the Diagnosis of PAA is Un- certain. Serum from five patients with some of the features of PAA was examined (Table II). These patients did not.have acute pneumonitis at the time of the examination and also lacked one
SERUM lMMUNOGLOBlJLlN LEVELS IN LUNG DISEASES-PATTERSON ET AL
or more of the clinical criteria for the diagnosis. One had a moderately increased IgE level of 4,000 units/ml. The others were in the range com- monly found in atopic subjects. Patients with Lung Diseases of Various Types and with Serum Precipitating Antibodies Against As- pergillus Antigen. Studies of patients with various pulmonary diseases complicated by Aspergillus colonization of cavities or Aspergillus empyema are shown in Table II I. All had strongly positive precipitin tests with multiple bands against A. fu- migatus antigens. In this group there were some patients with moderate eosinophilia but no pa- tients with a total count over 7OO/cu mm. IgG, IgA and IgM levels again showed no definitive pattern. Serum IgE concentration was over 1,000 units/ml in only two patients. One (Case 25, Table I I I) had neither eosinophilia nor atopic dis- ease but had a marked elevation of IgE to 18,000 units/ml. Patients with Polyarteritis Nodosum. Three pa- tients with a clinical and pathologic diagnosis of polyarteritis were examined. All had pulmonary in- filtrates and hypereosinophilia (Table IV). They showed no consistent pattern of abnormality in immunoglobulin levels and no definite increase in serum IgE concentration. Patients with Hypersensitivity Lung Disease Due to Inhaled Organic Dusts. Data in Table V dem- onstrate the results of studies in four patients with a clinical diagnosis of farmer’s lung and four pa- tients with a diagnosis of pigeon breeders’ dis- ease. Serum IgE concentrations in all were below 2,000 units/ml and were in ranges observed for nonatopic or atopic patients.
COMMENTS
Using the method of measurement of IgE used in this study, marked variation in concentrations in normal serum (1 to 2,700 ng/ml) and in serum
Figure 1. Gel double diffusion precipitin bands re-
suiting from reactions of rabbit anti-IgE with serum of patients. Rabbit anti-IgE is in center wells. Left, serum
from patients with PAA (Table I). Right, serum from patients with PAA (Table I) and with farmer’s lung
(Table V).
20 January 1973 The American Journal of Medicine Volume 54
SERUM IMMUNOGLOBULlN LEVELS IN LUNG DISEASES-PATTERSON ET AL.
from patients with nasal allergy (55 to 12,750 ng/ml) have been reported [8]. This marked vari- ation in the serum concentration in each group and in the marked overlap between normal subjects and patients with IgE mediated nasal dis- ease limits the diagnostic usefulness of serum IgE determination in common clinical allergic disease. Despite this, determination of serum IgE concen- trations may have potential clinical importance in certain conditions because the high ranges in both normal and allergic subjects are exceptional, and the normal serum IgE concentration has been re- ported to be between 6 and 780 ng/ml at the 94 per cent confidence interval [8]. The increase in serum IgE concentrations in parasitic infestation is of both theoretic interest and potential practical usefulness [11,12].
The possibility of increased IgE serum concen- trations in PAA was previously suggested by Hein- er and Rose [13]. However, this was reported as being in excess of 0.8 MS/ml, and the quantitative serum levels were not reported. The data in this prior report are not inconsistent with the more de- tailed data described herein.
Our results demonstrate that serum IgE levels may be markedly elevated during the acute phase of pneumonitis associated with PAA. Serum IgE determination is likely to be an aid in the diagno- sis of suspected cases. Although our initial studies were made with a sensitive radioimmunoassay for IgE, the markedly elevated IgE levels that were found indicated that IgE would be detectable by a more simple technic, the routine gel double diffu- sion method. This technic can detect antibody in concentrations of the range of 40 pg/ml [14] and antigen in a somewhat lower range because of the multivalency of protein antigens. The results of IgE determinations recorded in Table I and the precipitin reactions (Figure I) suggest that a sim- ple laboratory test may be readily available for supportive evidence for the diagnosis of PAA. De- tection of IgE by double gel diffusion would sup- port the diagnosis whereas a negative test would be against such a diagnosis. Definitive interpreta- tion of these tests will require larger series of se-
quential examinations of serum IgE concentra- tions in patients with PAA. It is possible that such studies will show markedly elevated IgE levels during the acute phase of PAA, with the complete clinical picture and lung tissue showing interstial granulomatous pneumonitis with eosinophilia, and a fall in IgE levels after resolution of the pneu- monitis.
It is obvious that elevated IgE levels similar to those in PAA may be found in other clinical dis- eases (Case 24, Table II I), atopic dermatitis [l l] and parasitic infestations [11,12] and that the dou- ble gel diffusion analysis would also demonstrate precipitin lines with anti-IgE if serum from these patients was tested by this technic.
The hypersensitivity reactions involving the re- spiratory tract in PAA have been considered to be a combination of two types [l]. These are the im- mediate or reagin-mediated type due to IgE and the antigen-antibody complex type due to IgG. Both of these reactions can be demonstrated in the skin by the immediate (IgE) skin reaction and the late (Arthus type) IgG skin reaction to Asper- gillus antigen. The serum precipitating activity is considered to be due to the IgG antibody [l]. Using sufficient amounts of serum in Case 1 (Table I), certain features of PAA have been transferred to a rhesus monkey [15].
Further evidence for the importance of the dual IgE and IgG mediated reactions in PAA is provid- ed by the markedly elevated IgE levels in the serum of these patients. This is in contrast to the absent or minimal elevation of IgE levels in the serum of patients with farmer’s lung or pigeon breeders’ disease who have precipitating anti- bodies of the IgG class but no apparent IgE me- diated hypersensitivity of the immediate type.
ACKNOWLEDGMENT
Drs. Gildon Beall, Robert Heywood and John Randal supplied serum samples in Cases 6, 12 and 7, respectively (Table I).
Our special thanks are due to Dr. Helen Dickie for allowing us to include many of her cases from the University of Wisconsin Hospitals.
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SERUM IMMUNOGLOBULIN LEVELS IN LUNG DISEASES-PATTERSON ET AL.
7. lshizaka K, lshizaka T: The identification of yE anti- bodies as a carrier of reaginic activity. J lmmun 99: 1187,1967.
8. Gleich GJ, Averbeck AK, Swedlund HA: Measurement of IgE in normal and allergic serum by radioimmuno- assay. J Lab Clin Med 77: 690, 1971.
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