Bayford D. An account of a singular case of obstructed
deglutition. Memoirs Med Soc London 1794; 275-86
5 Austin EH, Wolfe WG. Aneurysm of aberrant subclavian artery
with a review of the literature. J Vase Surg 1985; 2:571-77
6 Kommerell B. Verlagerung des osophagus durch eine abnorm
4
Key words: anemia; bronchiolitis obliterans organizing pneumo¬
nia; hemolysis; hypersensitivity; phenytoin
Abbreviations: BOOP=bronchiolitis obliterans organizing
pneumonia; PHS=phenytoin h)persensitivity syndrome
verlaufende arteria subclavia dextra (arteria lusoria). Fortschr
Geb Roentgenstr Nuklearmed 1936 54:590-95
7 Felson B. Ruptured anomalous right subclavian artery: aneu¬
rysm or diverticulum? Semin Roentgenol 1989; 24:122-26
8 Roberts CS, Otherson HB, Sade RM, et al. Tracheoesophageal compression from aortic arch anomalies: analysis of 30
operatively treated children. J Pediatr Surg 1994; 29:334-37
9 Gobel JW, Pierpont ME, Moller JH, et al. Familial interrup¬
tion ofthe aortic arch. Pediatric Cardiol 1993; 14:110-15
10 Dartevelle P, Bouquet P, Planche C, et al. Aneurysme
atheromateux d'ine artere sous claviere droit aberrante: a
propos d'un cas revele par une dysphagie et opere chez une
femme de 73 ans. Chirurgie 1978; 104:141-47
11 Kiernan P, Dearani J, Byrne W, et al. Aneurysm of an
aberrant right subclavian artery: case report and review of the
literature. Mayo Clinic Proc 1993; 68:468-74
12 Bower TC, Pairolero PC, Hallett JW, et al. Brachiocephalic
aneurysm: the case for early recognition and repair. Ann Vase
13
Surg 1991; 5:125-32
Campbell CF. Repair of an aneurysm of an aberrant retroesophageal right subclavian artery arising from Kommerell's
diverticulum. J Thorac Cardiovasc
Surg 1971; 62:330-34
Bronchiolitis Obliterans With
Organizing Pneumonia and
Cold Agglutinin Disease
Associated With Phenytoin
Hypersensitivity Syndrome*
Pamela Angle, MD; Peter Thomas, MD, FCCP;
Chiu, MD; and John Freedman, MD
Brian
Phenytoin hypersensitivity syndrome (PHS) is a
rare delayed hypersensitivity reaction which oc¬
curs following exposure to phenytoin sodium. Pul¬
monary involvement is uncommonly described.
Herein is reported the first case of histopathologic
bronchiolitis obliterans organizing pneumonia
(BOOP) found on open-lung biopsy in a patient
with severe PHS. New onset, clinically significant,
cold agglutinin disease was also documented. He¬
modynamic parameters mimicking sepsis were
present in the absence of significant clinical infec¬
tion. Rapid, dramatic improvement followed highdose steroid therapy.
(CHEST 1997; 112:1697-99)
Departments of Anaesthesia (Dr. Angle), Respirology
(Dr. Thomas), Pathology (Dr. Chiu), and Transfusion Medicine
and Blood Bank (Dr. Freedman), St. Michael's Hospital, Uni¬
versity of Toronto, Ontario, Canada.
*From the
Manuscript received December 10, 1996; revision accepted
March 2, 1997.
Reprint
requests: Pamela Angle, MD, Women's College Hospital,
76 Grenville St, Toronto, Ontario, Canada M5S 1B2
"D rovided here is the first description of histopathologic
bronchiolitis obliterans with organizing pneumonia
(BOOP) in a patient with severe phenytoin hypersensitiv¬
ity syndrome (PHS). The presence of cold hemagglutinin
disease was also documented for the first time. The patient
¦*¦
showed dramatic
therapy.
In
September
improvement with high-dose steroid
Case Report
1994, a 40-year-old black
man
underwent
craniotomy and started receiving therapy with phenytoin sodium
(Dilantin; Parke-Davis; Morris Plains, NJ), 300 mg daily. A
medical history revealed chronic use of tobacco, crack cocaine,
and alcohol. Results of a lung examination and a chest x-ray film
showed no abnormalities. Four weeks following phenytoin ther¬
apy, clear rhinorrhea, myalgia, high fever, diffusely spreading
pruritic maculopapular rash, and dry cough developed. The
cough became productive and was associated with dyspnea.
Six weeks after phenytoin therapy was initiated, the patient was
readmitted to the hospital. Vital signs were as follows: respiratory
rate, 24 breaths per minute; heart rate, 112 beats per minute; BP,
100/60 mm Hg; and temperature, 38°C. Examination revealed
diffuse skin exfoliation; conjunctivitis; facial edema; tender, en¬
larged lymph nodes; decreased breath sounds bilaterally with
diffuse inspiratoiy crackles; mild right upper quadrant tender¬
ness; and hepatomegaly.
Laboratory7 findings included a fall in hemoglobin level from
155 g/L (noted 6 weeks earlier prior to phenytoin treatment) to
133 g/L; WBC count, 29X109/L (35% eosinophils); subtherapeu-
phenytoin level; mildly elevated liver function tests; while
breathing room air, arterial blood gas values showed mild
hypoxia; and chest radiograph, diffuse, patchy, asymmetric, reticulonodular infiltrates. Administration of broad-spectrum anti¬
biotics and prednisone, 50 mg daily, was started. Phenytoin
treatment was discontinued. Tests for cold agglutinins were
positive. The Mantoux test and tests for HIV, heterophile
agglutination, antinuclear antibody, rheumatoid factor, Legio¬
nella, and sputum cultures for bacteria, fungi, acid-fast bacilli,
and Pneumocystis carinii pneumonia were negative. A skin
biopsy specimen showed a drug eruption. Serological tests for
Mycoplasma, adenovirus, influenza A and B, herpes simplex,
cytomegalovirus, and hepatitis A, B, and C were negative. Spiking
fevers, marked eosinophilia, and deterioration of liver function
tests continued (aspartate aminotransferase, 214 U/L [normal,
<40 U/L]; alanine aminotransferase, 247 U/L [normal, <35
U/L]; lactate dehydrogenase, 435 U/L [normal, <260 U/L];
alkaline phosphatase, 237 U/L [normal, <35 to 125 U/L]). The
admission hemoglobin level of 133 g/L dropped to 101 g/L within
48 h of hospitalization, and a mild coagulopathy developed.
Respiratory7 insufficiency culminated in ICU admission and intu¬
bation. A chest x-ray film revealed asymmetric patchy infiltrates
at lung bases (Fig 1). Sepsis-like hemodynamics developed with
hypotension; tachycardia (heart rate, 120 to 140 beats per
minute); cardiac output, 10 to 17.5 L/min; and systemic vascular
resistance, 300 to 500 dyne-s*cm~5 (normal, 770 to 1,500 dyneS'cm-5) requiring inotropic and fluid support. Bronchoscopy,
BAL stains, cultures, and cytologic studies were negative for
organisms. Urine was treated for a Staphylococcus aureus infec¬
tion. All other cultures
tic
remained negative for organisms.
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1697
showing status after intubation in
at bilateral (right greater than left) lung bases.
Figure 1. Chest x-ray film
ICU; of note are diffuse patchy interstitial and alveolar infiltrates
hemoglobin level
dropping
g/L.
negative
prior to phenytoin treatment, were positive with anticomplement
C3d and negative with anti-IgG. Saline-reactive cold agglutinins
with anti-I specificity of low-titer, high thermal amplitude were
The anemia continued
to 70
to
worsen
with the
Direct and indirect antiglobulin tests,
present, reacting in saline with adult RBCs at a titer of 1:512 at 4°C
and 1:4 at 30°C; with albumin, the titer was 1:8 at 30°C. Nucleated
RBCs, occasional cell fragments and spherocytes, and 1 to 2%
atypical lymphocytes were found on a smear. Transfusion of packed
RBCs following crossmatch by prewarm technique failed to show
the appropriate rise in hemoglobin and was followed by further
transfusion. The coagulopathy worsened (prothrombin time, 20 s;
partial thromboplastin time, 35 s; international normalized ratio, 3.0)
and was unresponsive to vitamin K, but did improve following
administration of fresh-frozen plasma. Factor analysis showed hep¬
atocellular injury.
An open-lung biopsy specimen showed myxoid organizing
granulation tissue present in bronchioles,inwhich was consistent
with BOOP (Fig 2, top). A mild increase eosinophils within a
chronic mononuclear inflammatory infiltrate was present in the
alveolar exudate (Fig 2, bottom). Lung tissue was negative for
acid-fast bacilli, fungi, P carinii pneumonia, vasculitis, or granu¬
lomata. Electron microscopy was negative for viral inclusions.
BAL culture later grew rhinovirus. Methylprednisolone sodium
succinate (Solu-Medrol), 60 mg, was administered intravenously
every 6 h for 48 h and then followed by a slow intravenous taper
over 1 week. This was followed by high-dose treatment with
prednisone (1 mg/kg) for 3 months, followed by a very slow taper
for a total steroid course of 1 year. Pulmonar)7 function tests done
10, 21, and 42 days after steroid administration showed a
resolving restrictive lung defect and reduced diffusing capacity of
carbon monoxide. A chest x-ray film, liver function, and all
hematologic abnormalities resolved.
PHS is
rare
Discussion
with few reports describing
pulmonary in¬
volvement. Fever, cough, dyspnea, hypoxemia, and bilateral
infiltrates on a chest x-ray film in the setting of a more
generalized
hypersensitivity reaction are typical.1 Herein is
the first description of BOOP in PHS. BOOP is character¬
ized by ingrowth of polypoid fibroinflammatory granulation
tissue from bronchioles into adjacent alveoli where an orga¬
nizing pneumonia forms. The infiltrate is predominantly
1698
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Top: histopathologic findings of open-lung biopsy
specimen showing myxoid granulation tissues in bronchioles,
alveolar ducts and alveoli with confluent areas
extending to consistent
with BOOP. Both the pleura (p) and
(arrowheads)
lobular septum (s) are congested and edematous (hematoxylineosin, original X25). Bottom: higher magnification of Figure 2,
top, showing chronic inflammatory cellular infiltrate with a few
(arrowheads). Asterisk indicates myxoid connective
eosinophils
tissue background (original X250).
Figure 2.
mononuclear, patchy, and thought to be part of the lung's
reparative process after insults, including hypersensitivity
reactions. Commonly, BOOP is sensitive to steroid therapy,2
associated with a restrictive lung defect and decreased carbon
monoxide diffusing capacity7. X-ray film findings vary and
often show multiple, patchy interstitial-alveolar infiltrates like
those described here. Use of crack cocaine, implicated in one
case of BOOP,3 was not thought significant here since this
patient ceased cocaine use after his first hospital discharge
and clearly suffered from a generalized hypersensitivity syn¬
drome, a finding not associated with cocaine.
Rhinovirus found on BAL culture was likely the result of
upper airway contamination during bronchoscopy. The clear
rhinorrhea at illness onset, multiple other case reports sug¬
gesting concomitant respiratory tract infections, and the
reported seasonal variation of phenytoin hypersensitivity7
reactions4 suggest a role for concurrent infection in triggering
or intensifying the syndrome or, conversely, infections may
be the result of phenytoin's effect on immune function.
Sepsis-like hemodynamics, responsive to steroids, have been
described rarely in PHS.5
Coombs'-negative hemolytic anemia has been repeat¬
edly noted in PHS. Coombs'-positive hemolysis, however,
was mentioned only once in the present review of the
literature.6 Here is provided the first full description of
acute cold hemagglutinin disease in PHS. Clear evidence
of new onset cold hemagglutinins with a positive direct
Selected
Reports
antiglobulin
test
for
of
complement only and presence
IgM anti-I autoantibodies of high enough thermal ampli¬
tude and titer to produce a clinical picture consistent with
both intravascular and extravascular hemolysis were
found. Such low-titer, high thermal amplitude-type cold
are responsive to high-dose steroids.7 Cur¬
agglutinins
no
consensus
exists regarding the optimal dose or
rently,
treatment duration of corticosteroids for BOOP, nor are
there guidelines for steroid use in PHS. This patient's
response to intravenously administered methylpred¬
nisolone, 60 mg every 6 h for 48 h with a slow intravenous
taper over a week, was followed by the regimen suggested
and Colby8 for BOOP: prednisone, 1 mg/kg for 3
by Eplerwith
a subsequent slow drug taper so that steroid
months
This proved to
therapy was used for a total of 12 months.
be satisfactory for the patient reported herein.
ACKNOWLEDGMENT: Drs. Victor Hoffstein and
Halpern assisted in the preparation of this paper.
JR, Rudin ML. Acute pulmonary disease caused by
phenytoin. Ann Intern Med 1981; 95:452-54
Epler GR. Bronchiolitis obliterans organizing pneumonia: defi¬
and clinical features. Chest 1992;
improved, and the IgA
contributed
vasculitis.
to
both the bronchial disease and
(CHEST 1997; 112:1699-1701)
Keywords: arantitrypsin deficiency; antineutrophil cytoplasmic
bactericidal/permeability-increasing protein; bronchi¬
antibody;
ectasis
a1-AT=a1-antitrypsin; ANCA=antineutrophil
cytoplasmic antibody; BPI=bactericidaPpermeability-increasing
protein; LPS=lipopolysaccharide; LBP=LPS binding protein
Abbreviations:
associated with chronic suppurative lung
Vasculitis
diseases, such bronchiectasis and cystic fibrosis,
researchers.12
has been
as
1 Michael
nition
chial disease and vasculitis
anti-BPI titer fell after antipseudomonal treatment.
This raises the possibility that anti-BPI antibodies
Stephen
References
2
detected, which produced granular cytoplasmic
staining by indirect immunofluorescence with specifi¬
city for a newly characterized antigen: bactericidal/
permeability-increasing protein (BPI). The bron¬
102(suppl 1):2-6S
3 Patel RC, Dutta D, Schonfeld SA. Free-base cocaine
use
associated with bronchiolitis obliterans organizing pneumo¬
nia. Ann Intern Med 1987; 107:186-87
4 Leppik IE, Lapora JK, Lowenson R. Seasonal incidence of
phenytoin allergy unrelated to plasma levels. Arch Neurol
1985;42:120-22
DiGregorio F, Stiff M, et al. Dilantin hypersensi¬
tivity syndrome imitating staphylococcal toxic shock. Arch
5 Potter T,
Dermatol 1994; 130:856-58
Spielberg SP. Anticonvulsant hypersensitivity
syndrome: an in vitro assessment of risk. J Clin Invest 1988;
6 Shear NH,
82:1826-32
7 Schreiber AD, Herskovitz
BS, Goldwein M. Low-titer coldof hemolysis and response to
mechanism
disease:
agglutmin
corticosteroids. N Engl J Med 1977; 296:1490-94
8 Epler GR, Colby TV. The spectrum of bronchiolitis obliterans
[editorial]. Chest 1983; 83:161-62
Antineutrophil
reported by
marker for
cytoplasmic antibody (ANCA), ahasserologic
been detected in
some small-vessel vasculitides,
some series12 but without a defined antigen specificity
or a clear relationship to disease. Bactericidal/perme¬
ability-increasing (BPI) protein is an important host
defense mechanism against lipopolysaccharide (LPS).
Autoantibodies directed against this protein recently
have been recognized to be associated with vasculitis,
cystic fibrosis, and inflammatory bowel disease.3-5
Herein is the report of a case of bronchiectasis and
a]_-antitrypsin (arAT) deficiency in whom infection
with Pseudomonas aeruginosa was closely related to the
development of recurrent vasculitis, worsening bron¬
chial disease, and raised levels of anti-BPI antibodies.
Treatment with antibiotics produced a clinical improve¬
ment and was accompanied by a fall in the level of IgA
anti-BPI autoantibodies. Findings in this index patient
linking infection, autoim-of
provide further information
and
and
vasculitis
suggest an etiologic role
munity,
infection in certain vasculitides.
Vasculitis and Bronchiectasis
in a Patient With Antibodies to
Bactericidal/PermeabilityIncreasing Protein and
a!-Antitrypsin Deficiency*
Ravi Mahadeva, MD; Ming Hui Zhao, MD,
Susan Stewart, MD; Nathaniel Cary, MD;
Christopher Flower, MD; Martin Lockwood, MD; and
John Shneerson, MD
A
patient with a^-antitrypsin deficiency is reported
herein; this subject developed aggressive bronchial
disease and recurrent cutaneous vasculitis after pul¬
monary infection with Pseudomonas aeruginosa, Au¬
toantibodies to neutrophil cytoplasmic antigens were
Case Report
a nonsmoker, presented with a 4-month
A 59-year-old man,
history of daily sputum production, hemoptysis, and a 5-kg weight
loss. These symptoms were unresponsive to treatment with
clarithromycin and doxycycline (Vibramycin). Examination re¬
vealed widespread expiratory wheezes and coarse crackles at both
bases. Spirometry showed an obstructive defect; FEVj was 1.1 L
(predicted, 2.6 L) and FVC was 3.1 L (predicted, 3.3 L).
Investigations revealed arAT level to be 0.3 g/L (normal range,
0.9 to 1.8 g/L); phenotype Z; cytoplasmic staining of ANCA,
*From the Departments of Respiratory Medicine (Drs. Ma¬
hadeva and Shneerson), Medicine (Drs. Zhao and Lockwood),
and Radiology (Dr. Flower), Addenbrooke's Hospital, and the
Department of Pathology (Dr. Stewart), Papworth Hospital,
Cambridge, UK.
received November 13, 1996; revision accepted April
Manuscript
18, 1997.
MD, Department of HaemaReprint requests: Ravi Mahadeva, MRC
Centre, Addenbrooke's
of
Cambridge,
tology, University
Hospital, Hills Road, Cambridge CB2 2QH, UK
CHEST/112/6/DECEMBER, 1997
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1699