Forensic Science International 228 (2013) e28e32

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Forensic Science International

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Case report

Unexpected death: Anaphylactic intraoperative death due to Thymoglobulin

carbohydrate excipient
Luca Roncati a,*, Giuseppe Barbolini a, Alda Tiziana Scacchetti b, Stefano Busani c, Antonio Maiorana a
a

Department of Diagnostic Services, Pathology and Legal Medicine, Section of Pathology, University of Modena and Reggio Emilia, Modena, Italy
Department of Clinical Pathology, Section of Immunopathology and Allergology, SantAgostino Estense Hospital, Baggiovara, Modena, Italy
c
Department of General Surgery and Surgical Specialties, Section of Anaesthesiology and Intensive Care, University of Modena and Reggio Emilia, Modena, Italy
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 24 November 2012
Received in revised form 5 February 2013
Accepted 25 February 2013
Available online 26 March 2013

Anaphylactic shock is a life-threatening allergic response characterized by severe hypotension, inducing

tissue hypoperfusion with possible multi-organ failure and death. We describe the rst case of fatal
intra-operative anaphylactic shock due to prolonged infusion of Thymoglobulin during Orthotopic Liver
Transplantation (OLT), resulting from recruitment of both mastocytes and basophils, activated and
degranulated. Post-mortem serological analysis on a preserved, pre-OLT sample of the patients blood
revealed specic IgE against carbohydrate cross-reactive determinants (CCDs), such as MUXF3 and nAna
c2, proving that anaphylactic reaction was triggered by the Thymoglobulin carbohydrate excipient
(sugar alcohol mannitol), rather than anti-thymocyte globulin itself. Our ndings are consistent with
scientic data reported in the literature, where only one case of non-fatal anaphylaxis to Thymoglobulin
has been described, despite the existence of proven cases of anaphylactic reaction to mannitol. This case
highlights the need to pay particular attention in future not only to active substances but also to drug
excipients, above all during intra-operative drug delivery. In view of the important role played by
basophils in this kind of anaphylaxis, the basophil activation test (BAT) could prove useful in preventing
anaphylactic death from CCDs.
Published by Elsevier Ireland Ltd.

Keywords:
Anaphylaxis
Thymoglobulin
Mannitol
Carbohydrate cross-reactive determinants
(CCDs)
Basophil activation test (BAT)
2D7 antibody

1. Introduction

 Sensitization: In this phase the immune system initially identies

the foreign substance (allergen); the plasma cells then synthesize IgE and IgG4 [4] antibodies (against this allergen). These
antibodies bind to high afnity Fc (fragment crystallizable)
receptors, present on the membrane of mast cells and basophils,
and to low afnity Fc receptors, present on the surface of
eosinophils, neutrophils, platelets and monocytes/macrophages
[4]. Allergen exposure occurs through injection, inoculation,
inhalation, ingestion or direct contact.

 Immediate response: In this phase, subsequent to the sensitization period (usually of 1530 days), the immune system
identies the allergen again, through one of the exposure routes
which binds to IgE on cell membranes. This triggers the
degranulation of mast cells and basophils with the release of
preformed mediators contained in their granules (histamine,
adenosine, chymase, tryptase, heparin) within 530 min of
exposure [5]. These preformed mediators are responsible for
clinical manifestations which, in ascending order of severity,
include: rhinitis, conjunctivitis, urticaria, bronchial asthma,
laryngospastic angioedema and anaphylactic shock.
 Delayed response: After a few hours from allergen exposure,
regardless of its persistence, secondary mediators (autacoids,
cytokines), synthesized de novo, are released from various
inammatory cells. These include Major Basic Protein (MBP) and
Eosinophil Cationic Protein (ECP), which are the main causes of
tissue damage.

* Corresponding author at: Dipartimento dei Servizi Diagnostici e di Medicina

Legale, Struttura Complessa di Anatomia Patologica, Policlinico Hospital, Largo del
Pozzo 71, 41100 Modena, Italy. Tel.: +39 0594224812; fax: +39 0594224820.
E-mail address: emailmedical@gmail.com (L. Roncati).

The allergens which are best known for inducing anaphylaxis

are drugs (antibiotics, neuromuscular blockers, aspirin and
NSAIDs) [6], contrast media, sera and vaccines, natural rubber
latex, insect venoms (hymenoptera, hemiptera) [7], animal food,
plant foods and vegetables [811]. In particular, anaphylactic

The term anaphylaxis refers to a severe whole-body immunoallergic reaction against a foreign substance denominated allergen,
giving rise to immediate hypersensitivity which, if not promptly
treated, can lead to the patients death [13]. The immediate (type
I) hypersensitivity consists of three stages:

0379-0738/$ see front matter . Published by Elsevier Ireland Ltd.

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L. Roncati et al. / Forensic Science International 228 (2013) e28e32

reactions occur more frequently in patients with combined allergy

to latex and plant foods given their glyco-epitopic commonality
leading to the so-called latex-fruit syndrome [12,13]. Carbohydrate cross-reactive determinants (CCDs) are in fact carbohydrate
moieties of glycoproteins that induce the production of highly
cross-reactive IgE [14]. They are oligosaccharides or polysaccharides which derive from the assembly of monosaccharides such as
mannose, fructose, fucose, galactose; they can be divided into Nglycans or O-glycans, according to their site of attachment to the
protein. CCDs have been identied in various allergens of vegetal
origin (latex, foods, pollens) or animal origin (venoms) [7].
Among drugs, Thymoglobulin (anti-thymocyte globulin) is
classied as an immunosuppressive product. It is a cytotoxic
gamma-globulin, obtained by immunizing rabbits with human
thymocytes, which targets antigens expressed on the surface of
human T-lymphocytes. It was introduced in the United States in
1999 for the prophylaxis and treatment of acute rejection of kidney
transplants. Its use was then also authorized for liver, pancreas and
heart transplants, and its administration has been extended to
graft versus host disease and aplastic anemia. Only one case of nonfatal anaphylactic shock from intra-operative Thymoglobulin
administration during cadaveric renal transplantation has been
reported in the literature [15].
Although high afnity Fc receptors are present on both mast
cells and basophils, attention has focused mainly on mast cells
from both the serological and the histological (Pagoda red)
perspective. This restricted view can be explained rstly by the
absence of a specic basophil protein to test in serum and,
secondly, by the fact that correct identication of basophils
requires sparingly used histochemical stains (toluidine blue,
Giemsa) or specic antibodies (2D7, BB-1, BSP-1, 212H6), only
recently introduced for immunohistochemical practice [4,16].
Previous studies by our research group have shown that the spleen
can be considered the human shock organ, given its closed
circulation, which relates to the periodic shutdown of the blood in
the red pulp sinuses. Further evidence in support of this assertion is
supplied by degranulated mast cells, stained by Pagoda red,
present in the sinuses of patients who died from anaphylactic
shock, but absent in control cases [17]. In a recent forensic case of a
patient who died from anaphylactic shock following prolonged
infusion with Thymoglobulin, the use of Pagoda red staining on
histological slides revealed the presence of basophils in the spleen.
This nding prompted us to look for basophils in other organs and
to evaluate their possible role in anaphylaxis.
2. Case report
A 62-year-old man, without known clinical history of allergic
reactions, affected by well-differentiated hepatocellular carcinoma
(grade II on Edmondson and Steiner), which arose on HBV-related
cirrhosis (MELD score 7), was submitted to Orthotopic Liver
Transplantation (OLT) after the retrieval of a compatible donor
cadaver. The neoplasia (5 cm) had been previously treated with
repeated cycles of thermal-ablation and chemo-embolization,
without, however, achieving complete tumor necrosis. Located in
Couinauds VII segment, the tumor was not surgically resectable
since it adhered closely to the suprahepatic right vein and to the
intrahepatic portal bifurcation. During an operation which lasted
about 12 h, crystalloids (12,000 ml), blood (3200 ml), colloids
(1500 ml), plasma (550 ml), platelets (360 ml), albumin (200 ml)
and Thymoglobulin (250 mg) were infused. Diuresis (850 ml)
persisted up to one hour from the induction of anesthesia, and
thereafter the patient became anuric.
Immediately after Thymoglobulin was administered, hemodynamic instability was observed, accompanied by two severe
episodes of systolic hypotension (50 mmHg and 40 mmHg,

e29

respectively), which required continuous intraoperative infusion

of noradrenalin. Following surgery, the patient was transferred to
the Intensive Care Unit (ICU) in a comatose state (GCS 3/15), with
hypoxemia (60.3 mmHg), hypercapnia (64.9 mmHg) and severe
metabolic acidosis (pH 6.893); still anuric, he was hemodynamically supported by persistent infusion of noradrenalin (1.5 g/kg/
min) and bicarbonates. Blood test samples displayed AST 17,480 U/
l, ALT 5350 U/l, PT 23%, creatinine 2.36 mg/dl, lactate 266 mg/dl.
Doppler ultrasounds revealed regular liver blood ow and patency
of the hepatic artery, portal vein and suprahepatic veins. However,
on suspicion of a primary non-function (PNF), the patient
underwent total hepatectomy with temporary porto-caval anastomosis, while awaiting a new compatible liver for an emergency
re-OLT. Subsequently, veno-arterial Extra-Corporeal Membrane
Oxygenation (va-ECMO) was provided. After about 4 h from the
placement of ECMO, a severe ischemia of the left leg was
ascertained, and the patient was readmitted to the operating
theater to undergo a femoral artery by-pass. In the meanwhile,
bleeding occurred from drainages and from the femoral access for
ECMO, with marked abdominal bloating. At relaparotomy, necrotic
ischemia of the right colon was observed, and it was decided to
terminate the re-OLT procedure. During fascial suturing the patient
underwent a fatal cardiac asystole, unresponsive to vasoactive
amines.
The Public Prosecutor, following the complaint of relatives,
began a proceeding to assess the cause of death and the existence
of medical malpractice during the maneuvers of organ explanation/transplantation. Consequently, the autopsy was ordered.
3. Pathological ndings
3.1. External examination
On external examination marked facial swelling, macroglossia,
laryngeal swelling and widespread cutaneous petechiae were
observed. The left leg was cyanotic with several blisters. There
were also recent scars in the right hypochondrium and at the left
groin.
3.2. Histology
Histopathological examination of autoptic samples showed
many necrotic foci in the pancreas and kidneys and focal intraalveolar hemorrhages in the lungs. The right colon was involved by
extensive anoxic necrosis. The aorta was characterized by severe
atherosclerosis with calcied and ulcerative plaques. A saccular
aneurysm was also present in its abdominal tract.
3.3. Histochemistry and immunohistochemistry
Besides hematoxylineosin, histochemistry and immunohistochemistry were performed. Pagoda red staining revealed the
presence of activated and degranulated mast cells in the spleen
sinuses, a typical nding in anaphylactic death (Fig. 1), and the
concurrent presence of activated and degranulated basophils in the
spleen (Fig. 2, arrows). Immunohistochemistry for puried antihuman basophils 2D7 (BioLegend), which specically recognizes
human basophils binding a still unidentied antigen expressed in
their granules, conrmed the conspicuous presence of basophils in
the spleen (Fig. 3). More specically, non-degranulated basophils
appeared in the white pulp of the spleen, whereas degranulated
basophils were found in the red pulp (Figs. 3 and 4, arrows). On
both the original (Fig. 5) and the explanted liver (Fig. 6)
histopathological examination with Pagoda red revealed the
presence of activated mast cells, mainly located in the portal
spaces. Degranulated basophils (Figs. 5 and 6, arrows) were also

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L. Roncati et al. / Forensic Science International 228 (2013) e28e32

Figs. 1 and 2. Spleen. Several mastocytes and scattered eosinophils stained by

Pagoda red are present in the red pulp (original magnication 20). Anaphylactic
degranulation is shown in the insert (original magnication 40). Near adjacent
eld. Besides degranulation of mast cells, the black arrows point to degranulated
basophils, weakly stained by hematoxylin, used for counterstaining Pagoda red
(original magnication 100).

observed, particularly in the explanted liver; which was characterized by extensive areas of centrilobular (zone III) necrosis.
3.4. Serology and biochemistry

Figs. 3 and 4. Immunohistochemistry for the 2D7 antibody, specic marker of

human basophils. Non-degranulated basophils are noticeable in the white pulp,
whereas degranulated basophils (black arrows) are present in the red pulp (original
magnication 10 and 100).

therapy, from the intra-operative administration of Thymoglobulin during cadaveric renal transplantation [15]. Each Thymoglobulin vial (10 ml) contained 25 mg anti-thymocyte globulin
(rabbit), as well as 10 mg sodium chloride, 50 mg glycine and
50 mg mannitol. Among these excipients, mannitol (sorbitol
isomer) is classied as a sugar alcohol, usually derived from

The post-mortem serological test performed with ImmunoCAPTM 100 system (Phadia, Uppsala, Sweden) on a preserved sample
of the patients pre-OLT blood, obtained the day before the
admission to the operating theater, showed high levels of specic
IgE against graminaceae, canine grass and peanuts, whereas no
signicant IgE values were detected for different classes of
antibiotics (penicillins and cephalosporins) and natural latex
rubber. Moreover, the test revealed the presence of specic IgE
against CCDs from bromelin (MUXF3) and native extract bromelin
(nAna c 2). Finally, tryptase-level evaluation in preserved sera
conrmed the anaphylactic reaction: pre-OLT tryptasemia was
5.72 mg/l while post-OLT tryptasemia, evaluated at the end of the
surgical operation, was four times higher.
4. Discussion
On the basis of the post-mortem serological test, this is the rst
reported case of fatal anaphylactic shock from prolonged intraoperative infusion of Thymoglobulin in an atopic patient with
specic IgE against CCDs. Hitherto, only one case has been
described of non-fatal anaphylactic shock, well controlled by

Fig. 5. Original liver. Degranulated mast cells and basophils are noticeable (original
magnication 40); in the insert degranulated basophils (black arrows) are weakly
stained by hematoxylin, used for counterstaining Pagoda red (original
magnication 100).

L. Roncati et al. / Forensic Science International 228 (2013) e28e32

e31

The basophil activation test (BAT) facilitates the identication

of a drug allergy, which is always the combination of ingredient
allergy and excipient allergy. The BAT is based on the detection of
degranulated basophils which expose cell-surface protein CD631
from the patients serum sample placed in contact with the foreign
substance being tested for allergic reaction [2931]. Through the
medico-legal expertise, it was possible to exclude a primary nonfunction of the graft, identifying the real cause of death in an
unexpected fatal anaphylactic reaction. At the end of the process
any prole of medical malpractice was not emerged. This case of
unexpected death is the rst case reported in the forensic literature
of intraoperative anaphylactic death due to a drugs excipient
(mannitol) and should alert the forensic experts to pay attention
also to the possible anaphylactic risk related to drugs excipients.
Moreover in atopic patients, BAT should be considered a careful
serological procedure in the prevention of anaphylactic responses
during invasive medical treatments.
Fig. 6. Transplanted liver, subsequently explanted with a clinical diagnosis of PNF.
Degranulated mast cells and basophils are displayed by Pagoda red staining
(original magnication 40 and 100).

fructose hydrogenation. Clinically, mannitol has been used as an

osmotic laxative and diuretic agent in the treatment of intracranial
hypertension, oliguric renal failure and acute glaucoma. However,
the anaphylactic reaction from mannitol has been reported by
some authors in vivo [1822] and in vitro [23,24] models. More
specically, Biro, Schmid and Lamb have described non-fatal
anaphylactic responses from mannitol infusion after anesthesia
induction in atopic patients, while McNeill and Hegde have
reported two non-fatal cases of anaphylaxis to mannitol after
treatment for intracranial hypertension and after ingestion of
cultivated mushrooms, respectively. It follows that the anaphylactic reaction was triggered by the carbohydrate excipient
(mannitol) rather than anti-thymocyte globulin. The present case
is therefore the rst case of fatal intra-operative anaphylaxis from
mannitol to have been reported.
Post-mortem serological analysis on a preserved sample of the
patients pre-OLT blood has allowed us to exclude the presence of
specic IgE against latex, another well-known substance responsible for peranesthetic anaphylaxis.
Prior to the hazardous infusion of foreign substances in a
patient, serological screening should be required for specic IgE
against CCDs and the more frequent allergens, for the ever more
common antigenic cross-reactivities and for related forensic
implications. Moreover, the possible occurrence of peranesthetic
anaphylaxis requires careful preoperative serological investigation
in the atopic patient.
The presence of extensive areas of centrilobular necrosis in a
recently transplanted liver, due to tissue hypoperfusion during
shock, justies the clinical diagnosis of primary non-function of the
graft. Moreover, Pagoda red staining and immunohistochemistry
for 2D7 revealed degranulated mast cells (a typical morphological
nding in cases of anaphylactic response) [17], and degranulated
basophils, which perform a key role in the maintenance and
enhancement of anaphylactic reaction [25]. The molecules
involved in these mechanisms should be the Slow-Reacting
Substances of Anaphylaxis (SRS-A) and the Platelet Activating
Factor (PAF), abundantly expressed in activated basophils [26]. The
presence of widespread cutaneous petechiae and the occurrence of
several necrotic foci in both pancreas and kidneys, with focal intraalveolar hemorrhages in the lungs, are compatible with the onset
of Disseminated Intravascular Coagulation (DIC). DIC, whose
pathogenesis closely involves mediators released by basophils,
is a possible serious complication during anaphylactic shock
[27,28].

Acknowledgments
The authors would like to express their thanks to Paul Angus,
who revised the manuscript in its nal version, and to Luca
Fabbiani, for his technical support.
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