Serum sickness & SSLR

Serum sickness
Serum sickness-like reac/on
Arthus reac/on
Kamonlak Bawornsomboonkul,MD

Background
• An#diphtheria an#body-induced serum sickness
• It was ﬁrst described in 1905 by two pediatricians
• von Pirquet and Schick
• they introduced a horse serum derived an#toxin against diphtheria
and scarlet fever
• observed a reac#on to the an#toxin
• 8-12 days aGer subcutaneous injec#ons of horse serum
• a clinical syndrome characterized by fever, cutaneous erup#on,
arthralgias, and lymphadenopathy
Lawley TJ, Bielory L, Gascon P, et al. A prospec8ve clinical and immunologic analysis of pa8ents with serum sickness. N Engl J Med 1984; 311:1407.
Saja alhawal, Manar Aldarwish, and Zainab Almoosa. Serum Sickness following Tetanus Toxoid Injec8on. Case Reports in Pediatrics, Volume 2021.

Background
• suggested that this illness was caused by immune complexes formed
in the children between their own an#body and the foreign horse
an#gen
• conclusion that products of the immune response could be harmful
as well as helpful
• the concept of immune complex disease was born
“Immune complexes and allergic disease” in Middleton’s Allergy: Principles and Prac8ce. 9th edi8on. 2020

“Hypersensi8vity disorder” in Abbas Cellular and Molecular Immunology. 9th edi8on. 2018
• The different forms of an0bodies that may cause disease
• An00ssue/cell an0bodies:
• An0bodies may bind specifically to extracellular 0ssue
an0gens and the recruited leukocytes cause 0ssue injury
• An0bodies may bind to cells (in this example, circula0ng red
cells) and promote deple0on of these cells
• Immune complexes:
• Complexes of an0bodies and an0gens may be formed in
the circula0on and deposited in the walls of blood vessels,
where the complexes induce inflamma0on
Types of an2bodies that cause disease

Immune complex-mediated (type III) hypersensi7vity
• IgM and IgG an#bodies speciﬁc for soluble an#gens in the blood form
complexes with the an#gens
• the immune complexes may deposit in blood vessel walls in various
#ssues
• causing inﬂamma#on, thrombosis, and #ssue injury
“Hypersensitivity disorder” in Abbas Cellular and Molecular Immunology. 9th edition. 2018

Pathogenesis
• Immune complex forma8on
• Immune complex deposit
• Immune complex mediated inﬂamma8on

Immunochemical factors
in immune complex bioac2vity
Rela%ve concentra%on of an%gen and an%body
• A major factor that inﬂuences the immunochemical characteris%cs of
immune complexes
• During the early stages of immuniza%on, the concentra%on of an%gen is in
excess over that of an%body
• As an%body produc%on increases, the number of an%body and an%gen
molecules reaches equivalence.
• rapid removal of the complexes from the circula%on by Kupﬀer cells in
the liver and macrophages in the red pulp of the spleen
• Finally, as the an%gen is removed from the circula%on, an%body excess is
achieved

Immunochemical factors
in immune complex bioac2vity
Rela%ve concentra%on of an%gen and an%body
• immune complexes formed in an%body excess are smaller than those
formed at equivalence.
• At equivalence, immune complexes tend to be large, because chances for
cross-linking are op%mized.
• extreme an%gen excess, immune complexes are generally small, because
all an%body-combining sites are saturated with an%gen and chances for
laGce forma%on are limited
• Immune complexes formed at moderate an%gen excess are believed to be
most pathogenic, because they remain in the circula%on for rela%vely long
intervals and are large enough to ac%vate complement eﬃciently.

“Immune complexes and allergic disease” in Middleton’s Allergy: Principles and Practice. 9th edition. 2020
• Graph of precipi0n curve.
• Fixed amounts of immune serum is
placed in series of test tubes, and
increasing amounts of an0gen are
added to each.
• At ﬁrst, small immune complexes
are formed in an0body excess,
• but as equivalence is reached,
large-laLce immune complexes
are formed and result in visible
precipitates.
• Eventually, an0gen excess is
reached, and only small immune
complexes are formed and do not
precipitate.
The rela0ve concentra0on of an0gen and
an0body is a major factor that inﬂuences
the immunochemical characteris0cs of
immune complexes

Deﬁni2on
• Serum sickness is a systemic, immune complex–mediated
hypersensi#vity vasculi#s classically aOributed to the therapeu#c
administra#on of foreign serum proteins or other medica#ons
“Serum sickness” in Nelson Textbook of Pediatrics. 21th edi8on. 2020

• Serum sickness: classic example of a type III
hypersensi8vity reac8on caused by an8gen-
an8body complexes
• In the rabbit model using bovine serum
albumin as the an8gen
• symptoms develop with the appearance
of an8body against the injected an8gen
Pathogenesis
Chapter-16 Hypersensi8vity. Essen8als of medical microbiology

Pathogenesis
• small complexes usually circulate harmlessly
• large complexes are cleared by the re#culoendothelial system
• intermediate- sized complexes that develop at the point of slight
an#gen excess may deposit in blood vessel walls and #ssues
• As free an#gen concentra#on falls and
an#body produc#on increases over days
• an#gen-an#body complexes of various
sizes develop in a manner analogous to a
precipi#n curve

Complement ac8va8on (C3a, C5a) promotes chemotaxis and
adherence of neutrophils to the site of immune complex deposi8on
Activation of complement and granulocytes
vascular (leukocytoclas/c vasculi/s with
immune complex deposi/on) and /ssue damage

• The processes of immune complex
deposi#on and of neutrophil accumula#on
may be facilitated by increased vascular
permeability, because of the release of
vasoac#ve amines from #ssue mast cells
• Mast cells may be ac#vated by binding of
an#gen to IgE or through contact with
anaphylatoxins (C3a)
• Tissue injury results from the libera#on of
proteoly#c enzymes and oxygen radicals
from the neutrophils
Pathogenesis

Pathogenesis
• Immune complex forma8on
• Immune complex deposit
• Complement ac8va8on: forma8on of
complement fragment
• C3a: potent anaphylatoxin
• C5a: potent chemoaPractant for neutrophils

• Radiolabeled bovine serum albumin is injected
intravenously into normal rabbits at day 0, and
sequence of immunologic events is followed.
• At about day 8, immune complexes are formed,
complement levels fall, and the animals
become ill.
• By day 15, foreign an/gen and immune
complexes are no longer detectable,
complement levels are rising, and animals are
recovering.
Graph of time course of “one-shot” serum sickness

“Hypersensi8vity disorder” in Abbas Cellular and Molecular Immunology. 9th edi8on. 2018
• Injec/on of bovine serum albumin into a
rabbit leads to the produc/on of speciﬁc
an/body and the forma/on of immune
complexes
• These complexes are deposited in
mul/ple /ssues, ac/vate complement
(leading to a decrease in serum
complement levels), and cause
inﬂammatory lesions
• resolve as the complexes and the
remaining an/gen are removed and free
an/body (not bound to an/gen) appears
in the circula/on
Sequence of immunologic responses in experimental acute serum sickness

Agents causing serum sickness
PROTEINS FROM OTHER SPECIES
• An%botulinum globulin
• An%thymocyte globulin
• An%tetanus toxoid
• An%venin (Crotalidae) polyvalent
(horse serum based)
• Crotalidae polyvalent immune Fab
(ovine serum based)
• An%rabies globulin
• Inﬂiximab
• Rituximab
• Etanercept
• An%-HIV an%bodies ([PE]HRG214)
• Hymenoptera s%ngs
• Streptokinase
• H1N1 inﬂuenza vaccine

Agents causing serum sickness
An#bio#cs
• Cefaclor
• Penicillins
• Trimethoprim sulfate
• Minocycline
• Meropenem
Neurologic
• Bupropion
• Carbamazepine
• Phenytoin
• Sulfonamides
• Barbiturates
DRUGS

Clinical manifestaiton
The symptoms triad
• fever
• rash
• joint involvement (arthralgia and
arthri#s)
Usually occurring 7–14 days aGer
exposure to the oﬀending agent
Other less common symptoms
• lymphadenopathy
• nonspeciﬁc headache
• gastrointes#nal complaints
• blurred vision
• myalgia
Saja alhawal, Manar Aldarwish, and Zainab Almoosa. Serum Sickness
following Tetanus Toxoid Injection Case Reports in Pediatrics Volume 2021.

• The symptoms of serum sickness generally begin 7-12 days aGer
injec#on of the foreign material, but may appear as late as 3 wk
aGerward
• The onset of symptoms may be accelerated if there has been earlier
exposure or previous allergic reac#on to the same an#gen
• It can occur within 12 to 36 hours in individuals thought to have been
sensi#zed during a previous exposure

• A few days before the onset of generalized symptoms: the site of
injec#on may become edematous and erythematous
• Symptoms usually include fever, malaise, and rashes
• Ur#caria and morbilliform rashes are the predominant types of skin
erup#ons
• Cardi#s, glomerulonephri#s, Guillain-Barré syndrome, and peripheral
neuri#s are rare complica#ons

“Immune complexes and allergic disease” in Middleton’s Allergy: Principles and Practice. 9th edition. 2020
• ORen, this was not only the first cutaneous sign of serum sickness but also the first sign of serum sickness itself
• occurring on the average at day 6 ± 1 aRer the ini0a0on of ATG therapy and disappearing a few days later
• Of pa0ents who had cutaneous signs of serum
sickness
• 75% developed a previously undescribed
cutaneous erup0on
• consisted of a band of erythema along the
sides of the hands and feet and fingers and
toes at the junc0on of skin on the palmar or
plantar surface with that of the dorsolateral
surface

Lawley TJ, Bielory L, Gascon P, et al. A prospec8ve clinical and immunologic
analysis of pa8ents with serum sickness. N Engl J Med 1984;311:1407–13.

• Pa%ents with bone marrow failure received treatment with 1 mg/kg/day of
horse an%-thymocyte globulin (ATG) administered intravenously for 14 or
28 days.
• The pa%ents also received 1 to 1.5 mg/kg/day of methylprednisolone
• Of the 35 pa%ents treated in this protocol, 30 developed typical signs and
symptoms of serum sickness 8 to 13 days a`er beginning therapy
• fever and malaise (100%), skin rashes (93%), arthralgias (67%), myalgias
(67%), gastrointes%nal disturbances (67%), and lymphadenopathy (20%)
Lawley TJ, Bielory L, Gascon P, et al. A prospec8ve clinical and immunologic
analysis of pa8ents with serum sickness. N Engl J Med 1984;311:1407–13.

• Symptoms typically resolve within 2 wk of removal of the oﬀending
agent
• in unusual cases, symptoms can persist for as long as 2-3 months
• The course of illness may be protracted if the culprit agent has been
administered as a depot or sustained release form

Diagnosis
• based on the characteris#c paOern of acute or subacute onset of a
rash, fever, and severe arthralgia and myalgia dispropor#onate to the
degree of swelling, occurring aGer exposure to a poten#al culprit
• Pa#ents who appear moderately or severely ill, or who are not taking
a medica#on that can be readily iden#ﬁed as the culprit
• should be evaluated with the following laboratory tests

Diﬀeren2al diagnosis
• viral illnesses with exanthems
• hypersensi#vity vasculi#s
• Kawasaki disease
• acute rheuma#c fever
• acute meningococcal or gonococcal infec#on
• endocardi#s
• systemic-onset juvenile idiopathic arthri#s (S#ll disease)
• Lyme disease
• hepa##s
• other types of drug reac#ons

Laboratory test
• CBC: thrombocytopenia is often present
• ESR and CRP: usually elevated
• Urinalysis: mild proteinuria, hemoglobinuria, and microscopic
hematuria may be seen
• BUN, Cr, LFT
• Testing to exclude infection

Not recommended as part of the rou#ne evalua#on
• Complement studies
• Methods of detec#ng circula#ng immune complexes
• Skin biopsy
Laboratory test

• Complement studies
• CH50, C3, C4
• serum complement levels (C3 and C4) are generally decreased and
reach a nadir at about day 10
• C3a anaphylatoxin may be increased
Complement studies

“Immune complexes and allergic disease” in Middleton’s
Allergy: Principles and Practice. 9th edition. 2020
• Pa0ents with serum sickness also had
pronounced decreases in serum C3
and C4 levels coincident with disease
onset
• The lowest levels of C3 and C4 were
closely correlated with the peak
immune complex values
• when circula0ng immune complexes
were cleared they returned to
baseline

Methods of detec7ng circula7ng immune complexes
125I-C1q-Binding Assay
• The hexamer C1q is a subcomponent of the ﬁrst component of
complement
• will bind by its mul#ple binding sites to immune complexes containing
IgG subclasses 1, 2, or 3 or IgM by noncovalent aOachment to a
speciﬁc site on the Fc por#on of the immunoglobulin
• Assay methods examine binding of radiolabeled C1q added to serum
by the complexes or use a variety of ELISA-based methods to detect
C1q binding

“Immune complexes and allergic disease” in Middleton’s
Allergy: Principles and Prac8ce. 9th edi8on. 2020
• Pa0ents were followed sequen0ally
with determina0ons of blood levels of
immune complexes.
• Pa0ents who developed serum sickness
developed high levels of circula0ng
immune complexes
• as measured by the 125I-C1q binding
assay
• reached a peak at day 10 ± 1, coincident
with peak clinical disease ac0vity

Skin biopsy
• Skin biopsies are not usually necessary for confirming the diagnosis
• the findings are variable and not specific for serum sickness
• Direct immunofluorescence studies of skin lesions often reveal
immune deposits of IgM, IgA, IgE, or C3

• when lesional skin biopsy specimens were obtained
during clinical serum sickness, deposits of IgM and C3
were found in he blood vessel walls of six of nine and
seven of nine pa/ents, respec/vely
• IgE and IgA deposits were also frequently present.
• These data clearly support the concept that serum
sickness in humans, as in the rabbit model, is an
immune complex–mediated disease.

Treatment
• There are no evidence-based guidelines or controlled trials on which
to base therapy recommenda#ons
• discon#nua#on of the oﬀending agent
• primarily suppor#ve

• Mild to moderate symptoms
• an#histamines for pruritus
• nonsteroidal an#-inﬂammatory drugs and analgesics for low-grade
fever and mild arthralgia
• Severe symptoms: fever >38.5°C (101.3°F), severe arthralgia or
myalgia, or renal dysfunc#on
• systemic cor#costeroids can be used
• Prednisone (1-2 mg/kg/day; maximum 60 mg/day)
• for 1-2 wk is usually suﬃcient
Treatment

• Pa#ents who are very uncomfortable or who appear acutely ill may
be treated with
• Intravenous methylprednisolone in the range of 1 to 2 mg/kg per day
in one or two divided doses
• Glucocor#coids can frequently be rapidly tapered, with a total
dura#on of therapy of less than one week
Lundquist AL, Chari RS, Wood JH, et al. Serum sickness following rabbit an8thymocyte-globulin
induc8on in a liver transplant recipient: case report and literature review. Liver Transpl 2007; 13:647.
Treatment

• The pa8ent is a 45-yr-old woman who underwent OLT for hepa88s C–associated
end-stage liver disease
• The pa8ent experienced intermiPent fevers, polyarthralgia, and acute renal
failure 9 days aRer comple8on of thymoglobulin administra8on
Lundquist AL, Chari RS, Wood JH, et al. Serum sickness following rabbit an8thymocyte-globulin
induc8on in a liver transplant recipient: case report and literature review. Liver Transpl 2007; 13:647.

• The pa%ent received 250 mg (3 mg/kg/day) of intravenous
methylprednisolone daily for 3 days.
• rapid improvement in her abdominal pain, polyarthri%s, fevers, and
urine output
• She was discharged to home on a prednisone taper on hospital day 11
(poseransplanta%on day 19)
• At the %me of discharge, she had full resolu%on of symptoms
• improvement in the fevers and arthralgias within the ﬁrst 48 hours of
treatment
• If severe symptoms persist following the administra%on of systemic
steroids for 3 days, therapeu%c plasma exchange should be ini%ated
Lundquist AL, Chari RS, Wood JH, et al. Serum sickness following rabbit antithymocyte-globulin
induction in a liver transplant recipient: case report and literature review. Liver Transpl 2007; 13:647.
Treatment

Treatment
• Once the oﬀending agent is discon#nued and depending on its half-
life, symptoms resolve spontaneously in 1-4 wk
• Symptoms las#ng longer suggest another diagnosis

Preven2on
• The primary mode of preven#on of serum sickness is to seek
alterna#ve therapies.
• In some cases, non–animal-derived formula#ons may be available
(human-derived botulinum immune globulin)
• If needed, the serum can usually be successfully administered by a
process of rapid desensi#za#on using protocols of gradual
administra#on outlined by the manufacturers.
• Serum sickness is not prevented by desensi#za#on or by
pretreatment with cor#costeroids.

Serum sickness-like reac2on
• immunological condi#on characterized by sudden development of
skin rash and joint inﬂamma#on with or without fever
• usually preceded by exposure to a drug [triggered by an#bio#cs
(par#cularly cefaclor)]
• present in both adult and pediatric popula#ons although it is seen in
children more frequently
• prevalence is unknown
Blanca R. Del Pozzo-Magaña MD, et Al. Paediatric serum sickness-like reac8on: A 10-year retrospec8ve cohort study. Paediatrics & Child Health, 2021, 428–435.

Serum sickness-like reac2on
• do not exhibit the immune complexes, hypocomplementemia,
vasculi#s, and renal lesions that are seen in serum sickness reac#ons
• SSLR is usually unrecognized or easily mistaken by other cutaneous
en##es
• ur#caria, ur#caria mul#forme, erythema mul#forme, infec#ous
rashes, or other drug reac#ons

E2ology
• mainly triggered by drugs, mostly β-lactam antibiotics
• one of the first drugs associated with SSLR in children being cefaclor
• a great variety of other drugs have been reported to trigger SSLR
• sulfonamide drugs, anticancer agents, anticonvulsants,
anti-inflammatory agents, griseofulvin, metronidazole, bupropion,
and more recently, biological agents such as rituximab, infliximab,
and efalizumab, among others
• vaccines and infectious agents have also been implicated in SSLR
development
Blanca R. Del Pozzo-Magaña,1 Alejandro Lazo-Langner. Serum Sickness-Like
Reac8on in Children: Review of the Literature, EMJ Dermatol. 2019;7[1]:106-111.

Pathophysiology
• the precise pathophysiology has not yet been elucidated
• the mechanism by which drugs or other agents trigger SSLR appears
to be diﬀerent from the classic serum sickness
• SSLR is not associated with an#gen-an#body complex forma#on and
the blood levels of complement are usually normal

• Some theories consider the possibility that
• drugs, or their metabolites may act similarly to haptens that bind
plasma proteins
• subsequently induce an abnormal immunologic response
• Other studies have suggested that
• drug metabolites by themselves have a direct toxic eﬀect on the
lymphocyte of aﬀected pa#ents
Pathophysiology

• More recently, Zhang et al. reported that in children
• antibiotics such as cefaclor may increase the intestinal mucosal
permeability by damaging its integrity
• leads to the passing of antigens to the blood circulation favoring
the development of SSLR
Pathophysiology

Clinical features
• Ini#al reports of pa#ents with SSLR described presenta#on of skin
rash associated with joint inﬂamma#on or arthralgia with or without
a fever
• The development of skin rash and arthralgia in children with SSLR can
present several days aGer exposure of the trigger, ranging from a
couple of days up to several weeks
• In the case of SSLR induced by an#bio#cs, the clinical features
typically appear aGer the course has been completed (approximately
7–10 days)

• pediatric SSLR seldom presents with lymphadenopathy or systemic
involvement
• malaise and irritability las#ng several days or weeks even aGer the
rash has resolved has been reported
Clinical features

Skin Rash
• The morphology of the skin rashes reported in the literature varies
widely including
• morbilliform rash, ur#carial and annular plaques with central
clearing, or erythema mul#forme-like lesions (erythematous
annular converging plaques with purplish/dusky centre)
• Unlike acute ur#caria, skin lesions in SSLR are not migratory, but are
ﬁxed
• Once skin lesions develop, they stay in the same area un#l they
resolve, and occasionally leave a bruise-like post inﬂammatory
hyperpigmenta#on behind that may last for several days

• The skin lesions usually start as small erythematous papules or
plaques on the trunk and then enlarge and progressively spread to
the rest of the body
• With regard to facial impact, periorbital or lip swelling may present
resembling angioedema
• do not develop tongue swelling or respiratory compromise as seen
in other allergic reac#ons
Skin Rash

• Unlike classical ur#caria, itchiness in SSLR is mild or nonexistent;
however, skin soreness or burning sensa#on may present instead
• oGen misdiagnose SSLR with erythema mul#forme
• because skin lesions in SSLR may present with a violaceous centre that
simulate target lesions
• Unlike erythema mul%forme, SSLR lesions do not have three rings
(typical target lesion), do not blister, and have no involvement of
mucous membranes
Skin Rash

Joint
• characterized by joint swelling and arthralgia, is also necessary to
make the diagnosis of SSLR
• Joints are usually aﬀected bilaterally but may present on only one
side
• Joints in the hands and feet are the most commonly involved,
followed by knees, and then elbows
• Purple discolora#on and edema may also be seen on the skin
overlaying the joints
• Parents usually report that children with SSLR avoid walking or move
abnormally

Fever
• Unlike classic SS, fever in children with SSLR may not be present.
• Concomitant fever ranges from 30% to 75% in these pa#ents

Diagnosis
• no validated diagnos#c criteria
• based on history and clinical features
• the laboratory proﬁle is usually nonspeciﬁc

Inves2ga2on
• leukocytosis on the complete blood test
• high erythrocyte sedimenta%on rate
• low levels of complement (C3, C4, and CH50); however, in other cases,
levels of complement have been reported as normal or slightly elevated.
• presence of circula%ng immune complexes
• mild proteinuria or hematuria
• abnormal liver func%on tests
• elevated crea%nine
• Skin tes%ng and radioallergosorbent test were usually nega%ve because
SSLR does not appear to be an IgE-mediated reac%on

• Skin biopsies are rare in children with SSLR because of their invasive
nature
• some#mes the histological features could help rule out other
pathologies that share clinical features similar to SSLR
• Histopathology is characterized by perivascular and mid-dermal
inﬂammatory inﬁltrate with admixed neutrophils, eosinophils, and
lymphocytes, usually without leukocytoclas#c vasculi#s
Inves2ga2on

Diﬀeren'al diagnosis
• Rheuma#c fever
• Ur#carial vasculi#s
• Systemic lupus erythematosus
• Drug-induced lupus
• S#ll’s disease
• Henoch-Schönlein purpura

Treatment
• usually, a self-limi%ng condi%on with no sequelae
• complete resolu%on of the symptoms can take several days and even
weeks
• Addi%onal to immediate withdrawal of the causal drug when this is the
case, medical treatment may be necessary
• An%histamines and nonsteroidal an%-inﬂammatory drugs are used to
control joint pain and itchiness
• When symptoms are more severe and prolonged, the use of a short course
of oral cor%costeroids is recommended
• prednisone (0.5–1.0 mg/kg/d for 3–5 days)
• intravenous methylprednisolone (10.0 mg/kg/d for 3 days)

• Un#l now, there are no current guidelines for medical treatment of
children with SSLR
• because there are no studies evalua#ng the eﬀec#veness and safety
of these therapies
• dosage and length of treatment are usually based on the severity of
the symptoms and the experience of the healthcare professionals
Treatment

• Currently, there are no guidelines for the management of SSLR in
children and the use of an#histamines, NSAIDs, and oral
cor#costeroids remains controversial.
• an inﬂammatory condi#on might respond beOer to a potent an#-
inﬂammatory drug than to an#-histamines or NSAIDs alone
Treatment

Prognosis
• typically, favorable because they have a mean recovery #me of 5–7
days with no evidence of sequalae, even if they do not receive any
treatment
• the rate of recurrence in children with SSLR is unknown but suspected
to be high
• avoidance of the trigger drug is highly recommended to prevent
severe recurrences
• classical desensi#za#on does not appear to have a role in pa#ents
with SSLR because protocols for desensi#za#on were designed to
treat Type 1 (IgE-mediated) mast cell reac#ons

Deﬁni2on
• Arthus reac#on is a localized inﬂammatory response, belonging to a
typical local subacute type III hypersensi#vity reac#on

• The Arthus reac#on is named for Maurice Arthus in 1903
• daily injec#ons of horse serum into the skin of rabbits
• resulted in a localized cutaneous reac#on characterized by erythema,
edema, hemorrhage, and necrosis
Background

Background
• Discovered by Nicolas Maurice Arthus in 1903
• Subcutaneously injected 5 cc. of horse serum into rabbits per 6 d.
• AUer the third injec/on: the slight infiltra/on was observed at the injec/on site, persis/ng 2 or 3 d.
• AUer the fourth injec/on: a local edematous reac/on occurred, and the absorp/on of serum became
slow
• AUer the fiUh injec/on: the infiltra/on became more severe, and edematous did not disappear un/l
aUer 5 or 6 d
• AUer the sixth injec/on: a white (not containing pus and absolutely sterile), solid, compact and thick
mass was produced in the subcutaneous cellular /ssue, las/ng for several weeks
• AUer the seventh injec/on: the skin became rapidly red, then blanched and dried, and even leading to
a gangrenous plaque
• This phenomenon was soon repeated in many laboratories and was en/tled the Arthus phenomenon
(Or Arthus reac/on) by Nicolle in 1907
Baozhen Peng, Mingwei Wei, Feng-Cai Zhua, and Jing-Xin Li. The vaccines-associated
Arthus reac8on, Human vaccines and immunotherapeu8cs 2019;15(11):2769–2777

Mechanism
• The mechanism of this phenomenon has been inves1gated in many studies
• intradermal injec1ons of an1gen into a local skin site of an animal subject preexis1ng
large amounts of immunoglobulin G (IgG) an1bodies specific to the an1gen.
• The an1gen will diffuse into the walls of local blood vessels and the immune complexes
which are comprised of an1gen, an1body, and complement in vessels precipita1ng close
to the injec1on site.
• Subsequently, the C3a, C4a, and C5a complements are ac1vated by the immune
complexes, and the ac1va1on of FcγRIII (Binding immune complexes) on the localized
mast-cells induces their degranula1on with an increase in local vascular permeability,
resul1ng in an inflammatory response.
• Besides the chemotac1c factors C3a, C5a, and C5b67 aSract large numbers of
neutrophils to immune-complexes followed by ly1c enzymes release, which can lead to
the injury of vessel walls with the development of hemorrhage, edema, thrombi, local
ischemia, and necrosis.

• The most common clinical manifesta#ons
• local #ssue hardening, accompanied by
obvious redness, swelling, and pain,
diameter less than 5.0 cm at or around
the site following the injec#on in mild
cases
• in some severe cases the diameter of the
redness or swelling can spread to the
en#re upper arm or extend to the injected
upper arm from shoulder to elbow
Clinical feature

• signs and symptoms usually begin 2–12 h aGer exposure to the
an#gen, develop gradually in the next few hours
• most of them resolve within one week without sequelae or even
persis#ng for few months, without scar leG aGer healing
• However, the mild necrosis at the injec#on site, sclerosis in the deep
#ssue, and even severe necrosis and ulcera#on in local #ssues, skin,
and muscles can be found in severe cases
Clinical feature

Diagnosis
• the diagnos#c criteria and principles of management of the Arthus
reac#on caused by vaccines have not been clearly deﬁned
• In general, the cases of Arthus reac#on were diagnosed by physicians
or expert panel according to
• the subject‘s vaccina#on status (e.g., immuniza#on program, dose,
injec#on site)
• main clinical manifesta#ons (e.g., limb local swelling, indura#on,
and other symptoms)
• other relevant informa#on

Treatment
• Most Arthus reac#ons reported were mild and usually self-limited and
generally did not need treatment
• Moderate cases: treated with an#-allergy drugs as required
• diphenhydramine (25 to 50 mg per adult, 0.5 to 1.0 mg/kg per child, 3 8mes
per day)
• promethazine (25 to 50 mg per adult, 1.0 mg/kg per child, 3 8mes per day)
• Severe cases with #ssue necrosis
• could be taken cor#sone 2 #mes a day, each 50 mg, intramuscular
injec#on, once a week

Treatment
• keeping the injected site clean to prevent secondary infec#on and
promote the regenera#on of necro#c #ssue
• relieve symptoms (swelling or pain), such as cold compresses cold the
aﬀected limb around the injec#on site, acetaminophen and limb
eleva#on

Serum sickness & SSLR

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