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Case 10-2013: A 30-Year-Old Man

with Fever, Myalgias, Arthritis, and Rash
John H. Stone, M.D., M.P.H., and Mandakolathur R. Murali, M.D.

PR E SEN TAT ION OF C A SE

Dr. Sheila F. Mitsuma (Medicine): A 30-year-old man with a history of intravenous drug
use was admitted to this hospital because of fever, myalgias, arthritis, and rash.
The patient was in his usual state of health until 12 days before admission, when
2 days after discharge from a detoxification clinic, he reportedly self-administered
heroin intravenously. Two days later, fever, chills, cough, myalgias, anorexia, and
malaise occurred and were associated with the gradual onset of joint swelling and
pain, an erythematous and nonpruritic rash, and episodes of severe diaphoresis. The
joint symptoms first developed in the ankles, and during the 3 days before admission, they affected his knees, hands, and elbows and were accompanied by weakness
of the arms and legs.
Two days before admission, the patient went to the emergency department of
another hospital. On examination, the temperature was 38.3C. The white-cell
count was reportedly normal, the blood alanine aminotransferase level was 110 U
per liter, and the aspartate aminotransferase level was 73 U per liter; the remainder
of the complete blood count and metabolic panel was normal. A chest radiograph,
electrocardiogram, and transesophageal echocardiogram were also reportedly normal. Cultures of the blood were obtained. A diagnosis of a viral syndrome was made,
and he returned home. Fevers resolved, but the pain increased and became more
severe in the arms than in the legs; the patient rated it at 10 on a scale of 0 to 10,
with 10 indicating the most severe pain. He walked gingerly and in small steps
because of his joint symptoms and was unable to raise his arms above his head or
grasp a cup of coffee. He came to the emergency department of this hospital.
The patient reported redness of the eyes and pain in the neck region. However,
he reported no headaches, sore throat, rhinorrhea, sinusitis, tinnitus, loss of weight,
impairment of his senses (smell, vision, hearing, and taste), or changes in bowel
and urinary function. One month before admission, wheezing, dyspnea at rest,
lightheadedness, and a dry cough developed, without fever or chills. The patient had
used intravenous drugs for 10 years, participated intermittently in needle-exchange
programs, and had enrolled in detoxification programs 15 times. Three days after
the onset of symptoms, methadone therapy was begun. He also had migraines,
long-standing Raynauds phenomenon, and recurrent epistaxis after repair of facial
and nasal-bridge fractures. He had a history of a fractured wrist and, after intra-

From the Department of Medicine, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical
School both in Boston.
N Engl J Med 2013;368:1239-45.
DOI: 10.1056/NEJMcpc1210260
Copyright 2013 Massachusetts Medical Society.

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venous drug use, an abscess in his left arm. He

suspected that he had hepatitis C virus (HCV)
infection, acquired after a remote exposure to a
known carrier. Testing for human immunodeficiency virus (HIV) 6 months earlier had reportedly been negative. He had taken ibuprofen for
muscle pain and had no known allergies. He was
unemployed and lived with his mother. He was
sexually active and monogamous with his girlfriend and did not use barrier protection. He
smoked cigarettes. His father had coronary artery
disease and had had his first myocardial infarction when he was in his 30s; his mother, sister,
and multiple maternal relatives had diabetes mellitus; a sister had systemic lupus erythematosus;
another sister had eczema; and a nephew had
Kawasakis disease.
On examination, the temperature was 37.2C,
the blood pressure 138/88 mm Hg, the pulse 106
beats per minute, the respiratory rate 20 breaths
per minute, and the oxygen saturation 96% while
the patient was breathing ambient air. The conjunctivae were injected, and dentition was poor.
Breath sounds were coarse, with mild wheezing,
and there was a tender, palpable liver tip 2 cm
below the costal margin. On the extremities and
anterior trunk, there was a fine, erythematous,
blanching, reticular, macular rash. The joints of
the hands, elbows, knees, and ankles were diffusely swollen and warm. There were also effusions in the wrists, metacarpalphalangeal joints,
and knees. Active movement of the large joints
caused severe pain; passive range of motion was
full, including that of the cervical spine. There
was diffuse muscle tenderness (especially in the
quadriceps and calves) and 1+ edema in the extremities, decreased muscle strength (4 out of 5)
with extension and flexion of the arms and hands,
and 3+ deep-tendon reflexes of the brachioradialis and patellar tendons. The gait involved small
steps and a wide stance; the remainder of the
examination was normal.
The hematocrit, hemoglobin, and red-cell
indexes were normal, as were blood levels of
electrolytes, calcium, phosphorus, magnesium,
creatine kinase, total and direct bilirubin, total
protein, albumin, globulin, and alkaline phosphatase and the results of renal-function tests;
other test results are shown in Table 1. Testing of
a specimen of blood for rheumatoid factor and
antibodies to cyclic citrullinated peptide and

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double-stranded DNA was negative. Testing for

antibodies against HIV type 1 (HIV-1) and HIV
type 2 (HIV-2) was nonreactive, and HIV-1 RNA
was not detected. Testing of blood for cryoprotein was also negative. A test for syphilis, with
the use of rapid plasma reagin, was negative.
Urinalysis revealed trace urobilinogen and was
otherwise normal. Cultures of the blood drawn
earlier remained sterile. A chest radiograph was
normal. A combination of acetaminophen and
oxycodone was administered.
Diagnostic tests were performed.

DIFFER EN T I A L DI AGNOSIS
Dr. John H. Stone: This 30-year-old man presented
with fever, myalgias, arthritis, and a rash. Two
critical pieces of information will frame my differential diagnosis. First, this patient was an injection-drug user, and therefore we must consider
all the perils associated with this behavior. Second, this patient presented with polyarthritis, a
condition that is distinctly different from having
joint pains or arthralgias.
Injection-Drug Use

The use of injection drugs is associated with many

potential causes of this patients symptoms. The
patient attributed the onset of his symptoms to
the self-injection of heroin 12 days earlier. I will
therefore focus my differential diagnosis on potential explanations associated with the use of
heroin itself, on the effects of adulterants used to
cut street drugs, and on the effect of infectious
agents associated with either bloodborne pathogens contracted through needle sharing or failure
to clean the skin adequately before injection of
drugs. The final diagnosis must be one that can
lead to a true polyarthritis, not just polyarthralgia.
Heroin

Heroin has been associated with rhabdomyolysis,

which may result from either the direct effects of
the drug or unrelieved pressure on body parts
that occurs in association with coma.1 Rhabdomyolysis might account for the elevated aminotransferase levels, assuming that their source is
skeletal muscle rather than the liver, but in this
patient the levels were too low for florid rhabdomyolysis. Moreover, the alanine aminotransferase
level was higher than the aspartate aminotrans-

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case records of the massachusetts gener al hospital

ferase level, implicating a hepatic origin. Similarly, the blood creatine kinase level was normal,
making rhabdomyolysis unlikely. Rhabdomyolysis also does not explain two key features of the
patients presentation the inflammatory arthritis and rash. I suspect that the weakness was
discomfort associated with moving tender joints
and painful muscles, rather than true deficits of
muscle power.
Adulterants

Adulterants are compounds added to street drugs

to increase profits for the seller. In the 1970s, a
mini-epidemic of severe musculoskeletal problems resulted from an unidentified adulterant in
brown heroin, so-called because of its color,
which contrasted with the usual white of street
heroin.2 Fever, paraspinal myalgias, polyarthralgia, and marked tenderness localized to periarticular structures, such as tendon insertions (enthesopathy), developed and resolved within days
of discontinuation of the drug. The joint problems were most consistent with periarthritis. It
seems unlikely that this patient injected brown
heroin, because he presented with polyarthritis
rather than periarthritis and, to my knowledge,
the adulterant that made brown heroin brown
which was never definitively identified is
no longer used.
Levamisole, a veterinary antihelminthic agent
once used to treat rheumatoid arthritis, colon
cancer, and the nephrotic syndrome, has become
the most common adulterant of cocaine.3 The
prevalence of levamisole in samples of cocaine
sold on the street is estimated to be as high as
70%.4 Levamisole can lead to a dramatic vasculopathy and even vasculitis of small and mediumsize blood vessels. The syndrome of levamisoleinduced vascular injury and tissue damage is
characterized by thrombosis, leukocytoclasis, and
necrotizing lesions in blood vessels.5 This syndrome is accompanied by a confusing array of
autoantibodies, including high titers of antineutrophil cytoplasmic antibodies (ANCAs), antiphospholipid antibodies, and antibodies to doublestranded DNA. The cutaneous vasculopathy
induced by levamisole has a predilection for fatty
tissues, often leading to large ulcerative and necrotic lesions of the breasts, thighs, and flanks
that mimic warfarin-induced necrosis. Necrosis
of the earlobe is a common and distinctive find-

Table 1. Laboratory Data.

Reference Range,
Adults*

On Admission

450011,000

8400

Neutrophils

4070

75

Lymphocytes

2244

17

Monocytes

411

Eosinophils

08

Variable
White-cell count (per mm3)
Differential count (%)

Basophils

03

150,000350,000

386,000

017

22

Glucose (mg/dl)

70110

125

Aspartate aminotransferase
(U/liter)

1040

133

Alanine aminotransferase
(U/liter)

1055

190

Negative at 1:40 and

1:160 dilutions

Positive at 1:40 and

1:160 dilutions,
speckled pattern

C3

86184

119

C4

2058

28

Platelet count (per mm3)

Erythrocyte sedimentation rate
(mm/hr)

Antinuclear antibody

Complement (mg/dl)

* Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts
General Hospital are for adults who are not pregnant and do not have medical
conditions that could affect the results. They may therefore not be appropriate
for all patients.
To convert the values for glucose to millimoles per liter, multiply by 0.05551.

ing associated with levamisole-induced vasculopathy and vasculitis.5-7 This patients fine, erythematous, blanching, reticular, macular rash
bears little resemblance to a levamisole-induced
lesion.
Other problems, particularly cocaine-induced
midline destructive lesions, are associated with
smoking or inhaling the drug, rather than injecting it.8,9 These problems generally remain
confined to the upper respiratory tract and tissues of the face and are not associated with a
disseminated vasculitis. Although high titers of
ANCAs result, the antigen specificity is for human
neutrophil elastase.8,9 Unfortunately, such patients
also have ANCAs directed against proteinase 3,
making the distinction between cocaine-induced
midline lesions and granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) difficult. We are not informed of this

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patients ANCA status, but his presentation does with a predilection for dependent areas, particunot suggest a syndrome related to drug-induced, larly the legs. Thus, the likelihood that HCV was
ANCA-associated vasculitis.
the cause of this patients presentation is low.
Testing for antibodies against HIV-1 and HIV-2
Infection
was nonreactive. Therefore, certain musculoskelInjection-drug use often causes bacterial infec- etal manifestations of chronic HIV-1 infection can
tions of the skin, soft tissue, bloodstream, and be ruled out, particularly seronegative spondyloheart valves. If appropriate antibiotic therapy is arthropathies such as reactive arthritis or psorilacking, these infections may pose a threat to atic arthritis, both of which are often more severe
life. The nature of this patients joint problems among HIV-infected patients.15 Although acute
may help us rule out a bacterial process. He had HIV-1 infection should be considered, the absence
true articular swelling of multiple joints in a of detectable HIV-1 RNA rules out this diagnosis.
symmetric fashion. The arthritis began in his Furthermore, the presence of arthritis, rather
ankles and extended to the knees, hands, and than arthralgia, is inconsistent with primary HIV
elbows. He walked gingerly, with small steps, and infection.16,17
was unable to raise his arms above his head or
In a minority of patients, acute infection with
grasp a cup. His inflammatory joint symptoms, HBV causes a syndrome resembling serum sickwhich are reminiscent of untreated rheumatoid ness. Robert Graves first described the illness
arthritis or serum sickness, are not particularly in 1843:
compatible with the joint manifestations that are
typical of subacute or acute infective endocardiLet me first direct your attention to a train
tis.10 In addition, the patients rash is not reminisof morbid phenomena sometimes observed
cent of the cutaneous manifestations of a dissemco-existing with arthritic inflammation. A
inated bacterial infection, such as Oslers nodes,
person labouring under inflammation of
Janeways lesions, and splinter hemorrhages.11
the joints gets an attack of hepatitis, accomThus, a bacterial infection, such as those acquired
panied by jaundice, and this is followed by
from injection-drug use, is unlikely.
urticaria . . . [One] gentleman, in conseFinally, we must consider viral pathogens that
quence of exposure to cold, was attacked
can be transmitted through injection-drug use
with arthritic inflammation and fever. After
and needle sharing. These include HCV, HIV, and
he had been about ten days ill, he became
hepatitis B virus (HBV). Given the lengthy incubasuddenly jaundiced, and in a day or two
afterwards a copious eruption of urticaria
tion period of these viruses, infection would most
appeared over his body and limbs.18
likely have occurred earlier than the 12 days before admission that the patient pinpointed as the
onset of his symptoms. HCV is associated with
Gravess description is a nearly classic rendia variety of potential musculoskeletal symptoms tion of the syndrome resembling serum sickness
that would rarely include a polyarthritis that re- caused by acute HBV infection and perfectly desembles rheumatoid arthritis.12,13 More common- scribes this patients symptoms. Polyarthritis and
ly, infection with HCV leads to joint symptoms urticaria almost always occur as part of the prothat are confused with rheumatoid arthritis, dromal stage of the syndrome, preceding the
partly because HCV infections are associated with icteric phase by several days to several weeks.
rheumatoid-factor positivity caused by the pres- These symptoms are usually abrupt in onset. The
ence of mixed cryoglobulins.14 Most patients with polyarthritis is symmetric, with a predilection
type II or type III cryoglobulinemia test positive for small joints of the hands and knees, and may
for rheumatoid factor because the IgM compo- appear in an additive or migratory pattern asnent of the mixed cryoglobulin is directed against sociated with morning stiffness. A rash occurs
the Fc portion of IgG, which is the definition of at approximately the same time as the arthritis
rheumatoid-factor activity. The nature of this pa- in half of all cases. The rash is most often urtitients rash was inconsistent with the diagnosis of carial, but erythematous macules and papules
HCV-associated cryoglobulinemic vasculitis, which and petechiae are also reported. The syndrome
would generally be accompanied by purpura usually persists for days or weeks, with a mean

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case records of the massachusetts gener al hospital

duration of approximately 20 days. Patients often

have both fatigue and generalized weakness at
some point in the course of the illness. The joint
and skin manifestations typically resolve completely before or at the onset of the icteric phase
of hepatitis. Approximately 40% of patients with
the syndrome ultimately become jaundiced.
On the basis of his symptoms of polyarthritis,
rash, fatigue, and liver-function abnormalities, I
believe that this patient had acute HBV infection,
acquired from needle sharing in the context of
injection-drug use. I suspect the diagnosis was
made by HBV serologic testing and the detection
of HBV DNA and HBV surface antigen (HBsAg).

DR . JOHN H. S T ONES DI AGNOSIS

Serum sickness associated with acute hepatitis B
virus infection.

PATHOL O GIC A L DISCUSSION

Dr. Mandakolathur R. Murali: In arriving at the correct pathological diagnosis, we must answer two
questions. First, do the laboratory tests support
the diagnosis of acute HBV infection? Second, can
the syndrome resembling serum sickness be explained in association with acute HBV infection?
The diagnosis of acute HBV infection is usually suspected after the detection of elevated
hepatic aminotransferase levels. In this patient,
the aminotransferase levels were mildly elevated
at the time of admission (alanine aminotransferase, 190 U per liter; and aspartate aminotransferase, 133 U per liter). During the next 2 weeks,
however, the hepatic aminotransferase levels rose
dramatically, with the alanine aminotransferase
level reaching a peak of 3566 U per liter and
aspartate aminotransferase 2022 U per liter on
hospital day 16. To determine whether these
high levels of aminotransferases were caused by
HBV, we examined HBV-specific markers.
Once a patient becomes symptomatic with
HBV, the characteristic laboratory features of
acute infection include the detection of HBV
DNA and HBsAg, the production of IgM antibody against hepatitis B core antigen (HBc), and
less often, the presence of hepatitis B e antigen
(HBeAg). In this case, testing revealed that all
these features were present within the first few
days after admission. The level of circulating

HBV DNA was extremely high (>380,000,000 IU

per milliliter), a test for HBsAg was positive, a
test for antibody against HBsAg (anti-HBs) was
negative, HBeAg was reactive, antibody against
HbeAg (anti-HBe) was nonreactive, and HBc IgM
was reactive. Taken together, these features result in a molecular and serologic profile that is
diagnostic of acute HBV infection.
After the diagnosis of acute HBV infection was
established, it was noticed that this patient also
had classic signs and symptoms of serum sickness, a disorder caused by antigenantibody or
immune complexes formed in the zone of antigen excess. A spectrum of biologically active immune complexes contributes to the inflammation
associated with serum sickness. In general, they
are small, soluble antigenantibody complexes that
are not removed by the phagocytic macrophages
that reside in the liver and spleen. The resultant
circulating immune complexes contribute to the
vascular and cellular phases of inflammation
(Fig. 1). The diverse antigens are composed of
epitopes of HBsAg, HBc, and viral DNA. Antibodies to these antigens bind their specific antigens and form immune complexes. Interaction
of immune complexes with complement proteins
and subsequent activation of Fc receptors, complement receptors, or both on phagocytic cells
are required for the development of serum sickness.19-21 Although we typically expect abnormalities in complement levels in association with
serum sickness, the normal C3 and C4 levels
noted in this patient on admission do not rule
out the diagnosis of HBV-associated, immune
complexmediated serum sickness. In this case,
serial monitoring of the levels of C3, C4, and
complement hemolytic activity (CH50) was not
performed. Consequently, the dynamics of complement activation were not captured in their
entirety. Serial measurement of immune complexes containing C1q and C3b would also have
been valuable in documenting the development
and resolution of serum sickness.
In summary, the diagnosis in this case is acute
HBV infection associated with a disease resembling serum sickness, mediated by immune complexes. Correlation of the serologic findings with
the patients clinical manifestations and understanding of the biology of serum sickness are
crucial to the understanding of this disease, its
diagnosis, and its clinical outcome.

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Figure 1. Pathways Leading to Serum Sickness.

The pathways leading to the vascular and cellular phases of inflammation in serum sickness are initiated by antigen
antibody or immune complexes. The immune complex interacts with the endothelial cells, resulting in the production
of kinins, and with complement proteins, resulting in the generation of anaphylatoxins. The kinins and anaphylatoxinderived vasoactive amines lead to the exudative phase of vascular inflammation. The neutrophils are recruited to the
vascular site by complement-derived chemoattractants, and subsequent engagement of the activating Fc receptors
(FcR) on neutrophils by the immune complex leads to neutrophil activation and release of inflammatory products
contributing to tissue inflammation. Platelet activation by the immune complex results in ischemia of the microvasculature and augments tissue damage.

PATHOL O GIC A L DI AGNOSIS

Serum sickness associated with acute hepatitis B
virus infection.

FOL L OW-UP
Dr. Mitsuma: Until the current eras availability of
effective antiviral agents, this patient would not
have received any treatment other than supportive care, and he probably would have recovered
uneventfully. Because of the magnitude of the viremia, however, he was treated with entecavir. By
day 30, the aminotransferase levels had normalized. Paralleling the clinical improvement, the
anti-HBs and anti-HBe became positive along
with conversion to HBc IgG antibody, signaling
the patients recovery from an acute reaction re-

1244

sembling serum sickness caused by acute HBV

infection. By day 65, the HBV DNA level had declined to less than 60 IU, the limit of detection
for this assay. Testing for anti-HBs and anti-HBe
remained positive; HBsAg and HBeAg were no
longer detectable. The patient was asymptomatic, with normal hepatic enzyme levels.
A Physician: Why does serum sickness happen
specifically with HBV and not with other diseases?
Dr. Murali: For serum sickness to occur, a prolonged phase of circulating immune complexes is
necessary. The prerequisite for that is antigenic
persistence, which is best exemplified by chronic
and often indolent viral infections, such as HBV
and, to a lesser extent, cytomegalovirus and enterovirus, among others. Persistent antigenemia
(e.g., as seen in subacute endocarditis and infections associated with shunts or tunneled catheters)

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case records of the massachusetts gener al hospital

and even the administration of medications such

FINA L DI AGNOSIS
as penicillin and sulfonamides are less common
causes of a reaction resembling serum sickness. Acute infection with hepatitis B virus.
A Physician: How do you make the decision to
This case was discussed at the medical case conference.
treat a patient with acute HBV?
Dr. Stone reports receiving consulting fees from Roche and
Dr. Mitsuma: Although I do not know whether
Genentech, grant support through his institution from Roche
antiviral therapy altered the natural history of and Genentech, and travel support from Genentech, BiogenHBV in this patient, we elected to treat him be- IDEC, and Genzyme. No other potential conflict of interest relcause of the magnitude of viremia, the distur- evant to this article was reported. Disclosure forms provided
by the authors are available with the full text of this article at
bance in synthetic function of the liver, and the NEJM.org.
We thank Dr. Anne Kasmar for her review of the case history.
continued rise in aminotransferase levels.
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Bosch X. The cryoglobulinaemias. Lancet
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15. Calabrese LH, Naides SJ. Viral arthritis.

Infect Dis Clin North Am 2005;19:963-80.

16. Lavreys L, Thompson ML, Martin HL

Jr, et al. Primary human immunodeficiency virus type 1 infection: clinical manifestations among women in Mombasa, Kenya.
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19. Germuth FG Jr. A comparative and
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20. Germuth FG Jr, Flanagan C, Montenegro MR. The relationships between the
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