The n e w e ng l a n d j o u r na l
case records of the massachusetts general hospital
From the Division of Infectious Diseases,
Beth Israel Deaconess Medical Center
(S.K.B.); Infectious Disease Unit, Depart-
ment of Pathology, Massachusetts General
Hospital (E.S.R.); and the Departments
of Medicine (S.K.B., E.S.R.) and Pathology
(E.S.R.), Harvard Medical School.
N Engl J Med 2009;360:1540-8.
Copyright © 2009 Massachusetts Medical Society.
1540
Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .
of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 11-2009: A 47-Year-Old Man
with Fever, Headache, Rash, and Vomiting
Sigall K. Bell, M.D., and Eric S. Rosenberg, M.D.
Pr e sen tat ion of C a se
Dr. Mary Berlik Rice (Medicine): A 47-year-old man was admitted to the hospital because
of fever, headache, rash, and vomiting. The patient had been well until 8 days ear-
lier, when severe pleuritic chest pain developed, worse on the right side than on the
left, and a maculopapular rash appeared on his torso, which by the next day involved
the scalp and the arms and legs, sparing the palms and soles. He also had tempera-
tures of up to 39.1°C, chills, diaphoresis, a throbbing frontal headache that radiated
to the vertex, a sore throat, swollen cervical lymph nodes, a cough productive of
thick yellow sputum, and diffuse myalgias and arthralgias without joint swelling or
erythema.
Five days before admission, the patient went to the emergency department of
another hospital for these symptoms. Measurements of serum electrolytes and glu-
cose and tests of renal function were normal; results of other laboratory tests are
shown in Table 1. Chest radiographs and computed tomography (CT) of the chest
and abdomen revealed multiple small nodules (the largest was 17 mm in diameter)
in both adrenal glands; imaging revealed characteristics of an adenoma but was
otherwise normal. Acetaminophen was prescribed, and he was sent home.
During the next 3 days, the symptoms did not improve, and the patient’s appetite
decreased. Bleeding from the left nostril occurred twice, and he vomited once; his
temperature rose to 38.9°C. Three days before admission, he was seen in the medical
walk-in clinic of this hospital. On examination, he appeared uncomfortable. The
temperature was 37.4°C, the blood pressure 112/75 mm Hg, and the pulse 93 beats
per minute. Photophobia was present, with discomfort on upward gaze. The neck
was supple. There were innumerable brown-gray macules on the trunk and face. The
conjunctivae were slightly injected; the tonsils were diffusely red and enlarged, with
a sparse white exudate. There was a tender, mobile, soft lymph node, approximately
4 cm in diameter, in the left submandibular area and smaller palpable anterior and
posterior cervical and inguinal nodes bilaterally and in the right axilla. The chest
was tender to palpation along the lateral ribs below the nipple line, more on the
right side than on the left. The remainder of the examination was normal. The urine
was positive for blood (4+) but was otherwise negative; results of other laboratory
tests are shown in Table 1. Specimens of blood, urine, and sputum were cultured.
Ketorolac was administered intramuscularly, and the patient was sent home with
n engl j med 360;15  nejm.org  april 9, 2009
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 case records of the massachusetts gener al hospital

Table 1. Results of Laboratory Tests.

Reference Range, At the Other 3 Days before

Variable Adults* Hospital Admission On Admission
Hematocrit (%) 41.0–53.0 (men) 42.7
White-cell count (per mm3) 4,500–11,000 4900 7,600
Differential count (%)
Neutrophils 40–70 65 86
Band forms <10 10
Lymphocytes 22–44 15 10
Monocytes 4–11 8 3
Basophils 0–3 1
Platelet count (per mm3) 150,000–350,000 185,000
d-Dimer <500 700
Glucose (mg/dl)† 70–110 163
Heterophile antibody Negative Negative
Rapid plasma reagin Nonreactive Nonreactive
Toxoplasma IgG antibody Negative Negative
Toxoplasma IgM antibody Negative Negative
Parvovirus B19 IgG index <0.9 1.4
Parvovirus B19 IgM index <0.9 0.1

* 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.

instructions to take doses of ibuprofen alternat-
ing with acetaminophen for fever and to follow up
in 3 days, or sooner if the symptoms worsened.
Three days later, he came to the emergency
department of this hospital because of persistent
symptoms and increased nausea and vomiting.
He reported photophobia, neck stiffness and pain,
and some pressure on initiating urination. The
pain in the chest and abdomen had resolved, and
there was no diarrhea, shortness of breath, hema-
turia, pyuria, or dysuria; there also were no palpi-
tations or changes to vision or hearing. The le-
sions on the chest and back had faded. A culture
of the sputum from 3 days earlier grew abundant
Streptococcus pneumoniae and Neisseria meningitidis,
and cultures of the blood and urine were sterile.
Nucleic acid testing of a urine specimen was nega-
tive for N. gonorrhoeae and Chlamydia trachomatis.
The patient had had syphilis at the age of 18
years, and he had lumbar disk disease with L5
disk herniation, for which he was receiving dis-
ability payments. Serologic tests for syphilis and
the human immunodeficiency virus (HIV) had
reportedly been negative 6 months earlier. He
lived with a single male partner with whom he
had been monogamous for the past 3 years. Four
years earlier, his partner had received a diagno-
sis of HIV infection and did not take antiretro-
viral medications, reportedly because of a low vi-
ral load and normal CD4 count. The patient and
his partner did not use condoms and reportedly
did not practice anal sex. He owned cats, had been
exposed to paint chips 2 weeks earlier when he
scraped a room in his home, and had not traveled
recently. His partner was not ill. The patient’s
illness occurred during the winter, and he had not
been exposed to mosquitoes or ticks. He smoked
cigarettes and marijuana and had done so for
many years; he drank alcohol rarely, after years of
heavy use in the past, and he did not use intrave-
nous drugs. Family members had had coronary
artery disease, hypertension, diabetes mellitus,
and polysubstance abuse; a sibling had died from
cirrhosis related to alcohol and infection with

n engl j med 360;15  nejm.org  april 9, 2009 1541

Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
hepatitis C virus. Medications included oxycodone
as needed for pain, diazepam, acetaminophen, and
ibuprofen. He had no allergies to medications.
On examination, the patient coughed frequent-
ly, the respirations were 28 breaths per minute,
and the oxygen saturation was 98% while he was
breathing ambient air. The temperature was 36.3°C;
it rose to 38.3°C within 2 hours and was 39.2°C
later in the day. Other vital signs were normal.
There was bilateral posterior cervical lymphade-
nopathy; the oropharynx was erythematous, with
no exudate or tonsillar enlargement. Neck flex-
ion caused discomfort; range of motion was full.
There was abdominal guarding. An erythematous,
blanch­ing rash covered the chest and upper back,
with no papules or nodules. The remainder of the
examination was normal.
Screening tests for influenza A and B anti-
gens were negative. Measurements of serum elec-
trolytes, total protein, and globulin and tests of
liver and renal function were normal; other test
results are shown in Table 1. An electrocardio-
gram was normal. An ultrasonogram of the abdo-
men revealed a region of hypoattenuation within
the pancreatic head that was thought to represent
a peripancreatic lymph node. A radiograph of the
chest showed a perihilar linear opacity suggestive
of mild subsegmental atelectasis. CT of the brain
revealed mucosal thickening of the maxillary si-
nus. A lumbar puncture was performed; results of
cerebrospinal fluid (CSF) analysis are shown in
Table 2.
The patient was admitted to the hospital. Van-
comycin, ceftriaxone, acyclovir, narcotic analgesia,
sumatriptan, and acetaminophen were adminis-
tered. Additional diagnostic tests were performed.
Differ en t i a l Di agnosis
Dr. Sigall K. Bell: I am aware of the diagnosis in
this case. Within a 24-hour period, 10 signs and
symptoms developed in this previously healthy
47-year-old man: the classic mononucleosis-like
triad (fever, sore throat, and lymphadenopathy),
rash, chest pain, cough, myalgia, arthralgia, dia-
phoresis, and headache. The symptoms persisted
for 8 days, and he ultimately presented with vom-
iting, neck stiffness, and evidence of meningitis
on lumbar puncture.
The differential diagnosis includes a bacterial
infection that spread to involve the meninges; in-
fection with an organism such as an atypical bac-
1542 n engl j med 360;15  nejm.org  april 9, 2009
Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
terium, fungus, or parasite that would not be de-
tected by routine cultures; a systemic viral illness
progressing to aseptic meningitis; and a nonin-
fectious process such as a rheumatologic disease
mimicking an infectious process. The clinician’s
priorities are to distinguish between bacterial and
aseptic meningitis; to ascertain whether meningi-
tis, encephalitis, or both were present; and to rap-
idly rule out life-threatening illnesses.
Bacterial infection
The recovery of S. pneumoniae and N. meningitidis
from the sputum, together with the finding of
mucosal thickening on CT of the head, raises the
possibility of a bacterial sinus infection progress-
ing to meningitis. Meningococcemia can rapidly
be fatal, necessitating prompt recognition and ini-
tiation of therapy. S. pneumoniae is a relatively com-
mon sinorespiratory pathogen, and meningitis
could have developed by hematogenous spread or
by direct extension from a sinus infection. The ad-
ministration of antibiotics to address these organ-
isms was appropriate.
There are several features of this case that
weigh against a typical bacterial infection. Despite
the cough, the physical examination and radio-
graphic findings did not disclose changes consis-
tent with pneumonia. Although thickened sinuses
were seen on the CT scan of the head, there is
insufficient evidence for a diagnosis of clinically
active sinusitis. The CSF profile revealed the clas-
sic findings of aseptic meningitis: a mild, lym-
phocytic-predominant pleocytosis with elevated
protein and normal glucose levels. A Gram’s stain
of the CSF did not contain bacteria, and blood
and CSF cultures, which were obtained before the
initiation of antibiotic therapy, were negative. In
routine clinical practice, physicians are often left
to ponder whether a presentation consistent with
aseptic meningitis is due to partially treated bac-
terial meningitis that results from antibiotics
prescribed for antecedent symptoms. In this case,
we can safely rule out classic bacterial meningitis.
The sputum isolates may indicate a tracheobron-
chitis, but they are more likely to be colonizers
in this longtime smoker.
Atypical bacterial, fungal, or parasitic
infection
Are there organisms that would not grow in rou-
tine cultures (so-called culture-negative organisms)
that could be associated with this patient’s sys-
 case records of the massachusetts gener al hospital

temic manifestations and aseptic meningitis? Like

Table 2. Results of Cerebrospinal Fluid Analysis.
meningococcemia, rickettsial disease is consid-
ered a “fever and rash emergency,” and it is there- Reference Range,
Variable Adults* On Admission
fore important to rule it out rapidly. The abrupt
onset of fever, headache, malaise, conjunctival in- Glucose (mg/dl)† 50–75 73
jection, rash, myalgia, and arthralgia is a feature Protein (mg/dl) 5–55 132
consistent with a diagnosis of rickettsial disease. Tube 1
However, the patient became ill in the winter and
Color Colorless Colorless
did not report any recent travel, so tickborne dis-
eases, including Rocky Mountain spotted fever, Turbidity Clear Clear
are unlikely. The patient owned cats, and cervical Red-cell count (per mm3) 0 48
lymphadenopathy was present, leading us to con- White-cell count (per mm3) 0–5 23
sider bartonella and toxoplasma infections. Bar- Differential count (%)
tonella can be manifested as encephalitis in the
Neutrophils 0 5
central nervous system, but this is uncommon in
an immunocompetent host. The pace of the pa- Lymphocytes 0 72
tient’s disease makes bartonella infection un- Reactive lymphocytes 0 1
likely, and serologic testing for toxoplasmosis was Monocytes 0 22
negative. Tube 4
Spirochetal infections, including secondary
Color Colorless Colorless
syphilis, Lyme disease, and leptospirosis, are im-
portant considerations. This patient had syphilis Turbidity Clear Clear
at 18 years of age, and his current illness could Red-cell count (per mm3) 0 1
have been a result of a new exposure or relapse.1 White-cell count (per mm3) 0–5 11
Meningeal involvement is common early in sec-
Differential count (%)
ondary syphilis, and fever, pharyngitis, headache,
Lymphocytes 0 70
anorexia, lymphadenopathy, and macular or mac-
ulopapular rash over the trunk and extremities Reactive lymphocytes 0 3
may occur (although the rash, like that of Rocky Monocytes 0 27
Mountain spotted fever, characteristically involves Gram’s stain Rare polymorphonuclear
the palms and soles). After reaching an all-time leukocytes; no bacteria
low in 2000, the incidence of primary and sec- Culture No growth No growth
ondary syphilis has increased dramatically in ho-
Nucleic acid testing for herpes Negative Negative
mosexual men in the United States.2,3 Syphilis simplex virus (types 1
must remain at the forefront of the clinician’s and 2) DNA
considerations, but in this case the rapid plasma
* Reference values are affected by many variables, including the patient popu­
reagin test was nonreactive. lation and the laboratory methods used. The ranges used at Massachusetts
General Hospital are for adults who are not pregnant and do not have medi-
Viral infection cal conditions that could affect the results. They may therefore not be appro-
priate for all patients.
This patient’s systemic symptoms and findings † To convert the values for glucose to millimoles per liter, multiply by 0.05551.
such as conjunctival injection, myalgias, arthral-
gias, rash, and gastrointestinal symptoms without
peripheral leukocytosis suggest a viral infection. ated with rash; this and other arboviruses would
Many viruses are associated with myopericardi- need to be considered if the patient had present-
tis, which could explain his chest pain. Enterovi- ed in the summer. Influenza, a common virus in
rus is the most common cause of aseptic menin- the winter, was considered, but tests were nega-
gitis, especially during the summer, although up tive. Infection with lymphocytic choriomeningi-
to 10% of cases of aseptic meningitis may be at- tis virus, which is a rodentborne arenavirus, is also
tributable to enterovirus even during other sea- more common in the colder months, but no expo-
sons.4 Culture or polymerase-chain-reaction (PCR) sure to rodents was described.
testing of the CSF is often positive for enterovi- Causes of fever and rash also include the clas-
rus in these cases.5 West Nile virus can be associ- sic childhood viral exanthems of parvovirus B19,

n engl j med 360;15  nejm.org  april 9, 2009 1543

Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
measles, mumps, and rubella, although these are
rare in adults. Parvovirus, the causative agent of
fifth disease of childhood, causes fever, rash, and
arthritis in adults; however, infection with parvo-
virus was ruled out by serologic evaluation. After
remaining stable for many years, the incidence
of mumps has increased recently in the United
States, with a series of outbreaks in 2006 in sev-
eral states, including Massachusetts.6 Before vac-
cination became routine, mumps caused 10 to
20% of cases of aseptic meningitis, which is one
of the most common extrasalivary complications
of mumps. Similarly, there was a sudden increase
in the incidence of measles in the United States in
2008.7 There was no reported history of child-
hood measles or mumps in this patient, and we
are unaware of his vaccination history, although
evidence of previous vaccination or infection could
be confirmed by serologic testing. A diagnosis of
measles or mumps is unlikely, given the patient’s
age, the character of his rash, and the absence of
parotitis.
Infection with herpes simplex virus (HSV) or
varicella–zoster virus can cause aseptic meningi-
tis or encephalitis, fever, and rash, but it rarely
causes disseminated disease in an immunocom-
petent host. However, it is critical to recognize
these viruses, since effective treatment is avail-
able. The initial description of chest pain and
truncal rash, especially if unilateral, raises con-
cern for varicella–zoster virus, but the subsequent
spread and character of the rash, which was
nonvesicular, is not typical of the virus. Nucleic
acid testing of the CSF for HSV DNA was nega-
tive, and we were not told of any change in men-
tal status or brain function. Given these test re-
sults, acyclovir could safely be discontinued.
Mononucleosis-like Illness
The presence of posterior cervical lymphadenop-
athy, fever, pharyngitis, and rash is characteristic
of a mononucleosis-like illness. Causes of mono-
nucleosis-like illness include acute infection with
Epstein–Barr virus (EBV), cytomegalovirus (CMV),
and HIV. The use of ampicillin has a strong as-
sociation with the development of a maculopapu-
lar rash in patients with acute EBV infection, but
rash occurs in 10% of cases even without antibi-
otic use. EBV mononucleosis is typically associated
with lymphocytosis or atypical lymphocytosis;
neither was present in this case. However, these
hematologic manifestations may be less pro-
1544 n engl j med 360;15  nejm.org  april 9, 2009
Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
nounced in adults than in adolescents. The het-
erophile antibody test was negative, but the tim-
ing of the appearance of heterophile antibodies is
variable, and a single negative test does not rule
out a diagnosis of acute EBV infection. Since the
patient had been symptomatic for 8 days, the test
should have been repeated, or EBV-specific sero-
logic testing could have been performed. How-
ever, acute EBV infection is unlikely in a 47-year-
old man, since more than 90% of adults in the
United States have serologic evidence of past EBV
infection.8
Primary CMV infection is also unlikely, since
50 to 60% of adults in the United States have
serologic evidence of previous CMV infection9;
this percentage is increased among men who
have sex with men. Primary CMV infection gen-
erally causes no or mild pharyngitis and mild
lymphadenopathy and is almost universally as-
sociated with hepatitis, which was not seen in
this case. It is unlikely that the patient had re-
cently encountered CMV for the first time, but
serologic testing for CMV should be performed
to rule out a diagnosis of primary CMV infec-
tion. Aseptic meningitis is a rare complication of
EBV or CMV mononucleosis.
Acute HIV Infection
The patient had a male partner who was HIV-
positive. The patient was sexually active, did not
use condoms, and was HIV-negative 6 months
before presentation. Does his failure to acquire
HIV infection despite repeated exposure over a
period of several years suggest that he was some-
how protected against infection? Homozygosity
for the CCR5*32 mutation confers protection from
infection, and this polymorphism is present in 1%
of white persons.10-12 Cohorts of highly exposed,
persistently seronegative persons have been de-
scribed in studies of commercial sex workers13-15
and serodiscordant sexual partners.16 Although
the mechanism of protection is not known, it is
hypothesized that repeated exposure to the virus
may augment host immune responses, similarly
to a protective vaccine. If this patient was not
resistant, his cumulative risk of HIV infection
has become substantial by this time.
This patient’s presentation includes most of
the symptoms and signs that have been described
in the acute retroviral syndrome, including fever,
headache, pharyngitis, nausea and vomiting, an-
orexia, myalgia and arthralgia, diaphoresis, and
 case records of the massachusetts gener al hospital

lymphadenopathy17,18 (Table 3). Aseptic menin-

Table 3. Commonly Reported Signs, Symptoms, and
gitis has been reported in 24% of cases of acute Laboratory Findings in Patients with Acute HIV-1
HIV infection,18 and myopericarditis has also been Infection.*
described.19 The presence of a maculopapular
Symptoms and signs
rash and oral or genital ulcers can help to distin-
guish this diagnosis from other mononucleosis- Fever†
like viral illnesses, although these findings are Pharyngitis†
not specific. Acute HIV infection accounts for Lymphadenopathy†
about 1% of patients with a mononucleosis-like Fatigue
illness and a negative heterophile antibody test20 Rash†
and about 1% of patients with symptoms of a Diaphoresis or night sweats†
viral illness who present to an urban urgent care Headache†
clinic.21 The diagnosis of acute HIV infection re- Anorexia†
quires a high index of suspicion, and it is seldom Nausea or vomiting†
considered on initial presentation, even in high- Diarrhea
risk populations.18,22 As in this case, it often takes Myalgia and arthralgia†
several encounters with the medical system be- Oral or genital ulcers
fore the diagnosis is considered. Nuchal rigidity, photophobia, or both (in patients with
aseptic meningitis)†
Noninfectious diseases Laboratory findings
Rheumatologic diseases such as systemic lupus Thrombocytopenia
erythematosus, Still’s disease, Kawasaki’s disease, Leukopenia
Wegener’s granulomatosis, and sarcoidosis may Lymphopenia†
mimic an infectious process. Epistaxis and hema- Elevated aminotransferase levels
turia in the absence of thrombocytopenia invite
* HIV-1 denotes human immunodeficiency virus type 1.
consideration of Wegener’s granulomatosis or sar- † This finding appeared in the patient.
coidosis; however, the inactive urine sediment in
this case makes vasculitic glomerulonephritis un-
likely, and the chest imaging does not suggest likely diagnosis. Acute HIV infection is charac-
sarcoidosis. Systemic lupus erythematosus is as- terized by high-level viral replication, a transient
sociated with central nervous system disease that decline in the CD4+ T-cell count, and evolution of
typically occurs as psychosis or seizures and is virus-specific antibodies. Occasionally, during the
more common in young women than in men. transient decline in the CD4+ T-cell count (and
Still’s disease affects both sexes equally and associated immunosuppression), patients present
has a bimodal age distribution, of 15 to 25 years with a concurrent opportunistic infection. There-
and 36 to 46 years of age, near the age of this fore, when a patient such as this one presents with
patient at presentation. It is characterized by an acute HIV infection, it is important to determine
evanescent salmon-colored rash involving the whether the illness is related to HIV alone or
trunk and extremities that typically is accompa- whether another pathogen may also be causing
disease. In this patient, the presentation and find-
nied by fever, myalgia, arthralgia, and pharyngitis,
all of which were present in this patient. Pleu- ings are consistent with acute HIV infection alone.
risy or pericarditis is not uncommon. However, To make this diagnosis, a test of the HIV type 1
as with lupus, the onset is typically less abrupt (HIV-1) viral load should be performed and inter-
than in this case, and leukocytosis, hepatitis, preted in conjunction with HIV-1–antibody tests.
and splenomegaly are common. Although there Dr. Eric S. Rosenberg: Dr. Peterson, would you tell
are reports of meningitis associated with Still’s us what your impressions were when you saw this
disease,23 it is exceedingly rare. patient?
Dr. Scott L. Peterson (Infectious Diseases): Those
Summary of us who saw this patient considered secondary
Taken together, the patient’s history of exposure syphilis and acute infection with toxoplasma,
to HIV, abrupt onset of illness, and constellation CMV, or HIV to be the most likely diagnoses.
of symptoms makes acute HIV infection the most Since he had frequent sexual contact with an HIV-

n engl j med 360;15  nejm.org  april 9, 2009 1545

Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

infected partner, we were most concerned that he antiretroviral therapy during acute HIV-1 infec-
had acute HIV infection presenting as a mono- tion. This question has not been adequately ad-
nucleosis-like syndrome with meningitis. dressed in the literature, and the best practice
remains unknown. There are several reasons to
Cl inic a l Di agnosis consider initiating therapy during acute HIV-1 in-
fection.25 First, antiretroviral treatment has been
Acute HIV infection. shown to suppress viremia in more than 95% of
patients24 and thus may offer symptomatic relief
Dr . Sig a l l K . Bel l’s Di agnosis to an ill patient with high-level viremia.26 Treat-
ment of this patient also could be considered on
Acute HIV infection. the basis of his neurologic involvement.26 The
most compelling reason to consider treatment is
Pathol o gic a l Discussion the potential for the preservation of HIV-specific
T helper cells, an immune response that may be
Dr. Rosenberg: This patient had an extensive evalu- a critical component in the body’s long-term de-
ation for common pathogens that cause mono- fense against replicating HIV.26-28 It has been sug-
nucleosis-like syndromes. Serum tested for EBV- gested that treatment that is initiated during acute
specific antibodies was negative for IgM and infection and subsequently discontinued has the
positive for IgG antibodies to the viral capsid an- potential to improve control of viral replication
tigen. Nucleic acid testing of plasma for the pres- and establish a lower viral load.29 However, this
ence of EBV DNA was negative. These results in- effect may be transient.30,31
dicate previous, but not acute, EBV infection. There are currently no published data from
Similarly, testing for CMV IgM antibody was neg- randomized, controlled trials that have adequate-
ative and for CMV IgG antibody was positive, in- ly compared treatment with no treatment during
dicating previous CMV exposure. Direct detection acute HIV-1 infection, and the long-term clinical
of CMV by means of antigenemia testing was benefits of early therapy are unknown. In addi-
negative, ruling out reactivation of latent virus. tion, the introduction of antiretroviral medica-
Acute HIV-1 infection is characterized by a tions during acute infection may result in a course
negative or weakly positive enzyme-linked im- of therapy many years longer than if treatment is
munosorbent assay (ELISA) for antibodies to HIV, delayed until the patient meets standard criteria
a negative or indeterminate Western blot analysis for the initiation of treatment in chronically in-
for HIV-1, and high-level viremia detected by fected persons.32 Receipt of therapy for a longer
means of nucleic acid testing. This patient’s ELISA time may increase the risks of medication-related
for HIV-1 and HIV-2 antibodies was weakly posi- adverse effects and viral resistance. In balancing
tive, and Western blot testing was negative for these considerations, we offer early treatment to
both HIV-1 and HIV-2. Quantitative testing for patients with acute HIV-1 infection who are ready,
HIV-1 nucleic acids was positive at 45.7 million willing, and able to take medications consistently
copies of HIV RNA per milliliter of plasma. Taken for many years.25,32 Regardless of whether treat-
together, these results are diagnostic of acute ment is begun, making the diagnosis of acute
HIV-1 infection. At the time of diagnosis, the infection may have important public health ben-
patient’s absolute CD4+ T-cell count was 432 cells efits by limiting the unknowing transmission of
per cubic millimeter, a finding consistent with the virus from a person with the high level of
the transient decline in the CD4+ T-cell count that viremia that is characteristic of acute HIV infec­
is characteristic of acute HIV-1 infection.17,24,25 tion.16,33-35
Although CSF was not tested for HIV, the men- Dr. Rosenberg: Dr. Peterson, how did you treat
ingitis was almost certainly secondary to acute this patient, and what is his current condition?
infection with HIV-1. Dr. Peterson: When results of the CSF culture
and HSV PCR assay were negative, antimicrobial
Discussion of M a nagemen t therapy was discontinued. The patient’s condition
slowly improved, and he was discharged 5 days
Dr. Bell: The central management question is after admission. HIV RNA was reported positive
whether a patient such as this one should receive on hospital day 3, but the diagnosis of acute HIV

1546 n engl j med 360;15  nejm.org  april 9, 2009

Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 case records of the massachusetts gener al hospital

infection was not definitively established until
2 days after discharge, when the HIV-1 Western
blot test was negative. Five days after discharge,
he continued to have disabling headaches. We de-
cided to initiate antiretroviral therapy to help re-
lieve his symptoms. A fixed-dose formulation of
efavirenz, tenofovir, and emtricitabine was begun,
with resolution of symptoms within a week. He
had no side effects, and approximately 6 months
later his viral load was less than 50 copies of HIV-1
RNA per milliliter of plasma, and his most recent
CD4+ T-cell count was 819 cells per cubic milli-
meter.
Dr. Eugene P. Rhee (Medicine): Does the level of
viremia affect the decision to treat?
Dr. Bell: Unless the level is unusually low,
which suggests that the patient is spontaneously
controlling HIV replication, the magnitude of
viremia at peak should not in and of itself influ-
ence the decision to treat.
Dr. Viviany Taqueti (Medicine): Why do you
think this patient did not become infected with
HIV until after several years of exposure? Do you
think he had a mechanism of resisting infection,
or had he recently changed his behavior?
Dr. Bell: Since he eventually did become infect-
ed, he most likely did not have two copies of the
mutant CCR5 (chemokine receptor 5) gene that is
protective against infection with a CCR5-tropic
virus, the most commonly transmitted form of
HIV. We do not know whether he recently changed
to higher-risk sexual behavior. One possible expla-
nation is that his partner may have become more
infectious, with a viral load that was transiently
increased. Since viral transmission among men
who have sex with men can occur during approxi-
mately 1 of every 100 sexual acts, depending on
sexual practice,36,37 the patient’s odds of eventu-
ally becoming infected were substantial.
A nat omic a l Di agnosis
Acute HIV-1 infection.
Dr. Rosenberg reports serving on the paid advisory board of
Viral Genetics and serving as scientific advisor and having equity
ownership in TBS Technologies. No other potential conflict of
interest relevant to this article was reported.

References
1. Rolfs RT, Joesoef MR, Hendershot EF,
et al. A randomized trial of enhanced
therapy for early syphilis in patients with
and without human immunodeficiency
virus infection. N Engl J Med 1997;337:307-
14.
2. Primary and secondary syphilis —
United States, 2003–2004. MMWR Morb
Mortal Wkly Rep 2006;55:269-73.
3. Heffelfinger JD, Swint EB, Berman
SM, Weinstock HS. Trends in primary and
secondary syphilis among men who have
sex with men in the United States. Am J
Public Health 2007;97:1076-83.
4. Elmore JG, Horwitz RI, Quagliarello
VJ. Acute meningitis with a negative
Gram’s stain: clinical and management
outcomes in 171 episodes. Am J Med
1996;100:78-84.
5. Lee BE, Davies HD. Aseptic meningi-
tis. Curr Opin Infect Dis 2007;20:272-7.
6. Dayan GH, Quinlisk MP, Parker AA, et
al. Recent resurgence of mumps in the
United States. N Engl J Med 2008;358:
1580-9.
7. Update: measles — United States,
January–July 2008. MMWR Morb Mortal
Wkly Rep 2008;57:893-6.
8. Ascherio A, Munger KL, Lennette ET,
et al. Epstein-Barr virus antibodies and
risk of multiple sclerosis: a prospective
study. JAMA 2001;286:3083-8.
9. Staras SA, Dollard SC, Radford KW,
Flanders WD, Pass RF, Cannon MJ. Sero-
prevalence of cytomegalovirus infection
in the United States, 1988-1994. Clin In-
fect Dis 2006;43:1143-51.
10. Huang Y, Paxton WA, Wolinsky SM, et
al. The role of a mutant CCR5 allele in
HIV-1 transmission and disease progres-
sion. Nat Med 1996;2:1240-3.
11. Paxton WA, Martin SR, Tse D, et al.
Relative resistance to HIV-1 infection of
CD4 lymphocytes from persons who re-
main uninfected despite multiple high-
risk sexual exposure. Nat Med 1996;2:
412-7.
12. Samson M, Libert F, Doranz BJ, et al.
Resistance to HIV-1 infection in cauca-
sian individuals bearing mutant alleles of
the CCR-5 chemokine receptor gene. Na-
ture 1996;382:722-5.
13. Rowland-Jones SL, Nixon DF, Aldhous
MC, et al. HIV-specific cytotoxic T-cell ac-
tivity in an HIV-exposed but uninfected
infant. Lancet 1993;341:860-1.
14. Rowland-Jones SL, Dong T, Fowke
KR, et al. Cytotoxic T cell responses to
multiple conserved HIV epitopes in HIV-
resistant prostitutes in Nairobi. J Clin In-
vest 1998;102:1758-65.
15. Rowland-Jones S, Pinheiro S, Kaul R.
New insights into host factors in HIV-1
pathogenesis. Cell 2001;104:473-6.
16. Wawer MJ, Gray RH, Sewankambo
NK, et al. Rates of HIV-1 transmission per
coital act, by stage of HIV-1 infection, in
Rakai, Uganda. J Infect Dis 2005;191:
1403-9.
17. Kahn JO, Walker BD. Acute human
immunodeficiency virus type 1 infection.
N Engl J Med 1998;339:33-9.
18. Schacker T, Collier AC, Hughes J, Shea
T, Corey L. Clinical and epidemiologic
features of primary HIV infection. Ann
Intern Med 1996;125:257-64. [Erratum,
Ann Intern Med 1997;126:174.]
19. Guillaume MP, Van Beers D, Delforge
ML, Devriendt J, Cogan E. Primary hu-
man immunodeficiency virus infection
presenting as myopericarditis and rhab-
domyolysis. Clin Infect Dis 1995;21:
451-2.
20. Rosenberg ES, Caliendo AM, Walker
BD. Acute HIV infection among patients
tested for mononucleosis. N Engl J Med
1999;340:969.
21. Pincus JM, Crosby SS, Losina E, King
ER, LaBelle C, Freedberg KA. Acute hu-
man immunodeficiency virus infection in
patients presenting to an urban urgent
care center. Clin Infect Dis 2003;37:1699-
704.
22. Hightow LB, Miller WC, Leone PA,
Wohl DA, Smurzynski M, Kaplan AH. Pre-
dictors of repeat testing and HIV serocon-
version in a sexually transmitted disease
clinic population. Sex Transm Dis 2004;
31:455-9.
23. Garrote FJ, Marco J, Obeso G, Rodri-
guez E, del Ser T. Aseptic meningitis and
focal central nervous system involvement
in a case of adult onset Still’s disease.
J Rheumatol 1993;20:765-7.
24. Kassutto S, Maghsoudi K, Johnston

n engl j med 360;15  nejm.org  april 9, 2009 1547

Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

MN, et al. Longitudinal analysis of clini-
cal markers following antiretroviral ther-
apy initiated during acute or early HIV
type 1 infection. Clin Infect Dis 2006;42:
1024-31.
25. Kassutto S, Rosenberg ES. Primary
HIV type 1 infection. Clin Infect Dis 2004;
38:1447-53.
26. Gazzard BG. British HIV Association
guidelines for the treatment of HIV-1-
infected adults with antiretroviral therapy
2008. HIV Med 2008;9:563-608.
27. Oxenius A, Price DA, Easterbrook PJ,
et al. Early highly active antiretroviral
therapy for acute HIV-1 infection pre-
serves immune function of CD8+ and
CD4+ T lymphocytes. Proc Natl Acad Sci
U S A 2000;97:3382-7.
28. Rosenberg ES, Billingsley JM, Caliendo
AM, et al. Vigorous HIV-1-specific CD4+
T cell responses associated with control
of viremia. Science 1997;278:1447-50.
29. Rosenberg ES, Altfeld M, Poon SH, et
al. Immune control of HIV-1 after early
treatment of acute infection. Nature 2000;
407:523-6.
30. Kaufmann DE, Lichterfeld M, Altfeld
M, et al. Limited durability of viral control
following treated acute HIV infection.
PLoS Med 2004;1(2):e36.
31. Streeck H, Jessen H, Alter G, et al. Im-
munological and virological impact of
highly active antiretroviral therapy initi-
ated during acute HIV-1 infection. J Infect
Dis 2006;194:734-9.
32. Hammer SM, Eron JJ Jr, Reiss P, et al.
Antiretroviral treatment of adult HIV in-
fection: 2008 recommendations of the
International AIDS Society–USA panel.
JAMA 2008;300:555-70.
33. Brenner BG, Roger M, Routy JP, et al.
High rates of forward transmission events
after acute/early HIV-1 infection. J Infect
Dis 2007;195:951-9.
34. Pilcher CD, Joaki G, Hoffman IF, et al.
Amplified transmission of HIV-1: com-
parison of HIV-1 concentrations in semen
and blood during acute and chronic infec-
tion. AIDS 2007;21:1723-30.
35. Pilcher CD, Tien HC, Eron JJ Jr, et al.
Brief but efficient: acute HIV infection
and the sexual transmission of HIV. J In-
fect Dis 2004;189:1785-92.
36. Wilson DP, Law MG, Grulich AE,
Cooper DA, Kaldor JM. Relation between
HIV viral load and infectiousness: a model-
based analysis. Lancet 2008;372:314-20.
[Erratum, Lancet 2008;372:1808.]
37. DeGruttola V, Seage GR III, Mayer
KH, Horsburgh CR Jr. Infectiousness of
HIV between male homosexual partners.
J Clin Epidemiol 1989;42:849-56.
Copyright © 2009 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

1548 n engl j med 360;15  nejm.org  april 9, 2009

Downloaded from www.nejm.org at EDWARD G MINER LIBRARY on April 17, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.